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W-35: Regulatory Flexibility in the Review of Biologics for Rare Diseases

Poster Presenter

Julienne Vaillancourt

Rare Disease Liaison, CBER
FDA
United States

Objectives

To evaluate how CBER exercises regulatory flexibility in the review of biologics for rare diseases as part of CBER’s plan to meet the PDUFA VI commitment to advance development of biological drug products for rare diseases by reviewing recent end of phase 2 (EOP2) meeting minutes.

Method

Using CBER’s IND and meetings databases we identified biologics intended for rare diseases, for which an EOP2 meeting was held between 7/1/2016 and 6/30/2018. A two-tiered review of each set of EOP2 meeting minutes was done to identify CBER’s consideration of certain flexible approaches. Co-authors: Tejashri Purohit-Sheth Diane Maloney Celia Witten

Results

We identified 16 rare disease biologic development programs, for which an EOP2 meeting was held between a CBER review office and the respective sponsor during the 2-year interval. Of these 16 investigational products, 13 had orphan designation for the intended indication. Fourteen of the 16 biologics were cell and gene therapy products, half being for the treatment or management of a rare cancer. For each of the 16 rare disease biologic programs, we found documentation in the EOP2 minutes that one or more of the following five flexible and feasible approaches were being considered by the review office at that point in development: a non-traditional clinical development program, evaluation of a novel endpoint, innovative use of a biomarker, use of an adaptive study design, and application of a new approach to statistical analysis. From our review of the EOP2 meeting minutes, we found that use of a non-traditional clinical development program was the most frequently considered flexible and feasible approach, as documented for 13 biologic programs, evaluation of a novel endpoint was the second most frequently considered flexible approach, as documented for 12 biologic programs, followed by innovative use of a biomarker, as documented for six biologic programs. The other two approaches, use of an adaptive study design and application of a new approach to statistical analysis, were each documented in five biologic programs’ EOP2 meeting minutes. Also, we found that concurrent consideration of multiple approaches was more frequent than consideration of a single approach by review offices at EOP2 for these rare disease biologic development programs, with four programs having two approaches, five programs having three approaches, and four programs having four approaches under simultaneous consideration. In this regard, the flexible approaches most frequently considered together were a non-traditional development program and evaluation of a novel endpoint.

Conclusion

The results demonstrate that CBER consistently considers flexible and feasible approaches in the review of biologics for rare diseases. Our decision to evaluate FDA’s official EOP2 meeting minutes for evidence of consideration of the five approaches was based on our view that they document a critical point in clinical development. We recognize that our study is a snapshot in time for each rare disease biologic along its own development continuum. It excludes rare disease biologic development programs, for which an EOP2 meeting was not held, and also excludes potentially relevant information that was not captured in the EOP2 minutes. Our evaluation was conducted by the CBER Rare Disease Program as a first step in implementing CBER’s commitment to ensure that its review offices consider certain flexible and feasible approaches in review of biological drug development programs for rare diseases as specified in FDA’s commitment letter for the Prescription Drug User Fee Act (PDUFA) reauthorization for fiscal years (FY) 2018-2022, known as PDUFA VI. Examples of such approaches listed in the commitment letter include use of four expedited development and review programs available to CBER and five other approaches. Data concerning CBER’s consideration of expedited approaches are available in CBER’s databases and routinely tracked. Since this is not the case for the other five approaches, we designed and conducted this study. Data from EOP2 minutes for this evaluation were identified in a first review by a pharmacy intern and validated by medical officers familiar with the program. Given these results, we do not see a need to conduct a second evaluation with an expanded scope. Instead, data from this evaluation will be used as the basis for educational and information-sharing activities as part of CBER’s Rare Disease Program to continue implementing the related PDUFA VI commitment through FY 2022.