Should I meet with FDA to talk about my development program and product?

Should I meet with FDA to talk about my development program and product?

Are certain meetings more helpful than others?

Is there ever a time when a meeting with FDA is a bad idea or isn’t cost effective?

How can I increase my chances for a successful meeting with FDA?

As a consultant in the regulatory field, I am often asked one or more of these questions.  On the basis of my 15+ years of experience working in the pharmaceutical industry, I can confidently say,

Do not hesitate to talk with the FDA about your development program and your product applications!

  • Talk with FDA early and talk with them often, but know the right time and the right things to talk about.
  • Meetings are an excellent way to get to know your review team, learn about their needs and any concerns they have about your product and application, and get them excited to help co-champion your product through to approval!
  • With rare exception, the benefits of an FDA meeting far outweigh the costs!

However, I don’t expect you to take my word for it – the data suggest that there is some truth behind my assertion that meetings are beneficial during development:

  • Vu and Pariser (2015) showed that during FYs 2008 – 2012, applications that included a pre-IND meeting during development (n=49) had shorter clinical development times (median = 6.4 years) than applications (n=83) that did not have a pre-IND meeting (median = 8.3 years).
  • Booz Allen Hamilton (2010) reported that during FY 2002 – 2004, end-of-phase 2 (EOP2) meetings had a positive impact on first-cycle approval rates. Of 46 products with EOP2 meetings, 52% received first-cycle approval.  Only 29% of the 21 products submitted during these years received first-cycle approval when an EOP2 meeting was skipped (Booz, Allen & Hamilton, 2010).
  • In FYs 2013 – 2014, over 80% (55/64) of all PDUFA V Program (New Chemical Entity [NCE]) applications had presubmission meetings (PSMs). Program applications with PSMs and documented agreements had higher first-cycle approval rates (93.3% [n=15], 58.2% [n=12], p = 0.03) and faster first-cycle approvals (by 1.53 months [p = 0.093]) that those that did not have PSMs or those that had PSMs but no documented agreements (ERG, 2015).

Meetings at all stages in development can be beneficial in moving a product and an application forward.  I mentioned previously that applications with pre-IND meetings have significantly shorter clinical development programs than applications that did not (Vu and Pariser, 2015).  If one considers overall approval as the only success metric, there is some suggestion that the most beneficial meetings occur earlier in development and later meetings have a modest impact on success at best.  Booz Allen Hamilton (2010) found that applications that included pre-NDA/BLA meetings had similar first-cycle success approval rates than those that did not have a presubmission meeting (47% versus 33%).  I think this is a bit misleading, as one should consider both overall development time and first-cycle approval.

Meetings at different stages in development have different purposes.  Pre-IND meetings are intended to answer critical questions about nonclinical safety, efficacy, and the pieces required in order to go forward in humans.  They can be particularly helpful for new chemical entities, novel indications for unmet medical needs, orphan drug products, and biologics, where the regulatory pathway is uncharted and/or aspects of the clinical program (e.g., efficacy endpoints) are uncertain.

In contrast, the focus of pre-NDA/pre-BLA/presubmission meetings rests on Sponsors asking questions regarding the content and format of their upcoming NDA/BLA submission, providing FDA with an opportunity to see the final pivotal study data prior to receiving the application, and allowing dialog regarding any major barriers to application filing.  By this point, there should have been frequent discussions with FDA regarding the efficacy, safety, and quality associated with the product and most of those issues should have been addressed.

There are several factors that influence the value of a meeting with FDA.

1) Purpose

Before you decide you want to talk with FDA, consult the Guidance for Industry Formal Meetings Between the FDA and Sponsors or Applicants (2015).  This document describes the different types of meeting options and provides references to the Code of Federal Regulations on which the meeting types are based.  Be sure that you are requesting the right meeting at the right time in the development program for the questions that you have.  Asking questions in a pre-IND meeting about the content and format of your NDA targeted for submission 10+ years down the road is not appropriate and will lead to frustration on both sides of the meeting table.

As you are preparing your meeting questions, ask yourself – do I really need to know FDA’s thinking on this topic?  Are there guidance documents, FDA presentations, or other precedence (e.g., SBAs from other approved programs with the same or similar indications) that answer this question for me?  If the answer is “yes”, a meeting isn’t needed, but some time doing homework is!  If the answer is “no”, ask yourself – will FDA’s answer to this question change how we develop our product or application?  If the answer is “no”, consider not asking this question.  There is no point to ask FDA for their guidance if you do not intend to heed it.  If the answers to any of these questions is “I’m not sure” then consult with a regulatory affairs expert for help.  Remember that every interaction with FDA forms an impression of both you and your company.

If you have no questions for which you need FDA feedback, don’t request a meeting!  Meetings are labor-intensive for Sponsors and for FDA and should only be requested when dialog is needed to move development forward.

2) Timing

One of the few situations under which an FDA meeting is unlikely to be successful is when a Sponsor intends to meet with FDA to obtain guidance, but does not have enough time to incorporate that guidance into their development program or product application.  For example, a Sponsor schedules a pre-NDA meeting 2 months prior to the NDA submission date.  Final written comments from the meeting would be provided 30 days after the meeting which would then give the Sponsor only 30 days to respond to any FDA comments.  Working backward and allowing electronic publishing 2 weeks prior to the submission date to build the eCTD, the Sponsor would have a maximum of 2 weeks to prepare and/or modify NDA submission components in line with FDA’s pre-NDA meeting recommendations.  That is not enough time for even the best and most ambitious of teams!  Don’t let timing be an issue – plan carefully and allow plenty of time to listen to FDA, discuss a path forward, and act on that plan consistent with all agreements made.

3) Preparation

Preparation is crucial to meeting success and broadly encompasses a well-conceived meeting request, a concise background package, and flawless execution during the meeting (see Jenkins and Wilson, 2010; Wilson and Jenkins, 2010).  Contrary to popular opinion, a successful FDA meeting is NOT one where FDA says “yes” to all your meeting questions!  To me, success is getting clear answers to all the questions raised in the meeting request.  Poor preparation of the meeting questions can yield ambiguous answers from FDA or sometimes very clear answers on useless questions!  A sloppy background package can lead to frustrated reviewers, general confusion during the meeting, and to questions from FDA during the meeting that gets the discussion off-track.  The meeting itself should be prepped as if it is an act in a play.  The agenda needs to be set and all those on the Sponsor side who are assigned to speak about specific questions have practiced their speaking roles and any backup contingencies.  In this way, it allows the dialog with the FDA to unfold with a focus toward the end goal of clear take-aways.

Be sure to leave time for FDA to offer additional thoughts or suggestions.  Vu and Pariser (2015) noted that 44% (n=32) of 73 pre-IND meeting minutes that they reviewed included additional comments from the FDA on topics that had not been raised by the Sponsor (e.g., clinical [78%], CMC [44%], regulatory [25%], and nonclinical [22%]).  I have attended a fair number of meetings in which FDA freely offered critical information at the end of the meeting that changed how the Sponsor developed the product or prepared their application.

4) Acceptance of guidance and recommendations. 

According to Booz Allen Hamilton (2010), 71% of applications with key issues identified during the pre-submission phase of development had not resolved the identified issues by the first NDA/BLA action date.  This was especially true for issues of efficacy and safety.  While the authors argued that there were many factors that could be responsible for this outcome, one factor they highlighted is a failure to comply with FDA requests, including postponing application submissions until the issue is resolved (Booz Allen Hamilton, 2010).  One of the easiest ways to ensure meeting success is to be certain that you clearly understand the issue, take the issue seriously, and then take steps to resolve that issue.  FDA may suggest ways to resolve the issue.  You can choose to follow their suggestion or you can discuss with them an alternative to resolving the issue.  Either way, following up with FDA to ensure that FDA agrees the issue has been adequately addressed will substantially increase your probability of success.

Final Note

The FDA has said in many conference presentations that meetings are for the Sponsor.  However, I would argue that while the Sponsor can and does benefit from meetings, FDA can benefit from productive meetings as well.  Evidence of this assertion can clearly be seen in ERG’s interim report of PDUFA V.  FDA review teams provided feedback on presubmission, mid-cycle, and late-cycle meetings and explicitly stated that through these communications, FDA gains a better understanding of the Sponsor’s data being submitted, and is able to develop shared expectations with the Sponsor and among the review team.  FDA also reported that these discussions enhance communication, predictability, and transparency, and permits better internal planning (ERG, 2015).  These comments suggest to me that with thought and appropriate planning, Sponsors should embrace meeting with FDA to discuss their development plans and product applications because it is a win-win for all.

The meeting of two personalities is like the contact of two chemical substances; if there is any reaction, both are transformed.”  ~Carl Gustav Jung~

References:

Assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs in PDUFA V (Interim Report: Fiscal Years 2013-2014 (10/1/2012 – 9/30/2014).  Prepared by: Eastern Research Group, Inc., 2015.

Independent Evaluation of FDA’s First Cycle Review Performance –Retrospective Analysis Final Report.  Prescription Drug User Fee Act III – Initiatives & Evaluations.  Prepared by Booz Allen Hamilton., 2010.

Jenkins L. & Wilson M.  How to prepare well positioned meeting questions within a strategic background package. Global Forum. 2010:2(5):10-12.

Vu HH & Pariser AR.  Pre–investigational new drug meetings with the FDA: Evaluation of meeting content and characteristics of applications for new drug and biologic products. Therapeutic Innovation & Regulatory Science. 2015:49(3):434-442.

Wilson M. & Jenkins L. How to make the most of your FDA meeting. Global Forum. 2010:2(1):8-10.