Hello, May -
Yes, tell your reviewing division contact (an email to the project management person is fine for this) that you are responding to their non-hold comments with protocol amendments and that you will submit the resulting version in due course as you begin enrollment. Now that your IND is "in effect," go ahead amend your protocol just as the non-hold FDA comments suggest (assuming you can do what is suggested and you, i.e., the sponsor, agree with those suggestions). Good time to fix those other typos, too.
The next key step is independent of FDA at that point, and that is to obtain IRB/Ethics Committee approvals for the amended protocol version, get that distributed to your investigators and provide any needed training, changes to CRFs, etc., and proceed with your study enrollment. You could have proceeded with the initial protocol first, but if the timing is OK, you're best to do as you planned and get the revision processed first so you can start enrollment with the updated version. You don't have to do this next step before implementation, and by regulation it may not even qualify as being required, but I recommend that in a timely manner, submit a copy of the amended, IRB-approved protocol you started enrollment with to your IND as an information amendment. Include a cover letter detailed how you responded to the non-hold items, point by point [quote one item from their correspondence exactly and follow it with your response], and describe how you altered the earlier protocol version. Including a red-line/strike-out version along with a clean copy of the update protocol with your submission is a good idea, so the precise changes can be easily observed. You may even include in that cover letter the date of the new IRB approval (at least the first one, if you have it) and of course, be sure to comply with requirements of letting FDA know about added investigators (use of Form FDA 1572 is important) that may come along and were not previously listed under your IND.
Depending on the phase of your investigation, many (perhaps most?) minor changes to your protocol after this will not need any pre-submission or pre-approval by FDA under your "in effect" IND. But any further revisions will of course require IRB approval and at least, as before, you might consider a subsequent submission to FDA so they have a current copy on file. Some/many sponsors do not do any IND protocol amendment submissions with every minor protocol revision during a year (unless required by regulation) and accumulate minor protocol changes as one annotated, omnibus update in their IND Annual Report submission. You can think of this tactic as not adding
unnecessarily to the burden of your review staff at FDA-for which they might find you a more collegial and agreeable sponsor. This is especially so when you end up with lots of minor amendments during a year, which seem to arise when investigators are finally faced with actually trying to operate under the protocol you so carefully wrote for them and now you are finally getting some useful feedback. Accumulating protocol changes during the year depends on whether the sponsor considers (or how you feel FDA staff might consider) the changes being made would meet the criteria for a required submission (e.g., new protocols, "significant" changes likely to affect risks, like increase in dosages, overall design changes including a much larger enrollment population, adding new testing or the omission of previously planned testing, and of course adding new investigators). Lots of other changes don't meet those regulatory requirements, but you have to at least keep careful track and still get IRB approvals for each one.
As with any controlled document in the study, be sure your protocol versions are clearly marked and you can document when each site placed the later versions into effect and that this aligns with relevant IRB approval dates. Be wary of methods like "amendments by memo," which are difficult to track when the protocol document is not re-issued and doesn't provide investigators and their staff with a single current, authoritative protocol document. If you have a separate study manual that provides additional details outside the protocol to manage study conduct, be aware that some IRBs want to review/approved those details as well, and that may even include the CRFs, by considering them a part of the "investigational plan." Some sponsors like to make changes to the non-protocol support documents (i.e., manuals) specifically because they might therefore avoid IRB review, which could be time consuming and possibly costly, when the changes in some cases really should have been included in the formal study protocol proper. Good luck on your study, and I hope your protocol is so well written that few if any amendments are needed during the year.
Best regards,
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Jan S. Peterson, MS, CCRA, RAC, ASQ CBA, ACRP-CP
Consultant
United States
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Original Message:
Sent: 31-Oct-2022 21:54
From: May Litt
Subject: IND approved - question on protocol amendment
I have the following scenario and am not sure how to proceed. For a drug study, the FDA issued an authorization to proceed letter for our IND. However, there were a few non-hold comments. We would like to immediately update the protocol with these comments. Would this require a protocol amendment or can we simply reply to the FDA confirming the changes and reply? I have honestly never seen this scenario. Unfortunately, the FDA had a few comments, which were addressed prior to IND approval, so these somewhat minor non-hold comments were a surprise, but we want to get the protocol updated now, before enrollment. Thank you!
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May Litt
Clinical Operations Consultant
Weirsdale FL
United States
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