This message was posted by a user wishing to remain anonymous
Dear Anon,
My response here is based on our actual experience with such situations in clinical trials that we conducted as sponsor under our INDs.
- This is not a protocol deviation, but a protocol amendment. Per protocol, there is a mandated safety review prior to proceeding to the highest dose and based on this review you are proposing a modification to the study design. Since this pathway was not outlined as part of your initial protocol (i.e. if not safe to proceed to the highest dose, we will continue with dose deemed safe after safety review), and is not what the IRBs approved, then this change to the protocol study design needs to be approved at a minimum by your IRB prior to implementation. The FDA can receive this as an amendment. (we tend to make simultaneous IRB and FDA submissions, as best practice).
- Additionally, the change should not be implemented without IRB approval, since there is no immediate harm to the volunteers (assumption being that you are already at a pause in the study to review safety data from the first two cohorts). Thus there is no reason to implement a study design change without prior approval from the IRB.
This is based on the below CFR reference (21 CFR 312.66); all changes to the protocol need to be approved at a minimum by the oversight IRB, except when there is a need to prevent immediate harm. This is not a significant protocol change, but still needs IRB approval prior to implementation.
Hope this helps.
21 CFR 312.66
An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
Original Message:
Sent: 23-Sep-2018 21:59
From: Bridgette Kunst
Subject: Interesting question: Protocol Deviation
Dear Anon,
I agree with Victor's assessment that any change to the protocol should be submitted to FDA as a protocol amendment and reported to the IRB. The proposed change is a lowering of cohort C dose level, which does not significantly affect safety of subjects, scope of the investigation, or scientific quality of the study, and therefore it can be considered a minor protocol amendment (see 21 CFR 312.30 (b)). The change can be implemented prior to submission of the protocol amendment. If there are additional minor changes expected to the protocol, the amendment can be held to submit all changes at once (see 21 CFR 312.30 (e)).
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Bridgette Kunst MA, RAC
Managing Director
bkunst@bridgereg.com
Original Message:
Sent: 21-Sep-2018 16:52
From: Victor Mencarelli
Subject: Interesting question: Protocol Deviation
Hi Anon.
This is truly not an area of my expertise but I am going to take a shot at giving my opinion based on the limited information here. I admit I have not consulted all of the regulation or the guidance documents so I don't know of the exact citations that might apply to a situation like this.
That said, it appears that the dose escalation is being avoided because the data in the A and B cohorts is potentially showing a safety signal as the decision on when to escalate appears based on the limited study design information provided to be dependent and pending the review of some of the safety data that might be available after the other two cohorts have been receiving the subject product for some period of time. This leads me to believe that the change should be reported as an amendment and should also potentially be reported to the supervising IRB(s) since there is obviously something happening with the subject product that was unexpected or the cohort C would never have been added to the original study design.
Again, this is just a logical inference based on your provided data. Without significantly more information about the product and the current study data that might be available it is almost impossible for me to provide you with any more specific information or suggestions. Things like understanding what is happening and why the company is choosing not to actively run the dose escalation in the study would be helpful to provide you with further options. But if, as I suspect, this is a case of safety signals appearing in cohort A and/or B and that is the basis for stopping or eliminating the escalation, I think you have a need to amend the protocol with both FDA and your supervising IRB(s).
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Victor Mencarelli
Director Regulatory Affairs
United States
Original Message:
Sent: 21-Sep-2018 10:11
From: Anonymous Member
Subject: Interesting question: Protocol Deviation
This message was posted by a user wishing to remain anonymous
Hello,
Consider the following situation:
According to the IND protocol:
Cohort A - Dose is 0.1X
Cohort B - Dose is 1X
Cohort C - Dose is 5 X
Prior to dose escalation to initiate the 5X dose in Cohort C, full safety data from Cohort A and some safety data from Cohort B must be analyzed.
The sponsor wants to now change the dose level in Cohort C to 1X. Note that the dose is not being escalated anymore and the patients are at no greater risk than they would be in Cohort B.
Should this protocol deviation be reported under a protocol amendment (and if so, is approval needed prior to dosing) or can the deviation be implemented and reported later under the IND Annual report?
Request you to kindly support your response with the appropriate FDA regulation/guidance if possible.
Thanks,
Anon