Early stage product and device development

For one of the studies, three months after the start of the recruitment, a CRA discovered that the site has a competing protocol

2012-01-18T22:13:00.003-05:00

Question asked on Linked in GCP group:Hi! For one of my studies, three months after the start of the recruitment, I discover the site has a competing protocol (same inclusion/exclusion criteria). What do you do in my place?

The question was commented as follows:

Stefania Bordin • I would suggest to check the Investigator availability in terms of time an recruitment potentials. Anyway, in order to avoid such risks during the fesibility phase and site choice the Investigator shoul have completed a questionnaire by indicating if he/ she has competitors' studies ongoing. In any case by signing the Protocol page he / she committs himself to conduct the trial according to Protocol which also includes all the time required to conduct the trial in the correct whay (beyond, for sure according to GCP ICH and all the regulations being applicable in this case). At the end, if you notice that the enrolment for your tiral is not good enough not even in terms of screening you can inform your head department and project manager in order to agree about the possibility to close the site.

Fatima EL GHAIB • Thanks Stefania.
During the feasibility phase, the Investigator completed the questionnaire indicating he has no competiting studies ongoing.
Just for information, how is it possible to use such a document legally?

Rebecca Georgevitch • He was already fabricating the truth prior to study acceptance. I don't believe this was a legal issue. At this point, I would be very cautious with this site and any Information given to me. He lied before he even began the trial. If they were open to enrollment and haven't enrolled in sometime, the sponsor/CRO may consider sending him a letter stating they will be shutting down sites that have less than x# of qualified subjects enrolled by a specific time. Try to close them down before the next IRB meeting/approval. This is costing them unnecessary money. I would also discuss future enrollment procedures with the PI and SC present.

Fatima EL GHAIB • Many thanks Rebecca :)

Shirley Isbill • There may be no need to do anything. It's not uncommon for study sites to run mulitple studies for several sponsors. The last study site I audited, had 30 active studies and they were recruiting for more. You can make an assessment of the study site staffing and comment to your study sponsor concerning the staff's ability to handle their clinical study workload. It would not be ethical for you to look at the details of the competing study; it might be a competitor's study of their drug for the same indication in your study.

Malaika Simmons • I agree with Shirley. Additionally, if there was a feasibility questionnaire completed that indicated that there were no competing studies, it may be a matter of opinion. For example, your study may be a fibroid study, and the site may have an ongoing endometriosis study. The PI may say that those are two different illnesses, therefore are noncompeting. However, we know that the inc/excl criteria will have similar if not nearly identical parameters.

That being said, you will still have to treat the site as you should all sites, and remind the PI /coordinator of the sites responsibility to recruit to the protocol specifications. It is a good idea to develop a recruitment plan (that includes methods as well as numbers) per site as part of the study initiation as a rule to mitigate under enrollment issues and reemphasizes roles and responsibilities (amazing that signing the 1572 does not immediately impart an overwhelming sense of responsibility! :-)).
Good luck

Fatima EL GHAIB • Many thanks to all of you! Your advices are very helpfull :)
In fact, when discussing with another site staff, it appears that they refused another study because very similar: same inclusion/exclusion criteria and same indication! It also appears that these 2 trials were both conducted by the same CRO (I was working for), that's why I had the possibility to read the competitive protocol.
The first site I was speaking about had been less realistic than the second one and accepted to conduct both studies, but finally wasn't able to reach his goal...

Kamakshi Sriram • Hi Fatima,
This is strange as while we are debating on the intentions of site one which has accepted to do competing studies at the same time, I have doubts on the intentions of the CRO now, who is going ahead and enrolling the same investigator for a competing study, the investigator would take the study up if CRO ( representing sponsor here as responsibilities are being delegated) is going ahead and even proposing a new study to the same site. The reason could be either the site is too talented..........or the recruitment period is over of the first study.............or sheer negligence on the part of the CRO.

Christoph Lohan (PgDip.) • Without having more details about the issue I would agree with Malaika. It may just be that the protocols are very similar but not wholly identical as they may target slightly different groups or conditions. In Oncology and Heamatology you will find it alot, e.g. breast cancer or AML. Woth looking at it in more detail.

Harpreet Kaur Anand • If Protocol is same, all Inclusion-Exclusion Criteria,Study Duration etc therefore its futile taking such studies.Its merely shows that the site is not interested in study, only concerned with the money they will receive from the it.
1) Patient recruitment will be less as site will be manage to enroll patient in both studies
2) This will be biased
If company is doing research on some molecule they must have targeted patients pool & site accordingly therefore if they will not get the sufficient data from sufficient number of patients then its useless conducting trial at such type of sites in near futute.

Rather than taking any strict action, the site should be warned about this & as per Miss Simmons PI should be reminded/educated of the sites responsibility to recruit to the protocol specifications.

Shirley Isbill • Fatima,
Re: It also appears that these 2 trials were both conducted by the same CRO (I was working for)

It's not uncommon for the left hand to not know what the right hand is doing; refer the common protocols to the CRO then forget about it.

Fatima EL GHAIB • I started in that CRO and on that study after the sites had been selected.
Kamakshi, I agree with you. As CRA I had to be informed by the CRO about the conduct of that competitive study so as to be more vigilant.
Thank you all for your active participation. Your comments are very constructive :)
20 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion0 . Lynda Cedar • It's common for a site to conduct similar studies (study design, same drug or simlar products), the same inc/exc criteria used.

- If a NDA is in place, the site is not supposed to disclose any information about its current studies, other than speaking about their experience with a specific disease or class of medication.
If a NDA is in place, allowing you to know about the other study, and even showing you the study protocol of the other sposnor, that is a violation of the NDA and confidential information provided to the site.
This disclosure is not ethical and might disavantage the other sponsor:if he does not know the same..

- Regarding the recruitment, no worries if a CTRA is in place and contains milestones for the recruitment, the site is going to deliver.

Maneesh Misra • You should consider Kamakshi, Rebecca & Malaika's comments seriously. The trial is not meant for only the Sponsors' drug & Study Design but also for effecasy & safety of patients. To fulfill the needs of NDA(Non Disclosure Agreements), you cannot compromise on the results of the trial which are more likely to be BIASED in this senarion mentioned by you.

It should be your moral responsibility to conduct the trial without any element of BIASED approach or ignorance as seen in this case. The PI may have taken the approach to enable the site to build more credibility & increase the list of achivements but as a professional we should take these issues seriously & act accordingly.

I am not in the correct position to advice you for the approach to be taken to resolve the violations, if any, as the details discussed is not sufficient for it. Ask your self & evaluate it agailst the GCP & IRB guidelines without any Biased thoughts & I am sure you will get the answer yourself.

All the participants made good approach & it is appreciable that these discussions will always help in learning more n more. I have also learned things from this discussion & everyones views & would like to Thank everybody.

Shannen Douglass • It is not uncommon for a site to have competing studies. As long as recruitment targets are being met, protocol is being followed and there is enough time for the staff to properly run both trials, you may not need to do anything at all.

Melvin paul • Hi Fatima,
Most often investigators do not disclose complete information as they feel additional project would help their profile. However in a situation like this it is good to speak to the investigator about your concern and let her/him know that there is an equal commitment that the PI should show to both the studies. You could suggest that he follows a fifty/fifty rule, where if he has two subjects screened on a day, then he should enroll one for one study and the other into the other study. If he could do this then he will ensure he has lived up to the commitments of both the studies. I quote this from a similar experience when i was a CRA. This startergy did work. However you will need to keep and eye on the recruitment time. If you see that the PI is not making any progress, it is better to either close the site or get permission to extend the recruitment time period.

Nancy Nahmias • Many times the site staff completes the feasibility, and the PI just signs it. It is up to the sponsor to do due diligence and review the feasibility and ask questions. Typically sponsors know what protocols are competing with theirs, and as a CRA I always ask this of the project lead.
Since the study has already started, I would put the PI's feet to the fire by ensuring you get regular enrollment logs, and having a lengthy discussion with the PI about enrollment at each visit. I would also mention that this competing protocol was not mentioned on the feasibility, but since they are participating ask the PI how he assigns subjects to a specific trial. If you get a lousy response to enrollment, I would tell the PI that you will close them if they have no enrollment after 3 months....

Bhugol Chandel, MD • Hi Fatima,

As long as the site and the investigator have time, patient population and the resources to enroll the patients, they need to be supported for their efforts to meet enrollment challenge.

Laura C. Collada Ali • What about the Ethics Committee? Is it possible that they do not point out such a case? Don't they have a register of ongoing studies?

Megan Mather • It is to be expected, especially when the PI is in a specialty, such as cardiac research, specific oncology, or neurology. Many moons ago I was a study coordinator working on migraines. I had as many as 7 studies all on migraines. As long as the site can provide a sufficient number of subjects and definite proof that appropriate washouts of drugs from trials are performed, there really shouldn't be a problem. The PI and coordinator should be interviewed on how they keep the trials separate and how they make sure they do not confuse the trials. All study documentation should be kept separate and away from other studies (no shared labs, etc.) and when information is addressed in a common patient file, if these are the PI's private patients as well, only the trial number should be listed in the patient chart. The one area I have special concerns over is during Phase I studies where they have "professional patients". We had to report a site in Florida where there were 2 Phase I units within one mile from the other and we found the patients were going from one unit to the other without washout and in some cases at the same time. Many of the studies were at risk, it was bad news!!

Stefania Bordin • I would suggest to check the Investigator availability in terms of time an recruitment potentials. Anyway, in order to avoid such risks during the fesibility phase and site choice the Investigator shoul have completed a questionnaire by indicating if he/ she has competitors' studies ongoing. In any case by signing the Protocol page he / she committs himself to conduct the trial according to Protocol which also includes all the time required to conduct the trial in the correct whay (beyond, for sure according to GCP ICH and all the regulations being applicable in this case). At the end, if you notice that the enrolment for your tiral is not good enough not even in terms of screening you can inform your head department and project manager in order to agree about the possibility to close the site.

Fatima EL GHAIB • Thanks Stefania.
During the feasibility phase, the Investigator completed the questionnaire indicating he has no competiting studies ongoing.
Just for information, how is it possible to use such a document legally?

Rebecca Georgevitch • He was already fabricating the truth prior to study acceptance. I don't believe this was a legal issue. At this point, I would be very cautious with this site and any Information given to me. He lied before he even began the trial. If they were open to enrollment and haven't enrolled in sometime, the sponsor/CRO may consider sending him a letter stating they will be shutting down sites that have less than x# of qualified subjects enrolled by a specific time. Try to close them down before the next IRB meeting/approval. This is costing them unnecessary money. I would also discuss future enrollment procedures with the PI and SC present.

Fatima EL GHAIB • Many thanks Rebecca :)

Shirley Isbill • There may be no need to do anything. It's not uncommon for study sites to run mulitple studies for several sponsors. The last study site I audited, had 30 active studies and they were recruiting for more. You can make an assessment of the study site staffing and comment to your study sponsor concerning the staff's ability to handle their clinical study workload. It would not be ethical for you to look at the details of the competing study; it might be a competitor's study of their drug for the same indication in your study.

Malaika Simmons • I agree with Shirley. Additionally, if there was a feasibility questionnaire completed that indicated that there were no competing studies, it may be a matter of opinion. For example, your study may be a fibroid study, and the site may have an ongoing endometriosis study. The PI may say that those are two different illnesses, therefore are noncompeting. However, we know that the inc/excl criteria will have similar if not nearly identical parameters.

That being said, you will still have to treat the site as you should all sites, and remind the PI /coordinator of the sites responsibility to recruit to the protocol specifications. It is a good idea to develop a recruitment plan (that includes methods as well as numbers) per site as part of the study initiation as a rule to mitigate under enrollment issues and reemphasizes roles and responsibilities (amazing that signing the 1572 does not immediately impart an overwhelming sense of responsibility! :-)).

Fatima EL GHAIB • Many thanks to all of you! Your advices are very helpfull :)
In fact, when discussing with another site staff, it appears that they refused another study because very similar: same inclusion/exclusion criteria and same indication! It also appears that these 2 trials were both conducted by the same CRO (I was working for), that's why I had the possibility to read the competitive protocol.
The first site I was speaking about had been less realistic than the second one and accepted to conduct both studies, but finally wasn't able to reach his goal...

Kamakshi Sriram • Hi Fatima,
This is strange as while we are debating on the intentions of site one which has accepted to do competing studies at the same time, I have doubts on the intentions of the CRO now, who is going ahead and enrolling the same investigator for a competing study, the investigator would take the study up if CRO ( representing sponsor here as responsibilities are being delegated) is going ahead and even proposing a new study to the same site. The reason could be either the site is too talented..........or the recruitment period is over of the first study.............or sheer negligence on the part of the CRO.

Christoph Lohan (PgDip.) • Without having more details about the issue I would agree with Malaika. It may just be that the protocols are very similar but not wholly identical as they may target slightly different groups or conditions. In Oncology and Heamatology you will find it alot, e.g. breast cancer or AML. Woth looking at it in more detail.

Harpreet Kaur Anand • If Protocol is same, all Inclusion-Exclusion Criteria,Study Duration etc therefore its futile taking such studies.Its merely shows that the site is not interested in study, only concerned with the money they will receive from the it.
1) Patient recruitment will be less as site will be manage to enroll patient in both studies
2) This will be biased
If company is doing research on some molecule they must have targeted patients pool & site accordingly therefore if they will not get the sufficient data from sufficient number of patients then its useless conducting trial at such type of sites in near futute.

Rather than taking any strict action, the site should be warned about this & as per Miss Simmons PI should be reminded/educated of the sites responsibility to recruit to the protocol specifications.

Shirley Isbill • Fatima,
Re: It also appears that these 2 trials were both conducted by the same CRO (I was working for)

It's not uncommon for the left hand to not know what the right hand is doing; refer the common protocols to the CRO then forget about it.

Fatima EL GHAIB • I started in that CRO and on that study after the sites had been selected.
Kamakshi, I agree with you. As CRA I had to be informed by the CRO about the conduct of that competitive study so as to be more vigilant.
Thank you all for your active participation. Your comments are very constructive :)

Lynda Cedar • It's common for a site to conduct similar studies (study design, same drug or simlar products), the same inc/exc criteria used.

- If a NDA is in place, the site is not supposed to disclose any information about its current studies, other than speaking about their experience with a specific disease or class of medication.
If a NDA is in place, allowing you to know about the other study, and even showing you the study protocol of the other sposnor, that is a violation of the NDA and confidential information provided to the site.
This disclosure is not ethical and might disavantage the other sponsor:if he does not know the same..

- Regarding the recruitment, no worries if a CTRA is in place and contains milestones for the recruitment, the site is going to deliver.

Maneesh Misra • You should consider Kamakshi, Rebecca & Malaika's comments seriously. The trial is not meant for only the Sponsors' drug & Study Design but also for effecasy & safety of patients. To fulfill the needs of NDA(Non Disclosure Agreements), you cannot compromise on the results of the trial which are more likely to be BIASED in this senarion mentioned by you.

It should be your moral responsibility to conduct the trial without any element of BIASED approach or ignorance as seen in this case. The PI may have taken the approach to enable the site to build more credibility & increase the list of achivements but as a professional we should take these issues seriously & act accordingly.

I am not in the correct position to advice you for the approach to be taken to resolve the violations, if any, as the details discussed is not sufficient for it. Ask your self & evaluate it agailst the GCP & IRB guidelines without any Biased thoughts & I am sure you will get the answer yourself.

All the participants made good approach & it is appreciable that these discussions will always help in learning more n more. I have also learned things from this discussion & everyones views & would like to Thank everybody.

Shannen Douglass • It is not uncommon for a site to have competing studies. As long as recruitment targets are being met, protocol is being followed and there is enough time for the staff to properly run both trials, you may not need to do anything at all.

Melvin paul • Hi Fatima,
Most often investigators do not disclose complete information as they feel additional project would help their profile. However in a situation like this it is good to speak to the investigator about your concern and let her/him know that there is an equal commitment that the PI should show to both the studies. You could suggest that he follows a fifty/fifty rule, where if he has two subjects screened on a day, then he should enroll one for one study and the other into the other study. If he could do this then he will ensure he has lived up to the commitments of both the studies. I quote this from a similar experience when i was a CRA. This startergy did work. However you will need to keep and eye on the recruitment time. If you see that the PI is not making any progress, it is better to either close the site or get permission to extend the recruitment time period.

Nancy Nahmias • Many times the site staff completes the feasibility, and the PI just signs it. It is up to the sponsor to do due diligence and review the feasibility and ask questions. Typically sponsors know what protocols are competing with theirs, and as a CRA I always ask this of the project lead.
Since the study has already started, I would put the PI's feet to the fire by ensuring you get regular enrollment logs, and having a lengthy discussion with the PI about enrollment at each visit. I would also mention that this competing protocol was not mentioned on the feasibility, but since they are participating ask the PI how he assigns subjects to a specific trial. If you get a lousy response to enrollment, I would tell the PI that you will close them if they have no enrollment after 3 months....

Bhugol Chandel, MD • Hi Fatima,
As long as the site and the investigator have time, patient population and the resources to enroll the patients, they need to be supported for their efforts to meet enrollment challenge.

Laura C. Collada Ali • What about the Ethics Committee? Is it possible that they do not point out such a case? Don't they have a register of ongoing studies?

Megan Mather • It is to be expected, especially when the PI is in a specialty, such as cardiac research, specific oncology, or neurology. Many moons ago I was a study coordinator working on migraines. I had as many as 7 studies all on migraines. As long as the site can provide a sufficient number of subjects and definite proof that appropriate washouts of drugs from trials are performed, there really shouldn't be a problem. The PI and coordinator should be interviewed on how they keep the trials separate and how they make sure they do not confuse the trials. All study documentation should be kept separate and away from other studies (no shared labs, etc.) and when information is addressed in a common patient file, if these are the PI's private patients as well, only the trial number should be listed in the patient chart. The one area I have special concerns over is during Phase I studies where they have "professional patients". We had to report a site in Florida where there were 2 Phase I units within one mile from the other and we found the patients were going from one unit to the other without washout and in some cases at the same time. Many of the studies were at risk, it was bad news!!

Tom Quegan • Very interesting discussion!
Fatima, there is another point that has not yet been discussed. Did/does the PI know that he has two competing studies? Does he have full oversight of all his studies, or does he delegate everything to study coordinators and sub-investigators?
As an auditor, I have been to sites where the PI could not tell me about critical parts of the protocol, so this may be something that you want to be aware of.
13 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion3 .

Molly Blake-Michaels • Hello Fatima,
The only comment I have to add to the discussion is that in cases where there are studies that compete for the same patients, it is always advisable to find out how the site will decide which patient will be enrolled into each study. For example, I have worked with sites in the past that have alternated studies; as eligible patients come in they are offered the study whose "turn" it is. If a procedure like that isn't in place, it is easy for an investigator's bias to result in different types of patients being enrolled in one study than the other (for example, if the investigator believes that heavier patients will do better on the drug in Study X, or older patients will do worse, it could easily affect their decision as to which study to present to the patient). The result of this bias can be that the full range of patients meeting the inclusion/exclusion criteria are not enrolled, at least at that site.

Anke Hoppe • If this constitutes a protocol violation, the chain of events starting with discovery of the issue and actions taken (e.g. re-training of PI, set up of recruitment plan, ensuring maintenance of confidentiality for each study etc.) need to be documented detailed in writing, signed and filed accordingly (ISF and TMF) and the site needs to inform their IRB.

Does the CTA address this kind of incidence?

Anupama Ramkumar • The objective of anyone who is assessing these sites(monitor,auditor etc) is to ensure that the data is credible and that the patients safety and well being is not compromised.
It is not uncommon for sites to be handling multiple trials at the same time and not only that but also be a highest recruiter!!
At all times if all the stakeholders can keep the objectives of data credibility and patient safety in mind ,there really are no restrictions.
Which means there has to be an audit trail which should include documentation to ensure that the inclusion/exclusion criteria are not being compromised and that the patient is not part of more than one trial.

Dennis McHugh • If inclusion/exclusion criteria and protocols are substantially equivalent suggest that they enroll in one trial on even days; the other on odd days or alternate weeks. This would be treating both programs equally and perhaps avoid bias. You do want to avoid investigator bias where they believe (consciously or unconsciously) that Study A might just have the superior intervention so they enroll the more challenging subjects there. That's an experimental model killer.

Patrick Martin • Fatima it appears that you are very conscientious and diligent in managing the site, which is great. Regarding your post: as I used to tell my team, when in doubt, ask.

There's nothing wrong in bringing those concerns to the PI in a professional and respectful manner. At the very least the site will know that you want open and honest communication. But the bottom line is do you honestly think that the site/PI has the ability to meet the obligations, including timely enrollment, for your study? If the answer is yes, then go forward. If no, then talk to your boss.

For what it's worth, if the site has expertise in a particular area then one would expect that other sponsors would be attracted to work w/ the site as well. If the site is large enough they may have the patient load to adequately enroll in your study and the other.
Best of luck with this.

The Site’s Side: Now You See Them, Now You Don’t - The Trend of Disappearing Study Sites

2012-01-17T00:25:00.003-05:00

Discussion brought from Linked in GCP group: The Site’s Side: Now You See Them, Now You Don’t - The Trend of Disappearing Study Sites.
CenterWatch cautions that over the last 5 years, the number of study sites has decreased, with the loss of veteran PIs most sharply in decline. How will this trend affect sponsors, other stakeholders in the business of clinical research and the provision of new products to the public if it continues?

The Site’s Side: Now You See Them, Now You Don’t – The Trend of... blog.gobalto.com
By: Sherry Reuter A January. 5, 2012 report from CenterWatch cautions that over the last 5 years, the number of study sites has decreased, with the loss of veteran PIs most sharply in decline. Specifically: The proportion of...

Commented about it: Angela Rhodes • I agree, it is becoming more burdensome for a physician to conduct trials at his office. The documentation burden is high and in many cases monitors are less 'helpers' to the site and more 'police'. In many cases budgets 'piggyback' on top of standard of care and do not compensate. However, the documentation burden is high, even on these standard of care. Docs just want to 'do their job' and not complicate their lives/practices further. Sponsors should have a 'team' that helps set up a research endeavor at the practice, use their expertise to develop a flow and plan. Make it less burdensome for Docs. This should be separate from CRA/Monitors.

Natalie Borde • Sometime physician are also given the option to hire in extra help to lessen the burden. But one must try to ensure that valuable information is not lost along the way. Interesting point "sponsors should have a team that helps sent up a research endeavor........from CRA/monitors". The "team' would also need to be one which is unbiased. Is there a niche in the market for this?? With reference 'expertise to develop a flow and plan', do you meant how the PI and his team can efficiently incorporate trial activities within the daily work environment?

Angela Rhodes • Natalie, each individual office has its own ebb and flow. I envision a 'site set-up' geared more toward, how are you going to find the subjects? At what point in your daily practice. (most don't have searchable databases) What records are you going to need, who is going to push the button on the machine, write it down. etc. In many cases a 'coordinator' does this. This coordinator is usually only doing research part-time or as an add-on to regular duties. I have found that if staff have a "package' and are told to follow the flow, check the boxes, etc. It is easier on the staff and you get better results.

Sherry Reuter • Dear Natale and Angela,
Wonderful comments that sound like they would indeed help sites.
The term 'site support' has so many different meanings, but you describe real help. Partnering with sites to make sure they succeed helps all stakeholders to be successful! Kind regards, Sherry

Jose Manuel Masso • I agree with the comments so far. The burden of clinical trials is increasing as we are asking physicians for more patients and more quality, which are in fact necessary. This means that on one hand there is a tendency towards more documentation, assessments, visits at sites in current clinical trials and on the other hand monitors are more under the pressure of the sponsors SOPs, audits and co-monitorisations and, as Angela mentioned, less prone to help the investigators. My opinion is that in order to be successful stronger attention has to be put during the site selection visits, to make investigators aware of all these things (burden of some clinical trials) and also I think that the role of trial coordinators at site is gaining importance and trial coordinators are becoming a substantial part in the current clinical trials context.

Natalie Borde • So Angela, what you saying is trying to guide and stimulate the site to look in the right direction to look for potential subjects. Basically what one could propose is creating a manual for patient recruitment. But you mentioned the study co-ordinator, it is not really their role to identify the subjects, but the PI or SI.

Hey Jose Manuel, hope you are well. As you mentioned, and I agree entirely subject recruitment etc, this topic is address during the site selection. Here one identifies where the potential sources are for subjects.

Perhaps the introduction of a site coach is needed. An addition to the CRA. To support the sites, for additional trainings, the steer the sites in the right directions ie. recruitment. keep the momentum going...

Lynda Cedar • The Trend of Disappearing Study Sites !...... hum, yes! That’s a true; because of different factors and main them are the strict and demanding regulation that increase the study cost and the current devastating economy.

1. Some sites disappear from here but were transferred to elsewhere (emerging countries). Their manpower is cheap, the subjects are compensated 90% less, the regulation is less strict, the Ethics are different, and the quality is consequently less.
For the sites of here that continued to serve (because sponsors need some generic studies to be conducted here), some of them could not survive to the ''devastating" economy, since 2008 and it does not end yet!....

2. As explained above by the members, the regulation is very demanding (but it has to be as such), however this increases the study cost for the sponsors and the small CROs cannot survive..... At the end the small CROs disappear, and some empire CROs, very big disappear too... ''big room, big mistakes" and therefore penalized for the errors..... In Quebec, big CRO as Phoenix Int'l then became MDS pharma services, then closed..... Anapharm changed 2 - 3 times names and becomes very quiet or even shutting down.... Atlantic Life Sciences, a small CRO, is in restructuration..... other examples are for elsewhere in Canada, Europe, USA.....

3. For the sites operating in the field of complex studies, new medications, biosimilars, etc.. point 2 is even worst: the development takes time and the cost becomes excessive, just few CROs have the expertise and are just surviving....Sponsors should be aware of.

4. Laid-off and points 2-3 create a lot of resources available for consulting.... individual enterprises. Sponsors changed their strategy of employment.

5. For studies of late stage (Phase III), a lot of diseases (diabetes, BP/CV, Parkinson, Alzheimer, Cancer, HIV, ) are still needing discovery and improvement .... but again, because of the excessive cost, pharmaceuticals need to be selective when picking a medication to develop or a treatment to improve.
In this sector of clinical research, outside our countries, the patients do not have treatments available and are more willing to try the new medication in development (phase III), the recruitment looks easier, the cost looks less. I'm not sure that they are saving more money and time, as per some discussions on this forum and other LI groups, sometimes the preliminary of ICH or GCPs is not followed.... therefore, it looks less expensive (in appearance) but if they have to redo some studies, it costs them even more....
The cost is only 7% to 10% less when studies are performed in emerging countries at performing and compliant CROs with GCPs and FDA standards/regulations.

Ivalina Hristova • @ Lynda Cedar: "The cost is only 7% to 10% less when studies are performed in emerging countries at performing and compliant CROs with GCPs and FDA standards/regulations."

Do have reference for this?

Karen Levorson • Lynda, I do not agree with you that regulations in emerging countries are less strict. In my experience, studies performed in India for example, are scrutinized quite well by the authorities and also by Ethics committees.
And as for your comment about ethics being different, I totally disagree. There are researchers (and probably drug companies) who are proposing studies that are not ethical, that they could never perform in their own countries and they are going to the poor emerging countries, misrepresenting what they are doing - I have experienced that during due diligence audits!! But these are definitely not the "norm". There are investigators and researchers without ethics in every country!
In emerging countries there are conditions that are different that can really influence the subject to stay in a study, that they think that their doctor would never propose anything that could possibly harm them and then to not complain about any adverse event because they have no other recourse but the study to receive medication for their disease - even at the "risk" of receiving placebo!!
My fear for the future is that when studies are conducted under such conditions, we will have "surprises" when they come onto the market!!
Otherwise, "the times they are a changing" for everyone in clinical research, it is truly a very "interesting" time with exciting challenges!

Lynda Cedar • Karen, I understand and respect your opinion but did I mention India? If the other emerging countries conduct the studies as India (some CROs of India) does, probably we would see more CROs shutting down here....!!!

That has been said, I work with some CROs in India when my clients pick them or I do for bioanalytical work for example, the quality is good, the studies are conducted under GCPs and FDA standards. However, these CROs are not that cheap as we largely assume, they are just a bit competitive (7 to 10% less than we (at my previous CRO) were charging.

Natalie Borde • hey all, I think everyone will agree with me, that all companies wanting to bring their product to market will try to pick a route of least resistance. But one must also keep in mind the patient population. Using the example of India, a company cannot do a complete trial in India and no where else. As the population of India does not reflect all ethnic groups. In addition to the choosing emerging countries, is that the patients here are medication naive.
13 hours ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion1 . Lynda Cedar • I agree with you Nathalie about mainly the resistance that sponsors may face. In comparing to here (I mean either, Europe, Canada or USA), the process and recruitment/enrolement look faster in the emerging countries ..... and that's is one of the most important things for sponsors.

In my previous comment, after reading those of others, I wanted to bring the economic issue that is contributing to the trend of disappearing of study sites.

Natalie Borde • recruiting faster means can mean time won in the long run.. more revenue for the sponsor.

Economics is certainly effecting the industry. I think if one looks carefully, i.e. organon was taken over by sharing and within 2 years was taken over by Merck. The economics is then filtering in down to the trial conduct. Sponsors may not be as patient as they use to be. Recruiting less sites, but more recruitment is what they want. Often sponsors hire CROs to do the work, but the figures provided by the CROs are not always realistic. Sponsor what to find a balance.

Lynda Cedar: @Natalie: Yes, I agree with you, I came across many times to CROs that promise unrealistic things (timing and/or prices), they have strong marketing/sales people, and sponsors should not fall in the trap.
On the other hand, when sponsors outsource the work to those who know what they are doing, the work is achieved right from the first time, no time nor money is wasted. Knowledge and experience enable CROs to gauge how trial protocols will manifest in the real life, the sponsoring companies can consequently plan and budget based on real-world projections.
CRO and Sponsors, both want to do more with less but that can be achieved only when experienced people drive the projects on both sides (Sponsor and CROs), they determine realistic milestones and budget, and that how they can hit the study objectives and the deadlines.

Localisation of signed Informed Consent - Where exactly do I have to store a signed informed consent and why?

2012-01-14T07:16:00.004-05:00

The following question was asked on Linked in, GCP group:

Localisation of signed Informed Consent - Where exactly do I have to store a signed informed consent and why? As I am in a discussion with a monitor I would like to ask you.
Please understand I think I do know my GCP, and think I have a normal/good common sense ;-). As we, the monitor and I, differ in this discussion about the exact localisation (as in detail - which dossier/file) and why, I am curious as what you will have to say, without telling you what/how I think about it. So you will have an open mind about it. I am working on site/hospital in hemato-oncology as a CCRC. Thank you so much for your attention.

The question was commented as follows:

Linda James • ICHGCP E6, 8.2.3 references that the blank models to be filed in ISF and Sponsor File.
8.3.12 reference states that signed forms should only be filed in the ISF. The protects data privacy of the patient too.

Jim Sheets • ICH says they should be "located in the files of the investigator/institution." It doesn't matter if they're all kept together in one reguatory binder at the site, separately in each patients' case history, or with individual patient case report form binders. As long as the access is limited and controlled, you are free to choose the system that works best for your site.

Lynda Cedar • The following procedure works for both, Investigator and sponsor sites. It is just one of the ways of handling study components.
Regarding the ICF part, the objective of the way is to prevent the confidentiality during the process and also in knowing where to find them (as put in the same place), it makes them easily accessible at any time as needed.

- At the pre-study period: at this step, the study has just started, it is new to the staff, it's important that all documents of recruitment stay at one place, with two persons (in case, one is absent). In having them at one place, it prevents to loose any important document at this step.
The confidentiality of subjects is protected better as only the staff involved with the recruitment of this study would access the subjects’ chart.
Either with EDC or manual recruitment, the status of the subjects enrolled can be known at a glance at any time
The ICFs are inserted in the subjects' chart.

- At the on-study period: when the ICFs have been signed, checked and considered final, the QA signs the form of transferring them/it into the reg. binder(s). This make the ICFs safe, and if needed (for any reason), they are easily accessible all the time.

- At the post-study: when all the study binders are considered complete, checked and final (after the study close-out), they are transferred to the archives.

@Dominique: I occupied similar position at the antitumor center, Institute Jules Bordet (Brussels, Belgium), for the patients of our hospital included in the clinical studies; I managed the files as explained above (little adjustment). That has been few years ago but if you want I can provide you with more details (privately).

Shirley Isbill • Re: - At the post-study: when all the study binders are considered complete, checked and final (after the study close-out), they are transferred to the archives.

Sometimes it is difficult to retrieve the ICFs and other records from an archive, especially a hospital record archive. The ICFs and other records need to be available to regulatory auditors.

Lynda Cedar • Yes, that is true. However, as the sponsor is responsible of archiving the study components, the originals are kept with him. If the study conduct was delegated to a CRO, a copy is also archived by the CRO (internally or externally).

As for the hospitals, as a monitor, I provide them with the visits at the study start and I recall and confirm the visit a long time before I show up; and most of the time I don't find the charts when I arrive...... Therefore, it would be better to make the info available to the auditors by the sponsor or the CRO and let them to decide whether they go to the hospital or not.

Dominique S. • Thank you all for your answers! I was so curious about the reactions. Thank you.

On our site the process is as follows (on study i.e. active recruiting enrolment period)
1. To file the original and signed informed consent in the patient medical file. It took me a while to ensure and convince some of the PI/SI to be very careful with a signed IC – now they all do it correctly! I don’t feel to change this embedded procedure. And this way medical personnel will know about the IC as well.
2. In ISF there is a ‘Note to File’ where to find the signed IC and the Inclusion and Enrolment Log Form. Inclusion Log also reveals date of IC.
3. If a monitor needs to view a medical file the only one who will provide him with one is my college or myself.
4. All monitors will have to sign a confidentiallity agreement about patient files and patient digital data on site.

This monitor states – “I cannot open a medical file if I have not seen a signed IC. If an IC is in the patient dossier I cannot verify it.” He wants to have IC in the ISF. I am totally content if he makes a copy and files it in the ISF. He does not want to do the copying.

As Linda and Jim refer to GCP chapter 8, I totally agree – the handy list. And indeed it only states “located in the files of the investigator/institution.” it does not mention the name of the binder or file. And the funny thing is that I just had a re-read of 8.3.13 which states [… To include original documents related to the trial, …] again “located in the files of the investigator/institution” – is this my final answer ;-)?

Thank you Shirley for the archive tip. Though sometimes a patient file is still easier to find than boxes with trial archives of trials conducted by retired physicians and no body knows…

And in my case a sponsor will probably never be in charge of archiving trial components of our site (as trial is closed). And as IC shows the true name of the patient, and not an anonymous trial number – I think this cannot be in the sponsor archives.

Thank you again for your reaction!

Shirley Isbill • If you intend to comply with ICH, sections 8.3.12 and 8.3.13 require that the source documents and signed ICF documents be filed in the investigator’s files, not the sponsor’s files (see essential document filing locations). Generally, the sponsor has no need to know the identity of the subjects which would be included in the ICFs (originals or copies). Additionally, 21 CFR 312.62 requires the Investigator (not the study sponsor) retain the drug study records including the ICFs. There is no provision within 21 CFR 312 for the transfer of storage of the study records from the Investigator to the sponsor; 21 CFR 812.140 does provide for this transfer, but for device studies only. As an FDA auditor I would cite an Investigator if he did not have the original drug study records and they were not available for review at the time of my audit. Having the sponsor supply Investigator records to an FDA auditor is not required or recommended anywhere, it impedes the FDA audit of the Investigator’s records and provides an opportunity for the sponsor to limit record access. The original ICFs should be filed in the Investigator’s study records.

Shirley Isbill • Re: This monitor states – “I cannot open a medical file if I have not seen a signed IC. If an IC is in the patient dossier I cannot verify it.” He wants to have IC in the ISF. I am totally content if he makes a copy and files it in the ISF. He does not want to do the copying.

You need to refer this matter to the sponsor; the monitor is creating an unnecessary problem and is lazy.

Dominique S. • Thank you Shirley. Indeed all our documents are filed on site with proper labeling. And yes all site required documents will be stored/archived on site according to GCP Chapter 8. In another comment it was mentioned as archiving could be done at sponsor, not in my case/on my site.

And thank you for the smile I had a about the lazy monitor ;-)

Lynda Cedar • @Dominique: I just want to clarify that at the time of archiving the study components by the sponsor, the ICFs are put in envelops that are closed with a legal stamp (red circle), and a note is printed on the envelops (can be opened by an authorized person only and in following SOP_____). The Sponsors and CROs have SOPs: how to disclose the subject ID all the time when needed, or how to disclose the randomization code when needed,......etc.....
On the other hand, the sponsor is responsible for archiving the study for 25 years Iin Canada), he has the rights to ask for the originals and copies are kept by the site (hospital) and the CRO, for their own interests.

When a study has been finished, completed, closed and archived, why a sponsor would access it if not needed? if so, the log-book of the archives is signed by the person who needs to access the study files, and the following information is collected: Date(s), time (in and out), title and position, and the reason.
The study files cannot be taken out of the archives, unless for a big big reason (as an inspection for few days) and it requests the sponsor permission.

Dominique S. • Thank yo Lynda for your explanation. I am not familiar with archiving at sponsor. In the Netherlands its 15 years - both sponsor and investigator are responsible as in chapter 8.

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Jim Sheets • Informed consents containing signatures should remain at the investigator's facility.

Lynda Cedar • The investigator keep a copy for his own concern, as the patients were enrolled and treated by him, they are his patients….. they per say ‘‘belong” to him (sorry for the English), I’m not sure, but I think (regarding the ICFs) he can decide to keep the originals and provide the sponsor with a copy.

The ICFs can remain with the investigator and kept with the medical chart, reg. binder or as by the site's procedure, however, the sponsor has the rights to decide to archive all the study components including the ICFs, mainly for some kind of medication (new medication that is not well known or the case of some biosimilars),

The sponsor is the first concerned by any happening with the medication, for many years after a study has been closed-out. In Canada, since 2001, the archiving period is for 25 years. In my experience, when sponsors wanted to keep the ICFs as well as the other components of the study, the attorney advised to put such document (ICF) in an envelop that is sealed legally , and a warning note written on it, plus a SOP of handling it. The regulatory authorities were consulted and were comfortable with this way of ensuring the confidentiality of the ICFs during their archiving for 25 years.
Sponsors are advised to archive the study components at 2 different places, to ensure that at least one copy stays safe.

Martin Robinson • As long as the signed copy is readily available (for audit, inspection or monitoring)at the investigator site it doesn't matter where you keep it as long as it is safe. Some investigators keep them all together in the investigator site file, others keep the forms with the patient notes
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Glenda Guest • And among all this debate, it is proper for the monitor to verify informed consent prior to looking into a subject's confidential records. Where that document is filed and how it is accesed are certainly flexible as this discussion has shown.

If a site has already disposed of the remaining drug supplies without completing the final inventory of what has been used/lost. What do you do?

2012-01-08T18:38:00.014-05:00

"In a close out visit, you find the site has already disposed of the remaining drug supplies and a final inventory of what had been used/lost/broken or returned was not completed. What can you do? "
The question was asked on Linkedin and commented as follows:

Parag Desai • Protocol violation has to be notified to EC. Ideally this situation should not happen if the same monitor is there, as the site should be trained at SIV and also reminded during monitoring to retain all records and ensure IP is returned. If its the CRA has changed then he should check all monitoring reports of past and in-house site file, also before going for close out tell coordinator list of things they should keep ready for close out. If this has happened at close out then there is gross error. There should be a co-monitoring by the PM or CTL for any study for quality checks. Ideally IP should go for destruction at close out.

Fiona Waddell • Agree with Parag but would add that as much evidence as possible should be collected to support investigator's claim of destruction activities.

Lynda Cedar • What kind of medication is it?
Anyone involved in clinical studies knows about the drug accountability and its importance in the study conduct. Its is the sponsor responsibility to select and pick a qualified site.

It is not a violation of protocol only, it is a violation of ICH statement.

What can you do other than reporting the violation immediately, document as much as possible: since the time the medication was received by the site until the last record ....
make sure that the medication was detected in the patients' body (either via PK or PD parameters measurement).

Jorge Garagorri • I agree with you Lynda. The drug accountability is one of the most important activities that a CRA should perform while a site. Personally, I consider this activity should be clearly defined in all monitoring activities to remind the site that the CRA is the only one in giving the "green light" to the site in order that they can dispose the IP medication.

Lynda Cedar • The medication is the sponsor's property therefore he determines how the medication not used is going to be handled either returned to him or to be disposed by a site. In any case , SOPs are followed to track and record exactly the handling of the medication from the time it quits the sponsor facility until its outcome as directed by the sposnor (return, destruction or re-use when possible).

That is determined and agreed on before the study starts, it cannot be missed as there is some cost for the medication destruction and even its return.

In any case, suppose that the sponsor did not specify anything about it at the time of study preparation, the site must be qualified enough to follow the preliminary of the GCPs and handle the medication use appropriately.
I'm wondering whether things like this still happens nowdays.

Fatima EL GHAIB • See 21 CFR 312.59 and 62(a)

Liping Zhou • Agree with the proposed actions. In some countries/regions, there is clear law/regulation to stipute the handling of investigational product, e.g no destruction should be performed prior to the check from authroity officer. If this is the case, it would be more serious. Additionally, except for the inventory log, any way is available to identify the study drug adminsitration to subjects? All of these need to be discussed with your study management team and QA department to evaluate the impact to the data, besides reporting to the EC.

Carla Duarte • I agree with all the opinions. Most of the site's should have a apropriate local, closed and with the appropaty conditions to kept the medication. This local must be closed and should have a responsable person and a pharmacy to have acess the medication, is important to have a back-up. The "Drug Accontability", should be fill in every time you have a patient in the site. If a patient lost any medication or if any of the medication was lost at the site, this should be comunicate to the monitor and describe what happen in the clinical file of the patient. We should perform according to the ICH / GCP guidelines, the use medication sloud be kept in the center for the monitor verify every time he perform a visit to the site. Most of the Investigator's meeting that I have been present, many persons site don't have any aknologe of this or other mather's. It is important, to help them to have information about this matter and another matter's concerning the GCP/ICH. But is important kept all the medication used and unsed in the site, according to the Sponsor indication. If the medication is in capsules and the visits in your center are to long, telephone to the patient betewen visit's to ask how they are doing and remenber to bring the medication on the next visit.
It is import for you the investigators if they want to perform clinical trials, they must have a dedicate study coordinator and person available to dedicate time to the study.

Christoph Lohan (PgDip.) • Leaving the violation statements aside! I am not sure how it is done in your part of the world, but in the UK you have a good chance of tracing back most of the missing information. Most IMPs are handled via a pharmacy, hence they should have detailed information about to whom what was dispensed. If the accountability logs haven't been filled in at receptition of closure of trial you ought to have the accountability of the IMP whilst the trial was open. On the other hand you have the research team who usually sees the patient at study visits and they most often document the study drug compliance. Finally you do have delivery notes from your end to match batch numbers and quanitity. Thus you can gather quite a bit of information around the missing IMPs.
Otherwise I agree that accountability and destruction procedure needs to be clear with start of study.

Michael Raucci • First check your reg binder for Invoices of all medication, these should of been filed asap once you recieved drug. If by chance you do not have all your drug invoices contact the sponsor and have them track all the medication that was sent to your site, including rescue medication. Their vendor will have copies of the inventory sent to your specific site. Once you have established how much medication was sent to your site you will then refer back to each and every source document of all subjects for that study. Reveiw each chart in detail. A good site will document any missed or lossed drug in the progress notes after each visit. My staff documents the amount used not used, rescue med taken, study med number etc... in the source at each visit. You should be able to come up with a very accurate drug accountablilty log. Of course you will document your errors in a memo to file notiy the IRB and make sure your PI is involed in the whole process. Progress notes are so key, make it your practice standard to document most details to create a paper trail incase of a Audit. Laslty, learn from you mistakes which I am sure you have.

Lynda Cedar • I suggest to read the SOPs to see how the medication was supposed to be handled by the site / hospital, then follow the record (if done) in looking at each place (physic, shelves, fridge, documents) where the medication passed through.
If needed, for example, if the data (when measurable assessment is possible: PK or PD) are questionable, ask the IRB permission and provide the patients with a questionnaire about the medication adminsitration (as much as they could remember). The IRB is able to designate someone to interview the patients (if a small size).

The QA has the duty to make sure that the clinical staff uses and accomplishes their tasks in respect of SOPs in place regarding: the log book of the Pharmacy access (by who, when, why and therefore all the information might be trachked if recorded). The reg binder is also a good tool (see Michael comments about it), the CRF completed by the person who dispensed the medication and by the person who administered the medication ( the date, the time and the dose received are reported).
If the patients are dosed at the hospital, go and get information from the pharmacist of the hospital.

Carla Duarte • I agree with all of you, but my experience as a study coordinator this process must be done every time the patient is in the center to perform a visit. If you do that or advice the sites to do that you will avoid many mistakes.
I'm from Portugal, and myself and the pharmacist perform according to what I have descrive.
What I'm try to transmite is that a center can be a god recretument center, but has dificulties with the guidelines of ICH/GCP.
If we want to make good clinical pratice, we must input to the sites so formations in ICH/GCP.
This is my opinion as a study coordinator.

Francois Peterlongo • The main purpose of the certificate of disposal is to prove that the remaining drug was not used "illegally", e.g. administered to patients outside of the protocol, or in "hidden study" (I have seen that occasionaly in the past!)
In the above situation, this would be a important concern of authorithies in case of inspection. So I would suggest (in addition to the above advises) to collect convincing evidence that all the drug not delivered to study subjects was actually disposed of.

harun njago • I do agree with all of you but this issue takes us back to the fundamentals i.e proper site and PI (and study team)selection, working closely with site for proper site management and preparation of the site for close out. It would be important to map this as a risk area during study start and closely monitor it to prevent this occurrence.
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Megan

Megan Mather • The first thing I would want are reports from the coordinator and the PI as to exactly what happened, how the medications were disposed of and all corroborating documentation that is available. What is done is done, but as a QA auditor, I would want everything possible fully documented and I would want to see that the Investigator Brochure spelled out what was to be done with the drug at the end of the study, how the PI and coordinator were trained, were they at the Investigator Meeting, if there was one, did their contract include that they fully understood their duties and responsibilites, etc. A full paper trail of training, study expectations, and sponsor information should be gathered so that a corrective and preventive action (CAPA) plan could be immediately compiled. If there was something that indicated that the sites were not aware of study responsibilities, then the other sites need to be made immediately aware of the drug accountability procedures. There should also be a CRA report from the site initiation visit.

Many times problems arise when the coordinator is new to the study, perhaps hired after the Investigator Meeting or taking over for another coordinator or the coordinator has too many studies. Sometimes the PI hands a study over to a coordinator and doesn't oversee the study as they should, and also there are times when the sponsor is new to clinical trials (small pharma company) and doesn't make sure that all aspects of a clinical trial are addressed in the Investigator Brochure/meeting or even in the contract duties. I went to a site that actually gave away the study drug because the area was poor and patients needed the drug.

About all that can be done in these cases is to get as much of the drug back as possible or document how it was destroyed and then again, document all that happened preferably separate statements from the PI and the coordinator, and then set the CAPA plan to show that all other sites were made aware of the error, that they are informed of the proper procedures, and that there is proof that policies will be put into place to ensure that the error will not be repeated. CRA training should also be required and documented.

Dominique Chesnais • The problem you have exposed is serious and needs a full investigation of its root causes. The CRA should have already collated some information of what the site said about that event and should be shared with CQA to investigate further.

As a simple reason, it could be a lack of experience in clinical research. However, any researcher knows that nothing can be disposed of or destroyed, without the sponsor's agreement or its representatives. It raises an issue that the drug accountability form was not clear enough for the site to see that the CRA had to review the whole drug accountability and counter-sign the form. Full and detailed drug accountability is essential at all stages, verified by a CRA.

If no drug accountability was performed by the CRA during the whole study, or very little, it is impossible to know about each subject's drug accountability. Therefore, the data at that site should be excluded from the efficacy analyses.

It is important to know where the drugs are gone. They must be returned at the sponsor's office or be really destroyed. No hidden and secondary use with IMPs.

CQA should help in defining the event as an incident or a case of serious malpractice, not only for drugs but also for the whole clinical trial at that site.

Lynda Cedar • I fully agree with you Dominique, the data will be questionnable and might be rejected if there is no record confirming that they were obtained after the investigational drug administration.
The Clozapine generic was developed before the patent expiration in one of the countries where patents are not protected as not recognized, therfore if no record can be found about the investigational drug outcome, the intellectual property of the sponsor might be compromized.

Does data generated by conducting clinical trial in one region will be applicable/useful for conducting a clinical trial in a another region?

2011-12-22T16:09:00.004-05:00

Does data generated by conducting a clinical trial in one region will be applicable or useful for conducting a clinical trial in another region having different environmental condition?

Marie-Christine Reymond • Your question should not find a correct answer without knowing the therapeutic area you deal with. For example, it is well known that cardiovascular risk factors are different from US and European subjects, so that your conclusive findings can not directly be derived between both. Hope it helps.

Satish Champaneria • Environmental conditions are didderent from region to region..and so does conditions and various factors..extrapolation of clinical trials will depend on segment of trials..dosage and other factors will have to be born in mind..

Lynda Cedar • @Kunal: In any case all the clinical data obtained must be included in the study file at the submission, mainly when the action (see the question) was not planned at the beginning of the study....and it would be helpful if you tell us the reason to change the region.

In general it is certainly helpful to have clinical (pharmacology) data and explore, design next studies. Examples: don't we go into first-in-man studies based on the data obtained in animals? Are not the data of international studies (late stage) pooled to complete the study?

Pooling the data obtained by different sites or in different regions, that cannot be generalised, further information is requested, clinical research is not white or black, most of the time grey zones come up, and therefore clinical and medical judgements apply.

What is the different environmental condition: is it genetic? Is it the life style; is it the culture of clinical research? Etc,
What are regions A and B?
What is the medication (therapeutic area)?
What is the stage of the clinical study?
Etc.,
Etc.,

At least for economic reasons: If not a large population is needed, try to run a pilot study (a sample) in the second region and then compare to the data obtained initially.

Dennis McHugh • Many examples including analgesia, infectious diseases, gastroenterology, anti-coagulation, cardiovascular medicine support the fact that populations respond differently. Genetics, environment, standard of care, and even subject expectations all conspire to effect outcomes. Even in the US where everyone came from somewhere else at some point and you might anticipate a degree of homogenization, there are regional differences. Multi-center trials combined with sufficient torturing of the data 'till it yields the "right" answer is the only way to go.

Lynda Cedar • Dennis, my understanding of the question is that data were obtained at site(s) in one region and the sponsor wants to continue the study in another region. You are right, Phase III studies involve different populations (that is even a FDA requiremnent: 18y and up, different gender, different race, style of life, etc.) and mainly when rare diseases are concerned, however, when changes happen in clinical conduct at the middle or at the end of study, there is no general answer, it should be taken case per case, andappropriate recommendations might be provided.

Kunal Desale • Thanks to all of you,
for all of your reference I want to repeat my question with example,
I wanted to know that, does data generated by conducting a Dermatological trial in one region ( e.g. European region) will be useful for conducting a clinical trial in another region ( e.g. Asian region) and if it is useful or applicable then, should sponsor have to conduct only BABE study or whole clinical research of same molecule in another region...???
hope you all get my point.

Dr. Akhilesh Sharma • Clinical Data generated from a region for dermatology study would be suggestive of its efficacy and safety in the concerned population. It would also provide inputs about the dugs efficacy and safety. However, it may not be plausible to extrapolate this data for another region(unless the other regions are part f multi-centric study and the differences in response outcome are included while powering the study and calculating sample size). Clinical situations and factors for a dermatology disease can vary e.g. for acne or psoriasis in Europe exacerbations are seen twice a year mostly during winter & when sunshine is inadequate. The seasons in Europe are different and vary in intensiy, for example as compared to Asian countries like India and China, so disease prognosis/outcome/remissions differs. Similarly, other factors like food habits, skin-cleansing etc also contributes to the prognosis of a disease in skin condition. Nevertheless, data generated in a region is good indicator if not confirmatory of what can be expected from a drug in terms of its efficacy & safety. On the other hand certain skin conditions which have a heavy immune and genetic involvement, the outcome becomes more predictive about the response of a drug in a captive genetic population rather than regional, though careful interpretations are required because genetic variations exist between regions and ethnic groups as we all know e.g. outcome of Gefitinib in Head & Neck cancer in US & Europe as compared to caucasians.
So as stated by Lynda multi-centric, multi-national studies are sufficiently powered enough to look at these differences. In case a study has been completed and results analysed for a region and if another region was not a part of the study but data is required in this 'another' region a proper statistical powering of the study is required based on endpoints to be evaluated and therefore the number of patients is based on the expected outcome in that population/group. This may be a full fledged phase of a clinical trial, however the sample size calculation becomes more easy (and sample requirement 'maybe' less) from the response seen in clinical trial conducted in another region. These are indicators more towards phase IIb/ III studies, I am not sure as to which phase of the clinical trial is being referred to here.

Lynda Cedar • Since it is about a bioequivalence study, the efficacy was demonstrated at the time of developing the original. Depending on how the comparison is assessed, via PK data, PD data or visual scale. If PK data or measurable PD data cannot be obtained, therefore it is about therapeutic bioequivalence. In fact, there is a difference (physiology - ADME) between Caucasian, Asian and black, and a population might be more or less receptive/sensitive to the treatment consequently.

I recommend a pilot exploratory clinical study and then do the adjustment as/if needed. Also, check about the local regulations, whether foreign clinical data can be used or not.

Anders Fuglsang • In a BE trial the primary endpoint is the T/R ratio. While regional differences in phenotype might affect drug response or PK for any given molecule, the T/R ratio or the variability associated with it might not be affected. This is why BE done on population X is often acceptable for a claim in population Y.

It needs to be said though that a good design in population X might need to be tweaked somewhat if the trial for some reason is to be repeated in population Y. Example: Blood sampling regimens in BE trials often need to be planned so that AUCt is 80% or more of AUCinf. Therefore, if population Y is on average (or median) more slowly metabolizing than population X, the timing of blood samples should reflect this.
A similar consideration might apply to equivalence in terms of PD.

Best regards,
A.

Lynda Cedar • Anders, that true if PK or PD data are possible to be measured. This is a dermatology study; the data might be observational, example: heeling, less lesions, decreasing of redness or size, itching, wrinkles, spots, etc.

Francois Peterlongo • The general question was thoroughly debated at the beginning of the ICH process. It was even a serious obstacle to the harmonization between the 3 ICH regions. I remember that Japan authorities were especially reluctant to accept that clinical trials results observed in western populations could be adequate to support product registration for Japanese population.

Fortunately, a consensus was finally found on scientific basis, ans it is the content of the guideline ICH E5 "Ethnic Factors in the Acceptability of Foreign Clinical Data". As far as I know, it is still the reference text about this question.

Lynda Cedar • Yes François, I was at school by the time of process of mutual recognition.

Sponsor still have some difficulties I think when importing data obtained outside the 3 ICH regions.

CRA found missing data in the source records. How he/she should deal with that?

2011-12-22T15:41:00.003-05:00

The question was posted and commented on a Linked in group:

Myrna Loughrey • Can the CRA still enter the data into the database? If the database is closed, the CRA must notify the project PM, inform the sponsor, and inform the PI. A note to file may be written to document the inadvertent error or directly write the error on the source and or the CRFs. This inadvertent error must be documented and appropriate folks must be notified. The documentation will help during regulatory or sponsor audits.

Bakhtiyar Valiyev • Hi Myrna, thank you for your response!
Yes, the database is open. I wonder how the fact of missing data should be considered? Should we consider these missing data a protocol and/or GCP deviation? If yes, what are the criteria?

Let's say some evaluation was done but was not recorded in the source records at the visit (e.g. urine pregnancy test). By the time of the monitoring visit, the CRA found that there is no result in the patient chart and may be some vague recollection of site staff that the test was done and it was negative.

What steps can be recommended the CRA to make (with regards to site staff, PI, trip report, follow up)? Is it enough to make an action item, e.g.: "the result of pregnancy test is missing in the patient chart; the site staff should enter missing data"?

As I understand in this case you propose 1) to write a note to file to document the issue or 2) add comments in the source records as well as to notify the appropriate folks (which ones in this case?). Any other options or the mentioned above will suffise?

Jim Sheets • You could just have the site staff record a late entry in the patient's medical chart (dated today), and then update your open study database with the new information. Issue a query and have the PI/subinvestigator sign.

Lynda Cedar • Jim, late entries are data (like vital signs for example) that were performed but the staff did not write it down or entered it in the data base for x, y reasons.
Regarding the pregnancy, since there is no proof that the pregnancy has been performed, no late entries can be considered. I came across to a similar situation, during the morning monitoring before the dosing (it was about a Phase I study), the data were not entered and the clinical staff ensured that the pregnancy tests were performed, I put a note to file, to document the event and for follow-up. Later, the site was able to demonstrate (via the log book of purchase) the number of units (pregnancy test) available before and after the day where tests were supposed to be performed. This was acceptable to the IRB/IEC.

Jim Sheets • Bakhtiyar says: "By the time of the monitoring visit, the CRA found that there is no result in the patient chart and may be some vague recollection of site staff that the test was done and it was negative". If the site can retrospectively remember such information, I don't see anything wrong with documenting something like "pregnancy test was performed on (date), and was negative" - PI sign/date with today's date. "Negative" is entered in the database. A pregnancy test result is easier to remember than a vital sign.

I don't believe proof is required in order to remember something and retrospectively document. Obviously, the ability to recall information like that has to be considered on a case-by-case basis.
2 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion0 . Lynda Cedar • Exactly, it is case-by-case, some sites do not perform the test to save money and declare that the test was done. How can we ensure that?

If I'm not convinced about it, to protect the sponsor and the rights of participating female, I reporte it as missing data (therfore a protocole deviation) and put a note to file to document it for track record and follow-up. This way, we are on a safe side, if a female was pregnant or becomes pregnant while she was under medication effect.

Myrna Loughrey • Bakhtiyar I inform my staff and the sites that I visit, if its not documented it never happend. The site can recollect all they want; however, if the study procedure is missed and not documented it never occured. Is it a protocol deviation? Yes of course it is! Study procedures written in the study protocol must be performed. There is no way around that. It's part of the study protocol!
What the CRA must do to move forward to ensure? It is an action item that should be included in the monitoring report, sit down with the site site staff and the PI and inform the site missing data and/or miss procedure is not acceptable, inform PM and discuss the occurence during CRA conference call (it might be occuring at other sites).
No other options but document..

Lynda Cedar • @Myrna: your comments are pertinent, if the study is multi-center, you should not inform the other sites but monitor them to see whether they are performing the pregnancy test or not. If a BE study, the process is much simple, I just report it as missing date (protocol deviation in the study report) and document it for follow-up.

Jim Sheets • It is documented...if you document it now, retrospectively. Sure, it does not meet GCP criteria for good documentation practices in that it is not "contemporaneous"; therefore, (if we want to use cliches) are we saying if it isnt documented contemporaneously it "didn't happen." Not sure I agree that is always the case.

Lynda Cedar • Jim, I respect all opinions, mine is just one of them: for me if a test was not done and discovered by a monitor or a CRA, it was not done (missing data and protocol deviation).
Let's give the site a chance, the usual good practice, if the staff forgets to report pregnancy test results, they would do report it quite rapidly, it cannot wait until the CRA dicovers it and then it is reported (as late entry).

Thanks for sharing and best regards.

Lynda.

Shirley Isbill • If a pregnancy test was done, there should be a record somewhere. If the test was not done (the conclusion in the absence of a record) then a NTF that it was done and was negative would be a false medical record entry.

Ann Baumann • From an ex-inspector point of view, I can tell you that this is definetely at least a major finding . If something is not documented, it does not exist. What irritates me, is the fact that "the site staff only vaguely remembers having performed a pregnancy test", which is a crucial test in a clinical trial.
I must agree with Shirley, a NTF stating that the test was negative is definetely a false statement. So you should document in the NTF what really happened.
1 day ago •

Myrna Loughrey • @ Ann: Thank you for your comment! " If something is not documented, it does not exits" This statement is what I've heard form all the regulatory inspectors I've encountered.

Lynda Cedar • I agree and that what Jim explained: it is not GCP reporting a test done while there is no record. In this case, regulatory inspector and strict monitors (like you and I) would state, if not done, it is not done. The only thing the site can do is a NTF documenting it: when the deviation was discovered and what were the actions undertaken. .

John T. Davidson • In my experience this is sadly more common that it should be. Having said this, the key to avoid this is for the Sponsor staff to develop a relationship with the Investigator and investigator staff that is transparent and where information flows rapidly and freely. This includes “bad” news.

I know the adage, “If it isn’t documented, it didn’t happen.” While I appreciate the sediment of the saying, the biggest mistake is to not document the incident at all since “any documentation is better than no documentation.” Of course I am not implying that anyone should make the facts up but if the staff only “remembers” doing the test, state this clearly and bluntly, stating that the documentation is retrospective.

To Ann’s point, if an inspector finds the incident, you are looking at a major, but in my experience if you have been careful to accurately document the issue before the inspection, you will at minimum gain the respect of the inspector and it will improve your working relationship with the Agency and at best the inspector could give you a break if it is a one off mistake.

So, document, document, document, but if you didn’t do it prospectively, document, document, document honestly, bluntly and transparently retrospectively since this may be the best you can do.

Bakhtiyar Valiyev • Myrna, Jim, Lynda, Shirley, Ann, John, thank you very much for your feedback! Your ideas and suggestions are very useful and give great hints as to how to deal with such cases in everyday CRA work.
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Batya Kornfeld • I think when coming across events of missing information either in the source documents or in the CRF it is essential to sit down with the site personnel discuss the issue and retrain the site to provide the re-occurrence of such issues. If a test was not done this is obviously a protocol deviation which needs to be documented and submitted to the EC and reported to the PM/Sponsor. If it was not entered into the CRF this should be done at once.
10 hours ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion.

Jorge Garagorri • Dear All,
A personal opinion is to notify this omission data as protocol violation inmediatly, request to the site to perform the pregnancy test asap and inform to medical monitor about this, also. In addition, request to the site an action and preventive plan to avoid this happen again and follow up with the site closely its implementation.
Since we cannot assure if this pregnancy test was done, late entry is not valid because ALCOA criteria is not being followed.
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John T. Davidson • Good discussion. George, I thought about the PG testing, but by the time the oversight of the PG test is found, it is likely the patient already knows if she is pregnant or not. This does make me think that the IRB and your Drug Safety group would have to be notified and of course legal would have to be brought in to the loop in the event the patient is indeed pregnant or worse experienced a miscarriage during the treatment phase of the study.

Lynda Cedar: Jorge and others (including myself) would report the event as a protocol deviation, in fact, is it a deviation or a violation of the protocol?

When a test is done but not as directed by the protocol or SOP, it is a deviation; but when not done, mainly dicovered by the CRA before any documentation or follow up was undertaken by the site, that is a violation involving the consequences brought by the members above.

Should an abnormal lab value automatically be considered an AE if the value was normal at baseline?

2011-12-15T23:41:00.001-05:00

The question was posted on a Linked in group: Should an abnormal lab value automatically be considered an AE if the value was normal at baseline? Obviously the investigator would classify as CS or NCS, but would it automatically be an AE?

It was commented 200 times as follows:

pallavi Borse • It is depend on the medication ,IF it is realated to the IP product then it is definately AE

Dr. A. D. Paul • Strictly speaking, an abnormal laboratory finding is to be regarded as an adverse event (AE), irrespective of its clinical significance. Whether such an abnormal lab. value is clinically significant or not, is its interpretation. If the abnormal lab. value is due to an investigational product, it constitutes the causality of the AE.

Sarah McLeod • The answer is yes unless otherwise specified by the protocol.

Biswajeet Dasgupta • ICH E6 ------ 1.2 Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and which does not necessarily have a causal
relationship with this treatment. An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal
(investigational) product, whether or not related to the medicinal (investigational)
product.

Valera Bussell, CCRC, CCRA • Thank you to all of you for your input. As you may have noted; there are varied opinions regarding the issue. Years ago, when I was a coordinator; I was taught that any change in lab values from normal at baseline would be considered an AE, but apparently many companies now view that differently and only consider Clinically Significant abnormal lab values to be an AE; the clinical significance being decided by the investigator. I would like to see the FDA's opinion on the issue. Thanks again for commenting.

Lakshmi Guduri • Completely agree with Valera. Even, I was taught that an abnormal laboratory finding is to be regarded as an adverse event (AE), irrespective of its clinical significance.

Dr.Avani Badani • I do not think an abnormal lab value should always be reported as an AE. There are scenarios where even 0.1 increase or decrease of parameter happens,and that isnt a AE by anycase. It should always be reported as an AE depending on PI discretion or Sponsor's reporting requirements.

Shahid Ashfaque • The official and most accepted definitions in most countries are based on ICH E2A guidelines and are as follows:
Adverse Event defined by ICH :
Any untoward occurrence in a patient or clinical investigation subject administered a pharmaceutical product and and which does not necessarily have to have a causal relationship with this treatment. Any unfavorable and unintended sign( including an abnormal laboratory finding, that is sign or symptom, or disease temporally associated with the use of any dose of a medicinal product, wether or not considered related to the medicinal product.
Having stated the above it is an Investigator's perogative as what should be reported as an adverse event (it is his/her responsibility to assess the safety of the subject). You cannot ask the investigator wether to report any lab value as an AE or not to report it. You query or advise but ultimately it is investigator's judgement based on his expertise and medical judgement
The GCP states as follows for the investigator:
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

Dan Rossignol • Small deltas from within normal limits to just outside the normal range are meaningless to patients and should not be used to define AEs (in fact, lab values can move from normal to abnormal just by being converted to different units and rounded!). Sponsors should devise standards that define a minimum delta that determines when a change becomes an AE, either as a discrete value change or a percentage change. These can be used in combination with claims of clinical significance by the site investigator.

In addition, when not dealing with potentially-overtly toxic drugs (eg cytotoxic chemo therapies) we had a derived list of treatment-emergent abnormal values (TEAVs) that were based on amount of change from baseline. By this analysis a change from high but normal to just outside of normal range might not be a TEAV as the percent change was small, however a dramatic change within a normal range would be flagged as a TEAV. This (as well as shift tables) was helpful to look at possible lab changes in populations that would go otherwise unnoticed as even though there could be dramatic changes, they would not be defined as adverse events.

Shahid Ashfaque • I totally agree with Dan Rossignol

Valera Bussell, CCRC, CCRA • And I totally agree with both Dan and Shahid. Seems like there could be a standard to go by, rather than relying on the investigator to decide whether to report as an AE or not.

Marie Gabrielle Laguna MD • I agree: it is investigator's judgement based on his or her expertise and medical judgement.

Shilpa Garg Agrawal • It is the investigator's judgement which would finally decide if it is AE or not. Also, it would depend on the protocol. For eg. if there is a change in the lab value, which shows exacerbation of the underlying disease, if the protocol states that exacerbation of underlying disease is not to be reported as AE, then, this will not be an AE. However, if the protocol states that exacerbation is to be reported as AE, then, it may have to be reported as AE. Also, although investigator's judgement is final, but the CRA should be vigilant to identify any such abnormal lab values which the investigator may state as NCS, If the CRA is concerned about it, the best thing is to discuss it out with investigator, and if still not convinced, the CRA should discuss the matter with medical monitor, and take it forward..

Dan Rossignol • I agree, and this all makes sense for the use of local labs, especially
when a lab finding leads to an intervention. For an international study in
very sick subjects, our group actually defined an AE as a finding that
necessitated medical intervention. That reduced the number of minor
observations including labs and physical exam finds that counted as AEs.

But another point on lab findings is what to do with central lab results.
Variability due to judgment can be reduced, by use of a good central lab,
especially when a large study is done on a very sick population. In this
case, the site investigator's opinion is not included in the results and
the use of guidelines to interpret the data (changes in values) can be very
important.

Marie Gabrielle Laguna MD • I like these type of discussions rather than job posts.. more....more.....more please! Let us exercise our brains!

Sara Lampinen • I agree with Marie, this discussion it great! This issue comes up so frequently, it's nice to see all the different opinions.

Dan Rossignol • LOL.. It seems that this issue comes up with every study! Where would there be a "master guidance" (besides the regs of course) on things like this so we do not have to reinvent the wheel each time?

These discussions are good, but for some us (eg. the currently in transition types), the job postings may be of use!

But I have another question on how AEs can be standardized for severity in non- cancer trials. maybe start another string.

Konstantinos Kakos MD • Dan Rossignol-

A central lab will always be a better solution than local labs for a multicenter trial,especially an international one. Collecting data will be much easier and problems in the trial set up such as different test methods, different validated methods, different reference ranges etc. are eliminated but the central lab would never replace the Investigator in his role of the judging if a lab finding is CS or not.

Steve Mcateer • I agree more or less with Dan, but would emphasise that the biggest issue with using the reference range as a tool is that there is a danger of just scanning the labs looking for flags, wheras the biggest problems can be found when results are still well within the reference range. As a lab professional, we tend to pretty well ignore reference ranges and concentrate on delta change within an individual. Any decent computer system can track these changes and flag accordingly (ask your lab to do it!). Just on a technical point, reference ranges are calculated from 95% confidence limits of a 'normal' population, so 5% of results MUST be outside of the quoted range if the range is valid - thats an awful lot of AE's to be notified!
Finally, re the role of the investigator - their responsibility is for their own patient, and they are well judged to comment on clinical significance, but unless they have full access to all other patient results, they cannot see trends in other centres, which coupled with their own NCS, might tell a whole different story - the CRA is usually the only person to see this (apart from the lab of course). My overall message is talk to the lab, get them involved in setting criteria at the protocol stage, but that mantra's an old one!

Dan Rossignol • I agree. And the turn-around time for a central lab takes it out of the
"timely information" loop as well, but central lab results are great for
analyzing final data in a clean, consistent way though.

Ana Isabel Alvarez Retuerto • I believe that while the ultimate decision is the investigator's, this is at the end a team effort to get the possibly most accurate data while keeping the patient/participant's safety as a priority and keeping compliance with protocols, so if something out of the ordinary comes up it should certainly be brought up by the team members, talked and discussed by the relevant investigator/s and depending on the study/protocol, the "unusual finding" and having the patient/participant's safety at the top priority, make a decision that stays contained within the protocol.

Shahid Ashfaque • Finally, re the role of the investigator - their responsibility is for their own patient, and they are well judged to comment on clinical significance, but unless they have full access to all other patient results, they cannot see trends in other centres, which coupled with their own NCS, might tell a whole different story - the CRA is usually the only person to see this (apart from the lab of course). My overall message is talk to the lab, get them involved in setting criteria at the protocol stage, but that mantra's an old one!

Steve,My comments on above paragraph:
I see your point but we are talking two different things. We should not confuse with the responsibility of Investigator with the responsibility of Sponsor.Although both are responsible for the safety of the patients Investigator is responsible at the level of his site and patients, while Sponsor is responsible for the aggregate analysis, while the study is ongoing it is blinded, and the safety plays the dtective through signal detection. All DIL letters during the trial to investigator is the method to inform EC and Investigator of any serious adverse events occurrence. The non serious adverse event trending can be better done by sponsor since they have the panoramic review. At the end the investgator brochure is the reference they can wisely use.

We are drifting from our main question what is an adverse event? is any abnormal lab value is adverse event. The answer is NO. Use your judgement by utilizing the wholistic approach to the compound under study and considering other variables of therapeutic are of study, type of patient population, and what is the end point

Patricia Hollis, MBA • it really depends on the protocol and who you work for.

Patricia Hollis, MBA • I would also like to add that many people depend on the job posts so please do not stop them.

Essack Mitha • I agree with Steve, that changes in lab values are as important as once off out of range values.

Thanks to those that quoted ICH GCP. I regard only CS abnormal values as AE's. The reason is simply that there are normal fluctuations in lab values that sometimes may go into abnormal range. HOwever, these could be due to variety of factors, including time of day. Once i am of the opinion that a lab value is CS, i report it as an AE.

I have sometimes encountered changes in lab value over a few visits, where the value is close to lower end of normal, and gradually elevates till it is close to upper end normal. Although these are still within normal range, i consider these as AE's as well, as the change in lab value could be significant, while still being within normal range.

S K. • Strictly speaking, Its automatically an AE

manorama Mpanwar9 • I agree with Essack Mitha. If the change in lab value is CS then it should be an AE but if it is NCS then it is not necessary to take it as an AE until it is the requirement of the protocol. We can take a simple example - if lab test of a same person is performed at 2 different labs on same day we can easily see the variations in the results. As, the variation can occur so there is no need of taking all changes as AE except for those values that are CS.

S K. • I do agree with Manorama, Consider this example: Suppose PI denotes the lab value as NCS in all visit 1, 2 3, & 4 for same subject. Finally in visit 5 too he got the value as NCS then PI may decide to consider it as CS and will report it as AE.

Konstantinos Kakos MD • I think that there's a greater confusion on the issue. Clinical trials is
not just following guidelines, there's logic involved. An Investigator as a
physician will take a number of factors into consideration before reporting
an abnormal lab value as an AE. Simple fluctuations in values from baseline
do not necessarily mean AE. Of course if the protocol strictly requires
reporting as AEs every abnormal value no matter what the Investigator will
have to do it.
Remember that lab tests are a tool allowing the physician to get a general
picture on the patient's condition, they shouldn't be looked at as simple
numbers of a scale.

Brad Brush • An AE must be reported, irrespective of the Investigator's opinion of causality or individual opinion of clinical significance. ICH guidelines aside, what if we all did not report an increase in a laboratory parameter (out of the reference range) and this occurred in a large number of subjects? We need this data!

Valera Bussell, CCRC, CCRA • Hi Brad,
As I am sure you have seen within the numerous comments; not everyone agrees that all abnormal labs should be reported as AEs. Something that I find interesting since the FDA guidelines includes abnormal lab values within their definition of an AE. It would be so nice if we could standardize some of these issues across the industry!

Dr. Darpan Gangil • It should be an AE.

Shalini Dayananda • I agree with Steve regarding the reference ranges being calculated from 95% confidence limits of a 'normal' population, so 5% of results MUST be outside of the quoted range if the range is valid -and the PI land up reporting a number of AEs which have actually not occurred. However, Protocols usually define the how much deviation from the reference range - e.g twice/ thrice of UNL to be reported as lab AE. Accordingly, the AE should be reported.
Coming to Investigator's prerogative to decide upon CS or NCS - in either case AE should be reported with an additional info stating NCS as per the Investigator. This will definitely ensure that the data does not go unreported.And, this will be irrespective of whether it is related or not to the IP.

Cristina Gonzalez • I would say it depends on the situation. If the lab value is a symptom of an underlying disease, the investigator will not consider it as an adverse event unless it indicates something different as expected. For instance, for liver metastases is expected the ALT and AST values will be higher than normal, however are not an AE themsleves if the liver metastases are confirmed and no other cause is found.
Otherwise we could fall in overeporting Adverse Events.

nithiyarajan nambirajan • hi, i am a DENTIST, now pursuing clinical research course, by seeing all this comment i got good information regarding AE, so thanks for all ur comments.....

Hamdi Akan • İf you are doing a hematology/oncology trial, this issue can a bigggg problem. The best way to overcome this, is specifying limits for expected abnormal lab. results related to the underlying disease and leave it to the investigator but by definition all of these are AE's

Valera Bussell, CCRC, CCRA • Again, thank you for the lively debate and all of the input; it should prove quite helpful; especially for those just getting into clinical research. Our SOP is to report all abnormal labs after baseline (assuming they were normal at baseline) as AEs, unless the issue is clearly addressed in the protocol. I.E. if some changes are to be anticipated based on the indication being studied and the protocol clearly states that these changes will not be considered AEs or will be assessed by the investigator, then they will not be reported as such. I would encourage all sites to be written SOPs in place at their site. Please let me know if you don't have written SOPs, but would like assistance in putting them in place. Perhaps if we could all address more of these "gray areas" in the forums; we could finally start moving toward real standardized processes within clinical research. Thanks again! Valera

Shilpa Garg Agrawal • Thanks Valera, I really liked the idea of having a written SOP for this specific issue.

Adrian Johnson • Unless it is specified otherwise in the protocol, an abnormal lab value outside baseline regardless of relationship to IP is considered an AE.

Valera Bussell, CCRC, CCRA • HI Adrian,
That was my opinion as well; however it appears that some companies (CROs) may have a different opinion on that and think that is should not be captured as an AE if the abnormal value is slight and not clinically significant in the opinion of the PI. I personally think that leads to confusion, especially on the part of the study coordinator who may be assisting in reporting AEs.

Dana Austin • Also, its dependent upon other variables, such as was it an "expected or unexpected" event? Those will help determine if it should be captured as an AE until resolution or not.

Dr. Datta Pawar • Anything new finding during study should automatically be reported as AE. Over-reporting is always beneficial than under-reporting. Though it may not be related to Investigational product.

Oussama OUESLATI • if the abnormal result is observed for the first time after medication this result must be registered as AE, In any way, the CRA have not to say the significance degree: it is the physician role!
The CRA have to notify this observation as AE.

Pat Sabatini • Adrian - I agree and it should never be left to the Investigator.

Valera Bussell, CCRC, CCRA • I would agree and as previously stated, it is our SOP that abnormal labs that were normal at baseline should be reported as an AE, unless it is explicitly addressed within the protocol. I lean toward the over reporting rather than take a chance on not reporting an AE that should have been reported. It is unfortunate that some of the CROs have decided to insist that the PI decide whether to report as an AE or not to report. I would prefer a directive from the FDA before we change our SOP. Thanks to all for your opinions.

Shamshad Ali • I totally agree that based on safety aspects any abnormal value should be reported as an AE

Essack Mitha • I can see that there will not be a strict guideline on what should be reported as an AE, as Investigators have their own opinions. However, the medical monitor and the sponsor get results of every subject on the study, so even if an abnormal result is not reported as an AE, the capturing of the lab data will show changes in lab values. It is this that is also taken into account when looking at the effects of IP, not only what the investigators report.

Dan Rossignol • I agree with Essack Mitha as eventually all changes, even if they occur
within normal ranges (eg platelet counts that can be high normal at
baseline and low normal post treatment) need to be evaluated (and compared
to placebo where possible) to see what is going on in the treated
population. While we talk about AEs or lack thereof, these are simply
"cut-offs" and should be understood to be "clinically significant" or "non
clinically significant" but in the end, there is usually more info across
all subjects over time (with post-treatment recoveries) that are evaluated
in the clinical study report. Signals seen at low dose IP may indicate
potential targets for close observation as you move to higher doses,
extended treatment, or treatment of more impaired patients.

Emmy Merkley • I think I have always followed the following criteria,. If the investigator deems it is clinically significant after repeat testing of an abnormal value to confirm the 1st abnormal value and it may require some kind of treatment, follow-up testing or obeservation, then it does become an adverse event.

Dan Rossignol • That seems like an ideal definition. Simple and clear. The requirement for
an intervention makes a case for significance as well.

YJ Bi • This is a great discussion! Just want to add my humble opinion:
During the collecting of data (investigational site/investigator and site monitor), in general, an out of range lab value should always be captured as an AE on the CRF. Once it reached datamanagement, usually involve medical monitoring and data review/coding/cleaning which is also done under FDA regulations/SOPs/study data specifications, Such AE can be kicked back via data query to remove or just confirm the AE on case by case basis (e.g. lower WBC while the patient had a flu/other viral infections, transient transaminase increase after a dozen beers previous night at a birthday party, etc).
As all AEs, the clinical significance and severity is rated by the investigator (while serious is by FDA definition). It not uncommen that an AE of out of range lab value, to be queried.
However, before CRFs is pulled out, an out of range lab value should be reported as an AE. But this can still generate an query. Such kind of query is a part of the datamanagement process, even site/investigator and monitor are doing the right thing to capture such AE.
Thus, out of range lab value is to be reported as an AE unless study specific documentation indicated otherwise on the CRF. It may generat a data query, then it may be handled differently depending on the data convention and clinical scenario.

Carlos Estrada, MD • I agree with Biswajeet Dasgupta, It is considered an AE, as an Investigator, I am able to suggest if it is related or not to the investigational product, but it is definitely an AE

Sebastian Antonelli • This discussion seems closed by now, but anyway, my 2 cents: in general, report an abnormal lab as AE when it triggers a medical intervention (thats why it is called "medically significant"), and such medical intervention could range from a medical advice (i.e. "you should really reduce the number of MacCombos per week"), a drug prescription, or med change, or dose adjustment or discontinuing of an ongoing med, or additional testings that confirm a diagnosis. If there are symptoms accompanying the abnormal lab, please don't duplicate entries, AEs should be diagnosis if possible. And every AE should have an action taken.

Sundarkia Hill • As a former CRA, I always required changes from baseline to be reported as adverse events. Even if it is exacerbation of a pre-existing medical condition, the exacerbation itself is an adverse event. Whether the reference range is set by the lab or by the investigator's judgment, any lab result deemed abnormal is an adverse event, regardless of clinical significance. Determining reporting relevance at the site level can lead to obscuring trends across the study which could give further insight into how the drug works. In my opinion, it is the duty of data management and the data analysis committee to adjudicate these events once they review data from all sites, from all countries, for the entire study. There will always be room for debate between sites as to what is relevant, even when a master guidance is given. Therefore, I believe the only necessary master guidance is to report all abnormalities and let those individuals privy to all study data determine relevance.

Carlos Estrada, MD • I agree 100% with Sundarkia, as a PI and Medical Monitor, the abnormal changes in labs need to be reported as AE's, and it is the discretion of the PI and/or Medical monitor ( or Data Safety Monitoring Board) to adjudicate the AE to a particular Drug/procedure/device or not.

Jacqueline Gough • Fascinating discussion that truly does seem to occur on a regular basis.As others have stated, the reference ranges are only useful for understanding where the patient's result lands with respect to the "normal" distribution of results. This is usually the reason that the investigator's opinion of clinical significance has been included in the determination of whether an abnormal lab value is considered an adverse event. What might be abnormal according to the reference ranges may be completely normal for a particular patient and only the investigator, with their more complete experience with that patient, can assess this. This is completely distinct from relatedness.Additionally, although it is conceptually more conservative to include all abnormal lab values as adverse events, there is a risk that any safety signal from that information could get lost in the noise of so many adverse events that are not clinically significant.Instead, perhaps adverse events should be reserved for what the investigator assesses as clinically significant and the actual lab values can be analysed for trends or items that the investigator has failed to notice.The purpose of collecting this data is to identify any safety risks associated with whatever intervention being studied. Patient management should, in my opinion, be left to the individual investigator.

Sundarkia Hill • While I agree with the group's interpretation of a reference range, I must disagree with the interpretation of clinical significance and its role in clinical studies. Clinical significance has no bearing on determining if an abnormal lab is an adverse event. The ICH definition of an AE shows an abnormal lab in itself constitutes an AE. If you are consistently not documenting abnormal labs as AEs and you are audited by a CRO, FDA, or IRB you will likely be dinged for not properly reporting AEs.

Clinical significance is followed for the purpose of monitoring the status of the event with the subject. For example, if I am a CRA monitoring a subject’s chart and found a lab value was 4 times the upper limit of normal, I expect to see active intervention by the investigator to bring this value back to normal (change in meds, retesting, etc). I would also make it an action item in my report to follow up on this abnormality to see if the intervention had an effect, resolving the AE.

Regarding AEs in general, sometimes the side effects of drugs are hidden in the small changes and I think it would do a disservice to the industry to ignore them. Although reporting these events can lead to queries, this is actually a good thing. The queries I often saw as a monitor would say something along the lines of “elevated ABC plus decreased DEF codes to condition XYZ. Please confirm if the subject has been evaluated for XYZ.” This could be from a small increase over baseline, just barely putting the result out of range. Something that would likely be marked as not clinically significant when looked at separately can become significant when looked at collectively for a subject and accross subjects at different sites. Such queries come from AE reports, not from the lab. This also shows the level of analysis of these events and can sometimes make the site staff dig deeper into something that may have been accidentally overlooked, simply because the changes were not significant in the opinion of the investigator. We should not rely soley on investigator opinion because every investigatior's opinion is subjective, no matter how experienced a physician one is. My advice is to report all abnormal labs and allow the data monitoring committee to adjudicate.

Dan Rossignol • Beautiful. Put writing of this sort in the protocol and you should have
everythingyou need (between this and the analysis of lab changes) And I
like your sense of humor. But I would consult regulatory to see if you have
to list the BK and Wendy combos as well in the example.

Valera Bussell, CCRC, CCRA • Thank you again for all of your opinions; I am especially happy to see that many of you agree with me that a change in lab value from normal at baseline to abnormal after starting the study drug should be considered an AE based on the FDA's definition of an AE and should not be based on the evaluation of how far outside normal range it is in the opinion of the investigator. I will continue to direct my research staff to capture these change as AEs, with the investigator merely evaluating the seriousness of the abnormality (clinically significant or not) etc.

Gulben S. • If the investigator classify it as CS then it would be an AE. Except 'special cases' if it is NCS it would not be an AE.

Carlos Estrada, MD • Again, as the question said, if the laboratory value is ABNORMAL, it should be reported as an AE, regardless of causality, if the laboratory value is DIFFERENT from baseline, it needs to be assessed first as CS or NCS, before being reported as an AE.

During an FDA audit this is something the inspectors will look at and you might get a 483 for not reporting as an AE.

It is the responsibility of the PI, Medical Monitor and or the DSMB to adjudicate the AE to a Drug/device/procedure.

Erika Tokaji • To ensure consistent reporting leading to meaningful safety profile and help both the sites and CRAs with SDV, the protocol should provide guidance what is to be reported as an AE. One commonly applied approach is to specify CTC severity grades as from which the result should be reported as an AE (usually grade 3, 4).

Artie Jhappan • My experience working in Phase 1 trials - only abnormal lab results that are deemed CS by investigator were reported as an AE.

Artie Jhappan • Often the regulations are broad and non specific.I think this is something that needs to be defined clearly in the protocol.

Artie Jhappan • Joyce -Excacerbation of an existing condition should be considered an AE.

Cynthia J. Robinson • If the lab value is significantly high from base line then it is the judgment of the investigator to determine if the value is an AE or not.

Pat Sabatini • If it were to either be written in the protocol or left up to the investigator AEs would be all over the map.

Valera Bussell, CCRC, CCRA • Pat,
I agree, but there are some CROs that don't want all abnormal labs captured as AEs and have specified that it should be assessed by the PI and then a decision made whether to capture it as an AE or not. Historically, all of the sites that I have worked with have reported abnormal values as an AE, even if not deemed CS. I see it the same as you apparently; where do we draw the line if we leave it up to a PI? Can they consider other issues as not worthy of capturing as an AE as well if that is the case etc.?

Abhijit Sharma • Abnormal lab value + Clinical significance = AE
Abnormal lab value - Clinical significance = Not an AE

Clinical significance= standardiztion in Protocol/PI judgement

In case of CNS abnormal lab value ratinale can be documented.

Pat Sabatini • Hi Valera - I'm not suggesting that all abnormal labs be captured as AEs but that CS must. The definition of CS has always been if it requries intervention. The same goes for the severity of the AE, this is not defined by the PI, there is a clear definition of this and every PI must be given the same yard stick by which to measure this. It is up to the monitor to verify that they are all using the same yard stick.

Meenakshi Manerikar • yes it is AE

Karolien Timmermans • Hi,If you look strictly to the definitions in ISO or GCP, an abnormal lab value should be documented as an AE. However, as already pointed out before, you also have to look at the clinical significance of the abnormal value.
Also, if no treatment is initiated to correct the lab value, i would not consider it to be an AE.
Nevertheless, I would obtain confirmation from the PI in the center and make a note in the monioring report.

Cynthia J. Robinson • Shilpa Garg, I agree it is the principal investigator’s (PI) judgment that makes the final Adverse Event (AE) decision. However, it also depends on the protocol and whether this is an exacerbation from a chronic illness. Prior to final decision, PI should repeat labs to confirm significantly high value. If CRA is still concern whether this entails an AE then CRA should collaborate with the Medical Monitor.

Muhammad Ather Latif • Abnormal value which has / could have relation with administration of investigational product and was not recorded in baseline or history of the patient/subject will be considered and regarded as AE. Its significance may be analyzed by PI later.

Priya Reshma • its very good kind of discussion....getting more information and also helping us to update our knowledge..........thanks to all

Jhappan • a stimulating discussion.... I like it

John R. Waldron, CCRP • This is definitely a case-by-case situation with no general rule or regulation to follow. Lab abnormalities that constitute worsening of the disease under study would not be an AE. For example, elevated liver enzymes in patients with known progressive liver metastasis. In addition, lab values slightly above or below ref range could be deemed normal for that patient, interpreted as NCS and not an AE.

On the contrary, lab abnormalities that constitute worsening of pre-existing conditions found in medical history would be an AE. All lab abnormalities that are study drug related should be interpreted as CS and listed as AE.

Samuel W Boellner, MD • depending on the study I would recommend a repeat

Luigi Nardacchione • We cannot consider the sponsors' or investigators' opinion (or interpretations) but just the official guidelines. So no doubt about it as per ICH E6 and related FDA/EMA requirements: it is sponsor and investigator responsibility to strictly follow them in order to protect patients and also not to jeopardize study results.

Helen Russo • While everyone continues to quote the untoward regulation, I think the boat has been missed...not all abnormal labs constitute an untoward event, particularly if the PI considers them NCS. Also, an abnormal lab value, in and of itself, would not be the AE, but rather the underlying condition, even if it's the probable/possible effect of the IP on liver fx, e.g. In other words, "elevated ALT" is not the AE.
As a monitor reviewing signed labs, I always tell my PIs that I reserve the right to ask them "why" they feel an abnormal lab is NCS if I disagree. It may be that they have reviewed that particular report away from others and not noticed a trend that I have, or they may have just missed it...it happens, but the bottom line is that it's the PI's responsibility to make these decisions, absent specific language in the protocol, and it's the monitor's responsibility to ensure the PI is doing so.
There are also instances where I was taught that an abnormality in particular assay is always CS and must be repeated to ensure it was not a lab error: minute elevations in serum calcium, e.g., a 0.1 mg/dL elevation is likely a lab error, but must be repeated to ensure that fact as even that small an elevation can indicate pituitary tumors; should the value return to WNL, there would be no AE. I had a PI overlook an elevation like this until the subject started presenting other symptoms and he ended up with a very serious problem on his hands!

Bottom line, if all lab abnormalities were automatically listed as AEs we'd be so completely overwhelmed we never be able to do our jobs.

Dianne Edwards • I agree with Joyce. If not part of the patient's MH; it is an AE unless otherwise specified in the protocol for the intented investigation under study and the change is expected and documented in the IB or PI.

However, that said, if the change in the value is clinically significant (outside of patient's "normal" normal value); increases in severity, frequency or duration - your must document this as an AE according to ICH E6 and GCP guidelines,

Dan Rossignol • Helen,
Excellent points here. It seems that the reporting of AEs as well as
careful analysis of trends in groups based on hard evaluations of changes
in lab values (not just changes that move from normal to abnormal) need to
be part of a final study evaluation. It will confuse things to have minor
changes reported as AEs. As has been stated, the protocol needs to be
clear on this.

Despite any protocol discussion however, the PI does have final say and
should be able to explain the AE claim. One problem that I have seen
however, is that investigators may be overly conservative in claiming Aes
in fear of an agency audit that picks up abnormal values and asks why they
were not claimed as AEs. This again is where the protocol language
(presumably approved by the agency) as well as careful monitoring protects
them.

Dr. Ashish Indani • I agree to the consideration that altered laboratory profile should be considered as Adverese event. These findings are, in fact, more important than clinical findings in many cases, especially when investigator is specialist of one perticular decipline. this is because, these investigations are performed for this very reason. Let's review a few facts
1) The investigator is always a medical professional and just like routine, the investigations may have been be left to his discreetion, if the designer would not want to note the sub-clinical (NCS) changes
2) The basis of calling for a perticular set of investigation by a Study designer is based upon the preclinical, previous phase clinical and Theory information of investigational product and the substance of disease, whatever is available.
3) the adverse event reported for a perticular drug must not always be bad. Infact we must keep example of Sildenaphil, Aspirin in consideration, that these drugs are highly sucessful in more than one ailments in different dosage. This whole phenomenon was based upon the evaluation of adverse events reported (Clinical in Sildenaphil and laboratory findings in Aspirin)

Considering the fact that in a clinical trial, we design the study with certain statistical qualifications as posted by Steve, hence frequency of such reporting will be automatically taken as significant or non-significant at the time of evaluation. There is also a reference data from previous phases and control of the study available to estimate and evaluate whether the changes in investigations are pertaining to the investigational product. For this analysis to go impartial and unbiased, Reporting of any any every change in the subject's overall status, including physician's assessment, any scores which are designed, any laboratory investigations etc. must be reported in time.

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Ramune Kanapieniene • I suggest reading the Journal of Best Clinical Practices "Documenting Clinically Significant Lab Values" by S. Eric Ceh http://firstclinical.com/journal/2009/0901_CS_Documentation.pdf

Vindu Seal • All abnormal lab values need not be documented as AEs. They have to be classified as CS or NCS and all NCS findings need to be documented as an AE. However if the abnormal lab value is falling within the defined alert parameter in the protocol then it has to be documented as an AE.

Vinette Zinkand • There are certain medication that we expect to see a change in lab results. In a study situation you would be blinded to those result unless they fall into a critical range that would necessitate clinical intervention. Then the lab result would be an AE or an SAE.

marita mcdonough • In most instances this would qualify as an AE unless specified otherwise in the protocol.

Dr. Dipti Kale • I think if should be classified into 2 categories clinically significantly abnormal and non-significant abnormal lab value. if it is clinically significantly abnormal value then it should be recorded as a AE.

Dr. Dipti Kale • many a times it happens any of the subject's lab value may be abnormal before taking IP and it may continue as the same after taking IP also and sometimes the subject may be nutritionally deficient . so it becomes necessary to track abnormal lab value right from screening visit to subsequent visit and it also becomes necessary to find out the causative factor. if it is done mandatory then it can increase work load for the site and central lab also. the abnormal lab value can be of significance and it can not also.

Lynda Cedar, Ph.D. • Change from the baseline for medical diagnostic values happen often in the clinical studies.

The changeis reported and interpreted by the medical staff as CS or NCS. If found unfavourable it is therefor reported as an AE and treated as such.

Sometimes, a healthy subject is accepted to participate while the values were within the range but bordeline. At the end of the study, such values might become out of the range of acceptable values. In this case, based on the medical judgement, the study medical doctor may decide to refer the subject to a family physician for more exploration and further diagnostic. At my site we document that the subject was informed and advised to consult his family doctor.

Anand Kawade • An abnormal lab value ( lab doing investigation has to state normal ranges for them) is always an AE, even if found incidently. but PI has to decide their clinical significance, intensity, and relatedness

Brown Kim • Great thread. I would love to see a lot more like this one. Thank you everyone for your well thought out replies to the question. I learned a thing or two.

Liljana Stevceva • FDA toxicity tables define the range that should be considered an AE as well as the grade of the AE.

Dr Faisal Khan • Yes, it should be considered as an AE and grading to that has to be agreed upon with the investigator

Binay Thakur • Not all abnormal laboratory findings are often associated with untoward medical occurences and therefore should not be recorded as AE up front. Further, for any particular parameter unless associated with any sign or symptoms such subjects would more resemble a healthy population (having similar degree of variations in the lab value) than a subject population. It would therefore be more prudent to know if there is any sign or symptoms associated with a lab abnormality before considering it as an "AE" unless there is sponsor/protocol specified guidelines such as "CTCAE or similar guidelines would be followed for recording AEs regardless of their clinical significance". Also parameters where laboratory error or false positives are anticipated, if deemed neccessary by the investigator re-tests should be done to reconfirm the abnormality and only then an AE should be recorded.
Objectivity in capturing AE data is good however at the end of the study to make a sense out of it would be very difficult, as each subject with the same degree of abnormality presents to the investigators with totally different case histories, this is where subjectivity is important and neccessary and therefore an investigator's judgment must be honoured (or argued with medical monitors if need be) while recording an AE.

Raji Varghese • AE reporting for abnormal lab values are mostly PI depended some values are CS and some may be NCS,it is better to leave at PI's discretion bcoz they know patients condition better than anyone else,to report all abnormal lab values means lot of reporting to be done.

Sergiy Gryshyn • I think that any lab abnormality is AE. Another question is, should we report it to Sponsor?.Any AE should be documented in SD with clarification is it clinical significant or not. Then we have to follow to protocol requirements. According to my experience, we have to be very careful with interpretation of AEs and have to understand what does it mean clinical significant or not. Leucopenia grade1 as per CTC during chemotherapy, is it significant or predictable and not significant? And doctor treats it.

Rosemarie Harris • It also depends on the indication (i.e. oncology) and how sick the patient population starts out at baseline.

June Rosas • Depends if at baseline if the value is normal for that patient. Also, depends on if the sponsor/ protocol.. wants this reported or not. But definelty should be documented.

Liljana Stevceva • This issues are defined in the protocol. Shouldn't the PI grade the lab abnormalities per protocol? I think yes.

Raji Varghese • Most of you are missing a point that investigator is the right person to mark a abnormal lab value as AE or not until and unless the protocol specifies so.Only the investigator is in contact with the patient it is just not the lab factor that is taken in to consideration there are other factors which is taken in to consideration as Konstantinos Kakos mentioned it is tool that is used to get the picture of patient's condition

Helen Russo • Agree with Raji, and as I noted before an abnormal lab value is a diagnostic tool, not a diagnosis, and in and of itself may/may not be "untoward." as with any other AE, one does not list the symptom (i.e., runny nose, swollen finger), but the diagnosis. An abnormal lab may or may not be an indicator of a problem or it may be a normal variant in the subject's life, but the lab, itself, would not be the AE...

Sergiy Gryshyn • According to ICH GCP, definition of AE doesn't content any Information about PI's judgment. Of course, it's theoretically, on practice, we can meet a lot of different decisions, etc. But in this case, who should be responsible for such decisions?

Traian Andrei Manu • I want to raise some issues with you in regards to what should or shouldn't be reported as an AE for an abnormal lab finding. First of all the majority of studies have a central lab involved and the results are pretty much standardized so you cannot go around saying if you change the units for a lab value you would have an AE.
In regards to what is abnormal you should keep in mind that the subjects involved in phase 2-4 studies are sick. It is very possible that their lab results wpuld come abnormal for some markers. Let's say for a RA study : of course you will have a PCR value for most of the subjects above normal. It is clinical significant because it shows that the subject has an inflamatory response to the disease.
According to GCP every abnormal lab finding can be considered an AE but ultimately the PI will decide if that is an AE or not. The role of the monitoring team is to make sure the lab results are not overlooked or not taken seriously.
Please keep in mind that nowadays central labs offer services for evaluating for soem alb results the difference from baseline to any other visit in the study so you will be able to see a trend for that subject, site , country and IP safety. Do remember that you also have services for a central lab aside the site's , CRA's role to verify the lab results, in regards to Hy's law and that lab values for the liver function if it's above Hy's law standards it will automatically be a SAE.

Lucian Popa • Andrei, regarding your post, the responsability of the investigator is to assess if the AE is CS or NCS, not to define what is an AE, for AE we have a standard definition in ICH-GCP and most of the times the protocol define what AE should be reported or not. The problem is that sometimes the investigators don`t want to record AE that aren`t related with IP or study procedures, in that cases is CRA duty is to identify and make sure that they are reported.

Adel M. Medhkour, MD • abnormal lab values occurring during a clinical investigation are to be regarded as AEs, unless (1) specifically highlighted in the study protocol to be a natural occurence without clinical relevance, or (2) such values are known historically to fluctuate during disease progression with or without the introduction of the investigational product, or (3) such change in lab value is a contributory to patient improvement or a pure sign of efficacy of the investigational product.
I don't think it would a good idea to report an efficacy variable or endpoint as an AE!

Rahul Dawkhar • Lab values: if abnormal, may be associated by many factors and to have a correct judgment study physicians can review the AE’s to give solid evidence, justifying the abnormality as an AE. Instead of jumping the gun, this practice would always help. All the data reported for LAB as abnormal values are extracted in a listing and reviewed on ongoing basis for the study by physicians.
Also protocol does specify some abnormalities that can be classified as an AE but only after considering other factors which a study physician can bring into the picture.

sumit saxena • Dr Sumit Saxena : As per the ICH GCP Guidelines and most acceptable by the industry
Adverse Event defined by ICH :
Any untoward occurrence in a patient or clinical investigation subject administered a pharmaceutical product and and which does not necessarily have to have a causal relationship with this treatment. Any unfavorable and unintended sign( including an abnormal laboratory finding, that is sign or symptom, or disease temporally associated with the use of any dose of a medicinal product, whether or not considered related to the medicinal product.
Still we have to correlate with baseline values and GCP said about abnormal laboratory finding it could be CS or NCS as per investigator discretion.

Jon Ruckle • "Normal" ranges are statistical definitions, and even healthy people can vary a little above or below those ranges simply because that is the way the body responds to multiple factors, even apart from a clinical trial. My opinion: as a clinician, and a PI with extensive Phase I experience in healthy/normal individuals, lab values outside the "normal range" should be assessed by the Investigator case by case, and should not automatically be classified as AEs.

Charles H Pierce MD, PhD, CPI • Hi, I am a bit late in this discussion but when I saw the question "Should an abnormal lab value automatically be considered an AE if the value was normal at baseline? Obviously the investigator would classify as CS or NCS, but would it automatically be an AE?" I had to answer as I had just given a Webinar on "Adverse Events".

The answer is an emphatic "No", a value of a laboratory variable above or below the reference range is not (NOT) necessarily an AE. In fact, it would only be an AE if, in the opinion (Medical judgement) of the PI backed up in the Protocol that the value was affected by the Investigational Medicinal Product (IMP) and indicated an effect of the IMP. I agree with Shilpa above on this clearly

For example, if the CK value was 2 or 3 times the ULR (Upper Limit of the Reference range) and the Protocol stated that above 5 times the ULR was an AE, one would not question that it was not. If the Protocol was silent in this circumstance but the patient admitted to painting his dining room the day before, I would also not think that this was an AE as an elevation of CK following muscular exertion wold be expected and not unfavorable.

Incidentally, the term we must all use is the "Reference Range" which is correct for the mathematical and statistical lab ranges we all use, which imply, correctly, that one could be "normal" either above or below the reference range. Basically, the term "Normal" range or "Normal" Value (for lab data) has no place in clinical research. For this reason alone one would never (NEVER) state that any value above or below the Reference Range would be, by definition, an AE.

Also agree with Biswajeet as far as he goes but it remains for the Protocol and/or the PI to decide whether or not the elevated or depressed lab value is an unintended or unfavorable sign. Charles if you wish clarification

Harold Doshan, Ph.D. • I have to agree with Dr. Pierce on all counts. One or more isolated changes in lab parameters that fall outside the reference range are not inherently AEs unless so stipulated per protocol. They are, like "sniffles" or "sore throat," possibly signs and symptoms of an AE (a "cold"), related or unrelated to study treatment, and either CS or NCS, as judged by the PI. It is normally the PI's call to report such occurrences as AEs, based in his assessment of the subject's condition.

Further analysis, including identification of progressive changes in the same or related lab results in the same or other study subjects can and should be evaluated longitudinally to shed additional light on what may, at first, be perceived as an isolated occurrence. Indeed, even temporal trends (so-called "shift analysis") that remain within the reference range may be suggestive of treatment-related effects. For this reason alone, all trends, both within and across study subjects, are evaluated as part of the study analysis.

The study staff has an obligation to report and annotate as "out of range" any lab result that fits that criterion, but to deem it automatically an AE is generally unwarranted.

Lynda Cedar, Ph.D. • I agree with Charles too. IThe lab vaues of baseline are used to see whether a significant change happens to the subject at the end of study or during its monitoring. The significance is left to the PI (medical judgement) which prevails on the study protocol. Additional tests even not scheduled by the protocol might be requested by the PI/medical doctor in charge of the study.

Example: if the CPK are significantly high, the subject might be not allowed to participate in a study. However if they become significantly high during the study or at the end, after a physical examination, medical history, the medical doctor might ask for a CPK-MB test, an ECG, ultrasound or any other test.

When speaking of borderline values, the same value might be considered normal for a patient but abnormal for another one. The results of blood and urine analysis are not considered individually. Each group of values reflects the function of a system: cardiovascular, kidney, liver, nervous, etc.

Andrea Bianchi • I agree with the mayority of the answers posted here, however, in every Regulatory Agency Inspection I have attended, the issue is always adressed in the same manner: if the protocol states a maximum lab value after baseline determinations, it should be at least consulted with the sponsor, before making a call on an AE; this electronic and paper trail, can make the difference between an observation in the final inspection report, or a protocol deviation.
The PI' s judment is always respected, as long as it has documented grounds, and means of demonstrating that there was at least a query regarding the finding.

Subhash Amrutham • I absolutely agree with Charles. Lab Abnormal value not necessarily be an AE; its purely Principal Investigator discretion.

Dadahayath Shaik• I agree with Dr.Charles

Ming Q. Lu, MD, PhD • An abnormal lab value will only be considered an AE if it is clinically significant. If the value was abnormal at baseline and it remains basically the same during the trial, it is not an AE.

Ming Q. Lu, MD, PhD • CIOMS VI group report is a good reference for detailed PVG guidance.

Diane Bartusiak • I agree with Harold: "One or more isolated changes in lab parameters that fall outside the reference range are not inherently AEs unless so stipulated per protocol." Populations like Oncology are evaluated using a wider range of reference values and these Oncology lab ranges are used when the sponsor is reviewing lab tables. Any laboratory trends will be captured by Stats or the study team. Therefore, it's up to the PI to classify, per protocol, whether any patient has an Adverse Event when a lab is slightly abnormal. It's helpful if PI can research a diagnosis/illness asssociated with lab change. Source documentation is crucial so the monitor can confirm that the site's AE reporting is within guidelines/protocol.

Carlos Estrada, MD • HI Guys, I believe we are loosing the original point, the question was: "Should an ABNORMAL lab value automatically be considered an AE if the value was NORMAL at baseline?" So, referring to this particular question, my answer as a Physician and Auditor is YES, it should be reported as an AE, regardless of it is Clinical or not Clinical Significant. If a Subject starts the trial with normal values at baseline and now it is abnormal, it is an AE.

ICH E6 States: "An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product"

Ming Q. Lu, MD, PhD • In the real clinical world, this will generate tremendous AEs which are not meaningful. e.g. normal range for diastolic BP is 90 mmHg, if the subject has 89 mmHg at baseline and 91 mmHg occasionally during the trial, it is just a common fluctuation.
Therefore, the answer is NO for the question "Should an ABNORMAL lab value automatically be considered an AE if the value was NORMAL at baseline?"

Helen Russo • Dr. Estrada, I think you just negated your own point with your ICH quote. An abnormal lab value, even if normal at baseline, is NOT necessarily unfavorable or unintended. As many have pointed out, labs fluctuate under completely normal circumstances. Reference ranges are just that, reference ranges, and it is up to the clinician to determine if a value outside those ranges constitute a clinically significant abnormality. If the answer to the question is yes, then the lab should be used as diagnostic criteria for an AE, if the answer is no, then it is NOT considered diagnostically relevant, and is noted as such by a physician on the report/subject's chart.
As a monitor and auditor, I've seen (and questioned) labs on both sides...an elevated fasting glucose in a non-diabetic noted as NCS, e.g., I've also requested repeat labs for things like elevated serum calcium which is only elevated under two (to my knowledge) circumstances: lab error or pituitary tumor.
Also, unless the protocol specifies differently, an abnormal lab value itself is not generally the AE, and many sponsors specifically ask that "symptoms" NOT be listed as AEs, which is what an abnormal lab value would be. Many times I have instructed sites to remove multiple symptoms and request the physician to use one diagnosis, this would include abnormal labs, i.e., elevatd WBCs, stuffy nose, earache, etc., in favor of a diagnosis of URI. I have also seen instances of wildly abnormal CK values, e.g., and cme to find out the subject was exercising extensively. Usually in a case like is, and absent of any other untoward signs/symptoms, the subjects are asked to discontinue their training and the lab is repeated until it return to normal. These situations are not generally AEs, or reported only once, and ended when the value returns to WNL.

The bottom line is that a blanket response of "yes" to the original question of "should abnormal labs be listed as AEs if normal at baseline" cannot be made.

Tim Pratt • We recently had a lengthy discussion on this topic prompted by "anaemia" as an AE.

Labs vary in what they consider normal, so a finding below an absolute value won't work (in this case it was 10). More appropriate, perhaps, is a relative, so a decline of X% from baseline. That, however leads to other problems - decline in haemoglobin during menses for example is normal.

We proposed to our DSMB, and they accepted a 2 part criteria for this particular value to be an AE - 1) a shift of X% from baseline (the relative method) AND 2) for which medical intervention/treatment was provided. the latter could be as innocuous as giving Fe supplements or as dramatic as transfusions. Our DSMB thought these criteria, in tandem, were very appropriate. This model is along the lines of that proposed by Dan R above.

Theresa Dunaway RN,BSN,MBA,CCRP • I think we are getting off topic here. I don't think there is one and only one answer for this question. Yes the protocol needs to state the labs that are significant to the study. The reference range for the lab being used for the study (if not a central lab) needs to be filed with the sponsor. Honestly it is the PI, and only the PI that makes this determination. If a woman's hgb is significantly decreased from baseline, there may be a problem. It should go down but not to significantly, if she is on a drug study you do want to acknowledge this. Also Dr Lu I don't think the example you gave is that accurate...we are speaking of ranges but not those that would be 'normal' for a particular patient.
I must say that for any lab out of range you do need to consider the baseline and relevance to a single individual. I do strongly believe in re-tests, I do believe there are errors and fluctuations, this is also for the PI to determine. But I agree with Dr Estrada, If the protocol doesn't state that small out of range results are acceptable then the PI has to consider the this as an AE.

David Radin • By definition "Normal" means the value is within the 95% confidence range. In other words you would expect out of 1000 subjects 25 of them would be "high" and 25 of them would be "low." If the protocol calls for reporting of abnormal labs int he absence of clinical manifestations then it would be an AE by protocol specific definitions. If, however, the difference is within what the clinician would consider an expected variation in a patient without an underlying disease burden it is simply "normal" and not an AE in and of itself.

Paula Singleton • For concern for the patient's safety, as well as the overall review of the study, I think any change from baseline should be listed as an AE. A case that comes to mind is a patient who had an infected injury and was prescribed an antibiotic which caused a marked change in one of the lab ranges, a factor that was a) not unexpected, and b) would have definitely been considered an AE had it not been for the antibiotic that was prescribed. In this case, the change in the lab value was not because of the study drug, it was because of the antibiotic. Regardless, I feel the change should be marked as an AE and then noted as a response to an antibiotic. For the patient's safety, any anomalies while on the study drug should be documented, and if not in the AE log then where?

David Radin • Which makes MY point -- unless the antibiotic makes the lab change ALWAYS you have a change due to a medication (an AE) which cannot be 100% attributed to the con med. A further examples are GGT and ferritin -- these vary so much without clinical manifestations that Medicare specifically excluded them from blood chemistries and will only pay for them if there is a specific supporting diagnosis/clinical syndrome. Abnormal labs without clinical manifestations can always be captured by Data Management and will not be "lost."

Paula Singleton • Good point. For my example above, if it creates an expected out of range value for any and all patients who take the con med, then it would NOT be an AE. but should it only create out of range values for some patients, it should be listed as an AE for those patients.

For the original question, Using the reasoning above, if the reason for the change is specific to the patient, isn't defined as expected for any reason, whether in the protocol or other documentation, I believe it should be an AE.

Andras Koser MD, MBA,CPI, FHM • I am not sure if any you who responded are PI's. I am a PI, and it is my duty and responsibility to determine what is an AE and what is not, unless I have specific instructions in the protocol. To do that the PI need to be involved, know medicine well and know their patients and their history.
We can speculate long on specific parameters we measure, there cannot be one rule for all.

Theresa Dunaway RN,BSN,MBA,CCRP • Thank you Dr Koser. I think we all need to look at Dr Koser's comment as the correct answer.

Charles H Pierce MD, PhD, CPI • Amen to what Andras has said. Also, I would work with Theresa any time as she understands this issue. I am and have been a PI and have >20 years in the Clinical Research industry. I suspect that any and all who answered this question as you and I did - that it is the PI who decides if and when (and in keeping with the Protocol) that a lab result outside of the Reference limits (ULR) is an AE or not. I have been astounded by the responses who suggest that any result above of below the Limits (and they sometimes wrongly use the term "Normal Limits") is an AE. Have just given Webinars on "PI Responsibility" and "Adverse Event Reporting" and nowhere in the Regs does it state otherwise. Period

Helen Russo • I think that last few responses have pretty much hit the nail on the head with regard that you CANNOT make a global statement that all abnormal labs s/b treated as AEs, and at the risk of repeating myself, in every initiation visit I have ever done, my "schtick" is that you are the physician and it's up to you to determine what is/is not an AE, however, I reserve the right, as a monitor, to ask you WHY you have made such a determination if it is unclear to me, and to put the reason in writing either on the lab orin a chart note, because if it's unclear to me, it's going to be to someone else such as an auditor.

I have also, frequently, requested physicians to differentiate between WNL and abnormal/NCS, because they absolutely do have different meanings, and as Dr. Pearce pointed out many incorrectly use WNL.

Theresa Dunaway RN,BSN,MBA,CCRP • Thank you the for the compliment Dr Pierce, I only have 11 years but it still feels good! Helen I agree there is a difference between abnormal/AE and NCS, but you as the monitor still has no responsibility here, your responsibility as well as a coordinator's is to review the documentation. Each of us involved (Coordinator, sub-Investigators, Monitors, sponsors and FDA) need to ask the PI what his rationale is. I have even seen Investigators debate on AE's vs. baseline and many other issues, but it is still their responsibility to make this determination and support it.

Lynda Cedar, Ph.D. • Any event or change that happens during the study is reported,documented and interpreted. Speaking of lab. values change, deviating from the baseline, the change is captured as an AE but its clinical signififance belongs to the PI (medical doctor) whether it is NCS or CS.

Helen Russo • Sorry Theresa, but I disagree, though I never have said that I have the responsibility. It most definitely is part of my responsibility to 1) make sure the data being submitted is accurate, and 2) that the physician reviewing the data is clear to the reviewer. If I do not understand a physicuan's rationale for for a decision, and ask him/her about it, then I am not doing my job properly and it will likely be questioned by someone later. As long as it is properly documented and does not go against something specifically in the protocol, I personally don't care if a physician determines soothing is CS or NCS, however if I see no support for that or that support isn't clear I have not done my job to the best of my ability.

Lynda, I'm sorry, but an abnormal lab, or rather one that is ouside of the reference ranges, is not globally an AE. For one thing, a lab value is a diagnostic tool not a diagnosis. I couldn't count the number of data queries I've seen over the years on exactly that: "elevated (insert lab value of choice) is not a diagnosis. Please use the correct medical diagnosis." forget the fact that if every out of range lab value were listed, each study subject would have likely have pages and pages of of AEs when combined with the usual AEs such as the flu, URIs, UTIs, sprains, cut, bruises, etc., that

This is precisely why most central lab reports have places for physicians to note CS/NCS and comments. In almost 20 years, I have never once seen an NCS out of range lab value listed as an AE even if it was normal at baseline.

Helen Russo • Oops, meant do not ask...

Theresa Dunaway RN,BSN,MBA,CCRP • Helen you are right. The accuracy and clarity of the documentation does lean on the shoulders of the coordinator and monitor. It is still the PI's responsibility to determine the significance, the support for that rationale (whether CS or NCS and/or AE) is only the PI's.

Andras Koser MD, MBA,CPI, FHM • We have a lot of action around this question. I am still standing by my previous statement. It is PI 's responsibility to determine what is CS, NCS, what is AE and what is not unless the protocol specify.
Of course if the monitor or the sponsor, of the FDA asks about one or another lab result, the PI's better have a good explanation why did not report this one way or another. Also any decision that could be later questioned should be well documented.
To be able to do this the PI must know EVERYTHING about the subject, the study, and has to be a well trained physician. You have a problem when you have a ghost PI, or an ungifted physician trying to be a "scientist".
Would be great if the sponsors grade us, P Investigators by the quality of work we do.

David Radin • As a PI with 18 years in clinical trials I whole heartedly agree with Andras

Charles H Pierce MD, PhD, CPI • Good point Andras and I also agree. Let me point out that the ACRP/APPI have a certification process for Investigators that would answer you main point. The CPI will be increasingly important down the path and, presently, one major Pharmaceutical firm lets Certified PI's pass on the Investigator training sessions so many have. Certification is not a substitute for experience and common sense but at least one knows GCP and why the Protocol is what is followed.

From what I have seen, those who know agree that a lab result above or below the "Reference Range" is not an AE unless the PI so states and that statement is in the Protocol. Actually, if the Protocol stated that "All lab results above or below the 'Reference Range' is an AE", I would not agree or sign it until this was removed.

Theresa Dunaway RN,BSN,MBA,CCRP • I agree as well...This is the point I was trying to make. The PI is responsible for this determination of significance and/or if it is an AE. With that responsibility he must be able to document and support it in a way it is relevant to the study to sponsors, investigators, regulators and colleagues.

Helen Russo • Dr. Koser, sponsors do "grade" PIs and sites for the quality of their work, though they may not always share that information. You can also usually tell, if you have a good monitor who knows what he/she is doing, by what your monitor is telling you. Sadly, there are monitors and sites who are conducting clinical trials without a good understanding of basic research techniques and when you combine an inexperienced monitor and site, and I'm trying to be polite when I use the term "inexperienced" as I've worked with both experienced monitors and sites for whom that term can only be loosely applied, you get a poor end result with things like potentially significant AEs being missed.
It has always been my standing that a physician is responsible for determining and documenting the CS of any abnormality noted during a clinical trial, this is not, unfortunately, always the reality.
Standard source documents are partly to blame as they tend to discourage any kind of written discourse in favor of "fill in the blanks and check box" responses. I strongly encourage my sites to add chart note pages to standard sources, and that "more information written in a source/chartis better;" and not all of the information is needed for transcription to the data forms. It is a pleasure for me to work with physicians who actually KNOW the study subjects to which I'm referring when I have a question, but again, that is not always the case

Lynda Cedar, Ph.D. • What do you call this event: when a subject is injured at home, transported to the hospital, got medications and surgery, and his participation is interrupted consequently... ?

By definition, an adverse event (AE) is any adverse change in health or side effect that occurs in a person who participates in a clinical trial while the patient is receiving the treatment (study medication, application of the study device, etc.) or within a previously specified period of time after the treatment has been completed.

Helen Russo • In my experience, this example is both unintended and untoward and would be an AE, and most physicians I've worked with would agree. In a double-blind study there is no real way to know if the test article caused some dizziness, verrtigo, decrease of special senses, whatever that caused the accident which caused the injury.
That is a completely different issue from an out of range lab, 1) which may fluctuate "normally," and 2) may or may or may not be of CS by any definition, and I think most physicians would agree. I've seen labs at panic levels which turned out to be NCS when evaluated by a physician, however they are generally followed closely along with other diagnostic parameters reviewed by those physicians before coming to that determination.
The bottom line is that one cannot make a global statement that ALL out of range lab values are AEs and that is what Drs. Pearce and Koser and others have pointed out. An abnormal lab is only part of the diagnostic puzzle and what may be diagnostically significant for one subject may not be for another.
If it is a case of a particular lab ending up out of range, regardless of significance, across the board for the study, the statisticians will pick that up when looking at the global study data.

Helen Russo • Also, a change in a lab may or may not constitute a change in health...

Lynda Cedar, Ph.D. • Helen, I agree with you on the first paragraph, in interpreting the happening of the event as an AE, it was even classified as SAE by the FDA.

Regarding the change of lab values, no one is saying that all out of range values are AEs or constitute a change in health..... Regulations, standards and medical judgement apply.

Modern CROs are using the Adverse Event Reporting System (AERS which is in compliance with the international safety reporting guidance (ICH E2B) issued by ICH. Adverse events in AERS are coded to terms in the Medical Dictionary for Regulatory Activities terminology (MedDRA).

Assessment of Lab values is as follows:
- If the lab value changes but it is still fluctuating within the range of normal values, whether it decreases or increases, it is not reported as an AE. However when reaching the borderline values or exceeding them a bit, the PI attention is needed, he decides about the follow-up.
- If a value was within the normal range (or acceptable in the PI judgement) and its change is major at any time of the study life, the change is reported as an AE and its interpretation as CS (clinically significant) or NCS (not clinically significant) belongs to the PI’s judgement. The follow-up will continue until the value is found similar to its baseline.

Theresa Dunaway RN,BSN,MBA,CCRP • I agree with Lynda, it is still the PI's call...significance in lab changes, AE vs SAE. We have regulations and guidelines to construct a framework and guidance in addition to the protocol, after that it is all up to the PI.

Lynda Cedar, Ph.D. • Totally agree with you Theresa and others about the PI's freedom in interpreting the significance of an adverse event, that could be lab value, a symptom or any medical issue. In fact, the subject's safety is under his responsibility and the sponsor.

Regarding what is called AE and what is not, there are many sources explaining it and guiding clinical staff about reporting it.

SOMNATH MONDAL • As per my understanding of definition of ICH GCP, an abnormal lab value must be considered an AE whether it is clinically significant or NCS. As because, a meticulous approach is essential to achieve a bright out come.
Hence, this must be documented in scientific manner ..............

Charles H Pierce MD, PhD, CPI • Please, Everyone, Read the entries above by several experienced Investigators (and others like Lynda, Theresa, et all). Lab values are reported with an attached "Reference range" which implies by definition that one (the patient or the value) could be "normal" and be above or below the reference range limits. So, a lab level above or below is not (NOT) an Adverse Event (AE) unless the PI deems it to be an AE.

The PI would, of course, review all lab values and then make the decision as to whether or not the lab value is CS or NCS. If it is deemed CS, then it would most likely be an AE. Nowhere in the ICH GCP Guidelines or the FDA Regs does it state that lab values above or below the "Reference Ranges" is an AE.(Period)

Binay Thakur • I have gone through the comments posted by Dr. koser, Lynda, Theresa and
Helen and find it very informative and interesting. I agree with the
comments posted by Helen that although it is a sole responsibility of PI to
determine what is an AE and what is not, it is always the duty of the CRA
to cross verify the decisions of the PI (unless it is very obvious) and
discuss with the investigator about what prompted him to mark a particular
event as AE. The outcome may still be the same however the CRA doubts, the
discussion and the conclusion must be documented clearly in the source of
the subject and in the monitor's notes for future
references/audits/inspections.

I am not as experienced as most of you ( as have only 5.5 years of
experience) but quite a time PI have changed their decisions (turning an
event from AE to non-AE) after discussion with the CRA. It happens
sometimes when your investigators are not well trained on AE recording
requirements.

So, the decision to make an event AE always rests with PI however it is the
duty of the CRA to find out if any AE is created just out of
misunderstanding or is not in compliance with the protocol lines or if you
are following a certain guidelines such as CTCAE for toxicity grading and
specific Sponsor requirements.

Theresa Dunaway RN,BSN,MBA,CCRP • Billy, remember the question, 'If a lab value is out of range and a change from baseline, whether CS or NCS is it an AE'. The CRA does need to inquire following review of the records, so do the investigators and coordinators. If there are many inquires, the site may need retraining. Let's not forget a good site with a good coordinator should be the first line of inquiry and these questions and support should be documented clear enough that the CRA understands the rationale. The CRA should be the last line of review and inquiry, not the first, but then not all sites, coordinators and CRA's are equal are they....

Liljana Stevceva • The key to the answer is the protocol. If the event is AE according to the protocol toxicity tables, than it is an AE. Usually, the toxicity table would specify the grading of the event as well.

SOMNATH MONDAL • I do agree with Linjana, obviously protocol is the ultimatum. But if the same event recur subsequently for a number of subjects then the question of reconsideration about the protocol arise.
Whatever the event CS or NCS one need to document it for future consideration and discussion have a decision among the team members first, if discussion found rationale , PI must have to convey the same to the Sponsor...for their judgement....and final decision.

Helen Russo • I think we're, again, losing site of the original question. Most protocols, particularly in recent years, address the issue of hepatic and renal toxicities, and in some cases, issues pertaining to bleeding events, platelet aggregation, etc. These are almost universal these days.
As Dr. Pearce stated earlier, there is nothing in either FDA regs or ICH guidelines which state, categorically, all lab abnormalities (or changes from baseline, for that matter) are AEs. It would be ludicrous to say otherwise, not to mention labor intensive for both the sites and the monitors. We would be completely overwhelmed recording and monitoring events which are, in most cases, normal variances.
I depend on my physicians to review labs reports and make a clinical decision as to their significance and part of my job is to ensure they are doing this in a timely manner. The reality is that sites are busy, and physicians are busy therefore, things get missed or looked at in isolation (one visit's labs apart from a subject's entire chart).
If this didn't happen, I would be put of a job, and quite frankly, I love my work! I appreciate physicians like Drs. Pearce and Koser who know and understand not only the laws governing clinical research, but their responsibilities to the study subjects and the study itself. I have had many discussions with physicians regarding lab reports, and when we've disagreed about their clinical decision (rare though that may be) I defer to the medical monitor. MOST cases, my site physicians/PIs are able to justify their determination quite easily, and I merely request them to put it in writing...

Helen Russo • Sorry, not liking touch pad typing right now, meant out of a job...

Theresa Dunaway RN,BSN,MBA,CCRP • Helen I think you are just restating the point we are all making. The PI calls it depending on this medical and study knowledge. A research site should have most of this documented for you, although we are all human and have oversights (or the FDA auditors would be out of a job!). And I think your job is safe my friend, the sponsor still needs someone to review the data on site for them and find these PI rationales and oversights. Good job my friend!

Harold Doshan, Ph.D. • Just a follow-up to Steve Mcateer's comment: It is true that reference ranges for lab tests are established as 95% confidence limits on data for each clinical laboratory. These ranges are recalculated periodically, based on the most recent set (often tens of thousands of lab tests) of data available to that institution. However, please note that these ranges are NOT a reflection of a purely "normal, healthy" population. Lab tests are most frequently ordered by physicians and hospitals for patients with medical complaints or undergoing treatment. Many of these patients may have abnormal labs associated with the conditions for which the labs were ordered. Other labs, of course, are ordered as part of routine physical exams and prove to be well within the normal range.

Taken together, the reference range arrived at is a composite of all of these results and if the sample size is large enough and represents an adequate mix of healthy and variably ill patients, the range for each test should generally reflect, but is likely to be broader than, that for a purely healthy population. For large labs with many, many samples, the fit is good. Differences in reference rangess for smaller, local labs can be explained by their smaller sample sizes and the possibility of skewing due to a larger percentage of ill patients (as well as different responses for their instruments, test reagents, etc).

All the more reason to tread carefully when calling a shift in a lab finding (by the same lab) from within to just outside the reference range an AE. Many protocols (especial in oncology) stipulate the extent of the deviation from "normal" that must be considered an AE. Lacking these guidelines, the PI must decide, but he/she should also consider whether the out-of-range value is, in itself, an AE, or whether taken together with other signs and symptoms points to a specific conditions that is an AE, whether related to study treatment or not.

Dominique Chesnais • Lab values are well investigated in clinical trial analyses and reported in the clinical study reports. Refer to http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm129456.pdf

In the FDA Structure and Content of Clinical Study Reports, lab data are reviewed in sections 12.4 and 14.3 about the following topics:

Clinical Laboratory Evaluation
Clinical Laboratory Evaluation of Individual Laboratory Measurements by Patient (Appendix 16.2.8) and Each Abnormal Laboratory Value (see section 14.3.4)
Evaluation of Each Laboratory Parameter
Laboratory Values Over Time
Individual Patient Changes
Individual Clinically Significant Abnormalities

Safety Data Summary figures and tables
Abnormal Laboratory Value Listing (each patient)

To report abnormal lab data, beyond CS or NCS, as AEs will be duplicating the information, unless the abnormal lab value is also part of a wider clinical pathology problem.

Babu R R • an abnormal value to be repeated to rule out the lab error. further if it reveals higher/lower than the normal range, if it is CS then it is AE. if it is NCS then it couldn't be an AE. correct me if am wrong

Lynda Cedar, Ph.D. • Hello Dominique. The comments above show 2 opinions regarding an AE statement, what is your definition of an AE: only when the change is found CS by the PI or at anytime when an out-of-range value is captured, or otherwise. Please explain.

In fact, the ICH integrated clinical report (or the link you posted above), the lab values are assessed as: it lists the range, the values at the baseline, at each study visit and at the end of study. Descriptive statistics are sometimes done.

The central lab provides an interactive file that is recognized by the computerized operating data base, programmed to capture the changes automatically. The programming is done by the IT, the biostatistician and the clinician to determine which change is determined as an AE. At this stage a change can be captured as an AE regardless to its relevance as CS or NCS in the medical judgement.

Thanks Dominique to share your practice with us. Lynda.

Dominique Chesnais • Hi Lynda, The first issue is that AEs are frequently under-reported by investigators during clinical trials. One needs to look at disparity between sites in reporting AEs, whatever their type. What benefits will it bring for an investigator to report an increase of one or two unrelated abnormal lab. values as AEs, as they are already noted in the lab. report as out-of-range and CS?

All study lab data are specified as CS or NCS after review by the investigator. Furthermore, they will be thoroughly analysed and reported, as required in the ICH E3guideline (Structure and Content of Clinical Study Reports). All out-of-range lab values will be highlighted in graphs, tables, listing and even discussion; same with the changes over time and values reported as CS. All that information strongly highlight some potentially pathological problems that Sponsor personnel should careful investigate.

However, when there are some increase of AST, ALT, GGT, alk. phosphatase, etc. the investigator should report a liver pathology; same about abnormal blood tests looking for blood disorders; too for the renal function markers. Drugs are reported as having liver, renal, blood toxicities, based on their clinical and biological signs.

In conclusion and in my opinion, it is these biological pathological problems that investigators should concentrate and not miss to report rather than some single, unrelated, out-of-range, CS laboratory values.

Lynda Cedar, Ph.D. • Hi Dominique. Thank you for adding your comments.
The liver enzymes and CPK are good examples to illustrate the discussion. They may respectively increase if a subject took alcohol or did exercise within 48-24 hours before blood testing. They are captured by the system of the central lab and the CRO computerized database as AEs. At this stage, the PI will look at them and decide about the outcome,.

I agree, lab values as per their name, medical diagnosis values, reflect the function of a system (liver, kidney, heart, etc.), a single value might be not relevant. Example, if Na+ is high, it does not mean blood pressure or kidney but if K+ if high the meaning is different.
When selecting a central lab, I ask them to provide the curve of calibration of the day, plus, to insert controls (small, medium and high) within the chain of tubes of analysis.

Thank you for sharing. Lynda.

Christoph Lohan • Based on the way the question is asked one near enough has to say that the "abnormal" lab result has to be classified as an AE. Rightly quoted by Mr. Dasgupta in its defenition.
Yet I would like to add that most often protocols are more diverse and more specific altogether if that makes sense. It is not only limited to AE as such. You will find other classifications such as "expected" adverse reaction and "unexpected" adverse reaction, of which both can be serious or not. Therefore a abnormal lab result could well be expected and therefore will not classed by companies as an AE per se. If it is tends to be unexpected, especially the SUSARs, then it will require flagging up to sponsor and regulator.
Thus I also agree with Ms McLeod "yes it's an AE unless stated otherwise in the protocol" :-) Happy discussing

Lynda Cedar, Ph.D. • Hi Christoph. To the best of my knowledge when an event is expected, it is reported as assuch but per the difinition of an AE that event is not an AE. If you can provide a specific example, it might illustrate the case.

Dominique Chesnais • >>>>>> SURVEY <<<<<<
I have initiated a basic survey (using LinkedIn Polls facilities with their limitations) based on a current discussion on reporting abnormal lab data as AE. I would be pleased if you could complete it at http://linkd.in/v0g4YI

Lynda Cedar, Ph.D. • Hi Dominique. It is a good idea of doing the survey. If I'm not mistaken, you asked the question differently.

The discussions have shown divergence: when an abnormal lab value that has changed comparing to the baseline is considered as an AE:
1) when captured by a computerized bata base as an AE,
2) only when found/interpreted as CS by a PI.

Sylvie JOUVE • In you protocol you also need to anticipate abnormal diseases' related values such as CRP when infection, AST/ALT (usually > x3 or 4 times is acceptables in some diseases) you also need to use age & gender related NR for at then having PI to apply his evaluation accordingly to these and medical practice

In the study report, you have to present lab data with predefined criteria for PCI or non PCI;
Declaring as a AE is as per PI judgement and usually we ask PI to declare rather than 'cancel" an AE.
So this is why a good knowledge of the disease and related abnormal vlaues can mak esome differences.
Hope this helps

Evy Moreno, BSHS, CCRP • I agree, this is a good topic to discuss because it happens all the time during clinical trials. So the combination of FDA regulations, the PI judgments and the input from the sponsor or protocol takes a role when deciding on A/Es

Nishat Hedayetullah • Going back to the original question (Should an abnormal lab value automatically be considered an AE if the value was normal at baseline? Obviously the investigator would classify as CS or NCS, but would it automatically be an AE) and seeing the recent exchanges, the clinical significance of the lab result should be considered in the context of the patient's overall health and in consideration of ongoing medical conditions and concomitant medications that are being taken. The treating physicain (not necessarily the PI) is best qualified to answer what the clinical significance is. Since the patient is on a clinical study, the treating physician/study investigator can discuss with the study sponsor whether the lab results have a causal relationship to the study drug.

Dipali joshi • It was really great discussion but some times we have to follow protocols and few protocols specify that "grade 2 or 3" abnormal values should be captures as AE , or some times baseline lab values will be considered.As I am handling Oncology trials where AEs are more frequent so capturing AEs differes from protocol to protocol and also based on the indication of trials.

Lori Jacobi • Again, the answer is yes, unless the protocol states otherwise. Generally speaking, anything that is a change from baseline is an AE regardless of it's clinical significance.

Lynda Cedar • Lori: indeed that it is, if located out of the normal range. The PI decides about its outcome.

Helen Russo • Lori, that's not correct. If every NCS lab were reported as an AE, sites, monitors, and data management would melt down. It is simply not feasible, nor does it meet the definition of an AE which is an "untoward and/or unexpected" event.
As many have mentioned, lab values WILL fluctuate outside of reference range values in a normal, healthy patient with no diagnostic significance. Others have pointed out, and many protocols include, specific ranges for analytes like LFTs, because drugs are metabolized in the liver and therefore can effect liver function. For example, historically, LFTs, depending on the specific analyte, are considered clinically significant if >2-2.5x the ULN, some sponsors alter this guideline up or down depending on the drug or use CTAE toxicity ranges.
The bottom line, is that I've never worked with a physician who 1) treats lab values in isolation, but as a diagnostic tool to determine a diagnosis, and 2) would agree that an NCS out of range lab would be an AE, especially absent of any clinical symptoms.

As for, global, study wide abnormalities or delta changes across a specific panel, that was statisticians are looking at. Once all the clinical data are gathered, changes like these are analyzed for statistical significance.

Prasad Vaishampayan • Great commnet Helen,,,an eyeopener !!

Andras Koser MD, MBA,CPI, FHM • 176 comments so far, read my comment somewhere at the beginning of this lengthy thread and you will find that that is is the right answer to the question. Many agreed so far. It is time to talk about something else. :)

Olusegun Adewusi • Adverse events after normal baseline records might signify the onset of traumatic episodes. So it should be a worthwhile 'in-vitro' investigation protocol afterall.

Lynda Cedar • Agree with Andras. It was a great question and great answers/discussions, great idea for surveys, now it's time to come up with another topic of discussions. Many thanks. L.C.

Charles H Pierce MD, PhD, CPI • Who would have believed that this one question would illicit such a wide range of responses. Some clearly wrong has been the largest surprise. I second my colleague Andras view that it is time to move on. Helen, above, and many other have it right that lab results are taken in context and / or according to the protocol and / or it is essential to remember that a patient or subject may be above or below the "Reference range" and be completely normal (by definition). 'nuff said. CHP

Andras Koser MD, MBA,CPI, FHM • If you have a great meal this thanksgiving but the turkey looks and taste different from the years before, or god forbid from your moms turkey it does not mean that it is bad. If you as a PI like it it is not an AE :) Happy Thanksgiving to all who participated.

MARIA KORKOVILI • We all already know what an AE is. Having at the same time laboratory experience I would say that an abnormal value should not be automatically regarded as an AE. Many times biochemical analyzers and haematology analyzers go through internal errors. Thus what I would recommend is run the test once more and then decide whether to report it as an AE or not. In addition, the nature and the sensitivity of the test should be taken into consideration.
Kind regards to all!

Anna Zimmermann • I think a laboratory value is something very specific. It is something real and possible to prove. Thus a change may indeed be automatically considered an AE.

Mickey O'Brien • Wow, that's a loaded question, for which there is not a black and white answer. Much depends upon the analyte, the amount of change from the baseline value, and the health status of the subject/patient. Effect upon related analytes would need to be assessed as well. Rule of thumb is to investigate ANY abnormal lab if the baseline lab was in normal range, but it is not necessarily an AE. Sometimes it is just lab error, but having worked for numerous labs, that can be an overused reason for not investigating further.

Paula Singleton • One thing I have learned in my 3 whole years in Data Management, is that if you assume you have the right answer, there is usually going to be someone, or some document, that can refute it, and refute it well. Or, if anything, bring into light new considerations you hadn't realized before-hand. This question, whether an abnormal lab value should be an AE, is completely and totally up to the Investigator/Physician. When I first answered this question, I looked at it from an outside perspective, as if it were a test question. If I were an investigator, what would I consider.

All things questionable, regarding labs and adverse events and so many other things, fall into the investigator's realm of responsibility. We have electronic edit checks that flag all out of range values, but not all of those out of range values show up on an AE log. I have learned to realize, in this industry, if you think you have the answer, there may be a chance you haven't looked broad enough into the question.

Cathryn Evans • THese things are generally quite clearly defined in the individual study Protocol and SAP, as well as GCRP guidelines. Not advisable to make an absolute statement without the context of the first two items.

Theresa Dunaway RN,BSN,MBA,CCRP • I agree with Cathryn, there is no absolute statement due to the variability in protocols and endpoints for each individual trial.

Nicholas McWilliams • Though I understand the desire/concern to not miss AEs, I think that people need to remember that the PIs are judging clinical significance for these labs. Just because out of range labs can be AEs doesn't mean all are required to be.

Nicholas McWilliams • Why have the PI assess significance then? The PIs have the ability to see the labs in a greater clinical context. If you require NCS labs to be reported as AE then you end up potentially creating a lot of noise in the safety data and end up risking creating a skewed and inaccurate label for your drug.

Nicholas McWilliams • If there are labs of interest then the protocol should state how they are addressed, including any threshold for abnormal values vs AE. Shift tables from baseline has been mentioned previously as a valuable tool in the context of detecting lab oriented signals, and I agree highly with that approach (sorry this had to get split into 3 comments)

Sateesh Kumar • It should be consider as AE once the Investigator indicates that it is clinically significant. All lab parameters should check by Investigator in each visit by judging clinically and also should compare with the baseline incase of significant increase or decrease in the values it should be captured as AE though it is not mentioned in the protocol. All these changes should be recorded in source as well as on the reports.It is a good practice to record abnormal values significance in source. It is an ideal procedure for Investigator who follows strictly ICH -GCP

Shweta Gupta • Here are my 2 cents.
It should be PI decision of CS or NCS. If it is CS than yes it is an AE. For e.g. For Hemoglobin the normal range for Adult males: 14-18 gm/dl. If the range on test report is 18.2 gm/dl and indication for IP is pain and PI thinks it is NCS it is not an AE.
Thanks!

JATIN SHARMA • As per my experience until or unless investigator has reported a abnormal value as Clinically significant it cannot be reported as AE this is the guidelines maximum sponsor follows and i am agree with the way its reported. To report any abnormal value as CS or NCS is investigators call.

Pharma JobLinks.com LLC • Yes, an AE is an AE. This should be included in the PI especially to track if this happens more often. Anything else seems fishy & like you're hiding something...

Ajay Reddy Jhampa • As per the E2A guidelines, AE is an

1. Any abnormality ( Untoward medical occurance)
2. After the first dose of Pharmaceutical administration ( After the first dose of study
drug)
3. It may or may not have casual relatiomship (Relatedness).

Therefore any abnormality that occurs after the first dose should be considered as an AE whether it is clinically significant or not. It is not an Investigators discretion.
FDA accepts data in SDTM standards and we submitted all AE's in AE dataset. If we get the information of clinically significance from the CRF, we submit this information of clinically significanvr in SUPPAE( Supplimentary Qualifier dataset).

Charles H Pierce MD, PhD, CPI • Please, folks, go back and read the many comments up to 4 months ago when this was started. It should be crystal clear by now that whether or not to call a lab result that is above or below the reference range limits an AE is a PI decision. A lab result above or below the reference range is not (NOT) an Adverse Event unless the PI (after review) states that it is an AE. To do or think otherwise is incorrect.

Agree with the ICH E2A definition but notice that it does not say that a lab result above or below the reference range is an AE by definition. I am sure you know that by definition one could be entirely "Normal" and be above or below the reference range limits. See earlier comments making this point that the terms "Normal limits" or "Normal values" has no (NO) place in clinical research.

I will be giving Webinar on this subject in January. Will let this group know of the date when set.

Sunee Thiravanitkul • I agree with Dr. Charles H Pierce that it depends on the clinical stage of the patient. Some out of normal lab value is just very much normal for some particular patients due to the underlining disease, e.g. low hemoglubin value in anemia patients.

Cathryn Evans • Thank you, Charles. To add to this comment, since all abnormal lab values must by regulation be tabulated and summarized in the CSR under the Safety Section, these abnormalities never go unreported. The clinical significance of the abnormality is what leads the investigator to include it as an AE — thus sometimes abnormal lab values are designated as "AEs"; other times they are retained in the Safety/Laboratory Test section of the report.

Helen Russo • @Dr. Pearce: This does seem to be the discussion that never ends!
@Cathryn: You pretty much said what I and a number of lab people have said: seemingly NCS trends get caught in the statistics.

Lynda Cedar • This question generated 199 comments, I wanted to bring it to 200.

In fact the statistics use the data captured by the computerised database which is programmed to capture any change in comparison to the baseline (called AE). After the medical interpretation some AEs are classified as NCS and others as CS associated with a number from 1 to 5 as selected by the PI.

In capturing all the changes versus the baseline is the only way to ensure that all the AEs were explored and interpreted by the PI .

What are the sponsor's considerations when assigning an auditor that is unable to understand the local language of the site?

2011-12-15T23:01:00.002-05:00

The following question and comments are brought from Linked in:

What are the sponsor's considerations when assigning an auditor that is unable to understand the local language of the site?

It seems that a local auditor is more familiar with the country's regulations, can communicate effectively with the local study stuff and read the medical records and other source documents without the need of a translator...

Lynda Cedar • If this auditor is able to communicate effectively with the local study staff and read the medical records and other source documents why should s/he need a translator?

If the documents are well developed, completed as they should be, following the study protocol, the SOPs, the regulations and other requirements (local), if the auditor is qualified and knows where to look, s/he may not need a translator mainly when s/he is able to communicate effectively with the study staff.

Yulie Feldman-Idov • I meant in case of a foreign auditor that does not understand the local language, can not read the source documents without translation and sometimes can not communicate effectively with the study stuff due to language barriers

Dominique Chesnais • The role of an auditor is to ensure compliance to the requirements of the protocol and annexes, international and local regulations, and sponsor's SOPs. His/her role is not to monitor a clinical trial, as does a local CRA, but to audit a clinical site within a clinical trial or project. Furthermore, clinical R&D is done in English language and, at least, a site member (PI, Sub Inv, Coordinator) and the CRA should be fluent in English.

An international auditor has better knowledge and experience of the global running of a project than a local auditor would have. A local auditor will be well aware of all local requirements and events in his/her country, but not beyond.

I agree that international auditors lack of regulatory knowledge of many countries where they audit. Local regulations are mainly written in the local language and never well translated in English or not at all. Few companies have built a database of local regulatory specificities.

International auditors assess a site and its trial with the international, FDA, EMA, English-written regulations, where the “most fear” inspectors are based. Also, local regulations are based on international requirements with few local conditions, which should have been taken into account during the clinical trial submission process. However, the sponsor is always responsible for the failure of third-parties.

About auditing medical records in a language that an auditor/inspector cannot read, they use some specific techniques to check CRF vs. patient’s source documents. It just takes longer to perform, it requires the help of a local person (CRA, site personnel) for the translation, but it is not as efficient as an audit performed in a language read by the auditor.

It is not feasible for most pharmaceutical companies to have a local auditor in each country where they perform clinical trials. It would be too expensive for companies and not enough challenging for local auditors, limited sometimes to few local studies, even none. On the other hand, it would be good for companies to contract the services of an independent, freelance, local auditor, working in pair with a sponsor international auditor.

Jim Sheets • I schedule my audits to coincide with a scheduled monitoring visit; this way I can utilize the local CRA's language to enhance communication with site personnel. "Across-the-table" auditing is sometimes used - the auditor has the CRFs and asks the coordinator to supply a value from the source. It's slow. Then, I might have the CRA or coordinator read sections of the medical chart.

If we use a large CRO (e.g., Kendle, Quintiles) that has a large, multinational team of GCP auditors, I may ask them to serve as part of the audit team. In any case, the lead auditor must research local GCP laws a priori; getting those regulations in English can sometimes be challenging - you may have to pay for translation.

Lynda Cedar • Thank you Yulie for the clarification. Now, Dominique and Jim answered your question.

The way explained by Jim how do pharmaceuticals proceed for auding and inspecting when they conduct clinical studies in countries where the English is not the language of work (typically emergent countries) is the most used one. However, efficient translator must be familiar with the terminology of clinical research and regulations. In such case, the local certified translator who was used to translate and certify the ICF might be used again. S/he knows about the study as he had the protocol and the ICF at the time he translated the ICF.

I agree with Dominique that foreign pharmaceuticals (US, Canada, Europe, etc.,) develop the study documents including the CTRA in English. The parties (pharma and sites) face this kind of questions at the end of study or other issues during the study, when either they are junior (not enough back experience) or do not use the CTRA that describes every thing about the study and how it will be handled at the different steps: pre-study, on-study, close-out and even post-study if required. The way how they perform the auditing and monitoring is included in the CTRA.

Yulie Feldman-Idov • Thank you all for the detailed explanations!

What is the time frame that sponsor /PI should inform completed patients regarding to the new unexpected SAE.

2011-12-15T22:44:00.003-05:00

This question was posted on Linked in, I wanted to share the comments with visitors of this blog.

Jim Sheets • ICH E6 4.8.10(p) (elements of the informed consent) require that the subject be informed in a "timely manner" of new information that may affect their willingness to continue participation in the trial.

Not all new, SUSARs affect the consent in such a manner. Determining which SUSARs have that affect is the responsibility of the EC/Sponsor/PI and/or Reguatory Authority.

If you have such a qualifying SUSAR, I (personally) dont believe it is accepatable to wait until the next patient visit to inform the subject.

Ludmila Sklyar • Thanks Jim, these patients already complete the study . In wich you think this should be documented.

Jim Sheets • Oh, completed patients...sorry, Ludmila. I don't know that there is such a requirement.

Lynda Cedar • I just want to add to Jim's comments: if the new unexpected SAE may manisfest later on, in months or years, therefore all study participants either on-study or off-study must be informed. In such case, the sponsor is the first concerned/responsible to keep the record of each participant and do regular follow-up (pharmacovigilance) requesting them to contact him immediately if they notify the symptoms of that SAE. The IRB/IEC has to be kept informed as well.

For the ongoing participants, a session of information must be held, as Jim explained, the subjects might change their opinion and drop out. The ICF should be amended to include the new information, supplement information is attached to the ICF, now need to resign, and of course, the event is documented as appropriate.

Ludmila Sklyar • Thanks Linda,thanks Jim. I was not able to found any info in ICH GCP re to the long term FU/new safety info and sponsor responsibility.

Dominique Chesnais • It is an excellent question. In theory and in normal practice, a subject ends a trial when s/he reaches the last visit, last assessment, as stated in the protocol, in the ICF and as approved by CAs and IRB/IECs. Investigators have a duty of care, but are not supposed to perform tasks beyond a protocol and annexes.

If a sponsor needs to inform and also to follow subjects, who completed a trial, regarding a SUSAR or a new unexpected SAE, there are significant changes in the protocol procedures and with the agreement/consent made with trial participants.

In your case, the sponsor needs to formalize all procedures that its safety and R&D teams foresee, not only in informing subjects, but also with the potential follow-up measures. For the investigators, IRB/IECs, CAs, some adequate scientific and medical rationales must be presented. For the participants who completed the study, a new ICF must be written; maybe also for the active subjects.

The most critical gap is for all sponsors, which end collating safety information at the last visit of their clinical trials, when few participants could have died, been hospitalized or been diagnosed with a cancer related to the IMP, some time after completing a trial. Such events are neglected and rarely recorded in the IMP safety/PV database.

There is a need to reconcile post-marketing safety procedures, where safety information must be thoroughly recorded and analysed, with the pre-marketing R&D approach, when data collation ends with each last visit.

Ludmila Sklyar • Dear Dominique , thanks a lot m I was waiting for your comments since yesterday.

So, there are no regulations or GCP instructions in regards to long term safety follow up and informing completed patients if a major SAE is identified?

Dominique Chesnais • Dear Ludmilla, Thanks a lot!

Your question is great, as you touch a grey zone. Maybe a topic to raise with PV specialists.There is no current process for clinical trial subjects who would suffer an IMP-related SAE after completing their trial or for a sponsor wishing to follow subjects after completing a trial (after 1 month / 4 IMP half-lives after last dosing / 6 months).

The only bit of information I have identified is related to DSUR in E2F at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500097061.pdf, or http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html, E2F in section 3.8.3. which reads:

Long-term Follow-up
Where applicable, this section should provide information from long-term follow-up of subjects from clinical trials of investigational drugs, particularly advanced therapy products (e.g., gene therapy, cell therapy products and tissue engineered products). When the development programme is completed and long-term follow-up is the only ongoing activity generating data for the DSUR, this could be the only section where new information is presented.

It does exclude other trials, but in all cases, it must be formalized by a process aiming at DSUR and an ICF, approved at least by IRB/IECs.

Ludmila Sklyar • Thanks for the links Dominique. I am surprised and disappointed. So what can I do as CRA in order to be adherence to the guideline that not exist, you now in this case my professional conscience is the best guideline . We have Long term FU each 6 month, but there is no section for new safety information, only patient data ( new illness ect ). Does PI need sponsor agreement to inform patients early than Long term FU date.

Jim Sheets • First, you must determine whether or not the new information requires an updated consent. That discussion usually occurs b/w the Sponsor/EC/PI and/or Regulatory Authority. Of course, the PI has the authority to unilaterally update the consent without Sponsor direction; however, most new SUSARs do NOT result in an updated consent document. One case seldom changes the entire risk assessment.

If you are still following them each 6 months and collecting new data, then they are not technically completed with the study, right?

Ludmila Sklyar • New IB and ICF submitted to EC already for the active pts following sponsor request. Regarding to the FU pts , you get the point ..only technically they are not completed , they are completed in eCRF , IWR ect. Well, PI is going to inform “completed” pts regarding to the new safety info and document this contact on the Long Term FU even if this occurred prior to the LTFU date. Do I need sponsor approval for this? Does PI allowed to decide by himself to do this?

Jim Sheets • GCPs do not require Sponsor approval for this action.

Lynda Cedar • I just want to add that the subject's safety is a concern of the PI, s/he is responsible to do all the efforts to preserve the subject’s health, and also, he must inform the IRB who protects the rights of subjects. As Jim specified the Sponsor approval is not required by GCP, ICH, regulations; and I haven't seen in my experience of CROs a sponsor who disagreed on informing the patients, the IRB or even the reg. authorities.
As detailed by Dominique, the ICH and GCPs are not rules, it is just a guide produced by experienced professionals (reg. authorities) to other (more or less experienced) professionals (sites/PIs and sponsors).

Some sites are afraid of drops-out, or think that active subjects might be affected psychologically (group-effect), which is true when a symptom is not measurable, they try per say to pass the information smoothly which minimises its impact.

By the new FDA guidance (draft issued in march 2011) the sponsor is responsible for AEs reporting upon his judgement, which is understandable as he knows the product better than anyone else in collecting data from the pre-clinical stage to the last step of the product development and testing.

Ludmila Sklyar • Thanks Linda and Jim, I will contact PI on Sun , in Israel Sunday is the first day of the week :) .

Frédérick Therrien • Interesting question! For subjects who completed the study, the AAHRPP process must obligate investigational sites to work in collaboration with sponsors to include, in the contract, the reporting timeframes for unanticipated problems involving risk to subject or other during the 2 years period following completion of the study. See tips sheet 25 on www.aahrpp.org (document library) for exact require contract languages.

Jim Sheets • @Frederick - Just a few points of clarification on AAHRPP, though, please:

* AAHRPP is a voluntary accreditation for ECs/IRBs and not required by law (correct?). Sites must usually acquire such accreditation so they may continue to receive federally funded work (e.g., NIH Grant) - at least that's the case in the U.S. with OHRP; there are different standards for a privately sponsored study here.

* A "UPIRTSO" event (Unanticipated Problem Involving Risk to Study Subjects or Others - see 21CFR56.108(b)(1) is not necessarily the same thing as an "unexpected, new SAE". Both privately sponsored and federally sponsored work (in the U.S.) must comply with 21CFR56.

* The wording on AAHRPP's Tip Sheet indicates:

"Following completion of this study under this contract, if [the sponsor] becomes aware of relevant findings from the study data that would directly affect the safety of the former study subjects, [the sponsor] shall promptly notify the institution of such relevant finding so that the institution may communicate such findings to the former study subjects. [The sponsor] shall determine the relevance of the findings and the institution shall inform former study subject as appropriate. [The sponsor’s] reporting obligation shall continue for two years following completion of the study conducted under this contract."

I interpret this to mean something more significant than a new unexpected SAE, and that reporting is then made to the local ethics committee for consideration...this body (not the Sponsor) then directly reports to the subjects.

Do you agree?

In any case, it's good that you shared this information; I did not realize that Sponsor's may be agreeing to such terms in the clinical contract with some (Canadian?) sites.

Ludmila Sklyar • Agree with you Jim. But thanks for interesting comments Frederick I am not familiar with these guidelines

Frédérick Therrien • I agree to all your questions Jim. I also agree that UPIRTSO shall not be limitied to unexpected SAEs. For Canada, I hope our site will lead the way.

In regard to element I.8.E. I do realize that AAHRPP may have made a mistake using the wording "former". My understanding as always been that this element must be applicable to current and past participants. This is why I prefer this wording that cover Element I.8.B, I.8.C. and I.8.E.

"During and for a period of at least two years after the completion of the study, [the sponsor] shall promptly report to the investigator any information that could directly affect the health or safety of past or current study subjects or influence the conduct of the study, including but not limited to the study results and information in site monitoring reports and data safety monitoring committee reports as required by the protocol. In each case, the investigator and [the organization] shall be free to communicate these findings to each study subject and the IRB."

Lynda Cedar • Hi Frederick. I'm not aware of that in Canada the period of follow-up is only for 2 years! I think it should depend on the medication mainly when investigational drug is biologic. The history of Thalidomide does still in mind; the side effects appeared 20 years later in the daughters of the mothers who received the medication during their pregnancy. The period of archiving in Europe has been changed to 25 years. Canada adopted it as well in 2001.

Frédérick Therrien • You are right Lynda. The follow-up period should be evaluated on a study-by-study basis and should not be limited to the 2 years period following the study closure.

This make me think about the power of "wording" that we should always evaluate.

Lynda Cedar • Thank you Frederick and looking forward for further interaction.

Happy Holidays to all visitors of my blog

2011-12-12T15:01:00.003-05:00

Another Holiday Season is upon us, it is a magic period to reflect on all that has happened throughout the year. I have traveling to my clients in helping them with consultancy work. I take this opportunity to thank them for their trust in requesting my services and in helping me to build my business and reputation.

I'm honored in announcing that l am in Stanford Who's Who book 2012.

I partnered with strong professionals in different fields: manufacturing, bioanalytical, clinical, regulatory affairs and business development. We are creating a strong CMO/CRO in Montreal, Quebec, Canada. We are determined and committed to deliver turn-key services of high quality in compliance with the high standards of the industry and regulatory agencies.

We provide the following services:
- manufacturing of clinical lots,
- Studies of stability and quality control
- We have 100 beds and offer clinical studies services: Phase I and bioequivalence. -- Our group of professionals is specialised in NCE, small and large molecules, biosimilars (Subsequent-entry-biologics) and vaccines, nutraceuticals and natural health products.

For more information please contact me at lynda.cedar@gmail.com

Wishing you all Happy Holidays filled with love, health and success.

Lynda Cedar, Ph.D.
Visionary Professional
Early stage development.

Has anyone ever heard of a principal investigator keeping studies open when the sponsor considers the study closed and wishes the study to be closed?

2011-11-16T18:59:00.001-05:00

The question was posted on Linked in platform and discussed as follows:

Dominique Chesnais • The scenario that you have described cannot exist, as one party will be in breach of compliance with the protocol and ICH GCP guideline. If the trial has reached its end, all sites should stop recruiting subjects and complete those in the active phase.

My second comment is about how you have defined your end of the study; it might be just semantics. The closure of the study should not be decided under some consideration and wishes of the sponsor, but in agreement with the end-of-study criteria, specified in the approved protocol and signed by sponsor and PIs. The study is completed when its criteria (number of subjects recruited, duration, etc) are met.

However, as you mentioned, "the sponsor considers the study closed and wishes the study to be closed", when it might not be really completed. In that case, the sponsor can terminate a trial at any time, as long as they perform the regulatory requirements stated in ICH GCP 5.21 (Premature Termination or Suspension of a Trial).

Under some exceptional circumstances, the end of a clinical trial does not mean the end of dispensing the IP. When there is no further second-stage (open phase) approved trial, it is possible to provide IP to subjects under compassionate use, considering also its regulations and guidelines.

Luis Squiquera, MD • I don't quite agree with Dominique. The primary responsibility of the PI is not only to the sponsor but to the patients. If you see that the new treatment/intervention produced a substantial benefit, the sponsor and the PI should continue providing the new treatment even though the trial is formally closed. Besides GCPs, we should not lose the focus on the "human subjects" in our research.

Dominique Chesnais • Hi Luis, I did not exclude that possibilty which is described in my last paragraph, as compassionate use. Otherwise, every one (sponsor, PIs, monitors, etc) must comply to the protocol, including completing the trial.

Luis Squiquera, MD • Hi Dominique. That's the idea! But we should not lose the point that the aim of our work is improving the quality of life of the patients and not just for the sponsor/protocol or our own personal interest. In fact, when people feel that you actually care about them, it shows in many aspects of your research such as retention or compliance to the directives of the protocol.

Theresa Walker • Hello,
Actually, this is a long term follow-up study and the IP hasn't been administered in over 10 years. The study is a study conducted at one site only. The PI at this site developed the investigational drug. The study is considered to have met all protocol requirements and ICH/GCP guidelines. However, the PI wishes to keep all studies open as his IRB requires studies to be kept open if the PI wishes to extrapolate any data. This is his purpose in keeping this study open. He is publishing and also presenting poster presentations. The sponsor HAS communicated they would provide him with any data he needs, as they also have the data he is extrapolating from the aforementioned study. So, the dilemma....The sponsor wants it closed and as the CRA I have been requested to close the study (s), however, I cannot finalize the study closure without the study being considered closed by the institutions IRB, as required.
I don't know what my next step should be as this has never happened in my 13+ years of monitoring/auditing clinical trials.

Lynda Cedar, Ph.D. • Hi Theresa, this is not usual case. I would go back to the CTRA signed between the sponsor and the investigator. It usually contains all what the parties agreed on. The sponsor can terminate the study at any time with or without the PI agreement. He has however to respect all the clauses of the termination and notifies the PI in writing. Also, the data belong to the sponsor, the PI has to obtain the permission of the sponsor for publication. Also the protocol (mainly if ICH protocol has been used) and the ICF might be good guides to follow.

Dominique Chesnais • Hi Theresa, it's a very amazing and exceptional case, in which you are caught between a sponsor and a PI. It is first the responsibilities of the sponsor to initiate the termination of the study by looking at the clinical trial agreement and by informing the PI and the IRB, and then you can perform your work.

I would be interesting to know how the PI has annually informed the IRB/IEC about the study status (as per ICH GCP 4.10.1) and the response of the IRB. How could an IRB maintain a clinical trial so long, when the IP has not been prescribed over 10 years? The sponsor and IRB could agree together to end the study.

However, to have run that study over 10 years at one site with an IP developed by the PI, there must be some other issues: unwillingness of the sponsor to develop (further) that IP, which did not fit its R&D program or pharmaceutical business, for whatever reasons; PI could also be a VIP holding the company hostage in one way or another. Only retirement or promotion of the PI could end the study!

Megan Mather • Hi Dominique, I would think that this would be turned over to the legal department of the sponsor. The PI/site is non-compliant. If the study has been completed per the contractual agreement, the sponsor's legal department should be able to close it from their end stating that they no longer are responsible for the actions of the site or its IRB and a letter should be sent to the site, the IRB, and if possible, the subjects that were in the study. If something happens to any of those subjects and the IP is somehow linked, the sponsor will want it plainly shown that they are not responsible. Whether the PI has developed the IP or not, all IPs are considered for lack of a better term (I am not an attorney), illegal substances, until approved. The sponsor must have documentation showing that all parties have been notified that they are no longer responsible for the IP or the PI/site.

Lynda Cedar, Ph.D. • Hi Megan, you get it all right. Despite the conflict of interest, the non-compliance of the PI and even the IRB, the study turned over the legal level.

The CTRA (Clinical Trial Research Agreement) which is required by the ICH and specifies that a sponsor has the right to terminate the study at any time. This is an ICH statement. The PI nor the IRB or anyone else has the rights to maintain a study alive if the sponsor decided to close it. The study close-out procedure is widely covered by the ICH, it involves the sponsor, the PI, the IRB and the subjects. The sponsor does not have access to the subject’s identification (names address and phone), therefore it is the responsibility of the PI and the IRB to inform them about the study termination as stated in the ICF.

Theresa Walker • Perhaps I should clarify a bit further.This is a follow-up study required by the FDA to follow the subjects for 12 years. Some of the subjects have completed, others are lost to follow-up and others continue to see their physician (an outside physician seeing subjects onbehalf of the PI. Back when this protocol was written this was acceptable. This is no longer the case. The IRB has a clause in its SOPs that state the studies at this particular institution cannot be closed as long as the PI is extrapolating data. This is indeed the case.However, from a pharmaceutical perspective and a CRA perspectiveI have been given a task by the pharm co. to close the study. Due to the fact that the sponsor should have a closure letter from the IRB to finalize closure the study is indeed considered open. Therefore, there will be continuing review reports every year until the PI decides to close the study once he has all the data he is needing. This places me at a great disadvantage as my gut tells me I CANNOT close the study if the IRB is not willing to have the study closed. It does appear that the sponsor's legal; department will need to be involved at this point, however, this PI IS a VIP.
Any suggestions would be greatly appreciated.

Lynda Cedar, Ph.D. • Theresa: This sentence ''The IRB has a clause in its SOPs that state the studies at this particular institution cannot be closed as long as the PI is extrapolating data." is conflicting with the Industry and the ICH standards. Has the sponsor agreed on this clause? I have years of clinical research experience (more than 12 years for sure), and to the best of my knowledge, the sponsor can terminate the study at any time with or without reason after notifying the site.

Dominique Chesnais • Hi Theresa. the sponsor has become quite impatient in the last stage of that study. All study requirements have been almost completed, but it wants closing the study in a rush.

The sponsor personnel and the PI should look back at the protocol, agreements, data, annual interim study reports and prepare a study summary report that will be presented to the FDA as the conclusion of the requested 12 years of follow-up. The PI should also be asked why the study should be extended further and s/he should clearly give all reasons, if any, to be also provided to the FDA.

With the FDA, the sponsor could agree if the 12-year follow-up study can be concluded. The FDA statement will then be presented to the IRB and PI for information and action.

The FDA initiated the 12 years of follow-up, for whatever reasons, and should therefore be part of the decision of closing the study, as neither the PI, nor the IRB are keen to do so.

Lynda Cedar, Ph.D. • Dominique: your approach is professional as always. However, it will take time for the sponsor to hear from the FDA. This case does not constitute a priority, FDA is busy with other hot dossiers.
I would suggest that the sponsor or his representattive prepares a document (kind of white paper) compiling the regulations, the standards of clinical research (ICH and GCPs) to support/explain/justify his decision of closing the study, and submits it to the PI by the legal department.
The sponsor should not interact with the IRB, unless, he was contacted by the IRB (directly).
In parallel, he can also submit to the FDA as you mentionned above.

Is it possible for patient to signed ICF at home while Sub –Inv/PI explain the new information to the patient by phone.

2011-11-16T18:43:00.003-05:00

Question is brought from GCP Linked in group:

Content: Patient is not able/ not willing to come to the clinic to signed ICF that has not been signed in time. Not signed ICF included only new administrative information. Subject already complete the study and I was advice to ask from site to perform following action;
the site discuss the ICF with the subject over the telephone,
- then fedex them a copy of the ICF and while the site and the patient are both on the phone they sign the forms (two forms one signed by subject and one signed by site).
- The patient-signed form is then shipped back to the site. Copies of the signed versions then are sent back to the patient and the originals maintained in the file with a memo/note to file clarifying the process and why there are two signed copies.

Thanks in advance for any feedback.

Commented about it:

Shilpa Raut • Hi Ludmila:

In my opinion, there is a catch in getting ICF signed as per the process mentioned above for the following reasons:

- How can we be sure that the patient is the one who has actually signed the consent form and not some one else?

Anna Zimmermann • Dear Ludmila,

I understand that the ICF as little as a complement to the ICF must obey the same initial process of obtaining. If the patient is not able to sign in the presence of PI this incident must be carefully described.
The ICF is a process and must take steps so that the subject really comprehends what it is.

Ludmila Sklyar • Hi Ladies, thanks for the answer. Good point Shilpa ! Honesty I am not sure that this is possible at all.

Fiona Waddell • This is not an ideal situation but sometimes we just have to be pragmatic and realistic and make the best of what has happened. The site staff have done exactly that and they have documented the entire process whilst resolving the unsigned consent form to the best of their ability. It should never have happened in the first place but it did happen and they performed due diligence to capture and report everything. Good for them!
Something to consider - Was the training for the site staff adequate or do they require additional training in the informed consent process? Due diligence on the part of the sponsor should look at updating (and documenting) the site's informed consent training.

Ludmila Sklyar • Hi Fiona, this site is one of the best we have for the study.The problem was technical ( let's say) an dnot related to ICF wording as results pt's refuse to signed. I am more interesting about regulatory point of you. Patient at home... Investigator on phone.... I am not comfortable with such a resolution.

Parag Desai • GCP says ICF process should be face o face.

Fiona Waddell • Whether this should have been done over the phone or not is all about risk rather than regulations as ICH GCP says NOTHING about this having to be a face-to-face meeting between investigator and subject. It is not an ICH GCP violation to do it in any other way but it is probably a protocol deviation. It is industry standard to do it face-to-face and it will be a regulatory expectation in many countries. There are risks involved with doing it over the phone and these should be identified (ID of of person on the phone, full understanding of PIS/ICF, signature of subject etc) but if these have been identified and resolved then there is no problem with taking PIS/ICF in this way as long as the risks are understood and resolved, the process has been documented and reported and it is in compliance with the protocol. Was this a problem of misunderstanding the PIS/ICF process/a genuine mistake/subject inability to comply/soemthing else? The reason should be identified and discussed with the site to ensure this does not happen again. I still think they did the best they could once the problem became apparent.

Ludmila Sklyar • Thanks a lot Fiona for your comments! I will ask site to add all details as note in to the SD file's. Hope it will be fine as I am sure site will have FDA Audit, they have high enrollment rate and I would like to protect them as much as I can..

Angela Rhodes • I currently use a remote consent process for ICF for a simple data collection for a device registry. I devised an SOP and sent it to the IRB for review. FDA law does not preclude consenting over the phone. I contact the subject, describe the study, mail the consent. Contact them again to see if they received the consent, discuss questions they may have, document the discussion. They mail the signed consent back in the returned self-addressed envelope. I receive it, I call them again to confirm consent, and document. Sign the ICF myself and enroll. In some cases the subject will come to the office after receipt and discuss with me. In others, they have taken the consent home and signed it. I do not use this for all consents. In most of these cases the person does not want to come to the office, no transportation, etc. I have used this a handfull of times. I would never use it for anything more than data collection studies. But, all parts of the process are documented in the record. I feel we could support this if an FDA inspection came along.

Jim Sheets • I dont see anything wrong with this. The identity is confirmed by the signature matching that on the original consent. The site should document the process thoroughly; ideally, the Ethics Committee should also be made aware, and that should also be documented. I also am not aware of any GCP requirement stating it must be done face-to-face.

In fact, I found the following in FDA's Information Sheets:

Q#35. May informed consent be obtained by telephone from a legally authorized representative?

"...it is acceptable to send the informed consent document to the legally authorized representative (LAR) by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile."
Also:"In the past, FDA has allowed sites to obtain consent by telephone and fax if, for some reason, consent cannot be obtained in person. For example, this might be appropriate if the potential subject lives in another state and the study site wants to screen the individual to determine his eligibility for the study before the individual spends a lot of money or time traveling to the study site. In such a situation, FDA would expect the consent form to be faxed to the subject or his legally authorized representative (LAR), discussed by phone, and faxed back to the CI. The purpose is to provide the subject and/or the LAR with an opportunity to discuss the information in the consent form and have their questions answered prior to the subject's enrollment in the study."

I interpret these FDA comments to mean that such a practice is acceptable.

Ludmila Sklyar • Jim, you are a special person :). I really appreciate and trust your input!

Jorge Garagorri • Hi all,
This is an interesting topic, but after reading the discussions, the Parag Desai's comment says ICF process should be face to face and other members like Jim states there is no problem in this process if and when this is documented.
Pherhaps as first step is asking the point of view from the IRB.
Regards,
Jorge

Lynda Cedar, Ph.D. • The site conducted the process in compliance with the industry standards and applicable regulations. Lubmila explained that it has been fully documented.

I just want to add that sometimes it is difficult to find eligible subjects, and when found, a site does whatever possible to include them. However, from a technical point of view, some subjects when they are contacted by a nurse on behalf of their physician, they find reasons to discourage the site, they become so demanding such they cannot be accommodated, or the site looks like discriminating subjects (subjects get what they ask for !!!!); most of the time, a type of difficult/ demanding subject is excluded by the clinical staff for incompliance.
In my experience, when we come across to this situation, rather than using FedEx, we use one of the clinical staff (research assistant) who will meet with the subject, explains to him the research face-to-face, makes sure that he understands the research, his rights and duties. This may prevent to include difficult/problematic subject in a study.
It is pleasure reading and learning from your experience and opinions.

Terry Stevens • A noticed a recent FDA Warning Letter where the institution was cited for doing something similar to this. They were cited not because this was wrong, but because the site had not submitted this change in Informed Consent process to its IRB/Ethics Committee for Review and Approval prior to implementing the process.

Dominique Chesnais • In ICH E6 GCP, there is no statement where and when a trial subject can sign a ICF. However, as practiced at most investigational sites, subjects are asked to sign the ICF just after receiving the document and some discussion, then they are included in the study. They are not given "ample time and opportunities to inquire..." (4.8.7)

In the new ISO 14155, Clinical investigation of medical devices for human subjects - GCP, it is stated in 4.7.2. that "the general process for obtaining informed consent shall be documented in the CIP ". Therefore, it is formalized and approved by IRB/IEC.

In your case, my recommendation would be to submit to the IRB/IEC the whole consenting procedure performed by the site/s by mailing the ICF to subjects, providing the consent by phone and asking the subject signing even at home. Once approved by the IRB/IEC, the site/s can do it without any fear of CA warning (as just mentioned by Terry above)

Saranya Kannaian • As far as I know, the ICF has to be signed by the concerned person in front of the investigator to make sure that the consent was given by the person who is really taking part in the clinical trial.

Saranya Kannaian • I know its difficult to get appropriate subjects for the study and then if we are getting the subjects, few of them would not be able to abide by the rules that have to be followed during the clinical trial studies.Being warm welcoming to the subjects is different and always fulfilling their demands is different.I dont think it would be fair enough to give such a long time for the subject to respond to the ICF....

Ludmila Sklyar • Dear all thanks a lot for your professional way of thinking! Dom and Terry your suggestion and opinion make me more stronger . We will submit all process to EC immediately.

Erika Timewell • Interesting discussion to follow. I have one question that I would like to ask. Why do we need to ask subjects to sign a new ICF if it is only some administrative information? Could it not have been enough to send it out to all patients and document that it had been sent?

Ludmila Sklyar • Hi Erika, good and simple queation and the answer is much more simple... sponsor request.

Dominique Chesnais • Hi Ludmila,
If the subject has already completed the study (as described in your introduction), why is s/he asked to sign an amended ICF, just for some administrative changes?

As per ICH GCP, an informed consent (1.28) is "a process by which a subject voluntary confirms his or her willingness to PARTICIPATE in a particular trial...". In your case, there is no further participation of that subject to expect, as s/he completed the study. Where are the needs to get that subject's ICF approval? (Question to the sponsor!)

When the sponsor submitted the amended ICF to the IEC/IRB, they should have highlighted the process about informing participants and getting their signature. They could have proposed that the ICF could be signed in a face-to-face meeting during a study visit or obtained via a phone call with the ICF sent by post, signed and then returned by subjects.

Ludmila Sklyar • Hi Dom, I fully understand your question and we ask this several times. It’s difficult to me to explain the meaning of “ administrative changes” without introduce some study story. The problem is that these changes explain some process that help to estimated/improved patient compliance but the program sponsor used for this purpose is not acceptable in Israel. We have few additional points that I prefer not to share , sorry . Any way it was very important to me to understand what GCP group members think about ICF signature process by phone. I learn a lot, thanks to all of you.

Angela Hudson Davis • Great discussion. Mailing the ICF to the potential study partipant should be the exception rather than the rule. I wasn't sure from the question, which launched the discussion whether this was the initial ICF or a reconsent. Also if the participant is unable to come to the site to be consent would they be a good candidate for the trial? Would the site have to mail the IP because they are unable to come for the site? What about the ongoing assessments?

Erika Timewell • It is a pity that sponsors do things like this, digging them selves deep into a ditch and creating problems for patients, investigators and CRAs.

Karen Hue • The process itself is ok, it is the applicaton and documentation of the process that usually lets people down.

If you process map what you want to do you will see where you need to have control steps in place and which activities need to be done by who, when and how.

Most regulatory documents do not tell you the "how" but the goal. It is our job to make sure we reach the goal successfully for each situation we find ourselves in during a clinical study.

Interesting question though and some great discussion.

Ludmila Sklyar • I would like to thanks once again to all of you for excellent answers and ideas. See you on next discussion..

Shirley Isbill • Sponsors do some strange things at times; I expect that this is a result of guessing what regulatory agencies will accept, just doing something because a superior official wants it done or just not thinking logically. If in fact, the subject has already "completed" the study, he does not need to sign a new ICF regardless of it's changes. In case the ICF change is for continuing follow-up and the administrative changes will expect something from the subject, then yes, he needs to sign a new ICF and that can be done via phone as Jim Sheets has explained. Keep in mind, FDA investigators like simple, logical activities especially when the applicable regulation does not provide sufficient guidance. FDA's information sheets provide good guidance as does the FDA's response to email questions which are publically available. FDA is very good at answering GCP compliance questions - use it !! gcp.questions@fda.hhs.gov
The following link is to the email database of questions/answers.

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/RepliestoInquiriestoFDAonGoodClinicalPractice/default.htm

The FDA database can be searched using http://www.firstclinical.com/fda-gcp/

Karolien Timmermans • Hi Ludmilla,
We had kind of a similar' problem'. During the study, we had to amend the protocol to increase the sample size. Since this change had impact on the ICF, the patients already enrolled had to resign the new one. Some of the patients did not sign the new version ICF in time, before they completed the study, and in some countries, yo can live hours away from the hospital. So, in order to still get the new ICFs, we had the PI call each patient, explain the change and send the ICF for the patients to sign.
It has been documented in a Note to File, explaining why it was done tis way, and for each patient, it was documented in detail when the PI called the patient, when he sent the ICF to the patient, when the patient signed and when the PI signed.

With respect to the question of Erika, as soon as something in a study changes that impacts the patient information, it should be renewed, e.g. if the ICF mentions 220 patient will be enrolled, and throughout the study, the sample size changes for any reason what so ever, it should be adapted. Since it is not possible/allowed to have multiple versions of ICFs, all the patients should have signed the same ICF, which is the last EC approved one.

Arash Amirpour • In my point of view, this is a GCP violation. ICH-GCP does not say anything about a face-to--face consent process. However, it does require the consent to be obtained by the investigator. This has been understood by the industry as investigator being present during the consent process and witnessing that the process has been conducted correctly, patient has been fully informed, and does not have any clinical question pertaining to the investigational procedures, and has not been unduly forced to sign the consent.
In this case, and for whatever reason, the patient is resisting the expected process of signing the informed consent in the same manner as every other patient enrolled in the same clinical trial. It is also dangerous to undermine the content of the ICF as being less important. The ICF process supports the foundation of a valid clinical trial. ALL efforts should be made to make it right.
Should sponsor decide to still keep this patient in the trial, and include his/her data, the deviation must be fully documented. This is a protocol violation and the full detail, including sponsor's justification for the process and the outcome, should be reported to the IEC/IRB.
FDA might have expressed approval of alternative ICF processes. But these are general deviations from the expected process and are usually reflected in the protocol, submitted to the authorities and the IECs/IRBs for approval BEFORE trial initiation, not after the patient has finalized its trial procedures.

Ludmila Sklyar • Thanks Shirley, I will use this link, it's realy helpful. With regards to the sponsor request .. I still beleave that both of us ( sponsor and me) just try to be on the save side of GCP as well as to protect pts and site.

Ludmila Sklyar • Hi Karolien. It's to know that we are not along in such situation :). Finnaly , I am going to perform following steps:

1.wording of NtF will be sent to sponsor for approval
2.submision of " on phone signature proces" to the local EC

and after that pts will signed ICF.

Ankit Shah • I am fully agree with Jim Sheets....All we need to do is to communicate the whole process with IRB/IEC with the generation of "NOTE TO FILE" with respective subject number and send a cpoy of it to sponsor as well as IRB/IEC. Otherwise no need of Face to Face Communication of PI and Subject, if Subject is able to understand the things on his own (No LAR is required) and even if LAR is required then take and verify the signature of LAR and communicate the same with Sponsor and IRB/IEC.

How should a mistake be corrected in the ICF?

2011-11-15T12:39:00.002-05:00

The question was asked on Linked in as follows

Imagine the following situation: a participant is recruited on 11OCT2010 but in the ICFhe/she wrote by mistake 11NOV2010. During a Monitoring Visit in December 2010 the issue is detected by the CRA. How should it be corrected? I propose 3 ways, please I kindly ask you to comment them (more options are welcome!):
1) the participant cancel the wrong date (11NOV2011), write the correct date (11OCT2011) and date and sign the correction using the date he/she corrected the ICF (let's say on January 2011). At the following monitoring visit the monitor verifies that the correction is done.
2) the same that option 1 but the participant writes in the ICF that he/she consented during the recruitment process, before any intervention was done.
3) the same that option 2 but not writing in the ICF but using a Note To File and attaching it to the ICF Just for your information: it’s a phase IV Clinical Trial conducted in rural areas in Africa. 5,000 participants recruited in 4 sites in 18 months.

Fiona Waddell• All 3 should be done. The patient makes the correction, the investigator confirms that the trial did not start for this patient prior to signing the ICF and the investigator explains what happened and how it was corrected in a File Note. You also need to look at how this happened to ensure it doesn't happen again. The monitor should verify the study site ICF process to ensure that there is a validation step included (ICF document has been completed correctly). There may be a need for additional training in this process.

Kristaps Danilans From my opinion File Note will not helps you much. As I understood only subject dated Nov, not both (subject and investigator)? If you notice different dates or months, I would suggest to add statement in the ICF explaining when actually subject agreed to participate and how this mistake happen. The statement again should be signed by investigator and subject. Also more information should be available in subject source documents.

Catherine POUZET • From my opinion a file not is not the solution: the key in clinical trial is tracability of the information : you have to document the correct date of participation of the subject : i suggest to ask your CQA representative to see what process to follow : be sure that if ICF is corrected that it will be for the one on the investigator site and the form for the patient; Source document and also monitoring report should be completed with an explanation of the correction; The PI should be retrained on ICF process : this should be noticed in a training log.

Jumoke Arogundade • What had happened at one of my sites, was getting the patient to sign a new consent form on the next visit, counter-signed by the investigator and a File note filed with both the new and the old consent explaining what had happended and how it was corrected. In the source notes of the patient's visit when the new consent his signed the doctor once again confirms in his case notes what had happened previously and the need to sign a new consent. This is evident for the CRA to monitor and an auditor/inspector to see

Saranya Kannaian • I think all the three steps should be followed.An explanation in the form of a file note is fine to be archived with the study file after the study is completed.More important is the signature of the participant (and when signed the document)as well as the sign and date by the investigator and also important is to make a note of why the change was made in the ICF itself, so that the information is visible immediately rather than searching for the file note, if the cause has to be explained later.

Saranya Kannaian • I agree with Fiona that there must be an additional training on this process.

Ludmila Sklyar • I agree with Fiona too, re to NtF , in some place CRA and PI should explain /document what happen to be sure that any study related procedures have not been done before ICF signature.

Anuradha Venkatraman• I agree with Ludmila that no study procedures have to be performed prior to ICF signature. Considering the situation stated by Daniel, where informed consent form (ICF) was post dated and suppose study related procedures were done on the subject/patient prior to the dated ICF. -ICF to be re-signed and dated by the patient and PI; -NTF detailing the reason for the error to be filed; and -I believe the same has to be notified to IRB/IEC as the safety of patient comes into picture in this scenario. -Apart from this, site has to be re-trained to avoid such errors as it could be a protocol violation if the study procedures are done prior to dated ICF. Kindly opine if I am wrong.

Lynda Cedar, Ph.D. • Hello Daniel. You are saying In 2) the same that option 1 but the participant writes in the ICF that he/she consented during the recruitment process, before any intervention was done. If no intervention was done, therefore, no mistake happened. In preventing drop-outs, some CRO ask the subjects to sign the ICF when they are very close to the first intervention undertaking. Exemple, if the subject gets sick while he received the information, but not enrolled yet, by signing an ICF, s/he is discounted , there is no AE record as no ICF has been signed. If you choose the option of correcting the date of the original ICF, you can do that too, cross, initial and date the change, in front of a witness. A note to file is always a good to have; if a key person who knows about the event forgets about it or change the job, the record is on file. This is typically true for studies of long life as Phase III, IV.

Subject had an accident during the visits to the hospital . Who should bear the treatment cost if the patient require the surgery?

2011-09-08T16:44:00.006-04:00

Subject had an accident during the visits to the hospital.Who should bear the treatment cost if the patient require the surgery? Sponsor or the Investigator or the Institution?

The question is brought from Linkedin GCP group.

Fiona Waddell. If this is a routine visit at which trial information will be collected ie the patient is not attending hospital purely for trial reasons then the patient bears the cost. If the patient is attending hospital purely for the trial and the hospital is arranging transport then I imagine that the hospital will be responsible for medical costs as the patient was under their care when the accident happened. If the patient is attending hospital purely for trial reasons and the patient has arranged his/her own transport then the patient bears the costs. The sponsor may agree to assist with cost but I don't think they have any legal responsibility.If the accident happened within the hospital or hospital grounds due to any negligence on the part of the hospital (eg water on the floor, broken floor tile etc) then the hospital bears the cost. If there is no negligence then neither the sponsor nor the hospital have any liability and the risk and the cost belong to the patient.

Jim Sheets • This should be defined in your informed consent, as per ICH E6 4.8.10(j) and (q) and possibly 21CFR50.25(a)(6). Fiona's points are also pertinent. There are other considerations, though. For example, is the drug you are studying a psychoactive substance that can possibly impair driving ability? I also encourage you to see FDAs "Information Sheet Guidance - A Guide to Informed Consent" http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm It states: "Informed consent documents should describe any compensation or medical treatments that will be provided if injury occurs. If specific statements cannot be made (e.g., each case is likely to require a different response), the subjects should be informed where further information may be obtained. The consent should also indicate whether subjects will be billed for the cost of such medical treatments. When costs will be billed, statements such as "will be billed to you or your insurer in the ordinary manner," "the sponsor has set some funds aside for medical costs related to.... Here's how to apply for reimbursement if you think you might be eligible" or "no funds have been set aside..." are preferred. Statements such as: "will be the responsibility of you or your insurance company" or "compensation is not available," could appear to relieve the sponsor or investigator of liability for negligence, see 21 CFR 50.20."

Lynda Cedar • Hello Guruprakash, - Can you describe please the accident happened: what, where and when? - Is there a relationship between the visit to the hospital and the study?

Dominique Chesnais • It is an event that happened during the participation of the subject to a trial; it is an adverse event. As it requires surgery, it might need hospitalization, therefore it could also be serious.Investigations should also be made why and how the incident occurred: was the accident the result of a sub-latent medical problem, e.g. heart (arrhythmia) or neurological problems, which could have been induced by the investigational drug or by the subject's participation to the trial. In other words, what Lynda has just asked above.Unless an obvious cause is found, e.g. injury induced in a car crash by another driver, incident at the hospital /institution due to work, professional error at the site, it is difficult to claim a responsibility of the hospital or physician.That subject would not have had that accident during the visit to hospital, if he or she would have not participated. S/he should not bare any cost and any issue with the insurance imbroglio.

Guruprakash Manohar • HI Lynda, Subject had an accident on the way to hospital for the scheduled protocol visits. He was riding back on a motor-vehicle. He had an accident in a road and diagnosed Fracture in Left leg.The visit to the hospital is scheduled protocol visit. Thanks for responding!

Lynda Cedar • Hi Guruprakash, Thank you for the information and clarification. Dominique brought good points. - The visit was scheduled by the protocol and the subject filled his duty and made it. - As the vent needs a surgery and hospitalisation it has therefor to be documented and classified as SAE. - Since no institution (hospital nor the site) are involved in the happening of the event, therefor the insurance would not cover the event as an error or omission made by the clinical/medical staff. - If the subject is under medication effect and was aware by the ICF that the medication may affect his alertness and was not allowed to drive but he did, he has therefor his part of responsibility in the happening of the incident. However as Dominique argued above, if the subject did not have to go to the hospital for a visit scheduled by the protocol the event would not happen.... That was exactly what a lawyer told us when one of our study subjects had a shoulder dislocation (skating on ice) while he was participating in a study. - If there is no possibility of relationship between the medication effect and the event happening therefore, the sponsor is not responsible to pay for the surgery nor for the hospitalisation. In Canada all people are covered by the medical system, the surgery of shoulder dislocation of our subject was not an issue for the study, the subject was covered by his medical card .... which means the government paid for. The event was documented and reported as SAE in the study. For sure, as clearly stated by Dominique '' the subject should not bare any cost and any issue with the insurance imbroglio''. You should look at the local policies (government or insurance coverage) and also maybe the sponsor and the investigator find an arrangement to cover the fee.

Rajendra Bhaktha • The patient on his way to hospital was riding back on a motor-vehicle. He had an accident in a road and diagnosed Fracture in Left leg. ---->Makes it fit for a motor vehical insurance claim as all the motor vehicals are suppose to have a compulsory third party damage cover (which is mandatory).

Dennis McHugh • Any consideration for personal responsibility. On the back of a motor cycle? I hope he has an organ donor card.

Cynthia J. Robinson • Is the hospital visit in relation to the study visit when the accident occurred? If so, the hospital should bear the cost because the subject is under their care. Otherwise, the subject should bear the cost. If the subject took study drug while visiting the hospital; impairment occurred from study drug. Then the sponsor would bear the cost. Who bears the cost should be noted in the informed consent. The event should be noted as an adverse event, if subject was hospitalized then as a serious adverse event.

Dr Nitin Nagrecha • Indemnity agreement and insurance agreement both covers clauses under which subject will be paid. Here the main Question is that whether accident occured because of influence of study drug on the person ? Critical questions may be what was his behavior before drug. His state of mind. Now there can be no person who can judge this except if someone was accompanying him. Now everything becomes legal and be couteracted by both parties viz subject and sponsors and at times investigator. Unless there is no conclusion of study drug's involvement., sponsor may not be liable for loss. Once it is proved then it is their responsiblity to pay subject. That are my thoughts.

Michael A. Swit • @Lynda: why is this an AE? The accident was not related to the the investigational product in any way.

Felix Schaller • An AE doesn't have to be related to the investigational product. If it were related, it would be referred to as an AR (adverese reaction).

Sergio Goldfeld • @Michael: ICH-GCP definition for adverse event: "Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment." Although this is not an ADR (Adverse Drug Reaction), this is an Adverse Event.

Richard A.M. de Rooij, MD • this is an interesting discussion but should not be about if this is an AE or not, nor about the cognitive affect of the drug. If the subject didn't particpate in the trial the accident wouldn't have happened A court can judge it is protocol related and by this the hospital and the sponsor could be held (co) responsible.

Lynda Cedar, Ph.D. • Dear Michael. You got excellent answers and great input from the other members, I don't have an additional comment. I also agree with Richard regarding the legal issues. If the subject was not involved in the study, this discussion would not even exist.... therefore an AE is not related to the medication intake only but all the happenings during the study to the subject and other aspects of the study. Each event must be documented and recorded to be tracked even years after a study has been finished and archived ..... Thalidomide is one of the best examples, the QA samples at CROs is another one, etc., etc. I learned from my experience that a study is a global event that starts one day and continues years later (even after archives). The industry is going to face this issue more and more for biologics and biosimilars for example.... The monitoring is fundamental, it has to be achieved by well trained and experienced monitors. I d not mean only the clinical operations side but the entire aspects of the study. Study must be conducted in respect of GCP/GLP/GMP, Ethics and standards. It also deserves to look at the legal aspects carefully (subjects and staff injury, medication quality, patents, contracts and everything). The role of the regulatory affairs should be broad, and not limited to the reg. submissions and inspections. Before starting a study we should be able to gauge how trial protocols manifest in real life, consequently, the sponsor and investigator can plan and budget based on real-world projections...they have to be prepared as much as their knowledge enables them to be. Thank you all for sharing your thoughts on this platform, I look forward to interacting further with all of you. Lynda.

Finaly Lopez Rasquin • I agree with Sergio, and thanks for reminding everyone the definition of AE, I was already concerned with those who doubted it was an adverse event, of course it is!!The discussion here is who should pay if the hospital, the subject or the sponsor.Of course it should pay anyone but the patient; would be very easy for him/her to show that is participating in a clinical study and take legal actions against the sponsor, so that's why they are insurance policies that protect both the subject and the investigator for these cases.Is easier and cheaper for the sponsor be responsible.

Sudeshna Lama • We all know bout AE,SAE ....However I feel you should read over the liabilty and indemnity part of the Trial protocol,also referring the Contract Agreement could clearly outline the parties responsible for handling such a case

Liping Zhou • I agree with the comments that an investigation should be performed to evaluate the relationship of the event(i.e. AE/SAE) with the study drug and/or the study procedure. After the causality is confirmed, the responsible person/party should bear the treatment cost as well as other related cost/compensation as defined in corresponding agreement or regulations (e.g.Insurance agreement, clinical trial agreement, informed consent form...). If needed, IEC and/or legal should be involved. And sometime, we have to take local common practice, ethical concerns into account.

Susana Navarro • Dear Richard, in Argentina, and in real life acontesimientos, an AE was expected or not, provided I believe and also according to the regulations of this country, the sponsor would be able to afford the costs. Sometimes agreed in the Bach, some directly sponsor not want to carry the expense. Then the regulatory bodies and ethics committees, requires the PI to have a prior inpatient services and care for these contingencies, the cost of running them. Which is an opinion and personally I think is not ethical and fair. For GCP standards one can not a priori in this situation so precarious. In Argentina we have a major health system which never leaves the patient unattended, until the parties decide who carries the costs, thankfully, but exposes patients to the national protocols of Health, or recharging prepaid system. It should be borne in mind that when a patient is exposed to an investigational drug, we do not know for sure, to be exposed, although EA is expected, there is also a gap that do not always have all the information.Thank Susan

How to criticize constructively — and encourage positive change?

2011-09-06T15:30:00.004-04:00

Question and discussions brought from Linked In platform (Clinical Research Professionals)

Martin Robinson • The aim of constructive criticism is to enable the receiver to benefit so that they can improve their performance. Help them to reflect on what they did - what went well and what could have gone better. Get them to do most of the talking and have them offer suggestions and solutions with guidance from you. It's important to reinforce what they are doing well already and agree an action plan to improve their performance in areas where they could do better. They may need support in terms of training, coaching, clarity around performance standards etc. Review the action plan with them periodically to see how they are getting on and use it as an opportunity for them to reflect on the progress they are making

Sanjiv Sharma • Criticizing for the sake of criticism will serve no purpose. The best way is definitely as suggested by Martin. The aim of criticism should always be improvement.

Shwetank Pandit • ya ur right mr Sehgal .Its Important to provide them a guidance to improve there their performance.

Dominique Chesnais • As an auditor, my job is to identify non-compliance issues and to report them. However, I always ensure 1. to refer each observation to an article/a section of the applicable regulations that was not fulfilled, 2. to understand the current working process (SOP), which might have led to the non-compliance and 3. to listen to the auditee(s)' way of working, working conditions, etc.

Audit findings are agreed with mutual respect between all parties of an audit and regulatory requirements are better accepted. Combined annual /quarterly review of all audit findings are even better tools for positive changes.

Gonzalo de Arbelaiz • I agree with Dominique's comment above; I always try that the audit process includes;
- Conscise description of the finding (the error, your criticism)
- A reference to what what not followed (shoud help the auditee to know where to read & learn next time)
- Auditor & team's suggestions about what could have been done to avoid getting to the error stage.
- Auditor & team's head analysis about why did it happen and why was it not detected? What can we ALL do next time to prevent it?
Naturally, this is neither possible nor needed for all findings, and is not only up to the auditor to resolve, but must be a team work.

A frequent error that I see from some colleagues from the clinical QA area is to "blame it on people", rather than identifying the gap in the process; which almost always includes more than one individual. In other words, only few people are so important as to have one big mistake depend on them only.

Also, constructive criticism is only half of what it takes to make encourage positive change, the person receiving feedback has to be open and be able to take it not personally.

Lynda Cedar, Ph.D. • I agree with most of the comments above, I just want to add that in order to be able to criticize constructively the auditor must have extensive experience of auditing and monitoring, and deep knowledge of the guidance, Ethics and industry standard.

An audit is successful when a site has a checklist developed as by the criteria of a successful inspection. Having this in place, it shows the site experience with studies how they behave in a real life. It also helps the auditor to see how does a site works, the culture of project management, if a site has a plan B when something happens during the study and not provided by the SOPs, it helps the auditor to detect the positive and the lacks, and then s/he can proceed as explained in the comments of above.

There is always space to improvement, one always learns from audits, each site and each sponsor is unique, the communication is one of the most important elements that a site as well as a sponsor should look at, because a study is a teamwork, the audit should be an indicator about at least the flexibility of the site and the sponsor to resolve situations if needed and as needed during the entire study.

Agnieszka Bialek • To be able to criticize you must know the personality of your trainee/associate. Not everyone is able to improve if receives negative reinforcement. People who can do that are really strong personalities.
Majority gets more motivation for improvement after they first hear about what went well and where they were strong.
I agree with Martin that it is right way to identify weakness, prepare actio plan for future and together with your trainee/associate check progress.

Lynda Cedar, Ph.D. • No! not at all, because nothing should be taken personal.

The auditor has to do his/her work, and makes sure the site is compliant with the standards of the industry and applicable Guidance. The auditor should follow the GCP, GLP, GMP (depending on what is audited) to justify each recommendation. S/he will issue an audit report, the document is reviewed by the site, then they sit-down to discuss the corrections to be made.

John R. Nocero • Agree - there is a way to criticize that is not personal. Criticism should never be perceived by anyone as a personal attack. If it is, I also think the person delivering the message should be careful in how it is delivered. Discussing why the error occurred, how it can be fixed and then how it can be corrected is very important.

Dr. Sunil Kumar Joshi • There are some people, self centered and difficult to change. The problem is with their attitude. Are there any such sites that provide us with guidelines for constructive criticism?

Ankur Sharma • I believe that criticism can have a positive or a negative effect based on whom you are criticizing and how you're doing it (whereby it can become a constructive criticism in some cases, while destructive in others!).
A lot depends on how the person who is being criticized perceives it. In that case - it becomes a double edged sword.Until you're a mystic or a psychologist, you can never know how a person would perceive what you have said (its not proven that how accurately even they can do it). There are instances when your criticism may be welcomed and it might even improve the work quality at your work place however at other times, the work may just go haywire - and at such time the team-work and the quality of results does get affected over a period of time. (You might get your work done at that particular point of time in the way you wanted, but in the long run - it would give you more management problems than you might have thought of - they might come subtly and not with a clear cause effect relationship).
However, having said that, it does not mean that criticism is futile and should not be done at all. There are times when it necessary (even useful) to criticize, but what I would suggest is caution.
The aim is to bring about a change in a person or the way some work is done. Criticism is the easiest way out of this. When I say that this was done wrongly and it should have been done in this way - I am taking the easiest way out - doing something which even a donkey sitting behind the desk can do - ordering.However, it might seem easy only in the beginning - its repercussions would take more of a genius than an Einstein.So why not do some hard work in the beginning.
So, what I would like to do is have a look at the work. See the positive points - note them down; look at the negatives - note them down as well. Call a meeting (it includes the person whom I want to criticize - or shall I use a better word - change!) Tell the people concerned about the agenda beforehand and give them some time.In the meeting talk about the beauty of the work first and the strong points I had seen and ask everyone to tell what modifications can be done in the work (I'm just giving an example - the things could be done in other way as well. What s important is to catch the nerve.) so that it can be done in a better way. People would come out with their suggestions. The aim is to get the people have a critical view of their own work first. Ask them to work on their own suggestions and give a your critical views here and there when they are working on it instead of giving it upfront.
In this way, you are not pinpointing anyone in particular and getting your thing done in a pleasant way.It is a kind of a carrot and stick policy. You are giving something sort of sugar and enteric coated pill of criticism with antioxidants - so that it is less bitter, slow and less harmful.
That is what I believe is a good way or 'criticism'. I have my own shortcomings though and might not be correct everywhere. Some people here might be wiser and more experienced than me. This is just my view. Criticisms of all kind are welcome!

John R. Nocero • Good Evening Ankur,
I agree with your point of view. If the person is perceiving the criticism as personal, it should be given in a way that allows the person to save face. I think it is hard for some people to truly evaluate themselves, and even harder sometimes to not feel like you are being attacked, especially when you put your heart and soul into a piece of work that you are proud of. Thanks for sharing.

Douglas Trudeau • I think for someone to first accept criticism with grace, they need to first acknowledge that their way of doing something is in some way, wrong. So the first step to criticism is to make the person aware of their own work, how it compares to others.

Once they have realized something is wrong, a simple suggestion or comment would suffice.

John R. Nocero • Good Evening Doug,From your experience, is this often difficult to do?

Douglas Trudeau • It depends on the person and the level of authority you have. For example, it can be extremely difficult to get a colleague to realize they're doing something wrong. However, a boss or manager, gentle comments or comparing results of work done by different people can clue someone in about how they might be doing something wrong.

Melvin paul • The term 'Critisizing' can come across differently to different people. To be honest majority of the people do not like any critisizm at all. However providing constructive feedback is always the best way forward. One can explain to the person how things could have been better if certain tasks could have been performed in a better manner.

Always provide the final picture or the outcome of any action and allow the person to decide in which way they would like to take.

You would see positive change only when there is constant support and assurance that making mistakes are human and we should learn from them and move forward and not keep repeating the same mistakes again and again.

Nilisha Ponkia • I agree with Melvin, the term "Critisizing" can come across diffenetly to different people. Because there are some people, who dont want to change their attitude because of they are self centered and very difficult to change.but for the critisizing u want that much power in ur hand to tell about the mistakes to the person who did the mistakes.

Dr Suketu Patel • we are not critisizing any one at personal level but we criticise the way job done( considering ethics and regulation)

Nidhi Saxena • Crticisim is going to effect a lot but it depends upon the behaviour of person criticising and the person who is critisized. It also depends upon the relationship between two. Positive changes can be expected if the tasks are discussed thoroughly and analysed critically. And emphasis should be given to appraise the better and positive things rather than concentrating on the negatives. At the end suggesting better ways of dealing with the situation.

Tushar Pagar-Patil • Dont you think Its all about one' skill

Victoria Locke • When dealing with people, it is better to provide "developmental feedback" rather than "criticism". Compare the results with what the expectations were, and ask them what they can do to improve so that the gap between results and expectations can be closed. When appropriate, I start with some positive comments, then lead into what can be done to improve, emphasizing that we always want to improve what we do...who wants to get stuck or deliver sub-par results?

Dr. Shiva Murthy Nanjundappa. MD (Pharmacology) • Critic should know the consequences of change he is expecting.
Critic should also know to handle emotions - self and others.
Even if you cricize, you should do with a smile.
Never allow personal intentions to disturb the spirit.
Know that there will be counters while cricizing and have the answers for all.
Proove that all said and done for the improvement.
Console others that sometime unintentionally mistakes can happen and there is room for corrections.
Give expamples of your own mistakes and tell them how you corrected over a period of time. This will improve the listening capacity of the group.

Hope these tips will help to handle the situation.

Shannon Inman • I manage CRAs and expect just as much from my employees as I do from myself. I tend to be very direct but often have difficulty selecting with right words when it comes to critisizing their work or job performance. I don't have the resources to attend lectures on the topic, but would be very interested in reading a book to help me improve my interpersonnal skills. Anyone with book recomendations that has delivered tangible results in this area of self-improvement?

Suganthan Thambiraja • I believe maintaing the self-esteem of the receiver is an important aspect of delivering criticism constructively. The criticism has to be thought out and delivered at the appropriate time and place.

Vinoth Kumar T • Good question Raman :)
I agree with what Ankur has wrote, constructive criticism may not be considered positive by everyone.

Personally I think the following steps should help.

1. Remember to keep your communication clear, open and flexible so that there is room for discussion for both of you.
2. Before you to criticize, it is very important that you emphasize the person's positives. You can probably appreciate the person's past good work, maybe his past achievements, skills, etc.
3. Now go straight to the point where he/she has done a mistake and provide a clear insight on the problem. Make them realize the price of their mistake and make sure they understand the consequences.
4. Offer solutions and directions in handling the problem so that he/she can be prepared before it happens the next time.
5. Make sure that you communicate regularly to that person so that he/she feels empowered and is convinced that they have a point of contact whom they can rely on.

Jenny Choi • A world with no criticism but only praising would make us no different than the animal kindom in my opinion. As a person who highly values constructive criticism, I think the best approach is to lay out the negatives and end it by shedding light on the positives the individual brings to the organization. Lead by sample.....

Renuka Gahlawat • Criticizing constructively to me means is counting upon both the good points as well as the bad points. So criticizing and praising go hand in hand. Merely criticizing the person would degrade the person and I feel every person on this living earth has in it some strength, hence the motive of the criticism should be to help re-discover the person through counseling. Also, it depends on the employee’s persona to take the feedback positively or negatively. So I feel criticism to encourage positive change is also an art.

Rekha Anand • That's a great discussion! Going through the comments the one that caught my attention was the use of "Developmental Feedback rather than criticism" from Victoria. I whole-heatedly agree with her.I personally feel that "criticism" is an art; with two key players: the giver and taker. During my academic curriculum I got to watch a video on criticism and the take was: The giver of criticism should pass a self test which is basically a period of cool to validate the criticism you are giving, followed by EPM formula ( Empathize, Pinpoint problems and Move Forward). I completely agreed with this as in absence of these simple rules you generally get defensive or evasive responses ..and you don't want them if you believe that the growth of colleagues is directly proportional to growth of the company.

The other part is the receiver of the criticism who should follow 4A theory. Anticipate,
Ask Questions, Agree to Something and Analyze. The best that works for me is agree to some part of criticism because that removes the silos and generally outcomes are prolific.

Habib GHEDIRA • Criticizing is a "parent-children"-like professional relationship that should not exist anymore. When you observe someone criticizing, it's always obvious that he can be criticized him self.

So the right way to achieve the aim is by undergoing an evaluation and reconstruction of means and methods of the action by 2 persons : one with the experience of the action (the action supposed to be criticized) and the other with former experience and/or knowledge concerning this action.

L. B. • Something that has worked really well in our team is that everyone is encouraged to find areas that can be improved. Everyone also has to watch out for human errors (his/her own and those of others too). This means that nobody, even the principal investigator, is safe from "criticism". When the team members see that the PI takes criticism very well, they will gladly follow by example.
In this way the team knows that improving the project is the common goal. Because comments target the project and not the person, nobody takes them personally or negatively. Everyone is reminded that to err is human, but all errors must be caught. It works.

Scott Pugh • The criticism sandwich:

http://confident1.com/how-to-deliver-a-criticism-sandwich

Shubhanjana Sharma • I and my colleagues have authored what we believe is the most extensive report on Clinical Trials in India. We have looked at the area as scientists rather than what is ordinarily available. We are charging for this. In case anyone is interested please free to contact me via linked in or tusharasnair@gmail.com. Also questions on Indian Clinical Trials are a joy - after all this work - so if anyone has any queries please write to me!

Amy Moore • I am probably saying something that has already been said....I think critism would be well recieved if the reciever has a high regard and respect for the person giving the critism. Respect is the key. Because know one will listen to critism from someone they do not respect. How do you earn respect? By treating others as if their lives add value to yours. We see every day examples of this...from the family member that keeps the family together to the coworker that seems to get along with every type of personality in the office place. How you treat people will determine whether or not they follow you...

Michele Eskridge • I feel constructive criticism should be started on a postive note first. Tell the employee what they are doing right and then carefully select your words to help them learn what you are attempting to help them understand.

Azadeh Nolan • I think everyone here has great feedback. One thing we all must consider is who we are talking to. One must evaluate the person (or persons in group setting) then choose an approach that works best with that personality type or context.

Michele Eskridge • I agree with you Azadeh however when you must critize a person you must remember that you are also trying to teach them so you need to evaluate the way the individual learns best. Personality of the person is to be considered but you still need to make your point. You need to be agressive in education of the person and all people learn differently.
There have been many times I have had to demonstrate a procedure and have the individual demonstrate back to me. This was a very educational, motivating expierence. I felt it to be constructive criticism turned around to an educational moment.

Elizabeth Brown, Ed.M., CCRA • The term "criticism" has a negative connotation for most, feedback is more universally accepted. Things to ponder: was the feedback solicited in the first place or is it voluntarily being given as part of a required evaluation associated with job performance. If the later, it is easier to accept when given in doses throughout the year and not only at the end of a year or end of a project. Getting others to buy into the feedback requires that the deliverer genuinely care about the receiver and is sensitive to body language and tone of voice. Asking the receiver if the feedback makes sense to them shows that the deliverer cares. Concrete examples (evidenced based observations) are best, are more objective and less confusing to the receiver.

Julie Campe • In management - as in parenting and auditing or monitoring - the general rule is: Focus on the problem, not the person. So instead of saying, "This sloppy documentation violates your own SOPs and quality standards and looks like careless work," say this: "The documentation is illegible and is missing items 1, 2, 3 and 4. ... Other sites have developed a checklist as part of their documentation to make it faster and easier to complete and then read later. And then the documenter has to hand-write in only a few spaces for the details of a particular case. Would you like to see a sample?"

abra ori • Find more quality articles at http://lnkd.in/_DPMqF

Jocelyn Clarke, SPHR • Great question! I find that a very simple formula often helps with delivery of constructive criticism -- the sandwich technique. By preceding and following the criticism (sandwiching) with sincere and relevant compliments/praise, you will soften the potentially ego-bruising blow. This may improve the odds that your message will be heard and absorbed.

Snehal Patel • I think crticism should be considered as a feedback in your department. Demonstration is important. The word "WE" is very important. "YOU" should not be used. This will certainly stop the "Blame Game".

Lelia Adelina Paunescu • I agree with Nighi. It is the dynamic between the 2: the one who is critisized, and the critic. The critic has an important role on how he/she is perceived. A certain tone of voice, a certain way of addresing the issue can be perceived worse than acctually it is or even in a negative way if is not said in a caring way that is meant to help improve. Otherwise could be misunderstood as the critic has the mind set that only his/her way is the right way. On the other hand, there are certainly people who when they are critisized, are taking it personally and can not see past that to improve themselves and their work. A criticism in a work place is as good as it is meant to help someone improve by both parties, otherwise should be hiring / firing type.

Artie Jhappan • No one enjoys crticisms.I think once we step away from the negativity of criticisms true self development begins. If I find myself being criticized I have learnt to listen and evaulate if the criticisms are valid first and if the intention is to improve rather than put someone down and then work to self improve. This takes humility...

FDA issues draft guidance: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring

2011-09-06T13:20:00.001-04:00

Discussions brought from Linked in platform (GCP group)

Luis Miguel Cuadrado • Thanks very much for sharing this Tina!! It´s been a long time since I waited these first steps into the new ways of monitoring: use of new technologies, new minds, risk based approach.

Times when everything should be checked are simply gone...

Phyllis Kent • I wish FDA had added that they will be understanding and will not penalize the sponsors when errors are found on the unmonitored CRFs. I can't imagine what a site will look like on inspection if there is only one monitoring visit as suggested in one place in this document. Maybe it would be ok at a Phase 4 site. I think most sponsors will not want to risk that their are errors in CRFs or that data may be disqualified because of inappropriate delegation which would go undetected using in-house monitoring. Monitors are the ones who keep the PIs on task and make sure that they are trained, training staff, involved, reviewing data, etc. FDA is just re-stating that the regs require only one monitoring visit per year and it is up to the sponsors to do enough monitoring (either in house, electronic or on site) to make sure that the study is conducted properly. The risk remains with the sponsor as always.

Tina Avanzato Chiodo • Phyllis - It would be "appreciated" if the FDA considers enforcement discretion if a sponsor's risk-based monitoring plan demonstrates systematic compliance, rather than 100% compliance. I will submit my comment to the FDA.

All - Comments on the draft monitoring guideline can be submitted to the FDA at http://www.regulations.gov.

Lynda Cedar, Ph.D. • Interesting Tina!
Nothing new in this guidance.
Monitoring should be systematic and 100% compliance. The monitoring performed should be adapted to the study progress, there should be no minimum. As Phyllis mentionned, it is of the responsibility of the sposnor to ensure the study is conducted properly...

Michael Smith • I wonder what the implications for QA would be. There is an argument that an audit function within QA could continue with its current approach - to validate any new risk-based quality system. Any thoughts?

Carol Bognar • Michael, in my experience changes in monitoring (reduced, risk-based, etc.) have a significant impact on QA audits. I have found that auditing unmonitored CRFs leads to auditors performing more of a QC effort and less QA. One of the biggest concerns I see is ineligible subjects being enrolled in trials and this not being discovered until later in the trial. Monitors (and auditors) will need to be trained on new methods of data review that are more efficient and performed in conjunction with the changes in the monitoring plans. The combination of centralized and on-site monitoring may be the best strategy to ensure data integrity and quality.

Michael Smith • I could imagine that many organisations could make more use of the data review/validation possibilities in their data management groups - perhaps these regulatory guidances will prompt more attention there.
re: new EMA & FDA documents: We can test reactions in the QA world at BARQA's annual conference later in Sept - perhaps at the GCP Clinic. Let's see what people have on their minds.......

Frédérick Therrien • At line 436, the FDA guidance document adress how communication of monitoring results are reported to the sponsor and CRO but not to the investigational site.

Perhaps this guidance document should define what should be the reporting timeframe, to the investigational site and/or the IRB, for findings that could affect the safety of subjects or their willingness to continue participation, or that could influence the conduct of the study or alter the IRB's approval to continue the study. Off course, reporting timeframe should be based on a risk-based approach.

Lorraine D. Ellis • Thanks Tina, for the discussion which I think will continue for some time since some of the directions in this draft guidance are definitely different from the current "gold standard" of monitoring.

It appears that, as quoted by my colleagues above, and according to regulations, the sponsor will continue to be responsible for the quality of the study and the monitoring. Since FDA is now more open to alternatives in monitoring methods, they are expecting the sponsor to outline in a monitoring plan (in more detail then most of the monitoring plans I have seen), the exact methods for all monitoring procedures and how they will ensure proper monitoring. To address one of the points above, perhaps FDA will inspect according to the monitoring plan requirements and expected results as they do with SOPs.

I think that on-site monitoring will not disappear as there is no substitute for visiting a site to determine deficiencies and apply remedial training or other remedial actions. However, centralized monitoring may find some errors earlier so that the monitor can go on-site to repair site performance before the problem grows. We have found that a combination of several monitoring methods proves to be the most effective in ensuring data quality.

Jeffrey T. Taylor, DMD • @Phyllis Kent, I couldn't help but feel a need to comment on, "Maybe it would be ok at a Phase 4 site."

You would think so. I worked with a sponsor who had us do one IMV for a Phase IV which had had no visits since the beginning of the study after over a year of activity. It was an unmitigated disaster with most of the issues surrounding consent. Phase IV require compliance also.

I cannot imagine a pivotal trial which follows these guidance literally. I would urge everyone to express their concerns to FDA. I cannot fathom this approach. I understand the intent. I understand the value in taking a "step back" and doing an overview; a broad based approach. Many of us understand the risks accepted in doing so.

There is no substitute to an on-site visit. The integrity of the study will be greatly compromised by a lesser approach. This is a "lesser approach".

Phyllis Kent • Jeffrey, I agree with your comments. The more I review this, the less I see anything new. The FDA minimum of one visit per year has not changed. But everyone recognizes that the minimum is too risky and therefore we develop monitoring plans to match the nature of each study. So we are already doing risk based monitoring. I think maybe this document was intended to encourage more database review during the studies to identify sites that are outliers and address them earlier. Again, I think many companies are already doing this and, with site monitoring, are aware of their riskier sites. We then increase our monitoring if we see an increased risk. I think FDA intent was not really endorsing less monitoring but a variety of monitoring approaches to use all of the tools available.

Lorraine, with respect to inspecting versus the monitoring plan, they already do this at the sponsors.

The issue I see is that if site monitoring were cut back, then more errors would exist in the CRFs. FDA would cite these errors during site inspections. Some errors will probably always exist. But with reduced site visits and less SDV, these would likely be more numerous. Of course, central monitoring can find blanks on the CRF or inconsistent data. But I do not see any way that increased use of centralized monitoring can minimize data omitted from the CRF (such as medical history, conmeds, changes in meds, adverse experiences) or captured incorrectly from the source (e.g.,start and stop dates, AE severity, etc.,) These are the same items that are likely to impact subject's qualification for a study and protocol compliance as well as safety monitoring.

I agree with Carol that the result of decreased site monitoring will be an increase in audit findings. That should result in increase in monitoring but I'm not sure that the loop is ever closed.

JeanMarie Markham • It's my sincere hope that all of these comments will be shared with agency during the comment period. I am a bit surprised at the somewhat "lax" approach the document appears to take. Especially in light of all the 483's issued in the past couple of years regarding monitoring quality. There are a number of efficiencies to be gained with EDC and EMR and some central monitoring. I agree with Phyllis we are already using "risk based monitoring plans" specific to each clinical trial to ensure proper oversight to optimize this function. There needs to be a balance. Although technology facilitates the capture of data - it is still only as good as what is entered into the system. SDV does require some F2F review to ensure patient safety and GCP compliance. We tend to forget that technology still requires human interaction; and that valid source documentation is only as good as the data being entered. It is still a search for the holy grail.

Jennifer Woodside • I'm writing from a Research Site, and we're very curious about how this might be implemented by different Sponsors/CROs. Despite many electronic records that could be centrally monitored, there is still so much on paper. Having read a few other online articles about how central monitoring would financially benefit Sponsors as on-site monitoring is a huge cost - it seems like they would apply themselves to making paper records more accessible remotely, or finding ways to replace them. I think as a Site, we will absolutely see a rise in "Portals" (basically a way to upload documentation into a online shared database) or other ways to try and chip away at making sites less paper bound, and more electronicly based.

I also wonder, if this change could place an unexpected burden on the Site itself. Potentially, we could be inundated with requests to confirm, verify, copy, check, look up, etc. Things that a Monitor on-site would be doing themselves, but as
a remote presence would require the assistance of the site to complete, or make documents available to them electronically?
10 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion1 .

Michael Smith • This deals with monitoring - does anyone know if FDA will issue related guidances on other parts of the "integrated framework" - their analogy, not mine? e.g. protocol design, CRF design, data analysis plan: Quality by Design......

Carl Anderson • I agree with Michael. It really would be great if FDA would give some guidance to study design, probably the number one root cause of GCP violations. Anyway, this guidance document is overdue and is a step in the right direction.

I think that Jennifer raises a legitimate concern about the potential unintended consequences of centralized monitoring. Sites definitely have something to say during the comment period.

Raeda Mustafa • Very interesting ! where a vast amount of clinical trials are being shifted to the MENA region and other emerging markets, investigators and clinical sites are being exposed to the GCP experience for the very first time. We (monitors) are visiting the sites, collecting the essential documents - even sometimes we instruct site personnel how to sign and date every page of the resume provided. The investigator might need a clarification for what an FDF would refer to exactly. After site initiation and prior to the first randomization, we always had to be there to ensure that I/E criteria are clear and not misinterpreted, protocol deviations throughout the conduct of the study is becoming a trend rather than being a single occurrence and most of the time the monitors' early involvement is highly important and I'm wondering if this would happen through the centralized monitoring .. this is not a one time or one visit work, it's considered part of the continuous qualification of the site, not only in our region I guess but everywhere else.

Rebecca Georgevitch • This guidance document is giving permission to run studies without regular on-site monitoring to confirm compliance for patient safety and data integrity. They're way off base. Per the FDA, patient safety is #1 and thedraft contradicts this statement. With the many mistakes that will most likely be found, this will cost everyone in the long run. Within the last 10 years, many drugs have been pulled off the market with on-site monitoring. I can't imagine the disaster with so few on-site visits and centralized monitoring. Huge impact on patient safety.

Paul Gittelson • I must disagree with Rebecca and Raeda. The guidance document really only clarifies what FDA has been saying all along. Namely, there is an undisputed sponsor/monitor responsibility to ensure the integrity of study data and that the rights and safety of study subjects are protected. The methods by which this may be accomplished may be as varied as are the studies themselves. The monitoring plan for a small oncology trial, or neurologic device trial, does not have to look like the monitoring plan for a large, multicenter erectile disfunction, seasonal allergy or weight loss study. If FDA discovers study misconduct or data discrepancies, the Investigator and Sponsor/Monitor will be taken to task for failing to detect and correct them, and a "clean" study will not receive regulatory citations irrespective of the monitoring plan adopted . While Raeda and Rebecca are correct in asserting that some studies will be disasters without regular on-site monitoring visits, that is not the case for all studies. The trick is to devise a monitoring plan that is sufficiently sensitive, robust and flexible to identify problems early on and direct resources where they are needed. For many studies, that will entail traditional routine monitoring visits as part of the monitoring plan, but there are studies that will require fewer, more selective visits. FDA is empowering sponsors and monitors to make those decisions. Don't ask FDA to be your clinical project manager.

Lynda Cedar, Ph.D. • That's true Paul. FDA does not develop the monitoring plan nor manage the study. The Sponsor is the first one who is responsible for the quality of the study, he should put in place the appropriate plan to achieve it. A study conduct involves a lot of tasks, the monitoring is just one of them. The monitoring and the number of visits should be customized upon study requirements. FDA evaluates whether it was adapted and appropriate or not.... that's all.

Should a patient sign an Informed Consent Form in his mother tongue or in a language he understands the best?

2011-08-15T04:41:00.006-04:00

The question was asked and commented by the GCP group of Linked in.

Shilendra pandey • the patient should sign the ICF in the language he understands best as the ICF contains information that need to be understood by the patient so well that he can take decision to participate in the trial and not come up later with complains that he was made a guinea pig.

Max Horneck • Dear Yulie,
actually this will not be an XOR. Usually people are most aware of their mother tongue however the real question is, have they been able to understand the risks and advanatages of the trial. Usually the investigator has to ensure that the patient will be able to make an educated decision. If the mother language does not contain adequate vocabulary or if the patient has left the community of the mother language at an age so he/she does not have the vocabulary to adequately understand the education given by the investigator a language best suitable should be selected. As far as I know there is no regulation that you have to sign informed consents in your mother language this is just a commonly used method because this fits most cases. However, the patient needs to fully understand the informed consent. I would be comfortable signing an English informed consent allthough this is neither my mother language nor the language I understand best.

Iftekhar Kazmi • Hi,
It is mentioned that informed consent should be taken in subjects understandable language. for more detail kindly refer below

* The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable. (http://ichgcp.net/48-informed-consent-of-trial-subjects)

regards. Iftekhar kazmi

Dainis Krievins, MD, PhD • Iftekhar is formally right. It’s true, GCP does not request directly mother tongue as language used for IC. However, it is very depends on auditors you may have. Some EMA auditors would give you a "finding", if you will not give IC in patient’s mother tongue. Of course, you may argue about GCP legislation, but we had no success with it.
Therefore, be aware, from one side patient should understand the IC (this is what really important), but for an other hand, beaurocrats from some regulatory agencies and auditors may see it in different way.

Yulie Feldman-Idov • Thank you for your comments. I agree with you that the patient should sign the ICF in a language which enables him full understanding of the ICF's content. GCP indeed does not require directly mother tongue as a language used for IC. However, like Dainis we have experience with requests to sign the patients in their mother tongue. Lately, we were requested by one of the sponsors to sign the patients specifically in their mother tongue. What do you think about this?

Jaime Morales Pintanel • they re not exclsuive. In my experience, you must have an ICF in his/her mother tongue and should be understable. My sites were located in places like Nicaragua, Iquitos, Tumbes, Buenos Aires and so and trust me, they gave no idea what is a pinta de sangre (pint of blood), for example.

Miguel de la Guardia • Yes, the document should be written in the language the subject understands best. But the language it is written in is not as important as how it is written. I have read documents in my native English that I can’t understand and I’ve read some that are well written in English, but the Spanish translation is comical at best. Literal translation of documents is often of poor quality or incomprehensible because the people doing the translation do not fully understand the context or colloquialisms of the various regions. As such, before those translations are finalized, a knowledgeable third party should proof read them for accuracy.

Lynda Cedar • All the communication with an enrolled subject in a trial must be in the langauge of the ICF signed by the subject. For more details, please read the regulatory Information at the FDA website (http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm)

A Guide to Informed Consent - Information Sheet Guidance for Institutional Review Boards and Clinical Investigators Contents):

Non-English Speaking Subjects:
To meet the requirements of 21 CFR 50.20, the informed consent document should be in language understandable to the subject (or authorized representative). When the consent interview is conducted in English, the consent document should be in English. When the study subject population includes non-English speaking people or the clinical investigator or the IRB anticipates that the consent interviews will be conducted in a language other than English, the IRB should require a translated consent document to be prepared and assure that the translation is accurate. As required by 21 CFR 50.27, a copy of the consent document must be given to each subject. In the case of non-English speaking subjects, this would be the translated document. While a translator may be helpful in facilitating conversation with a non-English speaking subject, routine ad hoc translation of the consent document should not be substituted for a written translation.

If a non-English speaking subject is unexpectedly encountered, investigators will not have a written translation of the consent document and must rely on oral translation. Investigators should carefully consider the ethical/legal ramifications of enrolling subjects when a language barrier exists. If the subject does not clearly understand the information presented, the subject's consent will not truly be informed and may not be legally effective. If investigators enroll subjects without an IRB approved written translation, a "short form" written consent document, in a language the subject understands, should be used to document that the elements of informed consent required by 21 CFR 50.25 were presented orally. The required signatures on a short form are stated in 21 CFR 50.27(b)(2).

Illiterate English-Speaking Subjects:
A person who speaks and understands English, but does not read and write, can be enrolled in a study by "making their mark" on the consent document, when consistent with applicable state law.
A person who can understand and comprehend spoken English, but is physically unable to talk or write, can be entered into a study if they are competent and able to indicate approval or disapproval by other means. If (1) the person retains the ability to understand the concepts of the study and evaluate the risk and benefit of being in the study when it is explained verbally (still competent) and (2) is able to indicate approval or disapproval to study entry, they may be entered into the study. The consent form should document the method used for communication with the prospective subject and the specific means by which the prospective subject communicated agreement to participate in the study. An impartial third party should witness the entire consent process and sign the consent document. A video tape recording of the consent interview is recommended.

sajana Vattikuti • Hi all, In my view during the site start up itself, the CRO or the Sponsor Start up team will be asking the languages used in your locality and its surroundings. Based on the languages we mention, the set of ICFs will be set to the site for proof reading, review and Ethics Committee approval. It is upto Subjects discretion, which language he is convenient with on discussion with the Investigator. The local languages and English are usually suggested to the Site Startup team during Study Start up or Site Selection. If at all the ICF available at the site were not understood by the subject the comment mentioned by Lynda holds good.

Miguel de la Guardia • @ Lynda - Very thorough review. Thanks.

Ludmila Sklyar • HI all. Thanks a lot for the question , Yulie and for review . I has this issue in one of my Audits . As resolution comment has been added in to the pt Source Data file, explain that despite the fact that pt mother tongue is Russian, Hebrew version of ICF was signed as the most understandable language.

Lynda Cedar • @ Miguel. - My pleasure. Any time. Thanks.

Cristina Gonzalez • Followin Sajana's comment, we do need to take into account the ICF whatever language is must be approved first by the ethics. For most of the trials in ww countries we can not foresee the patient's mother's tongue so...what we should do? submit to the ethics the most popular languages expected on each site? Is not far future situation...

Nethaji Bhosale • The language he understands the best

Dr. Socorrina Colaco • In India we usually prepare ICFs in English, Hindi, Kanada, Tamil, Telugu and other local languages and submit it for ethics approval. So the subjects can choose their preferred language.

Amit Hirve , MSc MRQA • He/she should sign the IC docs in his/her local language. IC documents should be written so that lay person can understand it and your mother tongue is the best language to understand something which is new and complex.

Cristina Gonzalez • One further question:if the Ethics Committees will be submitted with ICF in different languages, they would accept the documents in languajes other than local ones. Moreover, if a French ICF is submitted and approved, any change done in the French core document will affect to all the sites which have these ICF validated? Or could the Ethics trust in the French Ethics approval to accept their acceptance and avoid in that way to review all languages applicable?

Joseph Michael • The person should sign the ICF in language he/she understand best, in order to make proper judgment.

David BenJoseph • Of course the ICF should be in the language that the patient understands.
It could take long discussion about the definition of mother language. I organized many clinical trials in Bulgaria. For Europe it is clear that the ICF has to be written in the official language of the country. There could be minorities who does not understand well the official language. They could be considered non-eligible for the trial or they could have the documents in their 'mother language'. All ICF, questioners and diaries have to be translated. All the translations have to be verified and approved. The texts are specific so the best translators are not the philologists but medical specialist who deeply understand the terminology, meaning and equivalents in the local language. In case of mother language it could be for instance Turkish and it is possible to use a verified official translation. But the language could be Roma (Gypsy) and it cannot be translated because there is no written language. The next problem is that population that has problem in understanding the official language of the country could not understand the documents in their mother language because of poor education. If a patient cannot understand ICF, questioners and diaries, usually that patient cannot be compliant and should not included in a trial.
I think that most of the considerations are applicable in Latin America and Asia as well.

Dr.Arunava Banerjee • Thanks Lynda & David and rest. The issue is serious enough. Serious issue in many countries with mixed population group like India. As I am a Sub-Investigator in my site I have to take active part in ICF process. What I feel is the content matter of the ICF and patient information sheet(PIS) is most important.It is said that standard of language should be of 7th standard.Do you think the language of ICF and PIS nowadays are of 7th standard.I think they are not in most of the cases.These are always full of technical scientific words.
Now I work in a state where mother tongue is mostly Bengali. I have to go check the Bengali translations of English ICF in all the studies that our site participates. Simply in most cases my experience is horrible. Bengali translations are realy pathetic. There are many terms used in English which does not have an easy and understandable Bengali replacements.These are mainly scientific and tecnical terms. To be frank checking Bengali translations of English ICF is the most fearfull work that I have to do regularly at site level. Problem is such that if ever I myself have to participate in any clinical trial in my life I shall never go for Bengali ICF; I shall go for English one.But I shall definitely prefer to talk to my doctor in Bengali.
.We have to judge every patient individually. The education and social status are to be taken care of. It is common at my site that patients prefer English ICF although English is not their mother tongue.
In this matter we give open offer to the patient.In some cases a patient can be given 2 ICFs,one in English and the other in mother tongue.Let him go through the both and decide which one is more understandable to him and accordingly the ICF can be signed.
The source note should mention the whole issue in minute details and in that case I think auditors shoul not do much.Of course there are some of them who will create problems always.
Responsibility of the Investigator and EC is maximum here.

Mina Saeed • Hi All, in my view, the subject should sign The ICF in language he better understands so he can voluntarily sign after understanding the risks and benefits of the trial but, I agree with Ludmila, that to escape the audit findings we add a comment in the patient source data file that despite her mother tongue, the specific language version of ICF was signed as the most understandable language. However in Egypt there are two versions of informed consent ; Arabic and English, and the patient must sign the two versions with note to file needed to clearly describe this issues.

Tania Betts • I agree with the comments being circulated, however I also think we need to look one step further. It is one thing to consent the subject into the study but once consented, will the subject be able to independently complete whatever patient-reported outcomes are required for the study, for example, patient diaries and questionnaires? Will these also be translated?

Yulie Feldman-Idov • Dear Tania,
If the subject is not able to independently complete diaries or questionnaires as required by the protocol (due to language barrier or other reason), then he is not eligible for the trial. It is important to have validated translations of these documents.

Anirudh Kulkarni • I agree with "Dainis " Some auditors argue about this. Therefore a informed consent process documentation is utmost important. something like this.

"When the patient came ?...what happened in the discussion.?...what questions did he ask ? and finally a sentence "the inform consent discussion was conducted in, XXX language in which patient knows to read and speak fluently, however the patient is comfortable signing ICF in XX langauge..(This may again not satisfy all auditors)

The other option is Video tape regarding consent process.This is common problem in India. They know how to read well and understand English but they will sign in local langauge.

Yulie Feldman-Idov • Dear all,
Thank you for your input. It was very informative and some interesting issues were brought up.

In our site we often encounter patients who do not have the vocabulary in their mother tongue to adequately understand the ICF's content, and their understanding of the official language of the country is much better. In this case, like Ludmila, Mina and Anirudh noted, the patient signs the ICF he understands the best and we add an explanation in the subject's source document. Hopefully this will satisfy the auditor.

As some of you indicated, translations have their faults and I also often see them at our site. It is clearly the responsibility of the EC and the site personnel to clarify the problematic terms and phrases, so the patient could fully understand the content of ICF.

Thank you again for sharing

Lynda Cedar • @Yulie - The pratice is correct when the subject signs the ICF developed in the language s/he understands the best. The best should mean: (1) the language was selected by the subject and (2) s/he fully understand the contents of the consent, verbally and in writing.
At my site, the translation of the ICF and other documents is done by a certified translator. The IRB has the liberty to review the translation of the ICFs in English or French to another language. So far, I haven't heard about any problem of translating the ICFs.

Thank you for sharing. Lynda.

Yulie Feldman-Idov • Thank you for the clarification Lynda.
Regarding translations:
From my experience, although the ICF and other documents we receive at our site are validated and done by certified translators, there are often terms that are not clearly translated, (especially words that are simply absent in another language) or very sophisticated language is used. Sometimes even the investigators who speak both of the languages, have difficulties with the translated version. In one case we received a very poor translation of the Russian version of ICF. A few months later the Sponsor sent us a far more understandable version of the same ICF (by different translation company). So choosing a translator can play an important role here.
In some of the comments above were mentioned similar difficulties in other languages.
At our site we clarify the problematic terms to the patient but usually do not report this to the CRO/Sponsor. Like David noted, the best translator is the medical specialist who deeply understands the terminology, meaning and equivalents of the language.

David BenJoseph • Thank you Ylie for the comment. Actually in trials where I played from the side of CRO I made translations from English to Bulgarian. As a VP of local ethic committee I have always read carefully the translations comparing with the English original and always recommended improvements of the language that made most of the sponsors angry but usually they decided to fulfill the requirements of the ethic committee.
The important texts and questioners have to be specially verified by the sponsor by back translation and subsequent discussion. For instance my translation was free but through to the meaning. The sponsor was aware about a missing word or the number of words in Bulgarian text was different. Their translator suggested a version that was word by word correct but the meaning was completely wrong or missing. We had a month meeting of all CRA and the sponsor and we discussed the translations. I was forced to follow the suggestion but I insisted on the correctness of my version. Finally the sponsor approved my version.
Another problem from a ICF I reviewed for the ethic committee: the English original text was 1.5 miles; the Bulgarian translation was 1.5 km. The sponsor argued strongly for the translation made my an authorized translator. We, the ethic committee, insisted that it is not equivalent and it could not be accepted.
Finally my opinion is that sponsors and CRO should be careful with the translations especially 'authorized translations'. Ethic committees/IRBs have to control the translated documents and are responsible for patients' safety.

Lynda Cedar • @Yulie, thank you for the comments. In my practice, I experienced too what you explained above but later I put in place policies that prevent or at least facilitate the project management:
Regarding the ICF and recruitment:
1.The ICF (in any language) must stay simple and easy to understand by the subject. If an investigator is not able to understand the contents of the ICF or part of it (even words), therefore such ICF is not acceptable and cannot be submitted or approved.

2. The translator is certified for translation and has to demonstrate his capacity of fluently and fully using both language of the translation. Also, there are organizations in the US and Canada certified for translations in some fields (ex. clinical trials and medical research. The ICF should contain a minimum of technical words that have to be explained to the subject.

3. The ICF is not the only issue for those non-speaking English or French. After signing the, they have to comply with the rules and procedures of the study. Someone (interpreter ) to coach them. Indeed what happens if a subject falls in an emergency situation? At my site and province we are lucky, our staff is multi-ethnic, multilingual, most of the nurses, technicians and employees speak at least 3 languages!!!

4. We submitted our ICF template (initially approved by the IRB) to the sponsor for review and approval, if rejected (which never happens yet) we do not include subjects with very rare language (dialect). It is not worth for the study and wasting time.
When we outsource a study to another site (if not English nor French) we let them use the local language. They have the liberty to use their own ICF, we and the sponsor however reserve the rights to review it by our translator. In fact we always translate the ICF for our records, to know about its contents.

5. Finally, if the sponsor and/or the IRB is not able to review the ICF translated, therefore no subject with that language will be enrolled.

As a note, regarding David comment: in my view, it is not the sponsor or the investigator who has to decide whether to use miles or Km, the decision belongs to the subject, which unit s/he is used to. In absence of the subjects the decision belongs to the IRB.

Happy for sharing.

David BenJoseph • Dear Lynda,
Thank you for paying attention to my writing. Mile is not translated as kilometer. Actually these are measure units. So 1.5 mile is equal to 2.414 km. The distance is the same the units are different. So if a patient is tired after 1.5 mile or after 3 mile it should be the same distance for having standardized condition. It is not in power of IRB or the sponsor to change the distance in different locations. So in my capacity of a member and VP of an ethic committee I insisted on policies that the content should be exactly equivalent between texts in different languages concerning the same protocol (study). I hope that all we shall agree on this topic.

Lynda Cedar • Dear David,
Thank you for the clarification. I knew about the conversions (http://www.france-property-and-information.com/metric_conversion_table.htm) and I agreed on your comments. I just wanted to add that we should use the system of measurement that a subject understand better and is comfortable with.

David BenJoseph • You are absolutely right. For Europe usually it is in SI that is not so in UK and USA.

John Olszewski, Esq. • As with all things GCP, the best way to answer the question is to first ask, "Why?' So, for the present question, we must ask what is the purpose of the ICF? The ICF is primarily a legal document that provides one of several types of evidence that subject knew what he/she was getting into when enrolling in the trial. This evidence is used by FDA to assure compliance with the regulation that subjects knowledgably consent to participation, and it is used in legal battles against a sponsor/investigator where a subject claims that he did not know what he was getting into, i.e., that he/she was not "informed."

So, the answer to the question at hand is that the ICF document should be written in the language that would provide the best evidence in a legal battle or FDA inspection that the subject knew what he/she was getting into when deciding to enter a trial. That would be the language that the subject best understands. Any other language opens up a prosecutorial argument that the subject was not actually "informed" about the trial.

Of course, the ICF is intended to be part of the subject educational process and not be merely documentation evidence, but the fact is that most subjects do not read and comprehend the ICF regardless of the language.

Mark Lawrence • It may be that the limitations of a dialect mean that people habitually use the official language for scientific terminology anyway. To illustrate this, look at us English speakers. We habitually use Latin for science, beginning from a time when English was just a hybrid dialect spoken in a dark rainy corner of the Roman Empire. But as anyone who deals with user-acceptance knows, Latin medical terms can spell trouble. It's best to use language that people are comfortable with, if this is possible without over-simplifying.

Most participants don't read ICFs for science, they read them because they want to know what they are getting involved in, and what the risk is for themselves. At this point, regardless of the scientific terminology, it is imperative that language is used that people understand.

The best thing to do is to try out the ICF on a few people. For example find 10 people without medical training and with a fairly representative range of educational backgrounds and ask them a set of questions that cover the key points, such as "According to the form, what should you do if you experience bad side effects?"

That way you can refine the ICF and address any ambiguities in the language, technical terms, difficulties with the format and type. Repeat this process once or twice until everyone is fairly happy with the ICF (90% able to answer is a good target) and then use this as a master copy.

Once you've got a reliable master copy (which you'll enter into your dossier) then find some translators, and get faithful translations made into as many dialects and languages as you'll encounter in your test.

Not only is user-acceptance testing of ICFs the right thing to do ethically, but having evidence that you have carried it out can save your skin in lawsuits.

[declaration of interests: I operate First Read This Limited, a company that carries out user-acceptance testing of ICFs and PILs)

Ranjan Kumar A Subject of Clinical Trial should sign Infored Consent in language that she/he best understand. No doubt mother tongue is the most understandable language for any person but it can't possible to provide exact script of the consent form. Hence Informed consent form should be most closest script of his/her mother tongue by which subject undertand most

Jakub Wasilewski for sure subject should sign ICV in language he knows the best, no metter if it is official language in specific country or not. ICF must be fully understood by patient. Translation is not problem in this case. Bigger problem is discussion with patient - showing and signing ICF is only final step of consenting.

Lynda Cedar, Ph.D @Jakub - That is true. Read my comments about it above.

Anand Kawade Patient should signed the informed consent form as he/she signing routinely only after understood the study procedures, risks & benefits etc .completely.It may happen that patient understood the study procedures best in marathi( mother tounge) while he signed& dated in english as he officiated for that

Hugues Nicolaythe ICF should be in the language that the patient understands, without any doubt.

Lynda Cedar, Ph.D * Draft Guidance Document on Exculpatory Language in Informed Consent - On September 7, 2011, the Office for Human Subject Protections (OHRP) and the Food and Drug Administration (FDA) announced in the Federal Register the availability of a joint draft document entitled, "Guidance on Exculpatory Language in Informed Consent," and are inviting public comments on that document. The joint draft document, among other things, does the following: 1. Provides guidance on the regulatory prohibition on the inclusion of exculpatory language in informed consent. 1. Includes examples of language that OHRP and FDA consider acceptable as well as examples of language that the agencies would consider exculpatory. 1. Clarifies that OHRP and FDA have concluded that language in informed consent is not exculpatory if it informs subjects that, by agreeing to allow the use of their biospecimens for research purposes, they are giving up any legal right to be compensated for the use of the biospecimens. This represents a change from OHRP's November 15, 1996 guidance on point, "Exculpatory Language in Informed Consent," which identified as "exculpatory" certain informed consent statements in which subjects gave up any rights they might have in their biospecimens. OHRP and FDA now consider these statements to be acceptable for inclusion in informed consent, and they are restated as examples of acceptable language in the draft guidance. Thus, for example, it would now be acceptable to include language in a consent form such as "I give up any property rights I may have" in biospecimens, or "I voluntarily and freely donate" the biospecimens to a particular institution. When finalized, the draft document will supersede OHRP's November 15, 1996 guidance entitled, "Exculpatory Language in Informed Consent" and question number 52 in FDA's January 1998 guidance entitled, "Institutional Review Boards Frequently Asked Questions - Information Sheet Guidance for Institutional Review Boards and Clinical Investigators." The Federal Register notice of availability, the joint draft guidance document, and instructions for how to submit comments can be accessed on the OHRP website at http://www.hhs.gov/ohrp/newsroom/rfc/. The joint draft document can also be accessed on the FDA website at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ProposedRegulationsandDraftGudiances/default.htm.

Yulie Feldman-IdovThanks Lynda

Lynda Cedar, Ph.D. My pleasure Yulie. Any time.

prasad pendyala M.Pharm The main aim of ICF is that need to be understood by the patient so well that he can take decision to participate in the trial or not so it should be in a language that the patient can understand to his best of knowledge about the risks

Yvonne Quinn For future reference I suggest you also add a note in the chart if the subject has a mother tongue ( French) and is also bilingual ( English) and is fluent in both. The note should indicate the language preference of the subject because of his fluency in both laguages. Of course the study nurse and PI will confirm that the subject has read and fully understood the contents and their questions have been answered.

Liping Zhou I agree with majority of you that the subject should be provided an consent form in the language that she/he understand the best. Here we more focus on the consent form itself but it is also important to ensure that the consent process should be performed in the language that the subject understand the best. We do see sometimes the investigators could not speak local dialect (e.g. mandarin vs.cantonese)... According to ICH GCP 4.8.6, the language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable.

Deepak Assudani, MBBS, PhD I had a related query to this one. Is it acceptable if the contact details of the investigator on ICF is in a different language than the rest of the ICF. Sometimes the ICF has a blank space for the site to write the contact details of investigator, which they may write in english although the ICF is in some regional language. Although ideally both should be same, but would regulators look at this as a serious finding?

Haresh Dodia Mr. Deepak, it must be same as the language of ICF. Volunteer may not be knowing the english and that's why he/she given the different language ICF. Additionally, contact detail is one of the most critical thing which volunteer use in case of emergency/adverse event. If the volunteer does not understand the language properly, how will he/she contact the investigator? However, if any document/ICF support that the subject know English language in addition to language of ICF, it could be acceptable for that particular subject.

Lynda Cedar, Ph.D @Deepak: at the time the subject is asked to sign the ICF (developed in the language that he fully understands) the investigator is usually known. A blank space might be left in the ICF for contact information if needed, it will contain only names and tel. numbers. In fact, as long the ICF explains to the subject what to do in the case he needs to contact the research team, names and tel numbers can be provided later on (inserted in that blank space).

Deepak Assudani, MBBS, PhD. Thanks Lynda and Haresh. As Lynda has rightly mentioned that generally the investigator and the site address is known to the patient. In such a case, its not clear whether these details on ICF have to be provided in the ICF language itself (considering it is not documented that patient can read english as well as Haresh mentioned). None of the guidelines have specifically addressed this.

Lynda Cedar, Ph.D. @Deepak: I'm sorry for the miscommunication... even for recurrent participant (BA/BE for example), the information is provided verbally and in writing at the session of information about the research. If at that time the contact information (cell phone and names) is not known yet, it can be inserted in the blank space later on. As a note: only written information provided is valid, this is the only way that it can be tracked.

BARNALI BISWAS • Take a simple example of any document if it reads, say in french and signature done in english. The logic is simple that the person understands the local language but signs in english, which is most common by everyone for any purpose. In case of clinical, Now it will entirely depend upon the subject in which language he understand the best. Example, ICF in french completely understood by the volunteer and signs in english. which is acceptable as GCP says that the ICF should be understandable to the subject. signing in the document itself confers that the subject is aware and agreed with the document.

David BenJoseph • Dear Ms Biswas, How do you make difference between signature in French and in English? Both languages use Latin characters and I don't see how the name will looks differently.

Traian Andrei Manu • Regardless of what language you would use you'd have to document also that the subject understands better the official language or his mother language. You could have in the same country sites that would only use mother language and other sites using the official language. Of course you would have to 360 degrees verify the translations and everything. Upon this there is going to be a problem with the CRA verifying the mother language ICFs, but that's another discussion.

Suresh Lakkireddy • The language used in ICF in witten and oral should be understandable to the subject, need not be the mother toungue, which is more rational and also the GCP requirement.

T.B. (Puma) Smagge • Of course the mother tongue should be offered. What the person signs up to is what the person best understands.

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2011-07-03T08:28:00.002-04:00

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Can the Reference Biologic manufacturer, file an ANDA for a Follow-on?

2011-06-30T23:13:00.003-04:00

Question asked on Linked in:
Following patent expiry, can the Reference Biologic manufacturer, file an ANDA for a Follow-on? Does competition need always to come from outside?

Commented as follows:

Christopher O. • First, in the US the notion of an ANDA for biologics is not applicable, especially after enactment of the Biologics Act in 2010. Nor are applications under 505(b)(2) generally permisssible for "biologic products" under the new Act.

A reference product sponsor can always "rebrand" its product or change its pricing to compete with follow-on manufacturers, either before or after patent expiry. Given its investment in its brand and the probable small reduction in price, accompanied by a reduction is profit, it is hard to imagine why such a sponsor would ever choose to do so.

In the small molecule world, where pricing is very diiferent and volume more important, "authorized generics" have become a significant part of the market. It seems unlikely that, for the forseeable future, a reference product sponsor would create an "authorized follow-on biologic" to market at the same time as its reference product (especially since the follow-on would likely have the same labelling as the reference product, perhaps apart form a trade name, and the marketing effort would away from product differentiation to demonstrate interchangeability).

Neha P. • Thanks for clarifying Christopher. It seems the referece sponsors do not face as big a threat if the possibility of "rebranding" exists (if ever needed). However, I am still a bit unclear on the ANDA issue, was not Enoxaparin (Sandoz) approved under one in the US?

Michael A. S. • Enoxaparin was not originally approved under a BLA, but an NDA. Thus, an ANDA is possible if, as Momenta/Sandoz persuaded FDA, they could show that their active ingredient was the "same" (not similar as under the new Biosimilars law) to the branded product.

Hareesh P. • @ Neha - Chris did answer your question well. Just wanted to add another perspective, whenever the Innovator gets into authorized generics they do so thru' their generics team (ex. Sandoz for Novartis, Hospira for Abbott etc) and they do with a branded generic or a generic name and diff packaging via a diff field force. Also, one of the practices in the industry is to source the authorized generic thru' an alliance or contract the mfg out ...essentially both the Innovator product and authorized generic are not manufactured from the same site. Guess with Biologics, as we move forward there would emerge the concept of "Authorized Biosimilars" too .... but it is still early days !!!

Atul S. • I agree in wholesome with Christopher, @Hareesh, the process is anyway downstream in striking cost efficiencies, which will follow similar patterns but would be very slow in pace or you may never know it would be a similar-similar of Biosimilar to the ref products.....!!

Christopher O. • It is correct that Sandoz' enoxaparin product was approved based on an ANDA, and that the FDA found sufficient "samness" to permit a finding that the the active ingredient in the generic drug product is the same as the active ingredient in the RLD.

In response to Aventis' citizens petition, objecting to that approval, the FDA said that "an ANDA applicant for generic enoxaparin must provide sufficient
information to show that the generic drug product contains the "same" active ingredient (enoxaparin) as Lovenox. We have concluded, based on our evaluation of current data and other current relevant scientific information and our scientific experience and expertise, that the following five criteria (or standards for identity) together provide suffcient information to conclude that generic enoxaparin has the "same" active ingredient as Lovenox:

Equivalence of physicochemical properties

Equivalence of heparin source material and mode of depolyierization

Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species

Equivalence in biological and biochemical assays

Equivalence of in vivo pharacodynamic profile ..."

The FDA went on to discuss each of these factors in great detail.

The factors that the FDA may use to assess "sameness" of two other future products may well be different. But the enoxaparin approval may serve as a guidepost for determinations of "sameness" of future products that are not primarily manufactured using cell-based techiques, no matter how large.

It is important to note that, in very recent comments about the FDA's future regulatory approach to biosimilars applications, an FDA official specifically referred to the enoxaparin approval (suggesting to me that it may be a model, even for applications under the Biologics Act).

After enactment of the Biologics Act, with narrow exceptions, an application for approval of a "biological product shall be submitted" under the terms of the Act, and not under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) (i.e., not as an NDA, ANDA or a 505(b)(2)). A "biological product" is defined by 42 USC 262(i), as "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide)or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings."

As I understand what the FDA has said about enoxaparin, it is manufactured through depolymerization of heparin, which, in turn, is prepared by processes involving extraction from animal tissues (i.e., porcine intestinal mucosa or bovine lungs).

It could be that, at the time Lovenox was approved under an NDA, a regulator may well have judged that, because it is a low-molecular-weight heparin, enoxaparin is something other than a "biological product" within the statutory definition set forth above. I haven't reviewed the Lovenox NDA approval (NDA 20-164) to learn why the FDA approved it under an NDA rather than a BLA, or wther the issue was even considered. Once Lovenox was approved under an NDA, it makes some sense for an application for approval of a generic equivalent to have been made and approved under an ANDA. I am not sure how frequently this might occur in the future, at least for products that, whatever their molecular weight or structure, are not manufactured solely using chemical synthesis (including synthetic biological techniques).

So, it would seem that your question is far from naive and may have been more complex than my initial response suggested. I hope this discussion has been helpful.

As always, the views expressed jn this post are mine alone, and do not necessarily reflect the views of my law firm, Schiff Hardin LLP, or any of its partners or clients.

Neha P. • Thanks a lot everyone for your input. This discussion was certainly helpful.

Atul S. • @ MR Cristopher, in isolation (or for that matter for Enoxaparin) or any heparin product still is a bit different in terms of its source (production), I suppose things would be entirely different in other cases of big molecules.

Ronald A. R. • I think it very possible we may see more "authorized" biosimilars and true biogenerics in the U.S. and other major markets than most presume.

For example, if I headed a reference product manufacturing/marketing company with a biologic facing U.S. patent and data exclusivity expiration, I'd seriously consider having one or more U.S. licensees or captive/related/proxy companies bring out a biosimilar/biogeneric, and even meet or slightly beat the price of competing biosimilars. This way, the competition never gets traction in the marketplace, while I retain dominant market share. As the ref. product manufacturer, I would presumably have at least a decade of experience making the product, fully paid-off manufacturing facilities, economies of scale and low manufacturing costs that few, if any, upstart competitors will be able to beat. In this context, rather than lose say 20-40% (pure guesses) sales of my ref. product to biosimilar competitors, I can price the competition out of the market (particularly, if mine is a genuine interchangeable biogeneric), and perhaps even prevent competitors from bothering to develop competing biosimilars. Yes, my profit margins will go down due to the cheaper biosimilar/biogeneric, but probably not as much if I were to allow others to launch biosimilars. Why would I want to allow others to disrupt my monopoly on the product? For example, in the context of facing serious competition in the U.S market, would Amgen (and J&J) really lose much by bringing out its own biosimilar/biogeneric version(s) of EPO? I think it very possible that given the alternative - multiple competing biosimilars - a reference product company can make more profit by retaining its reference product monopoly vs. losing both substantial revenue and commanding market share to biosimilar competitors.

Am I off-base in my reasoning?

Neha P. • Hi Ronald, actually that is exactly the kind of thought process that led me to pose the question. I agree to you completely. A reference sponsor does not seem to lose too much, if the cards are played right.

Christopher O. • Although it is only a matter of opinion, at this point, I disagree with the suggestion that a reference productmanufacturer will "lose say 20-40%" of sales of a reference product to biosimilar competitors. It will be much greater, although the price drop will not be as significant as such "branded" manufacturers have experienced with Hatch-Waxman generics. Any price decrease, particularly if bosimilars are demonstrated to be nearly as effective as the reference products (or maybe better), with similar levels of safety/toxicity, the formularies will shift prescriptions, to the extent that they can effectively exert economic force, from a reference product to a biosimilar. If a biosimilar is deemed by the FDA to be an "interchangeable," the effect will be more pronounced.

In the Hatch-Waxman world, the shift, because of Medicaid/medicare through the formularies, is 80%. Authorized generics probaly account for more than 10% of total sales, at a price higher than generic small-molecule drugs, but lower than the reference product.

If a similar pattern appears with biosimilars, understanding of the obtacles to direct competition that will likely exist as a result of potential labelling and other regualtory requirements, the share of the market that may be capture by biosimilars is likely to be much greater than 20% - 40% of the reference product sponsor's sales. I believe that experience in the EU with biosimilars may support this estimate See, e.g., http://www.urchpublishing.com/articles/biosimilars_should_capture_significant_share_biologicals_market_europe.html and http://decisionresources.com/News-and-Events/Press-Releases/BAS-11410-(1).

It is the fear of such market degradation that is at the root of efforts by reference product sponsors to obain a lengthy data exclusivity period, or multiple exclusivity periods, and to seek exacting FDA regulation of biosimilars (such as requirement in all cases for many and expensive human clinical trials).

As always, the views expressed in this post are mine alone and do not necessaarily reflect the views of my law firm, Scchiff Hardin LLP, or any of its partners or clients.

Biologics are usually protected by a number of patents. Which could be the most imp. patents for estimation of generic launch of biologic drugs?

2011-06-27T08:49:00.006-04:00

Question asked on Linked In:

Biologics are usually protected by a number of patents. Which could be the most imp. patents for estimation of generic launch of biologic drugs? it is said that 'for biologics, process is the product.

Commented as follows:

Leighton Howard • I think this is very difficult to answer generally, and should be looked at on a case by case basis. However, generally speaking, there will be platform technology that protects methods of preparation of biologics, but there will usually be specific patents to vectors that are very specific to the biologic active ingredient, and which cannot be circumvented. Since the platform technology patents are often filed a little earlier, they should expire earlier than the vector patent and become less important when assessing loss of exclusivity.

Lynda Cedar • Issues of biosimilars are at different levels of their development and commercialisation. Since all agreed about the concept of <>, it cannot be other than taking biosimilars case per case.
It sounds that for some cases of biologics, the only solution is suugesting to extend the period of their patents for example, or decrease the price after the expiration of the patents, or, or....or. . No miracle solution can be found before the technologies of formulation and analytical improve and evolve which can be also patented by their innovators.....

Ronald A. Rader • Estimating patent expiration and, related to this, presumed market entry is not a simple task, and no matter how extensive a job one does, a relevant patent could be missed, particularly patents licensed-in from others, with these more difficult to identify. Thus, to be truly exhaustive, particularly where small- to medium-size public companies are involved, besides looking over all of their in any way relevant patents, you may want to check their SEC disclosures for mentions or, if lucky, copies of relevant licensing agreements.

Innovator companies have had decades to prepare for patent loss and biosimilar/biogeneric competition. It would be foolish to presume that some, if not all, of these companies have not laid traps for those who think relevant patents will expire when they appear to. For example, reference product manufacturers can go out and exclusively license everything in any way related to their product. Even more aggressive (or savvier) companies might redesign their manufacturing process (and product) as biosimilar/biogeneric competition approaches to incorporate unique, unavoidable (must have) processing technologies for which they have their own rather fresh/new patents and/or have licensed-in this technology from others.

Lynda Cedar • That is logical. Sponsors spent time and a lot of money to develop that such complex product. It`s normal to take all precautions to protect it and prevent the competion... but the patient must remain the priority and therefore something must be done to resolve the issue .....

Himanshu Jain • Now, innovator biologics have 12 years of market exclusivity in US, hence, it would be more difficult for generic companies to launch biogenerics in US.

Mike Chace-Ortiz • That's 12 years from the date of first approval! For many products, including a number of blockbusters, this period has already passed or close to passing and the same is true for many patents protecting these older products in the US. More importantly, if biosimilars come to market using the BLA rather than ABLA routes, that market exclusivity doesn't apply anyway. So, in most cases, it's probably fair to say that patents, not exclusivities are likely to govern US constraint dates.

Readers might be interested in our recent White Paper on the topic of the US FOB market available at http://science.thomsonreuters.com/info/newport_whitepapers/

Akhilesh Kumar • any complex developmet for products like biogenics have scope.The question is vital that cheap generic formulation have great scope for the company ,distributors and stockist.The consumers are not getting benefits since MRP always on higher side.The margins are less turnover are larger.The concept of pharma products thru prescriptions and direct selling generic products are having same mrp.In any case patients are not getting benefits.As such,maximum retail price shoud be lesser and generic products should practice by doctors,institutions.privatehospitals and nursing homes/consumerdoctors and retailers should be allowed to sale the products .It is only possible when uniform policy to be made

Bruce Pokras • One big difference in the U.S. FOB market versus the small molecule generic market is that many FOBs will not be interchangeable with the innovator product. So the FOB manufacturer will have to market to doctors in order to get them to write the script with their product's name rather than the innovator product's name.

Peter Wittner • I am wondering how important it is to take into account all the latest patents that Ronald described as the "unavoidable (must have) processing technologies". Why are they "must haves" if the idea here is to produce a Biosimilar rather than a 100% identical clone? As Bruce points out they are rarely going to be interchangeable in regulated markets so why bother trying to go for a 100% identical copy?

Ronald A. Rader • I was referring to what is essentially purposeful, accelerated "product drift" for the sake of confounding biosimilars development. As biosimilars start to enter later-stage development, but before applications are filed, a reference product manufacturer can modify its process (product) with unique technology unavailable to others such that the new reference product remains the same (for regulatory purposes; receives a sBLA, which will likely involve proving comparability in trials), but now has unique, difficult-to-reproduce-without-needed-specific-technology molecular or other modifications -- enough to make biosimilar development difficult or impossible.

An example of a "must-have" (must license) technology might be a glycosylation enzyme either added or co-expressed such that a unique reference product glycosylation pattern results, but with similar enough active agent such that a sBLA is granted (with comparabilty trials, if needed), and with the resulting modified active agent having unique enough glycosylation such that no one can closely match this (without using ref. product company enzyme patents and/or its exclusively licensed enzyme technology). Biosimilar developers encountering non-reproducible structures in active agents will have considerable difficulties; and, minimally, will have to waste a lot of effort trying to show that these unique structures are not needed for biosimilarity. Other biosimilar developers may simply give up when encountering difficulties copying a product. [Keep in mind recent Genzyme experience, with even the same company unable to reproduce glycosylation patterns, with a new, full BLA filing required for the 'same' product manufactured in a new facility at larger scale. So, glycosylation patterns matter a lot, even if not proven to affect safety or efficacy].

Yali Friedman Nice to see old friends in this thread. The best resource I know of for biologic patents is his database at www.biopharma.com

Vijayakannan RamachandranIt would be nice if FDA publishes same patent monitoring system like Orange book patent (small molecules) for BLA to estimate the patent life of launched products. For the BLAs, where the structures can be elucidated by chemical means or have definite molecule structures (Mol Wt) should be followed the path of small molecule.

What do you think about re source doc cross-check - without on-site MVs?

2011-06-23T10:44:00.006-04:00

This question is from Linked in group:

Virtual trials and GCP: As Pfizer announced a few days ago, it started the ‘virtual’ trial,
http://www.outsourcing-pharma.com/Clinical-Development/Pfizer-begins-virtual-trial-and-calls-for-innovation-in-research

Pfizer has begun what it claims is the world’s first ‘virtual’ trial and says that such innovation is needed to make sure clinical research is sustainable.

The REMOTE trial, which is designed to assess Pfizer’s drug Detrol LA as a treatment for overactive bladder (OAB), uses mobile phone and web tech to record data from participants remotely rather than at clinics.

Pfizer spokesman Andrew Widger told Outsourcing-pharma.com that, if successful, the participatory patient-centred (PPC) model could offer considerable financial benefits.

“One significant area will be a decrease in the cost of monitoring visits, which can represent as much as 50-75 per cent of a study budget.

“Another significant cost factor for clinical trials is the set up cost for actual trial sites and the maintenance cost for sites that are recruiting no or very few patients. Again the single site concept may reduce these costs significantly.”

Commented as follows by:

Amanda Grim • Pfizer is getting it's feet wet in what is probably a phase 4 study of Detrol, a marketed drug with a presumably good safety profile. Manufacturers of these reporting devices for patients have been pushing for this type of virtual reporting since at least the 1990s.

Aliya Arinova • Thank you, Amanda. If so, the discussed info is obviously incomplete. Indeed, this is the last 2 years' trend of using the communication channels other than on-site monitoring visits, mostly in observational, registry studies. But even in such projects, there's an issue of data validation via SD cross-check. Without saying of the studies with actively administered IP.
I wonder, how will things develop further and how this issues will be resolved...

Shirley Isbill • I'm not sure how FDA will manage the problem of not being able to conduct source data verification for these studies since there will be no data source to compare to CRF data. FDA already allows direct data entry to CRFs even though the CRF data can not be compared to any other source data to verify that it is complete and accurate. If Pfizer is controlling the original source data, there is the potential for data manipulation that will be extremely difficult to detect. I'm interested in what data, if any, the study sites will maintain for review by FDA investigators.

Lynda Cedar • I agree on the difficulty of controlling and verifying the original source data, I doubt that the FDA opinion would differ. Visual scale data and measurement are very difficult to asses even for clinical studies occuring on-site!!!!
It is indeed an experience to follow and learn from.... thank you for sharing.

Richard Malloy, MS, RRT, MRQA • I would more than yawn, which is what I did when I read this release, if it were a non-approved, GCP trial. this is simply fluff. Means nada, costs about the same I guess, and the results are for salespeople to use. Nuff said. Call me when they wanna do this on a Phase II or III trial. As awlays...rich

Francois Peterlongo • This experiment might very well be the begining of a new approach in "how we assure data are true". If the cost cuts are really significant, we can be sure this new approach will be strongly pushed.

Actually it means that we should get out of the current paradigm, where the proof of accuracy of study data is entirely based on their consistency with source data. We all know this is not a absolute "proof", but this was the best we had. Now the paradigm would become : if the data originates directly from the patients, then they are the best possible estimates of the study endpoints. (of course this applies to endpoints that can be assessed by patients).

It looks like regulatory authorities, especially FDA, already supports such vision, as suggested by its strong support to (e)PRO.

In this new paradigm, the main focus of GCP quality system would no longer be to ensure consistency source data ->CRF data, but to provide assurance that no alteration can occur in the processing of patients' provided data to final database.

Grzegorz Rychlik • Pfizer's experiment shows further exploration of new (cheaper) assessment methodology in specific data collection areas. From the press release which was quated it is rather difficult to draw conclusion beyond the fact that exploration of such tools takes place.
Thanks for sharing the info and alerting about this interesting development.

Richard Malloy, MS, RRT, MRQA • Au contraire, I see little evidence that the Food & Drug Administration (FDA) is ready to accept a whole lot of wholesale change. I think they are willing to venture in to the 20th Century computer revolution, slowly to be sure, but things like remote source document verification and no or lesser-monitored trials, I do not think the agency is there yet. AS WELL IT SHOULD NEVER BE! ANYONE WHO BELIEVES PHARMA WILL PLAY THE GAME BY AN HONOR CODE - well let me talk to you about real estate investments. The agency is well aware that 80% of us (Pharma) will abide by rules, whether we are audited or not but likewise, 20% of us will try like hell to break every rule to save a Euro or a Dollar. What Pfizer does, with a marketing, Phase IV trial, is irrelevant to me. I do not think they would get a Peer-reviewed publication to publish their results and I doubt an agency would alter their label, predicated on this study. Let us calmly wait and see. Cheers my associates and friends!! … rich

Aliya Arinova • Thank you, my dear colleagues, for sharing your view. I'd like to continue the deliberations further:

I feel that the trend is to gain the SD reliability by making them totally electronic. In this case only, if I get it right, the data exchange between the SD DB & e-CRF could be trully valuable and efficient. I suppose (provided the regulations are met) this is quite doable technically.

This can happen very soon in Western countries. As to Eastern Europe, Russia, China, India - this is still a long way to get it, I'm afraid.

Would it mean that the countries above will be put "on-hold" just because the cost of the "alive" monitoring will be more and more undesirable? Will this "electronization" affect the clinical trials market there in the nearest future?

James Wheatley • My concerns with this type of data collection are the following. First, the subjects are not trained in clinical research and therefore may not have a full understanding of what should be reported & what procedures should be followed. Second, without any visits subjects may forget their instructions. Quality study visits are also a great way to capture data not previously reported and to clarify any discrepancies in self reported data.

In regards to SDV, this design is reminiscent of diary studies. Since the data is directly entered, there will be no transcription errors. However, common problems I've seen in diary studies are subjects not completing the diary correctly, not fully understanding their instructions, and not capturing all pertinent information (i.e. AEs). This is why I stress for study coordinators to review their subjects' diaries at every visit. It may take 10 minutes but can save us hours.

I agree that there must be better ways to perform the different aspects of clinical research, but I don't think that reducing data verification is one of them.

Aliya Arinova • I agree completely with Francois - obviously, GCP would have to be up-dated, provided the discussed trend becomes a routine.

Aliya Arinova • James, you're absolutely right and Iagree with you completely.
To make subjects enter the information correctly, CRO or Sponsor should probably provide them with the home mini-office and smartphones...to let them fax, email, etc documents (including diaries) to the monitor/CRA and to ensure in this way the real data monitoring...
I wonder whether this will be less expensive than on-site monitoring....

Francois Peterlongo • I just found more details on this trial at
http://blog.pharmexec.com/2011/06/14/pfizer-asks-patients-to-test-themselves/

Jodi Macko RN, BSN • Ok...I'm confused. Subjects are as likely to fail to report important details during office visits as they are in diaries. Are we talking about eliminating subject visits to the site or eliminating routine monitoring visits? Eliminating Investigator oversight is an entirely different animal. If we are speaking of direct data entry, I think on-site monitoring may not be necessary. We have audit trails to ensure accountabiliy, do we not? I don't think doing away with source docs would eliminate the need for monitors. Someone needs to cross check patient entries with clinic notes, lab results, medical histories, PEs, AE evals., etc. I am one monitor who would be perfectly happy to give up traveling if I could do everything remotely. Am I missing something?

Deborah Hill-Williams • What about patient safety and rights? If safety data changes how will this be conveyed to patients and how will re-consenting take place? How will the validity of patients being real people be confirmed? If the source is not written, it doesn’t exist. If the original copy of a consent form is not reviewed by a CRA then patient agreement to participate cannot be proven. The consenting process must be documented on the source and verified per federal code. The data and monitoring systems we use now evolved for very good reasons; their not broken, and yes it takes time and money to set-up a database and to verify the data. The process being discussed has great potential for fraud and error. Good research holds up to validation and without cross checks between a database and a real source we risk demoting clinical research to the level of mythology.

Pucci Andrea • Actually, it is not so clear what Pfizer is going to do (few details).
Anyway, I agree with Amanda Grim: this "virtual trial" seems not to be so innovative.
Instead, I see a lot of problems such as following the current Infomed Consent procedure, assuring patients rights and safety as Deborah Hill-Williams claimed, training patients on how to use the smartphone diary app, shipping the drug not to an authorized Pharmacy but to patients' houses, assuring that the data inserted by the patients with the app are the same that are recorded on the clinical DB (validation), managing the Site TMF, and so on.
...less expensive? Maybe but this is not the point and do not forget what Aliya Arinova said: "....without saying of the studies with actively administered.

Shirley Isbill • Pfizer's study involves an already approved/marketed drug. I want to see how a pivotal trial for a new drug is handled by FDA and the study sponsor. It would be interesting if the Pfizer virtual study showed the drug to be less effective than the study on which approval was based.

Phyllis Kent • Shirley, I doubt we would ever hear about it! Monitoring has been eliminated in Phase IV paper trials for years. The paper CRFs were simply mailed in to the sponsor. As stated above, these are not early phase trials upon which the approvals are based. Other cases of direct subject reporting have been used for at least 15 years...the phone monitoring of pacemakers, for example. Consumer preference polling is done in shopping malls...no monitors...used for marketing.

The point presented by Aliyah regarding electronic transfer from source to database is very complex. If the only source available is collected for the study, then a direct transfer would work and eliminate on site monitoring of the source. But there are all of the other aspects of monitoring that would still need to be performed live. However most studies involve patients with medical history and concurrent events and medications. These would need to be recorded in their medical record in addition to a source document for the study, thus calling for SDV.

In my opinion, electronic data capture has added time to monitoring, not reduced it. More training, problem solving, more technical glitches, multiple computer systems to work with which are different at every site and still cross checking with paper sources. If the site uses a source worksheet to collect data, you have doubled the SDV time as now you have to check that versus both the medical records and the eCRF.

We have a long way to go to eliminate monitoring as we know it.

Lynda Cedar • That's completely right.... FDA and sites are not there yet...the procedures have to be put in place first, then the training .... and perhaps we can go into that way of monitoring.... otherwise it is just a mess and wasting of time.

Jodi Macko RN, BSN • All great points. I agree there will always (that's a strong word) be a need for monitors. Legalities, ethics and data integrity depend on us; however, innovation must be a part of research as well. Perhaps we are underestimating the power of our ever improving technologies. I can turn the camera around on my iPhone and talk face to face with my husband while traveling. I can electronically upload scanned legal documents to the TMF. If two people witness someone on camera holding up their drivers license, maybe we have a positive ID. I never see subjects when I monitor but a copy of a picture ID is sufficient. It will be challenging and a royal pain working through the glitches, but does that mean we should stop exploring? Material resources, like jet fuel, are in short supply. Perhaps it would be irresponsible of us not to pursue alternatives to on-site monitoring or at least reduce it. I'm sure participants would appreciate fewer visits as well. Maybe subject compliance would be less of an issue, too. Thanks for some great discussion!

Dr. Socorrina Colaco • And What about the exposure to Radiations linked with the usage of mobile phones.....
especially if the trial is of longer duration..it may encourage the subjects to sue the company....

Aliya Arinova • Wow! Great comments - thank you,peers!
I liked Jodi's view - anyway, we won't avoid the technology breakthrough. We just already have and sure will have to do with it, let them into our routine - just as we do right now, using more and more sophisticated devices and gadgets. Hopefully they will be more safe (vs. what's people are concerned about cell phones and smartphones currently).

Finally, the only "almost 100%" proof of real person identity is the retina image (which also can be faked, as we know from blockbusters :o))...

Won't be surprised if very soon we're be provided with portable RI scanners...

But unless this happens, the issue of evidentiary base remains quite actual.

Etanercept and quality attributes changes .... do you think this will create an impact, certainly an important finding !!!

2011-06-17T10:44:00.004-04:00

From Linked in group (Biosimilars). The question is asked and responded as follows:

Quality changes in commercially available etanercept (Enbrel) were found by Sandoz researchers over a period of time. Since the drug remained on the market with an unchanged label, this would indicate that the changes were accepted by the health authorities.
The research analysed multiple commercial batches of the glycosylated recombinant therapeutic protein etanercept (Enbrel) which were available on the EU and US markets.
Glycan mapping and caution exchange chromatography were used in order to study the glycans and different acid/basic variants present in the molecule.
Results showed highly consistent quality attributes for batches expiring before the end of 2009. From 2010 onwards batches with a different quality profile appeared in parallel to the original version.
Major differences were found in the glycosylation profile and in the amount of basic variants present in the molecule. Variants containing N-glycan G2F decreased from 50% to 30% and C-terminal lysine increased from 15% to 30%.
This seems to be good news for biosimilars – which are trying to prove ‘similarity’. Since, if the originators themselves can show such variation in quality attributes, then biosimilars may find it easier to prove ‘similarity’ than may have been thought.
Subhra Lahiri • Yes the findings will be having a very big impact of future licensing . When innovator is having variation from batch to batch , then the regulators of would be biosimilar should stress on " Upto what degree of biosimilarity is acceptable".

Rajiv Dua • Health authorities are of the opinion that changes in quality attributes are only acceptable if they do not change the safety and efficacy. But this seems to be based more on a principle than on scientific fact.

Subhra Lahiri • Hi Rajiv - What extent of changes in Quality attributes are acceptable - this is a critical point to understand . Saftey and efficacy is totally based on Quality attributes - then how you will judge ?

Lynda Cedar • The issue for Subsequent-entry-biologics (biosimilars) is not the efficacy but the safety. After has been put on the market, sponsor does not have to demonstrate again the similarity if it has changed since the approval.

If the safety or the efficacy become compromised, I guess the authorities would proceed as applicable in such case.

Hareesh Parandhaman • Thanks Rajiv and Subhra for the comments.

Lynda - that's a nice point u made w.r.t. safety. However, the discussion here is around acceptability in "batch to batch" variations and flexibility from a Regulator perspective. Here, the report claims almost doubling 915 o 30%) or halving (50 to 30%) of the variants ...which is significant. It goes w/o saying that is these variations can lead to safety issues, then the Regulator would come in strongly (whether it is the Innovator or a follow-on)!

Rajiv Dua • I totally agree with Subhra and Hareesh Sir… Safety and efficacy is totally based on Quality attributes, if the variation is too high then the regulator need to take action …because it can have a impact on safety..but in some cases the variation in batch does not harm clinical safety or efficacy …To evaluate such changes , a comparability exercise need to done between the pre- and post-change product, which is focused on the quality level and sometimes, depending on the magnitude of the change and the existing product understanding, also requires comparative data on the preclinical and clinical levels.

As Well as demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product.

Peter Gaskin, BSc (Hons), PhD, ERT, MTOPRA • Interesting results and as you say some potentially good news for biosimilars. Whether or not this information does prove to be beneficial for biosimilars will in the end depend on what happens when the safety data is placed alongside the quality information so that it is clear if there has been any detrimental effect or not.

Lynda Cedar • @ Hareesh, I meant that Health Canada is ahead with its guidance, it covers HC appraoch / position related to the biosimilars, before and after the similarity has been proved.
The guidance is flexible enough, I don't think that it would change soon , and actually, there is no reason to do so, as most of the time the questions stay not answered....It just reflects that sponsors who want to develop biosimilars should have a multi-disciplinary team to be able to take the appropriate decisions...

Thank you for sharing. Lynda.

Hareesh Parandhaman • @Lynda - cant agree more with you. Not every sponsor that attempts will make it past the finish line ...this is a MARATHON !

Eszter Birck-Wilson • Hi Haresh,
could you share with us where this important information is coming from? Any publications available? It would be great to have access to it.
Thanks and kind regards,
Eszter

Lynda Cedar • @Hareesh - ... all what I said is in the guidance. If you want a copy please let me know.

Hareesh Parandhaman • @ Ezter - unfortunately, LI does not allow us to paste http links here. Plz write to me and will send you the article.

@Lynda - is this a product specific guidance, if yes then please send it to hareeshcp@gmail.com

Satakarni Makkapati • I read the article and I agree to an extent that such variability shown within Enbrel lots is some good news for biosimilars manufacturers. However as a counter argument -- this highlights the significance of having a good control over the process and being able to characterize the process well in the extended design space. I have been a firm believer of the notion that only companies that can build scientific rigor into their product development can sustain in biosimilars space and not all companies that stated early can hope for dominating the terrain. This is especially true for Asian companies, who enter clinical phase even before they understand the molecule enough. The results discussed in this article must be a good wake up call to set ups developing biosimilars !!

Lynda Cedar • @Hareesh : It is about Health Canada guidance for subsequent entry biologics (the process submission and approval. Please find it at the following link and I'm send it to you by email too.
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/seb-pbu/seb-pbu-2010-eng.pdf

sunit maity • I see here taht we are only discussing about Enbrel. The document does cover not only Enbrel but also NESP and Rituxan. Every originator product has batch to batch variation and it is not a small variation, these are major change.
There are many points one need to consider here..................
1. Did originator company submit the data to regulator of these changes?
2. What was the view point of Regulator
3. If not, then it is a serious concern............because the batch release criterion is changing every time...........
Problem here is also for biosimilar company....
1. Because if you have to show analytical comparibility, then which innovator to choose..........
This paper has opened up a very interesting discussion though..........I guess SANDOZ is preparing their entry for these biosimilars

Lynda Cedar • Agree with you Sunit. This is almost all about it, the originator company does not disclose all the information (per say in details) of the process. This brought the reg. agencies to adopt the concept ''Process is the Product" . Yes the batch to batch varialibility is a major issue.
In Canada, the guidance posted above says the biosimilar company is responsible of selecting the reference and the process to develop the biosimilar. Originator companies are not obliged to disclose the infrmation that is not in the patents.

Subhra Lahiri • Lynda - That's great in Canada that Biosimilar company will pick up the reference . If the same will be accepted in the other part of the globe ? I know in India it is the only innovator and Indian RegulatoryAuthority has constituted a group for it . Lets thegroup member send the the info to the regulators in India.

sunit maity • Lynda and others, I have another query to everybody..............now we have understood that Innovator companies can produce the material with complete different analytical specification but then how the biosimilar companies will fix the specification. What is the limit? take for example we all knew that intensity of darbepoetin isoforms decreases (very well mentioned in all the literature)...but the SANDOZ paper has thrown that out of the window. So what will be the limit.....it has to be so broad then............

Another thought, what if Innovator companies have modified the amino acid sequence without altering the tertiary structure of molecule also...then what?

Gillian Woollett • All:
Please see "Worldwide Experience with Biosimilar Development" in mAbs, March/April2011 (an open access paper at http://www.landesbioscience.com/journals/mabs/article/15005/ ) that Mark McCamish of Sandoz and I published this Spring that discusses exactly this issue, and how to use the variation in the reference products specifications, as determined by the biosimilar sponsor, as the basis of the design space for their biosimilar. All comments most welcome.

Hareesh Parandhaman • @Gillian - gr8 article and timely in terms of publishing it. I liked in particular the emphasis laid on physico chemical characterization and inter-relationship between sound process development and analytics. In my experience this is where most companies need to invest time and efforts and not be in a hurry to get to the market ..... this is essentially the Qbd philosophy that regulators have been preaching.

Ronald A. Rader • These and other biosimilar targets were originally developed and approved decades ago. Can anyone comment on the extent to which these now-legacy approvals might be loose or ill-defined (using current technology) enough to allow the extent of variations reported here?

Have other biopharmaceutical product lot-to-lot comparisons have been published? Anyone have a list? Do other studies show comparable variability between lots and over time?

How do the reported lot variations compare to those encountered by Genzyme, with FDA requiring a full BLA for "the same" product but with its processing scaled-up (and changed enough to affect glycoform patterns) at a new facility?

Rather than this seeming good for biosimilars, the variations reported (approved?) may simply reflect FDA not having the resources it needs to keep up with changes in every product or otherwise failing. Should FDA be doing more of its own in-house lot release testing, rather than relying on sponsors?

Hareesh Parandhaman • @ Ronald - you made a good point about these legacy products being developed decades ago.However, the technology for development and analytics used will be that of today .... this is the plain truth.

To your second point, I strongly believe that more and more companies will be purchasing different lots of respective Innovator products and in the time to come, we shall see more and more of such publications.

On your last comment, while the Regulator may create certain in-house capability, they may not do it all themselves. For example, if in the next couple of years if there are 5 companies filing for Etanercept and for most (if not all) have performed the above exercise and the concordant results from each of them shall speak for themself. There will be no need for any Regulator to "re-do" all of this.

Thank you for the post and enriching this discussion ! Hareesh.

Paul Declerck • @all,
bath to batch variations is a well-known phenomenon and that is why the setting of limits of specifications is very important. Changes in one or more quality attributes subsequent to process changes is a concern that exists much before biosimilars were introduced and, to my opinion the current observations/publications are 'neutral' with respect to the position of biosimilars. On the contrary, it demonstrates that, potentially, on a long term 'biosimilarity' between two products may disappear. On its turn this adds to the fact that biological products cannot be considered interchangeable and that switching should be avoided.
In this same context I would also like to stress that the (regulatory) acceptance of changes in quality attributes after introduction of a process change of an approved product is considered on a case-to-case basis. And, importantly that one should always look at the type of process change and at the impact on all quality attributes, not just one or two !

Ronald A. Rader • Regarding Hareesh's statement:
"However, the technology for development and analytics used will be that of today .... this is the plain truth." To me, this implies that all analytical methods used for product specifications/release are kept fairly up-to-date/state-of-the-art.

But can and does FDA force BLA holders to update and change their product testing, specifications and or other CMC aspects simply to keep these current, with this perhaps involving substantial changes in the process and product, e.g., requiring filing a sBLA and maybe even relaunch of the new/updated product? Or restated, if a product is approved, marketed and not showing any significant safety problems, does FDA require updating of CMC aspects, e.g., development or adoption of new reference standards, adoption of new/improved analytical methods, even process changes -- simply to keep things more in line with the current state-of-the-art? [Off-hand, I don't think it does or can do this].

I recall starting in the 1980s FDA issuing regulations requiring plasma derivative manufacturers to implement a series of improved viral inactivation methods after the HIV epidemic became apparent. But are there precedents involving single, specific products where, lacking any ongoing safety problems, the agency has on its own contacted license holders and forced manufacturing processes or other CMC aspects to be substantially altered?

Gillian Woollett • Bottom line is that a biosimilar can be as similar to its reference originator biologic as that biologic is to itself over its lifetime IF comparability is the standard used for all biologics.

Big question though is that for a manufacturing change to ones own product, comparability is the interchangeability standard as the label does not change, whereas for a biosimilar it is not clear how to demonstrate that switching between originator will not somehow create a safety or efficacy issue (required in BPCIA - although studies per se are not required). As an immunologist by training I do not even know of a theoretical basis for that presumed problem, but it is a burden put on biosimilar sponsors that is not currently put on any sponsor (originator or biosimilar) when making a manufacturing change (and to prove a negative to boot).

And to Ron's point, comparability is getting harder, and while FDA does not require updating routinely (beyond cGMPs etc.) the moment you ask for any change, you do open up the books to anything they see as needed whether related to that change or not.

Lynda Cedar • Gillian, I agree on what you are saying but what is the alternative / solution proposed to biosimilar sponsors or other decision makers involved in the product development, approval, interchangeability, liability, etc....

In Canada (1): if the change is related to the GMPs implementation and operations, the sponsor is requested to contact the regulatory agency (HC) to validate its licence issued for manufacturing clinical lots. (2) if the change happens to the biosimilar (subsequent-entry-biologic) after it has been approved, the sponsor is not requested to demonstrate again the similarity as the SEB was approved as a new product, and HC considers it as such. There is nothing in the guidance so far that talks about (2).

Gillian Woollett • Lynda: I am not sure that I understand the question.
I would agree that post approval each product is standalone and comparable only to itself. If the process is well controlled I don't think drift is a big issue - only acceptable differences are in marketed products. Even if differences are real, as long as they don't affect clinical outcomes they simply become less relevant parameters. Knowing which is which ahead of time is tough of course. But we do have a lot of experience collectively with comparability, especially with the older, commercially-successful products to which biosimilars will be made.

So what I am saying is that if a biosimilar sponsor can show their candidate to be highly similar/comparable analytically they should have a significantly reduced preclinical and clinical burden , just like comparability for manufacturing changes (and to an earlier point Genzyme simply showed that comparablity is an extremely high standard).

AND THEN the big debate for the US is whether the biosimilar can be interchangeable with its reference without cumbersome and expensive switching studies. Afterall could you ever fail those studies and not simply have shown you were not biosimilar all along? And if this ill-defined and entirely hypothetical immunogenicity risk is real, why are we not doing such studies today when a sponsor undertakes their own manufacturing change (for a originator or biosimilar product).

Also, if the only issue is switching aren't all single use biosimilars automatically interchangeable with their reference originator from day one of their approval?

So I am not saying comparability is ever easy for anyone, but I am saying good for the goose is good for the gander. Plus makes implementation completely straightforward in every highly regulated market that has comparability - indeed every product on which comparabilty has been used is clearly available, self-evidently, as a reference product for a biosimilar.

Paul Declerck • 1.I would like to stress (again) that a process change is not to be compared to setting up independently a totally new process. Please take into account the particular properties/characteristics of the entire process in the production of a biological. So for the sake of scientific correctness we should never use any argument based on 'manufacturing process changes' to deduce anything regarding the status of biosimilars.

2.Switching between biologicals, in the abscence of any expected clinical benefit for the patient, is in general considered to potentially result in an increased unnecessary risks such as immunogenicity. So the benifit/risk ratio is negative.

3.Suppose one does a (long term) study to demonstrate that a switch from reference to biosimilar A appears to be safe, this does not show yet that the reverse switch is also safe and, more importantly, it will not at all provide information whether or not regular switching between these two products is safe. In addition we should also realize that we have different biosimilars compared to the same reference. So what might be proven for reference versus biosimilar A with respect to switching can never be extrapolated for reference versus biosimilar B and also not for biosimilar A versus biosimilar B.

4.To my personal opinion it is clear today that it is not warranted to claiming interchangeability and suggesting that switching between innovator and biosimilar (in any direction) or between biosimilars does not imply concerns.

Lynda Cedar • Gillian: How do I disagree on what you are saying as you are summarising the issues surrounding the biosimilars!!!....

I know you have experience about biosimilars and I thank you for sharing it. Regarding the clinical development of biosimilars, comparability is just part of it. The product due diligence determine the rigft proposal and design .... that's the meaning of taking biosimilars development case per case.

Regarding the 2nd and 3rd paragraphs of your comments: Health Canada made it clear in the guidance, the pharmacovigilance and risk management plans are part of the evaluation. The total safety cannot be demonstrated during the clinical development. This is the case of products approved as new (which the case of subsequent-entry-biologics).
Also, in HC guidance a section has been reserved to the reference selection.

The debate about biosimilars is a concern for all the stakeholders, all are like stuck in a one-way drive without exit.

Gillian Woollett • lynda: Agree with so much of what you say, although the majority of my experience is with originator biologics - especially given that we developed comparability as a concept with the FDA when I was at PhRMA in the mid 1990's.

This debate has been made so unecessarily complicated (and rhetorical). Much more that it needs to have been if we believe in our science and agree that it is universal (and even global!).

My fundamental point is that standards can be consistent, but data is ALWAYS case by case.

And I agree it is the entirety of any application (and post market commitments) that is the basis of an approval for ANY product, including ALL biologics.

Paul: Stress as much as you would like, but please add reasons too. Please outline the immunological basis of any switching being a problem (originator batches or biosimilars with originators). I know of no even theoretical model and I am most willing to learn. The only immunological problem is any one product precipitating an adverse reaction due to immunogenecity with clinical consequences. Switching per se is not a cause, although repeat dose with a "bad" product will exacerbate the situation. Plus, how is this any different from a product that has become immunogenic as the result of a manufacturing change (the oft-cited example being Eprex in Europe - nothing to do with switching). After all we routinely switch between different batches of an originator product and if my contention on standards is supported and implemented in the US as it is in the EU that is the same thing. Indeed my logic says that switching may reduce the opportunities for multiple doses with the "bad" product and so help improve safety!

All: I know of no problems that have been caused by switching between different pre and post manufacturing change batches of originator biologics, or in Europe between originators and biosimilars. Can anyone on this list cite even one?

Hareesh Parandhaman • @Gillian/Lynda/Paul - you have all made gr8 points.

@All -If we all agree with the fact that a manufacturing process change can create a structural difference and therefore could cause unknown immunogenic problems. For such changes in the past, the regulator has not emphasized CT's. However, when it comes to Biosimilars the whole argument has been so extensively complicated and at a point, one really wonders as to how much of a cost difference can a biosimilar offer to the patient, given this load of expensive "clinical development" .....!!!

So, I agree with Gillian's view that if standards exist/under development, they need to apply uniformly to one and all !!!

Interchangeability - does anyone have views on designing comparative clinical trials with a forward switch and a reverse switch between the Reference product & the Biosimilar under evaluation and would such data then make a strong case for Interchangeability ....???

Gillian Woollett • I can only say that comparability is our current, used every day, interchangeability standard, and it very very strongly focuses on analytics - back to Janet Woodcock's testimony of less than 1/50 to 1/100 comparability protocols require any preclinical or clinical studies at all.

Note the BPCIA does NOT require clinical studies to resolve switching, but sets up the interesting requirement to prove a negative of:
"for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alteration or switch"

Is this even do-able? And that is not a philosphy of science trick question.

And of course the burden is on the biosimilar sponsor, whether it is do-able or not.

And my biggest worry is the loss of comparability options for all sponsors, irrespective of their business model.

Lynda Cedar • Since 1990, the EMA changed/adjusted its guidance few times. Health Canada was involved by the topic too but the interchangeability changed the discussions very quickly. In Canada, each province has its law and definition of interchangeability and substitutability.... the fact is well reflected in HC guidance.

Similar does mean identical, therefore, because of the nature of biologics, the clinical development cannot be standard, the comparability is just part of the process, for some products (biosimilars), pre-clinical and even clinical studies might be required. I find Health Canada flexible and consitent as it considers a biosimilar as a new product, and allows the sponsor to propose any plan of development. Comparability might interesting to present when enough accumulated data are available.

In my opinion, it is critical to do a full due diligence of the biologic, to determine the best strategy for its biosimilar generation.
Thank you for sharing.

Gillian Woollett • Scientifically, nothing is identical, not even generic drugs, but legally they have been interpreted that way because of the ability to determine pharmaceutical equivalence. Scientifically the only "sameness" applies only to the criteria measured, and there is no perfect knowledge for any product. HEnce, the need for risk:benefit, and even that is in the context of a population and not he individual. An impoerfect system but the best we have.

Hence my argument for consistency in standards. And why I am careful to say that a biosimilar will be as similar to its reference originator product, as that originator is to itself over its lifetime IF comparability is the standard applied to all biologics. And in the US, as elsewhere comparability for manufacturing changes is the interchangeability standard as the label does not change. And indeed if comparability is the standard, ALL the originator data as represented by its label is relevant and therefore the biosimilar will be as safe, and as pure, and as potent as its reference.

As to who decides, I would suggest it has to be the competent authority who sees the data, and in the US that has to be the FDA.

I agree that it is always critical to be diligent, but it is also crucial to be consistent and dare I say, fair. Patients should expect no less.

Lynda Cedar • Gillian: we are saying the same in different words I think ... we can continue to dig and dig but all technical / scientific input was brought by different members contributing to this discussion.

Once again, I agree on that the last decision of approving any product (evaluating the data, submission, etc. ) belongs to the competent authorities, always and worldwide (not just in the US).
The concern of stakeholders about biosimilars is not the efficiency but the safety; all agreed on that the patient safety must always remain the highest priority.

Gillian Woollett • Lynda - I think we are agreeing too. Although I think you may have meant efficacy (or in the US for PHS Act biologics we say potency)

The critical point on safety is that the entire safety data base of the originator reference product is as relevant to the biosimilar, as it is to that originator product itself subsequent to its last manufacturing change using comparability, if we use comparability as the standard (even if we call it highly similar quality attributes) in all settings.

To me comparability is actually a very high and challenging standard, and we had better believe in it and defend it on scientific terms as an originator industry, even more than as a biosimilar industry. And the same for global regulators who buy into ICH Q5E.

And all these decision have been made by the FDA before, even for separate sponsors, in the context of FD&CA biologic drugs approved as 505(b)(2)s or 505(j)s [ANDA] - with 8 of the former and 2 of the latter.

Lynda Cedar • That's fine.... the entire world is looking toward the US-FDA...
Thank you for sharing and please stay in touch.

Nathaniel Lipkus • This has been a great discussion to follow. Thanks to Gillian, Lynda and everyone else for your efforts.

Hareesh Parandhaman • Cant agree more Nathaniel .......

Lynda Cedar • Thank you Nathaniel for closing the discussion nicely.

Lynda Cedar • If a bio similar product has the same glycosylation pattern but differs in the percentage of glycoforms when compared with the innovator molecule, is this acceptable?
If yes what is the range of acceptable variation?

GOPALKRISHNA LAKKIREDDY • Hareesh, Just to add a comment..

We found these changes in glycosylation pattern of Enbrel. In the process of further evaluation, we found that the initial batches had more of complete i.e., more sialylated and processed glycoforms where as later batches of Enbrel had less sialylated i.e., less processed glycoforms. May be this was due to the change in the manufacturing site of Enbrel???
Secondly, in case of Enbrel the glycoprofile is not directly effects the activity where as if such a change in glycoprofile of products like Rituximab could have been unacceptable.
The range of quality profiles I see with in the innovator molecule help me in fixing quality criteria of biosimilars especially quality attributes like glycosylation (as there is no established pharmacopeial guidelines for most of the molecules). This batch to batch variation in innovator molecule gives a lot of cushion for biosimilar manufacturers.

Thanks,
Gopal

Subhra Lahiri • Hi Gopal: A few queries - 1. Whether your change of site is within India ? 2. Whether infrastructure is completely different ? 3. Whether the changes in Sialaytion or glycoforms were in acceptable range?

Thanks
Lahiri

GOPALKRISHNA LAKKIREDDY • Hi
Manufacturing site of Enbrel is not in India its about the Amgen facility in the USA. I am not sure about the infrastructure of the Amgens facilities but my understanding is the new site has larger capacity.

In terms of 'acceptable' changes in Enbrel glycosylation pattern, as I said earlier Enbrel glycosylation pattern does not effect the activity directly but can effect the residence time in human body. Because the molecule is still marketed, I guess, Amgen must have captured the change in their post-marketing surveillance, so may be it is in the acceptable limits.

I hope, I answered part of the question if not full.

Thanks
Gopal

Paul Declerck • as commented before: pre- versus post-manufacturing change differences should not be compared/extrapolated to reference versus biosimilar differences!

- a manufacturing change implies only a limited change one are limited number of steps in the entire process whereas a biosimilar is developed totally independent.

- to decide on the acceptability of differences one should not focus on a single quality attribute evaluated only in the final drug product but one should take into account all parameters that are being evaluated in all steps of the entire process.

- let 's also be reminded that the relevance of observed differences will always have to be considered on a case-by-case basis.

Ronald A. Rader • What might have caused the changes observed between batches? Might Amgen have switched-in new upgrades, such as a higher yield CHO host cell line; switched culture media, such as to animal-free media (with etanercept originally, e.g., in its FDA SBA, reported as using animal product-containing media); or maybe just changed its source for say BSA or another media supplement; or changed to more productive vectors, promoters, etc.? Or is there simply too little publicly known about the product's actual manufacture and/or about changes in manufacturing at commercial scale to even be able to speculate on the causes for observed changes?

Or contrary to one comment about this involving Amgen's main CA facility, might different manufacturing facilities actually be involved? Surely, Enbrel for the U.S. and other major markets is manufactured at multiple facilities, or at least multiple facilities currently hold sBLA approvals for its manufacture. I would consider Amgen negligent, if for such a blockbuster it did not have multiple manufacturing sites either actively making the same product or preapproved and ready to be adapted to etanercept manufacture. For example, wasn't etanercept originally manufactured for Immunex (before acquisition by Amgen) by a CMO, Boehringer Ingelheim; post-acquisition Amgen obviously switched to primarily its own in-house CA manufacturing; in 2002 (back when there were dire fears about a worldwide mammalian cell culture capacity crunch), Amgen arranged for manufacture by Genentech (which dedicated 2 x 12,000 L bioreactors); Amgen received supplemental approval for West Greeenwich, RI, manufacture in 2005; and of course, Wyeth/Pfizer has its own manufacturing facilities for its licensed international markets, which could be approved for manufacture of comparable product to Amgen. So there are likely multiple facilities actively manufacturing comparable product. Does the product's labeling, such as lot numbers, contain public decipherable information about the manufacturing site?

What approvals (if any) are required for Sponsor to observe subject undergoing study procedure.

2011-05-19T12:59:00.002-04:00

The following question is brought from Linked in GCP group:

Both PI and SSC obtained verbal approval from pt for Sponsor staff to observe the administration of study drug. Do you need to obatin Ethics Committe approval for the sponsor presence. Some feel that the presence of the Sponsor may be seen as coercive i.e. subject feels compelled to continue treatment as the sponsor is present.
I would be interested to hear what people think.

Jim Sheets • Interesting. With the public's increased suspicions of the Investigator/Sponsor relationship, I would think it would cause a subject to consider discontinuing treatment.

Lynda Cedar • By the study protocole, the sponsor and/or his representative (monitor) has all rights to be present during any step of the study. He has however to notify the site.
In my practice, as soon as the CTRA is signed and the study is confirmed, we ask the sponsor to complete a form of releasing the study: the monitoring, visits and other aspects are discussed and agreed on.

Sponsor does not need to notify the IRB or obtain its permission. It is about a team work involving the sponsor and the investigator.

It is commnon that monitors are present for dosings and by the same time, they review the available study documentation, they can collect some indirect feedback from the PI and clinical staff.

The subject and sponsor interaction is coached but there is no reason to prevent it, unless the subject refuses to interact with the sponsor or any body other than the clinical staff.

S Isbill • If the subject consented to the presence of the monitor/sponsor during dosing, it can be done but the consent should be in writing and the consent form approved by the IRB.

Lynda Cedar • The subject is one of the x participants of the study, he has the right to refuse interacting with the sponsor who would be notified about this fact, but the subject does not have any right to prevent the sponsor presence at the doising or at any other time.

Jim Sheets • It seems rather intrusive to the patients' privacy, especially if they don't want you there and may not have envisioned such an interruption in the doctor-patient relationship after reading the informed consent language. (What about the whole "respect for the dignity of persons" principle?)

Lynda Cedar • Again, it is a team work collaborating and operating under the ICH, guidance and Ethis standards.
The sponsor does not intent to violate the privacy nor do anything that would compromise the patien-physician relationship or any aspect of his own study.

Sorry, but I'm not able to figure out how is the sponsor going to <> the patients' dignity by his presence at the dosing...... I don't buy it unless some one has specific experiences and would like to share about it.

Jay E. Westfall • The characteristics of the investigational drug, device, or biological product being studied and how it is administered, or any invasive diagnostic procedures associated with the study, may dictate sponsor observation at times. I tend to see this with device studies where a sponsor representative (i.e., medical officer) observes the surgical implantation of a device and may offer technical advice (i.e., possibly improve patient safety). If this is a requirement or a possibility, this should be discussed as part of study implementation and this addressed with investigators who will be involved. The investigators should then inform their IRBs/IECs about the possibility of sponsor observation of subject activities and ask whether the ICF should inform the subject about this.

Preyas Parikh [LION] • Hi,
Sponsor or none of the representative should be present at the time of Site - patient Interaction. Sponsor's Rep. cant even interact with the Patient. The reasons are as below:

* The Subject has the rights to maintain his/her confidentiality of participation in the Study. Monitor can verify the Study Data but Monitor cant interact with the Patient. In exceptional cases where there is a chance of misconduct or for the patient's safety concern, they can directly approach the patient.

* The presence of a Sponsor's Rep. during the Drug Infusion is leading to a concern about the Bias. Because it is a responsibility of a Sponsor to train the Site for such a study procedure in advance with a detailed orientation. There is an obvious question which may arise in future that why Sponsor Rep. is present in the process of Drug infusion? Do you have the trainings about the Same & Many More.

* If there is a serious error which has been observed on some particular site regarding Drug Infusion Process & Sponsor wants to verify the same. Then definitely they have to document the same that why they want to be there at site & should take prior approval from the EC & Site's Competent Authority.

Auditor may question a lot in such type of exercise because this is not a routine practice.

Yes, Subject should also be informed if the Sponsor's Rep. is present at site during the Infusion Process with a genuine & valid reason.

Valera Bussell, CCRC, CCRA • Preyas, If you think about it; the Sponsor's representative (i.e. study monitor) is privy to the subject's identity all the time. They regularly review medical records etc. The identity is protected when handling the data and publishing information regarding the study. Obviously, when information regarding the subject or one of their visits is sent to the Sponsor, it is redacted at that point; because data is handled on that end and it could start to become compromised at that location.

Lynda Cedar • We are not talking about the information recorded, that is certainly confidential and coded, but about a physical presence. It is the site responsiblity to implement procedures to protect the subjects' identity.
Study participants wear a bracelet with their ID code. There is no way that a sponsor monitoring the study can identify them physically. His representatitive is qualified and is not going to ask a subject to provide his name and there is no reason for such request.
The sponsor's representatitive is not allowed to talk to a subject, unless there is a reason, and it was agreed on at the time of the study release.

As Jay mentionned above and as I said, it is a team work, we should not prevent the sponsor of using his worth resources .... even his presence makes our clinical staff nervous which normal.
In one of our studies, the nurse representing the sponsor was present at each doising, she was monitoring the sensor subcutanous insertion for continuous glucose monitoring. That sensor was not functioning as expected, we were glad having her present, she changed them immediately and saved us tremdous time.

Angela Katsoulis • Thanks for all the interesting comments. I think adding something in the ICF upfront indicating that the Sponsor may be present during certain procedures and that the pt has the right to refuse will cover some of the issues that were raised.
It appears there is notthing in the regs or guidance docs that actually says the Sponsor can not have direct contact with the patients.
As an FYI in this case, the procedure I was observing was an intra ocular injection. I wanted to better understand the procedure from the patient's persepective.

Preyas Parikh [LION] • Just one clarification for Ms. Valera.

The Sponsor's Rep. is not the Study Monitor. Study Monitor has all the rights in context of reviewing the data.

Sponsor's Rep. is the Individual who is being appointed by the Sponsor to overlook the entire study on behalf of the Sponsor & they have the separate hierarchy.

This is the practice which is being followed in India.

Valera Bussell, CCRC, CCRA • Great comments; however I would tend to agree with you Angela. I see no reason that a Sponsor representative should not observe the procedure to assure that it is being performed correctly; as previously stated I think that public release of data is where the intent to keep their personalized info hidden is the issue. Naturally, as within normal clinical practice, perhaps when an Intern is present; it is good practice to verbally inquire of the patient (subject) if they mind the person observing. The HIPAA rule is observed as long as their personal medical information is not released to anyone and that they sign a release (separate or within the IC) that stipulates that their information may be seen by the Sponsor,IRB, FDA and other pertinent regulatory bodies involved in the study.

Valera Bussell, CCRC, CCRA • Hi Preyas,
In the US; a monitor is considered a representative of the Sponsor, whether through direct employment with the pharma company or if employed by a CRO to whom the Sponsor has delegated specific authority in managing the trial. Perhaps it is different in India.....

Jim Sheets • Ok, how about common decency? If I'm a study patient, I certainly would not be under the impression after reading the informed consent that a stranger could stand next to my doctor as they perform a potentially invasive and possibly embarassing procedure on me (well...depending upon how the drug is administered or what you're watching eg., surgery). As a patient, if I protest are you going to say "tough, you signed the consent"?

I certainly agree with Jay. Device implant studies are typically done this way, with the Sponsor rep in the surgery suite. That is more to train the surgeons on proper implantation procedure and use of the tools. In that case, the Sponsor's presence is necessary in order to proceed safely.

Why is it that biosimilars are only being priced at a 20-30% discount to the brand?

2011-04-30T18:15:00.002-04:00

Why is it that biosimilars are only being priced at a 20-30% discount to the brand? Is it because marketeer's are assuming enforced price controls by government or is the cost base prohibitive?

Question brought from Linkedin: Biosimilars (Follow-on Biologics) Group.

Sunil Soni • Hi Asa - just joined the group; saw this and wondered whyno one had responded. In some ways the answer is obvious. The head of Sandoz, Jeff George, was quoted as saying in the last week or so that development costs for a single molecule range from $50 million to $200 million or more. Coupled with the fact that these products are not interchangeable in the main (as small molecule generics (SMG) are) then as you say the cost structure is very different and the revenue model much different to SMGs. There I hope that triggers others to have their say.

Michael A. Swit • I agree with all of Sunil's points and have a few addtional comments.

What drives price decreases in the small molecule generic world is substitution following a FDA (in the U.S.) determination of therapeutic equivalence. For all practical purposes, the small molecule generic business is a commodity business as it depends on interchangeability. As more equivalent generic manufacturers enter the market with the same product, prices erode, sometimes to the point of negative margins (hence the emphasis among generics in the U.S. to be the first to challenge patents to become potentially eligible for 180-day exclusivity).

In the biosimilar world, with the chances of an interchangeability deterimination, while possible under the new U.S. law, being very small, there will be little price competition because the drugs are not commodities. Thus, the biosimilar busines model is, essentially, a brand vs. brand form of competition with a lot less downward pressure on pricing. In addition, the higher barriers to entry of the cost of developing a biosimilar means there will be far fewer players than in the small molecule generic world. Thus, even if a biosimilar was found to be interchangeable with the innovator, the potential lack of a second interchangeable biosimilar due to the higher barriers of entry will create less competition.

Tara Sharpe • Surely one must also consider the cost to delelop 'copy cat' drugs. While it is relatively simple to analyse a small molecule formulation and then attempt to develop a generic version, for biologics the IP surrounding the manufacture usually means you have to go back to the 'R' of R&D in order to bring a biosimilar to market, and manufacturing costs will be equally as high as the originator. Thus it takes longer, cost is higher and so price is higher in order to achieve ROI.

Manoj Babu • In my opinion, I think it has a lot to do with competition. Granted that cost basis is high (even excluding sunk costs) from production, quality checks and even marketing expenses. Take the example of Rituxan by DRL that is sold at a price much cheaper than the corresponding brand price in the US. In fact DRL sells it cheaper than the Roche brand of the 'same' product in India. I have a sneaking suspicion that if there were say over 4 players selling EPO biosmilar in US (whenever and if that might happen), the price erosion would be more along the lines of 50-70% rather than 20-30%.

Karl Simpson • Is the complexity of mAbs and the current/next generation biologics going to make that cost barrier even higher?
It seems it is going to be a business for the big-companies who have the deep pockets and resources to support the development programmes.

Michael A. Swit • On Manoj's comment, I agree that there might be more price erosion if you had over 4 biosimilar EPO products. However, what is the chances of that happening given (a) the costs to develop and the need to market as a brand product and (b) the technical difficulties presented, as suggested by both Tara and Karl's comments?

Manoj Babu • Following up on Michael's comments, I feel fairly confident that once a plausible biosimilar pathway is defined, companies like Teva, Hospira, DRL, Mylan, Glenmark etc., will make it to market. Based on what I heard (and hopefully understood properly) at a recent IP (PIV) conference in Virginia, the onus is on the generic company to jump through all types of hoops. From that vantage point, it may be tough to develop a substitutable generic. But companies like Teva have the expertise and the pockets to get market share even through a 'branded generic' strategy. Also, it is my personal opinion that the regulatory difficulties are more complex than technical difficulties. Don't get me wrong, mab's, IgG's, Interferrons, IgF's etc., are pretty complex to culture, purify & analyze......but the scientific talent and creativity exists at all the above mentioned companies to cross those hurdles. The regulatory hurdle on the other hand is politicized and more subjective, despite brilliant lawyers and lobbyists on both sides. It will be interesting to watch things unfold.

Louis J. Cantolupo • An interesting presentation from Biocon recently highlighted the difficulties in making a biosimilar. Run your-favorite-branded-mAb through an MS and note all the peaks. A biosimilar has to match that otherwise it's not similar. He (half-jokingly) said that the biosimilar companies tend to know more about the originators molecules than the originator themselves, this coming from scientists the biosim developers have hired away from the originator companies.

Philip Ridley-Smith • Interesting that someone should mention EPO. Given the number of possible isoforms involved and possible leathalness there is considerable development work required to ensure you are making the desired drug product. Unfortunately, it does mean going back to the big "R". However, I have seen companies offering cells line already producing the required biosimilar. How true this is I don't know.

From a manufacturing point of view you are having to develop a new process as there is scant information, not surprisingly, on the originator process. It all adds up. There are certainly no reduced requirements on the manufacturing front- safety, traceability and quality are still paramount. Of course last but not least is functionality!

Sunil Soni • I hadn’t realised the pent up desire for “others wanting to have their say”…

Let me acknowledge the various contributions by touching on a number of the points made and introducing some known facts to the discussion.

Biologics comprise the fastest-growing segment of the pharmaceutical market (fact). Nearly one-quarter of the top 100 drugs in 2007 were biologics, and 13 of them achieved mega-blockbuster status of more than $2bn in worldwide sales (fact). Many of these drugs will reach patent expiry within the next 10 years, driving interest in follow-on biologics and so both generic drug manufacturers and large pharma companies are angling for a share of this expanding niche in the $75bn (€60bn) global market for biologics (fact).

Teva (a generics giant) has formed a strategic partnership with Swiss custom manufacturer Lonza to jointly develop, manufacture and market biosimilars (fact).

Merck is partnering with Parexel to help its Merck BioVentures division. Under terms of the deal a dedicated Merck BioVentures unit will be set up within the Parexel organization. This development I find most interesting and exciting… and for the following reasons … Merck has been developing a humanised yeast technology platform since its 2006 acquisition of GlycoFi.. Merck is gearing up to deliver yeast strains that will support a continuous stream of three preclinical candidates and three lead optimization projects per year. Many of Merck's products can be considered second-generation biologics, reformulated or improved versions of branded drugs and these products could potentially obtain patent protection and command premium pricing.

In early November 2010, the Food and Drug Administration held a two-day public meeting to gather input from a variety of industry stakeholders to determine the future of a regulatory pathway for biosimilar development in the United States (fact). In Europe, 14 biosimilars have been approved to date with no significant safety issues reported (fact). The biosimilars that have been reviewed in Europe include three classes—human growth hormones, epoetins, and recombinant insulins. These drugs have been fairly safe and that was supported by the audience when the FDA asked if there were any issues they should be alerted to and no one responded meaning that the European experience has so far been a positive one (fact).

When, in 2003 and then again in 2004, I asked the EU rapporteur responsible for drafting the European legislation (REGULATION (EC) No 726/2004), not that long ago in the scheme of things, what was the driver for the introduction of the concept of a “similar biological medicinal product” into EU legislation, he told me in no uncertain terms that it was the joint expression of the generics industry and national member states. In Europe, at least, that will mean the conglomeration of companies and regulators will work very hard and creatively towards delivering biosimilars. There is a political need (fact).

Louis J. Cantolupo • Hi Sunil - You seem to be very educated on the topic. What are your thoughts on evergreening and will this hold up in the US and EU?

Sunil Soni • Hello Louis, I'm not entirely sure I understand what it is you are asking. Can you expand a little on your question. Also I am mindful that I've hogged the discussion of late, so perhaps you can make your request to all members.

Louis J. Cantolupo • No need to apologize, Soni.

I just realized evergreening might be a little off-topic for this discussion as it doesn't have any relevance on what people would pay for a biosimilar. But I suppose indirectly it does since it prevents a biosimilar from launching.

Evergreening, as I understand it, is the notion that originator companies would slightly modify the first generation molecules in a manner that would give them extended market exclusivity. Such modifications could include things like formulation of the compound.

Many of the biosim folks believe this to be an unfair tactic and the laws, as currently written or proposed, are very vague.

Asa Cox (1000+ Direct in Pharma) • Thank you Sunil for sparking this discussion again!

For the benefit of the less educated ones (like me), can someone list the key contributing costs for the development of a biosimilar?

Why would one cost $50m and another $200m to bring to market?
What are the 'R' challenges that make it so expensive?

I have heard that some companies are creating stable clones with biologic activity for less than $2m and within 9 months.

Sunil Soni • So I’ll attempt to give an opinion on the issue raised by Louis and in doing so acknowledge the valuable contributions others have made to this discussion. The development of biosimilars is, in the short- to mid-term, a game reserved for those with deep pockets and a steady nerve. Based upon Teva’s long and successful experience of litigating patents in the small-molecule space, might we then expect Teva and the like to be one of the leading candidates to contest many of the process patents currently covering multiple biologics (e.g., Cabilly II). Might we then expect the eventual outcome of this litigation to be that: 1. court verdicts reveal that many of these patents are too broad to be enforceable and, therefore, 2. companies marketing branded biologics will be forced to more often rely upon product patents (a situation analogous to that found with small molecule therapies).

Philip Ridley-Smith • The most significant expenditure will be for the clinical trials associated and required for a biosimilar. The manufacturing is only one part and it is the Phase I and Phase III trials that provide the eye-watering numbers.

Lynda Cedar • As Michael and others explained : technically it is like developing a brand vs brand, therefore (some products are exceptions) the cost is alsmost the same.
The interchangeability is therefore the challenge to accomplish, because of the risk, the healthcare professionals are relacting about its prescription and substution...

The process of formulation (manufacturing) and bioanalytical measurement determine the similarity between the inovator and its generic version. The clinical development is just the outcome/feedback.

The regulatory aspects, the evaluation of the data available about the inovator, the appropriate clinical design are essential for the budget evaluation.