The Role of Statistics in Briefing Books for FDA Meetings

Briefing documents are necessary for achieving productive (and hopefully successful) meetings with the FDA. The FDA describes the materials as the “meeting package”; many companies refer to these materials as the Briefing Package, Briefing Document, or Briefing Book (as often the documents are printed hard-copy, bound, and shipped to the FDA for use by their reviewers). The FDA has specific guidance on what a briefing document should contain.

While the format and order of the information is left up to the Sponsor, the required content is generally well-established. A balance must be reached in preparing information that is relevant to the discussion topics in sufficient detail to allow the FDA to adequately prepare for the meeting, yet avoiding too much information such that efficient and effective review is not possible in the timeframe provided. Meetings with the FDA are rare, and usually are at critical junctures in the drug development process. Thus, everyone wants the meeting to be successful. The Briefing Document is absolutely critical to helping the Sponsor meet that objective.

The major difficulty in putting together an effective briefing document is 2-part. Firstly, well-thought-through questions from each discipline must be prepared, and while the questions themselves may take up only 1 or 2 pages of text, the process for working through the optimal language for each question can take many weeks. Most often these question require subject-matter experts to draft, but also require regulatory input to ensure proper wording, and executive input to ensure the questions are consistent with the Sponsor’s strategic planning. The Team develop the questions will depend upon the context of the issues in the drug development program at hand. For instance, key disciplines required to help develop questions may include manufacturing, pre-clinical (or non-clinical), pharmacokinetics, clinical, program development, medical writing, regulatory, and biostatistics. Secondly, once the questions are generally established, supporting information will need to be weaved into a ‘story’ that not only provides the basic information on the product (eg, chemical name, proposed indication, attendees and objectives of the meeting) but also provides data that supports the Sponsors position. Justification of the Sponsors proposals regarding the study protocol design, the dose(s) selected, the endpoints proposed, etc, are critical aspects of a briefing book, and must be well-thought-out, with the data provided in the package supporting those proposals. Some of the toughest FDA discussions I've been involved with have related to the doses selected for study (usually due to inadequate or incomplete exploration of a more thorough dosing range in Phase 2) or to the endpoints selected (particularly in orphan diseases, where no prior regulatory pathway to approval has yet been established by another product). The more clear the messaging is in the briefing document, the easier it tends to be to reach agreement with the FDA on these (and other) tough questions.

The role of the biostatistician in the development of briefing documents will depend on the purpose of the meeting and the stage of development of the product under question; certainly where a study design is being put forth, the biostatistician is a key figure in the process. A Preclinical meeting may require statistical input for the overall development plan section, or for the initial study proposed in the briefing package. For an EOP2 meeting, where the upcoming Phase 3 program is being discussed, a biostatistician will need to be brought into the discussions regarding the individual Phase 3 studies, the power of those studies, endpoint determination, the methods of analysis of the primary and secondary endpoints, experiment-wise alpha-control, and sample size. For a pre-NDA meeting, the biostatistician may be needed to discuss dataset formats (eg, CDISC standards), required integrated analyses across multiple studies, and CTD considerations.

The influence of statistics on the drug development process (and on clinical trials) cannot be ignored; drugs succeed or fail based on the strength and weight of the evidence. Statistics is the tool by which much of the evidenced is measured, and therefore serious consideration of the statistical nature of the development program should be carefully gauged. A biostatistician who has experience with multidisciplinary Teams and regulatory meeting experience is a valuable asset to a project team at these key junctions of drug development and should be involved in the development of briefing documents and in attendance at key regulatory meetings from the early stages of the clinical trial process.

See how NovusLife helped a small biotech complete an important briefing book here.

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