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We’re catching up on some final guidances the FDA has been issuing recently. We realize any given guidance may be relevant to only a small subset of our audience, but the one we’re looking at today has broad relevance for the OTC drug professionals among us who interact with the FDA.
Last month, CDER’s Office of Nonprescription Drugs issued final guidance on formal meetings between FDA and sponsors or requestors of OTC monograph drugs. It finalized a draft of the same title from February 2022 and is classified as “procedural.”
At a high level, the guidance does three statutory jobs at once:
Section 505G(h) required the FDA to establish procedures for these meetings.
505G(i) required procedures for joint meetings involving multiple requesters.
And 505G(l)(1) required FDA to issue guidance specifying the procedures and principles.
This document satisfies all three for these kinds of meetings.
If you work in the OTC monograph drug space, this is basically the operating manual for getting FDA advice. Two things make it different from the meeting process you may know from the NDA world. First, it runs on its own meeting taxonomy with its own clocks. Second, because the monograph order process is public, what you submit in connection with a meeting can end up public, too.
Excuse the length in this one — there’s a lot here!
Who and what this covers
The guidance applies to formal meetings requested by sponsors or requestors of nonprescription drugs without approved NDAs governed by section 505G, or by organizations nominated to represent their interests in a proceeding.
It calls all of them “meeting requesters.” (Fun fact: Section 505G was introduced by the CARES Act in March 2020.)
It also covers meetings for advice on clinical investigations under an IND, where the purpose of the IND is to support a determination of whether a nonprescription drug is generally recognized as safe and effective under certain conditions. It does not apply to nonprescription products being developed for submission in NDAs or ANDAs under section 505.
The three meeting types
This is the core taxonomy. Let’s run through each!
Type X is the urgent and unblocking category.
It covers a meeting necessary for an otherwise stalled OTC monograph order development program to proceed, with the guidance’s own example being a meeting requested within three months of FDA issuing a refuse-to-file letter for an OMOR.
It also covers a meeting to address an important safety issue requiring immediate action, a meeting concerning a clinical hold on a qualifying IND, either to get FDA input on how to address the hold or, after a response has been submitted and reviewed, when FDA and the requester agree the program remains stalled and a new path forward should be discussed, and a dispute resolution meeting under 21 CFR 312.48 to resolve differences with the FDA regarding IND requirements.
One procedural note that’s easy to miss here is that before submitting a Type X request, you should contact the FDA to discuss whether a Type X meeting is actually appropriate.
Type Y is for milestone discussions during an OTC monograph order development program. Three kinds qualify in this case:
Pre-IND meetings requested before you submit an IND.
Overall data recommendations meetings to discuss the data recommended to support either a positive GRASE determination after FDA has stated its intent to make a final GRASE determination, or an OMOR submission when you have an interest in initiating an OMOR but have not yet begun a development program.
And pre-OMOR submission meetings.
Each of those three has its own footnote stating essentially the same thing: the FDA generally will not grant more than one request of that kind for a particular development program as a Type Y meeting, and any subsequent request of that kind would generally be granted as a Type Z meeting.
So the constraint is one Type Y slot per milestone type, not one Type Y slot per program, if that makes sense.
The pre-OMOR submission meeting carries the most specific expectations. You use it to present a summary of the data supporting the OMOR, discuss the proposed format, get FDA feedback on the adequacy of the submission, including format and content, presentation of data, structure of dataset, and fileability, discuss the projected submission date, and discuss whether the OMOR is Tier 1 or Tier 2.
The guidance says it should be held far enough in advance to allow a meaningful response to FDA feedback, and generally not less than 3 months before the planned OMOR submission.
Type Z is the catch-all type: any meeting that is not a Type X or Type Y!
Four formats, and the FDA gets to pick
In addition to the three meeting types, there are also four formats.
Hybrid in-person face-to-face, where core attendees from both sides generally participate in person at FDA, if feasible, while non-core participants may join virtually.
Virtual face-to-face video conference, with core attendees’ cameras on.
Teleconference, audio only.
And written response only, where FDA sends written responses in lieu of a meeting.
An important detail we caught on the hybrid format is that if your core personnel are not planning to attend in person, the guidance says you should request a virtual face-to-face meeting instead. If core personnel are suddenly unable to travel due to illness or unexpected travel issues, they can join virtually.
You can request a specific type and format, and for any meeting type, you may request a written-only response. But the FDA reviews the request and determines whether to grant it, the appropriate type, and the appropriate format.
So in essence, the format is FDA’s call, generally informed by the complexity of your questions.
The clocks and timing around meetings
Three timing rules matter here: The FDA’s OMUFA II response-time goal, its meeting-scheduling or WRO goal, and the deadline for submitting the meeting package.
Type X: For requests that qualify for the OMUFA performance goals, the FDA’s response-time goal is 14 calendar days from receipt, and its meeting-scheduling/WRO goal is 30 calendar days. The meeting package should be submitted with the request
Type Y: For requests that qualify for the OMUFA performance goals, FDA’s response-time goal is 14 calendar days from receipt, and its meeting-scheduling/WRO goal is 70 calendar days. The meeting package should be submitted no later than 50 calendar days before the meeting date or expected written response date.
Type Z: For requests that qualify for the OMUFA performance goals, FDA’s response-time goal is 21 calendar days from receipt, and its meeting-scheduling/WRO goal is 75 calendar days. The meeting package should be submitted no later than 47 calendar days before the meeting date or expected written response date.
Note that the written response timelines match the scheduling timelines for the same meeting type.
We noticed a scheduling wrinkle here that you’ll want to be aware of. The FDA schedules for a date when all expected FDA staff are available, consistent with the type granted. But if the date you requested falls later than the standard scheduling window, FDA should schedule within 14 calendar days of your requested date.
Now hold the scheduling window and the package deadline side by side.
For a Type Y meeting scheduled at the outer edge of its window, day 70, a package due 50 days before the meeting lands around day 20 after your request.
For Type Z at day 75, a package due 47 days out lands around day 28.
And if FDA schedules your meeting earlier than the outer bound, your package deadline moves up with it. An earlier meeting date actually shortens your preparation runway.
Type X has no runway at all! The package is due at the time of the request, so it has to be finished before you ask.
Getting the request right and the OMUFA split
Submitting electronically is a statutory requirement under 505G(j). Beyond that, the guidance draws a distinction that’s kind of easy to miss.
It says all requesters should submit through the CDER NextGen Portal, but to qualify for OMUFA II performance goals they must. Same portal, different “force.”
The same split runs through content. A nine-item list covers what the request should include:
Monograph file number if assigned
Pre-IND or IND number if applicable
Product name if applicable
The relevant OTC monograph or proposed therapeutic category
Chemical name, established name, and/or structure
Indications
The meeting type requested with rationale
Suggested dates and times, plus dates you are unavailable
A list of proposed questions grouped by FDA discipline with brief context for each
Then it gives a separate 8-item list of what the request must include to qualify for OMUFA performance goals:
A brief statement of purpose, including background, a brief summary of relevant completed or planned studies/trials or data, the general nature of the critical questions, and where the meeting fits in the development program
The proposed format
Specific objectives or expected outcomes
A proposed agenda with estimated times per item
A statement of whether you intend to discuss information exempt from disclosure under 505G(d) or other laws
A list of planned attendees with names and titles, plus names, titles, and affiliations for consultants and interpreters, if applicable
A list of requested FDA attendees with explanation
The date the package will be sent
To our eyes, you should treat that second list as an actual filing checklist. It’s going to be what stands between you and the performance goal timelines.
On requested FDA attendees, the guidance is candid about the tradeoff. Asking for FDA staff who are not otherwise essential may affect the ability to hold the meeting within the time frame for that meeting type. If you request nonessential attendees, justify them and state whether a later date would be acceptable.
Ten questions in one hour
The meeting request should generally have no more than ten questions, listed consecutively regardless of discipline. The FDA asks you not to use subquestions because they get counted toward the total anyway.
Three parts to your first question means numbering them 1, 2, and 3, not 1a, 1b, and 1c. Three clinical and three nonclinical questions can sit under subheadings but should run Clinical 1 through 3 and Nonclinical 4 through 6.
The limit in questions is because there’s a limit on time: meetings are generally one hour, and you are asked to limit questions to what can reasonably be answered in that time.
What goes in your package
The package must be submitted electronically, and the guidance says you should send it through the CDER NextGen Portal.
Content should be organized according to your proposed agenda, sequentially paginated, with a table of contents, electronic linkage, and appropriate indices, appendices, and cross-references so reviewers can navigate it during the meeting as well as before.
The package generally should include fifteen items, starting with the same first six from the request, then:
The USP active ingredient monograph if applicable
The proposed OMOR tier, dosage form and route and dosing regimen
A full attendee list with titles and affiliations including consultants and interpreters
A background section
A brief purpose statement
The proposed agenda with times
The final questions numbered identically to the request
Data to support discussion organized by discipline and question
Two content instructions deserve your attention here.
First, protocols, full study and trial reports, and detailed data are generally not appropriate. Summarized material should describe results with some degree of quantification, and if applicable should state the trial endpoints and whether endpoints were altered or analyses changed during the trial.
Second, if your development program deviates from current guidances or current practices, the guidance says the deviation should be recognized and explained, and known difficult design and evidence issues should be raised for discussion.
The FDA also generally expects your non-FDA attendees to be limited to those listed in the package and expects advance notice of changes.
Preliminary responses and the gotcha
For Type Y and Type Z meetings, the FDA sends preliminary responses to your questions no later than five calendar days before the meeting date. The FDA says it generally does not send preliminary responses for Type X meetings.
You then have a short window! Within three calendar days of receiving the preliminary responses, you should tell the FDA whether the meeting is still needed. If it is, send a revised agenda marking which questions you consider resolved and which you still want to discuss.
Here’s the “gotcha” we’re seeing here: