Why Seek Formal FDA Advice?

FDA offers formal advice at no cost to developers of medicines regulated by both CDER and CBER, with the aim of supporting medicinal product development from Phase 1 through to marketing. This system provides an invaluable resource to developers, providing guidance and alignment on CMC, nonclinical, and clinical components of development programs, and reducing the risk of potential setbacks such as clinical holds, delays in marketing application submissions due to missing requirements, and refusals to file marketing applications.

Given the time and effort required to prepare for an interaction with FDA, it is crucial that the Applicant navigate the available options carefully in order to obtain as much value as possible from any one procedure. This paper will discuss the scope and procedure for each meeting type, based on FDA’s December 2017 Draft Guidance: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products1, as well as providing Scendea’s recommendations on strategy, timing, and meeting preparation, based on the first-hand in depth experience of our team of regulatory experts.

Meeting Types & Scope.

Several PDUFA meeting types are available to Sponsors. Typically, designation of a particular meeting type is dictated by the specific topic for the meeting and the stage of development.  Notably, all meeting types are free of charge, however the FDA can deny a meeting request if the proposed discussion topics are outside the scope of the requested meeting type, there are required elements missing from the meeting request, or it is premature to hold the requested meeting. As such, it is critical that Sponsors request the meeting type most suited to their specific queries at the appropriate time for the discussion and they include all of the required elements for a meeting request. The scope of each meeting type is discussed briefly in this section.

Type A Meetings

Type A meetings tend to be viewed as emergency meetings, described by FDA as “necessary for an otherwise stalled product development”. Situations in which a type A meeting may be appropriate include:

• Dispute resolutions

• Clinical holds

• FDA Non Agreement Special Protocol Assessment Letters

• Post-action meetings requested within 3 months after an FDA regulatory action other than an approval, such as issuance of a complete response letter

• Refusal-to-file letters.

EMA Scientific Advice also allows discussion of issues relating to interpretation and implementation of draft and fully published EU guidelines. In the case of medicines targeted for Orphan indications, additional questions may be asked concerning the maintenance of Orphan status at the time of Marketing Authorisation Application (MAA) submission. 

Scientific Advice also provides an opportunity to interact with the Paediatric Development Committee (PDCO) and pose questions in this regard, as an agreed Paediatric Investigation Plan (PIP) is a requirement in Europe ahead of submission of the Marketing Authorisation Application.

Type B Meetings

Type B meetings are considered the most prevalent meeting type as they are closely associated with specific applications to FDA. The available Type B meetings are as follows:

• Pre-IND meetings

• Pre-emergency use authorisation (pre-EUA) meetings

• Pre-new drug application (pre-NDA)/pre-biologics license application (pre-BLA) meetings

• Post-action meetings requested 3 or more months after an FDA regulatory action other than an approval, such as issuance of a complete response letter

• Meetings regarding risk evaluation and mitigation strategies or post marketing requirements occurring outside the review of a marketing application

• Meetings to discuss the development program for products granted breakthrough designation.

Type B (End-of-Phase, EOP) Meetings

The scope of Type B (EOP) meetings is exactly as implied in the name, when product development has reached the end of a particular phase of development and is ready to move to the next phase.

End of Phase 1 meetings are granted for certain products under the following legislation:

• 21 CFR part 312 subpart E (drugs to treat life threatening & severely debilitating illnesses)

• 21 CFR part 314 subpart H (drugs under accelerated approval for serious/life threatening illnesses).

For all products in development, End of Phase 2/pre-Phase 3 meetings are available under 21 CFR 312.47.

Type C Meetings

The term “Type C Meeting” tends to be used as a catch-all for any meetings that do not fall under the scope of Type A, B, or B (EOP) meetings. Common topics for type C meetings include, but are not limited to, discussion of Chemistry, Manufacturing, and Controls issues or early consultation on the use of a biomarker as a surrogate endpoint in a clinical study.

Strategy & Timing.

Given the wealth of options available when seeking a meeting with FDA, it is crucial that Sponsors carefully consider the most appropriate strategy for their specific development program. The timing of certain meetings is an important consideration, in order for the Sponsor to extract as much value as possible from that interaction.  It is especially important when requesting pre-IND, EOP1, EOP2 and/or pre-BLA/pre-NDA meetings, as FDA will only grant one of each of these meetings so Sponsors need to ensure they have reached the point where all relevant topics can be discussed.

Type A meetings provide an avenue for urgent discussion when required, i.e. when a development program has stalled.

As such, these meetings are incredibly important for Sponsors, and must be approached in a strategic manner. It should be noted that prior to submission of a meeting request, the Sponsor is required to contact the relevant FDA review division to discuss how appropriate a Type A meeting is for the specific situation. Sponsors should note that for Type A (and some Type C), the meeting request and briefing package should be submitted at the same time. Due to the critical nature of Type A meetings, they are often held over teleconference, or face-to-face at FDA.

When requesting a Type B meeting, the specific category sought is largely determined by the stage of development, and is fairly self-explanatory, as follows:

• Pre-IND – sought prior to submission of an initial IND (i.e. pre-Phase 1). Typically, only one meeting of this type is granted per IND, but FDA occasionally allows exceptions. A pre-IND number must be requested before submission.

• Pre-emergency use authorisation (EUA) – sought prior to an EUA submission. FDA notes that Sponsors seeking Pre-EUA dialogue should follow the recommendations laid out for Pre-IND meetings.

• Type B (EOP) meetings – held once clinical data are available from the relevant Phase 1 or Phase 2/3 Trial. Generally guaranteed to be granted, but early discussion with FDA is encouraged to determine the acceptable data package (e.g. need for a full CSR).

• Pre-NDA/ BLA – held during the months leading up to NDA/BLA submission, but no later than 2 months before NDA/BLA submission date. Used to ensure NDA/BLA dossier is fully compliant with regulations and to solicit feedback on key items such as of pivotal clinical data or the extent of available stability data. Note that in some cases it is possible to request a separate meeting to cover CMC, Clinical and/or Administrative aspects of NDA/BLA.  The Sponsor should engage directly with the designated FDA RPM to secure these types of meetings.

• Post-action – considered a Type B meeting when requested >3 months after an FDA action (other than authorisation).

• Risk evaluation and mitigation, or postmarketing requirements. This discussion is typically started pre-NDA/BLA, but is ongoing during review in order to reach agreement before final approval. 

• Breakthrough designation development – available throughout development following Breakthrough Therapy Designation (note that BTD requires preliminary clinical efficacy data, so usually sought after Phase 1/2 data available).

Type B meetings are most often conducted via Written Response Only (WRO) or via Teleconference. Face-to-face Type B meetings are considered rare.

Type C meetings can typically be held at any stage of development as questions arise. The appropriate strategy for seeking a Type C meeting depends entirely on the specific requirements of each development program. Generally, these meetings elicit a WRO, for example when discussing CMC or facility topics. A common exception is Type C meetings in which the use of a biomarker as a surrogate endpoint is discussed. In this case, a Type C meeting is more likely to be via teleconference or face-to-face.

Preparing For A Meeting With The FDA.

Regardless of the meeting type sought, it is essential that a Sponsor prepares well in advance for an FDA meeting in order to extract as much value as possible from the procedure. Initially, the Sponsor should supply a meeting request to FDA including the following key information:

• Brief overview of medicinal product & indications.

• The questions to be asked of FDA with adequate background information supporting each question.

• A suitable range of meeting dates.

Meeting requests can include any combination of CMC, nonclinical, clinical and regulatory questions.

We recommend that the questions asked of FDA should propose a position for agreement, rather than providing options for FDA to choose from. As such, the Sponsor should present their preferred option but be prepared to adopt a backup option at a later date if FDA disagrees.

Following receipt of the meeting request via the appropriate route of communication, the procedure will start on the appropriate timeline, which varies by meeting type. An overview of FDA timelines is provided in Table 1. Within the relevant timeline, FDA will respond to the meeting request, offering either a face-to-face meeting, teleconference, or written responses only.

The complete meeting briefing package should be supplied by the sponsor within the timelines outlined by FDA. This package typically provides the questions from the meeting request, each supported by a short company position statement. More extensive details to support each company position should be included in the background information section.

Table 1: Summary of FDA Meeting Timelines

If a meeting with FDA is granted, the Sponsor can expect to receive FDA’s pre-meeting responses within a specified timeframe before the meeting (timeframe for responses is dependent on meeting type). On review of FDA’s initial responses, one of the scenarios below may arise.

• The Sponsor is entirely in agreement with the comments made by FDA, and can choose to cancel the meeting

• The Sponsor wishes to discuss some or all of the points raised by FDA, in which case they should provide a response to each question raised that they would like to discuss in the meeting. These responses are typically required at least 1 day ahead of the meeting, but this timeline can vary by FDA division. If needed, the Sponsor can negotiate with FDA on the proposed response timeline.

If a teleconference or face-to-face meeting goes ahead, preparation is key. At Scendea, we recommend preparing well in advance for a meeting, to ensure that the Sponsor’s team are aligned on their answers to any possible questions that may be raised by FDA. Some Sponsors may wish to consider bringing external experts into the meeting, such as a regulatory consultant or a Key Opinion Leader for the disease of interest.

Conduct of A Meeting With The FDA.

Meetings held with FDA proceed in a similar manner whether held face-to-face or via teleconference. The meeting will be chaired by FDA and typically lasts 60-90 minutes depending on the amount of time requested/allotted. Sponsors should aim to move through the questions efficiently during the discussion meeting, in order to cover all the key topics.

Typically one Sponsor representative (usually specialising in regulatory affairs) will field questions from FDA to the appropriate specialist team member. Typically a presentation is not required, but Sponsors can choose to include a small number of slides if they feel that they would be beneficial.

During the meeting, be succinct with responses to ensure adequate time is available for all discussion points.  Once FDA agrees with your position, move on.  At the end of the meeting, if the FDA does not do so, the Sponsor should summarise agreements and commitments.  It is also advisable to request that the FDA PM email a list of FDA attendees/titles to Sponsor representative and the Sponsor will provide the same to FDA.  The Sponsor should also inform FDA that they will submit internal minutes with the IND or to the open IND. 

Best Practices Following A Meeting With The FDA.

Following a meeting with FDA, the Sponsor should ensure that the names and titles of all participants are recorded and include these in the meeting minutes. Scendea recommends that the Sponsor take internal minutes, to be supplied to FDA within one week of the meeting. FDA provides the official meeting minutes within 30 days of the meeting, and in our experience will take Sponsor minutes into account, if provided early enough.

Once FDA meeting minutes have been received, the sponsor should conduct a careful review to determine if there are any points for clarification. If so, these queries can be sent to FDA by parallel formal IND submission and via email to the FDA PM. In some cases, a follow-up call may be requested if the Sponsor deems it necessary.

Relevant Associated Procedures.

PDUFA meetings are not the only formal opportunities to seek input from FDA. A range of biosimilar (BsUFA) meetings is available to discuss the development & review of biosimilar or interchangeable products. Additionally, specific to CBER, INTERACT meetings are available ahead of the pre-IND stage for developers of innovative investigational products (ATMPS) to garner non-binding advice on all aspects of the proposed development program.

Summary & Conclusions.

While the specific strategy for seeking a formal interaction with the FDA may vary across development programs, there are fundamental meetings available that add value to the development of almost any eligible medicinal product. 

Engaging the FDA within a formal meeting procedure provides an opportunity to work collaboratively with the FDA on a Sponsor’s product development; the information obtained during these meetings provides guidance on how to move product development to the next step, whether that be moving into a first in human clinical trial or a marketing application seeking authorisation for a Sponsor’s product.

Our key recommendations are that Sponsors make themselves aware of the meeting types available, ensure that the timing of the meeting request is appropriate, and include all of the required information in both the meeting request and briefing package allowing the FDA to provide thorough responses. By doing so, the resulting meeting will provide the level of guidance required to inform the overarching development strategy. In many cases, meetings with the FDA act as key corporate and product development milestones and the advice garnered therein will undoubtedly enlighten the development program moving forward.