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

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.