The new product review process with the Center for Drug Evaluation and Research (CDER) within the Food and Drug administration (FDA) is often a complicated endeavor involving many steps, reviews, and negotiations between regulators and biopharmaceutical developers. The statisticians at CDER/FDA and those working for the product developer/sponsor play a key role in helping move the product development process forward smoothly and efficiently. This review summarizes the key roles and responsibilities of FDA and biopharmaceutical industry statisticians throughout the product lifespan, including the NDA/BLA (New Drug Application/Biologics License Application) review cycle, and interactions between industry and FDA statisticians.

CDER Review Teams and the Role of the FDA Statistician
Regulation of new drugs and biologics within the Center for Drug Evaluation and Research/FDA is performed by multi-disciplinary review teams within each of the respective medical review divisions. At a minimum, these teams comprise clinical, pharmacology, chemistry, statistical, pharmacology/toxicology reviewers and are led by regulatory project managers and senior management. The primary goal of the review teams is to review and evaluate new drug or biologic submissions under the IND (Investigational New Drug) and NDA/BLA and provide collective guidance on the product development plan to the product sponsor, to negotiate and agree upon study designs and endpoints relevant to the target indication, and a myriad of other aspects germane to product development. Guided by set timelines and processes, these review team regularly meet to discuss the scientific and regulatory elements of the submission, identify issues and propose solutions, and generate feedback for the product sponsor.

The statistical reviewers within CDER are organized within the Office of Biostatistics (OB), which falls under the Office of Translation Science in CDER. The OB statisticians support one or more of the medical divisions within the Office of New Drugs where they serve an important role by providing biostatistical and clinical trial design expertise, often drawing from other programs in the same or similar therapeutic areas and product classes. Each review team comprises a primary statistical reviewer and a statistical team leader. During the IND, the FDA/CDER statistician provides essential input on clinical trial designs, key efficacy and safety endpoints, and statistical analyses necessary to ensure that the proposed clinical trials/studies are statistically relevant, and the analyses are appropriate. The statistical reviewer is always interacting with other team members, e.g., clinical reviewer, to ensure that the statistical guidance accounts for clinical and other scientific aspects of the product development. Each submission to the IND is reviewed by members of the review team followed by a secondary review by a senior member for each review discipline. Depending on the complexity of the submission, other senior members may also perform an independent review. For example, a submission containing a proposal to develop and validate a new biomarker may require a tertiary review by a statistical biomarker expert.

Typically, the review team members, including the primary statistical reviewer and statistical team leader, assigned to review product submission during the IND stage will be responsible for the NDA/BLA review for a specific new drug or biologic. During the NDA/BLA review, the statistical reviewer performs an independent, rigorous, statistical analysis of the submitted clinical trial, and other relevant data/information, supporting the applicant’s claims of efficacy and safety. The reviewer is not only attempting to validate the primary and key secondary efficacy and safety findings but is also critically evaluating and analyzing the data for consistency, missing data patterns, robustness of treatment effect, risk/benefit assessments, patterns of patient drop out and other clinical outcomes, at a minimum. Throughout the review cycle, the statistical reviewer and team leader are essential in communicating with other member of the review team and senior leadership on important issues and findings and any impact such findings have on the application. The reviewer’s statistical analyses and evaluation are included as part of the multidisciplinary review evaluation, which is a collective document written by all members of the NDA/BLA review team. Additionally, the statistical reviewer plays an important role in evaluation of the applicant’s proposed product label, discussions around any post-market commitments and requirements.

The Value of the Statistician to the Sponsor 
Drugs are approved by negotiation, so like the FDA, statisticians are extremely valuable to the sponsor as the submission moves through the regulatory process. Primary roles in program and study design include providing:

• Specifications;
• Reporting;
• Regulatory submissions; and
• Participation in regulatory negotiations.

Again, similar to successful FDA statisticians, a solid background is needed in acting with regulators to determine just what is ‘approvable’ and how to best translate the technical components of the design and how to put the study and program into a package that can be easily navigated by the sponsor team. In meetings with the FDA reviewers, the statistician prepares briefing documents that provide specific technical information and can even develop alternative scenarios during negotiations.

In review sessions with the FDA, the statistician may discuss study design and endpoint determination. The importance of being at the table is recognized when, perhaps, clear statistical representation is needed to explain issues or concerns that non-statisticians may find difficult to understand. 

Interactions between FDA/CDER and Product Sponsors
Meetings between product sponsors and the FDA/CDER review division occur frequently during the IND and NDA/BLA review cycles. There are three meeting types:

• Type A – meetings to move along a stalled program or for a dispute resolution, address clinical holds, or Special Protocol Assessment (SPA) meetings following FDA receipt and review of protocol under SPA.
• Type B – meeting to discuss a pre-investigational new drug application (pre-IND), certain end-of-phase 1 (EOP) meetings, EOP2 and pre-Phase 3 meetings, and pre-NDA/BLA meetings.
• Type C – meetings for everything else not covered under a Type A or B meeting, e.g., a meeting to discuss a sponsor’s biomarker development and validation plan.

There is a specific pre-meeting process including a formal written request from the sponsor or applicant including sufficient outlining of the purpose and content of the meeting. The sponsor can request a face-to-face meeting (FTF) or written responses only (WRO). Upon review of the meeting request, the review division determines if the meeting should be granted and may change the meeting type and/or format, i.e., FTF or WRO. If the meeting is granted, the sponsor is required to submit a formal meeting briefing package to the IND within a set time, as per the FDA guidance.

The meeting request should include pointed, concise questions for discussion and include discipline-specific discussion, i.e., chemistry-related issues, trial endpoint-specific questions, etc. In the formal briefing document, greater details are provided depending on the stage of development and meeting purpose. For example, a pre-IND meeting briefing package often includes details covering the pre-clinical development program, high-level findings from key toxicity studies, a discussion of the target indication and an outline for the phase 1 clinical study. In contrast, a EOP2 meeting package may include high-level findings from the Phase 1 and 2 clinical trials and a detailed proposal for the Phase 3 program. The statistician is essential in the construction of briefing materials as statistics-related questions should be stand-alone, specific and written in a way to generate a thoughtful response. Statistical references can be included, where relevant, to support the plan.

Review of the meeting materials by the FDA/CDER review team is of great importance and often includes at least one internal meeting to discuss the package prior to the planned meeting or WRO deadline. Each reviewer, including the primary statistician, reviews the meeting materials and proposes draft responses to discipline-specific questions. Often product development questions require frequent internal discussion with others on the review team and other OB statisticians due to complexity and need for regulatory consistency. Depending on the content and focus on the meeting, the primary statistical reviewer may also present internally on the sponsor’s proposal, e.g., a confirmatory trial design, to brief the other team members and senior leadership. Finally, if the meeting is face-to-face (or a teleconference) the review division sends out their draft written responses to the sponsor’s questions and any other formal communication prior to the meeting. Otherwise, if the response is a WRO only, the review division aims to deliver formal responses by the targeted due date. These interactions are critical to the overall product development providing a pathway to gain formal guidance and insight on the product development, and regulatory perspective, from the review division.

What to Expect During the Meeting
In general, formal meeting between the review division and the sponsor include a short introduction by each party followed by a focused discussion around any topics for which there is disagreement or a need for clarify. The well-functioning meetings are those in which there is full transparency by sponsor/division on key issues that could impact the success of the product development, an open discussion to understand sponsor’s plans with an opportunity for the medical division to seek clarity, a summary of discussion points and agreements during the meeting and outstanding items of either the sponsor or the review division. Following the meeting, the review division submits formal meeting minutes outlining the issues, next steps, and agreements. Importantly, the review division may opt to not address any items or questions from the sponsor that were not included in the briefing package. Also, the members of the review division often attend multiple meetings per day and therefore the meetings need to stick to the agenda to avoid an abrupt ending.

Outside of the formal meeting process, communications between sponsors and the FDA/CDER review division generally include information requests from the review division to the sponsor. For example, the statistical reviewer may submit an information request seeking additional information on the proposed statistical method planned for the primary analysis of a trial. The communication is in writing and generates a written response by the sponsor but does not generally lead to a meeting. Other forms of communication might include updates from the sponsor to the review division including preliminary trial findings, changes in clinical site investigators, a quality control finding, or other items not requiring formal discussion. 

Be Wary of Miscommunications
As can easily happen in any type of meeting, the opportunity for miscommunication arises and can be especially damaging during the review process. During the review, watch out for non-specific questions from the sponsor/applicant and vague responses from the review division. Over-interpreting or ignoring written communication provided to the sponsor is problematic and can create confusion around what is required or expected. A meeting briefing package containing material irrelevant to the meeting objective, or excessive detail and verbosity, can confuse or misdirect the reviewers assigned to the submission. Other challenges include requesting formal agreement with the review division on a design or endpoints based on limited or insufficient data or information. For example, over-interpreting findings from a proof-of-concept study or subgroup finding from a negative trial may contribute to the inability to agree on future plans/trial designs. Industry and FDA statisticians are responsible for providing clear, specific questions and responses (both verbal and written) to avoid creating confusion among the non-statistical members.

In summary, the recommendations for clear communication between sponsors and FDA/CDER reviewers include:

• Communicate early and often in the product development to include a pre-IND communication on proposed pathway. This is especially important for novel products and for rare disease indications for which there is limited regulatory precedent.
• Maintain an open and transparent line of communication with the medical division.
• Ensure open transparency regarding potential product development issues, e.g., manufacturing problems, safety signal in confirmatory trial, etc.
• Provide preliminary proposals on trial design, modeling and simulation, novel approaches and seek early statistical input and consideration.
• Submit clear and succinct briefing documents including relevant and timely questions.
• Avoid unnecessary meetings, e.g., seek review division input via WRO.
• Limit the number of key opinion leaders during formal discussions with the review division.
• Importantly, involve statisticians in all stages of design, development and in all subsequent meetings. They play a vital role in the successful outcome of a clinical trial and ultimately of a product development program. 

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Joshua Baker, PhD is VP of Biometrics for the CRO PHASTAR. He has many years of pharmaceutical industry experience, developing and leading a number of biostatistics departments. Josh also has extensive regulatory experience (IND, CTA, BLA, MAA, and post-licensing) in all geographies, including submission strategy and preparation. He has participated in multiple advisory committee meetings at the FDA for new therapeutics (small molecule and biologics). Josh leads PHASTAR’s US statistical consultancy and operations.

LaRee Tracy, PhD is Director of Biostatistics for the CRO PHASTAR and a lecturer at San Diego State University in the School of Public Health She has over 25 years of experience in clinical research, industry regulations, and clinical operations. LaRee worked for 16 years for the FDA as a CDER statistician where she was involved in new drug development across several therapeutic areas including infectious diseases, oncology and rare inborn errors of metabolism diseases. She has expertise in biostatistics, experimental and observational study design, infectious diseases epidemiology and FDA review processes and regulations. LaRee has held roles with the CDC, FDA, U.S. Army, and recently retired from the U.S. Public Health Service Commissioned Corps.