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.
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