"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.
6 days ago • Unlike • Like • Reply privately• Flag as inappropriate • Flag as promotion0 .
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.
0 comments:
Post a Comment