While the old adage “It’s easier to beg forgiveness than to ask permission” might have worked well as a child, it rarely applies when dealing with the FDA. The FDA recently published a final guidance titled “Formal Dispute Resolution: Sponsor Appeals Above the Division Level”, which outlines procedures for resolving scientific and medical disputes between sponsors and the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) that cannot be resolved at the division level (CDER/CBER 2017).

One of the key take-aways from the final guidance is that advice from the Agency communicated in meeting minutes or other correspondences is not considered appropriate subjects for a formal dispute resolution request (FDRR). This is especially important for Sponsors utilizing the 505(b)(2) pathway, as meetings with the Agency are crucial for setting the key deciding factors around their development program, such as what studies can be relied upon and therefore do not have to be conducted by the Sponsor. Negative responses by the Agency, which often can be avoided with the right preparation, are therefore difficult to reverse and can result in unnecessarily long and expensive development programs. This is why Premier Consulting strongly advises Sponsors to carefully approach the initial Pre-Investigational New Drug (PIND) meeting, or any other initial correspondences with the Agency, with the proper guidance and expertise.

Formal Dispute Resolution Requests- What Can Sponsors Appeal?

The final guidance published recently is the most recent in a long string of guidance’s outlining the formal dispute resolution procedures for Sponsors that wish to appeal a scientific and/or medical issue to the Agency. Examples of regulatory actions that are appropriate for a request for FDR include:

• Complete response (CR)
• IND clinical hold (partial or full)
• Request for breakthrough therapy designation denied
• Request for proprietary name review denied
• Refuse to receive for an ANDA

The performance goals for the resolution of all appeals affecting an IND, NDA, BLA, biosimilar biological application, or ANDA is within 30 calendar days, as established by the Prescription Drug User Fee Act of 1992 (PDUFA, for IND, NDA, and BLAs), the Biosimilar User Fee Act of 2012 (BsUFA, for biosimilar biological applications) and the Generic Drug User Fee Amendment of 2012 (GDUFA, for ANDAs) (CDER/CBER 2017).

The guidance also outlines the procedures for submitting a request for FDR. In response to an FDR, the guidance states: “In general, the FDA will send a written decision to a sponsor who requests formal dispute resolution. The written decision will grant or deny the appeal, and respond to all components of the appeal. Specifically, the decision may agree or disagree with the entire proposed outcome desired by the sponsor, agree or disagree with parts of the proposed outcome, or suggest a resolution that is different from that proposed by the sponsor,”

(CDER/CBER 2017). In general, if a Sponsor’s appeal is denied at one management level, the company can appeal to the next level up within the Agency.

While it is rare that an appeal is granted in full, the appeal process frequently gives Sponsors a clear path forward and are therefore an important option for development programs that are at an impasse or stalled. The short PDUFA performance goals also generally allows the company to get the response they need in a timely manner, resulting in the tradeoff of a short delay initially for a potential long term pay-off (Sutter 2013).

Why Are Meeting Minutes Treated Differently?

According to the final guidance, the Agency’s stance is: “advice communicated in meeting minutes and other correspondences is not a regulatory action taken by CDER or CBER; therefore, it would not be an appropriate subject for a formal dispute resolution request (FDRR) by a sponsor. Agency communications such as meeting minutes or other correspondences (e.g., general advice letters) typically include recommendations and/or advice made to a sponsor that generally conveys CDER’s or CBER’s current thinking on a particular topic raised by the sponsor. Sponsors are not bound by such recommendations and/or advice.” While this sounds like a convenient loophole—the FDA could later just change their mind with more information, right? – the fact remains that the FDA’s advice is still entered in the official record for the program, and complete reversals on the Agency’s advice are rare.

The appropriateness of meeting minutes as a topic of a FDRR was a contentious point when a draft of the guidance was published in 2015 (Sutter 2017). Two groups in particular, the Pharmaceutical Research and Manufacturers of America (PhRMA) and the law firm Hyman Phelps and McNamara, have both openly objected to the elimination of the ability to appeal agency advice in meeting minutes. In their comments on the draft guidance published by the Agency in 2015, PhRMA stated: “FDA often communicates decisions of great significance to sponsors- particularly essential study design decisions – in these letters, even if they are not officially binding. Excluding these disputes from the FDR process significantly narrows its scope in a manner that is likely to harm sponsors’ ability to gain certainty and a fair hearing during drug development – especially when a particular division may be adamant about its position on a key study design issue” (Sutter 2017).

What Can a Sponsor Do to Appeal Negative Feedback?

When given advice from the Agency, Sponsors have the choice to follow the advice in the meeting minutes or to use an alternative approach “if the approach satisfies the requirements of the applicable statues and regulations”, the guidance states (CDER/CBER 2017). However, the question would still remain if the Sponsor’s alternative approach meets the legal requirements of the Agency, essentially leaving the Sponsor where they started in terms of getting the key advice they need. Furthermore, the Agency typically only grants one Type B meeting (Pre-IND, End of Phase 2 [EOP2], Pre-NDA, etc.) per stage of a development program, leaving the Sponsor with limited options for getting additional advice. One option presented by the final guidance is to approach the review division and/or the next highest management level outside of an FDRR in a meeting established under PDUFA, for example in a Type C meeting. However, this inevitably adds time and cost to the development program. Type C meetings are typically scheduled to occur within 75 days of FDA receipt of the written meeting request, as opposed to the 60 daysfor the FDA to grant a Type B meeting. Furthermore, it is often difficult to fully debate the contentious points from the initial meeting within the time constraints of the Type C meeting, which could result in key points remaining unresolved. This lack of direction can be incredibly costly to a program, such as resulting in a clinical hold during an IND application.

How Can Premier Consulting Help?

Unfortunately, it is all too common that Premier Consulting is approached by a Sponsor that has had their Pre-IND meeting and not gotten the advice they need from the Agency to properly move forward to the IND stage. A successful Pre-IND meeting results in a complete understanding of the public information that is being relied on and a thorough presentation of the studies to be conducted. Instead, some Sponsors have tried to go around the Pre-IND meeting by submitting exploratory questions to the Agency, only to have the Agency declare the questions to be the Preliminary meeting package, and their response to be the Pre-IND Written Responses. Therefore, the Sponsor has lost the ability to have a full, detailed Pre-IND meeting. In other cases, the Sponsor has submitted vague questions or has not provided justification for their proposed development program, thinking they can simply appeal any decisions or have a second meeting later on. However, in these cases the Agency has no choice but to default to traditional 505(b)(1) programs by recommending a large, thorough (and costly) development program that may be unnecessarily burdensome. The Sponsor then has a large uphill battle to later convince the Agency that their advice is inappropriate due to additional information that the Sponsor failed to provide in the first meeting. While Premier Consulting can, and has, helped Sponsors through a follow-up Type C meeting following an unsuccessful Pre-IND meeting, these meetings are rarely as productive as a properly conducted initial Type B meeting.

The easiest way to avoid these review roadblocks is to get the necessary advice the first time around, and not to rely on a potential “do-over” or appeal in a second meeting. Having a properly conducted Pre-IND meeting can result is a great reduction in the time and cost to your development program. Premier Consulting has a vast history of conducting successful Pre-IND, EOP2, and Pre-NDA meetings with the Agency. Contact us for more information.

References:

CDER/CBER (2017): Formal Dispute Resolution: Sponsor Appeals Above the Division Level. Guidance for Industry and Review Staff. Silver Spring (MD).

Sutter, S. (2013): If At First You Don’t Succeed, Try Dispute Resolution. In Pink Sheet.

Sutter, S. (2017): US FDA To Sponsors: No Dice On Appealing Advice Through Dispute Resolution. In Pink Sheet.