Pediatric Study Plans: BIO Comments on FDA Draft Guidance on Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the &ldquo;Draft Guidance for Industry on Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans.&rdquo; BIO commends FDA on the release of this Draft Guidance and shares the Agency&rsquo;s commitment to ensure that safe and effective medicines are available for children.</p>

A. Comprehensive Approach to Pediatric Drug Development
BIO strongly supports a comprehensive approach to pediatric drug development crafted in the best interests of children and greatly appreciates recent public comments made by FDA leadership championing this approach.
Recognizing that drug development is typically planned across multiple indications over many years and is dependent upon complex factors that ultimately determine the feasibility of studies in distinct populations across these indications, the Pediatric Research Equity Act (PREA) limited required pediatric studies to the adult indication under investigation. FDA should, therefore, continue to be clear about what is required in the Pediatric Study Plan (PSP) under PREA, as amended by the Food & Drug Administration Safety and Innovation Act (FDASIA).
BIO believes, however, that these statutory obligations do not preclude the Agency from embracing a more comprehensive approach to pediatric drug development. BIO recommends that FDA:
  1.  Allow Sponsors the option to include, in addition to the required components of the PSP under PREA, information needed to support discussion of additional, potentially beneficial, yet non-obligatory, pediatric uses of a product under the Best Pharmaceuticals for Children Act (BPCA),
  2.  Reward this optional disclosure by agreeing to review and provide comments on these additional, non-binding proposals as they may apply to the Sponsor’s future Proposed Pediatric Study Requests (PPSRs) and, ultimately, issuance of Written Requests for Exclusivity, and
  3. Clarify that any changes to these optional studies included in the initial PSP will not require an amendment to an agreed-upon initial PSP.
BIO strongly believes this optional, earlier dialogue on a comprehensive pediatric drug development plan, including both required research under PREA and potential pediatric uses under BPCA, will result in a more efficient pediatric drug development process. Please see the attached table of specific comments for suggested edits of, and insertions to, the text of the draft guidance to facilitate this approach.

B. Review Timelines for Initial and Amended PSPs and Communication Regarding Requests for Waivers/Deferrals

The deadlines by which the Sponsor should submit a PSP are given in Section IV, but the timeline for PSP review is not outlined in the draft guidance. BIO believes that including the timelines for the PSP process outlined in Section 506 of FDASIA and the current Pediatric and Maternal Health Staff (PMHS) Standard Operating Procedure (SOP) for Review of Pediatric Study Plans (PSPs) and Written Requests by the Pediatric Review Committee (PeRC) would provide greater clarity to the draft guidance. BIO also requests that FDA clarify whether the full review process (i.e., 210 days) should be expected for amendments to the PSP and whether the PSP can be amended prior to submission or during review of a Biologics License Application/New Drug Application (BLA/NDA) or applicable supplemental application, if the information to be updated is unrelated to the application being submitted (i.e., to clarify commitment dates or potential changes to deferred studies due to enrollment or retention issues, design issues, etc.).


While BIO welcomes earlier, more formal agreement on Pediatric Study Plans, there is still a disconnect between the timing of FDA’s agreement on a PSP and, where applicable, final waiver/deferral decisions. BIO believes that, at a minimum, it would be useful for Sponsors to receive a recommendation as to whether their requests meet the standards specified in Section 505B(a)(3) and 505B(a)(4) of the Food, Drug, and Cosmetic Act.
If this issue is not addressed, earlier PSP agreements may not ultimately translate into earlier or more efficient pediatric drug development. If final waiver/deferral decisions are not made until the time of approval, FDA should describe (1) the circumstances under which changes to an agreed-upon initial PSP, with respect to waivers/deferrals, will be made; (2) how and when they will be communicated to the applicant, noting that the earlier in the review process the better for Sponsors; and (3) how these changes could affect approval of the application.
Furthermore, in order for comprehensive planning (discussed above) to facilitate more efficient pediatric drug development, it will also be imperative for Written Requests for Exclusivity to be issued in a timely manner in response to Sponsors’ Proposed Pediatric Study Requests (PPSRs).


C. Nonclinical Studies in Juvenile Animals
To provide a unified approach to assessing the safety of therapeutics for pediatric populations, the need for nonclinical studies in juvenile animals should be aligned with, and reference, established guidance for nonclinical safety studies, as follows:
  • ICH M3 (R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
    •  Section 12: Clinical Trials in Pediatric Populations
  • ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals
    • Section 3.6: Nonclinical Studies to Support Trials in Pediatric Populations
The aforementioned International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance documents require an integrated assessment of the totality of the data (e.g., drug target, completed nonclinical and clinical study results, patient population, disease indication, and the strengths/limitations of existing nonclinical models available) to evaluate safety concerns unique to pediatric patients and determine the questions that could be appropriately addressed by juvenile toxicity studies. This approach is essential to providing the most thorough scientific assessment of safety for pediatric patients, as well as maintaining Agency and Sponsor commitments to the 3Rs of Animal Testing (Reduce, Refine, Replace)1, which aim to eliminate unwarranted animal studies.
Alignment with ICH M3 (R2) and ICH S9 also provides consistency with EMA/CHMP/SWP/169215/2005: Guideline on the Need for Non-Clinical Testing in Juvenile Animals of Pharmaceuticals for Paediatric Populations. That guidance also relies on an evaluation of the totality of the available data against the unique considerations of the pediatric population under consideration to determine whether additional toxicity studies will provide clinically meaningful data. Compliance with these established guidance documents will more effectively support global drug development.
D. Global Pediatric Development
BIO recommends that FDA and the European Medicines Agency (EMA) work collaboratively to harmonize their regional programs in order to promote more efficient pediatric drug development. BIO has been engaged in, and supportive of, the development of many aspects of the current FDA pediatrics program and looks forward to the opportunity to provide input on the development of any harmonized documents and procedures at the appropriate time. Recognizing, though, that harmonization will be a lengthy and complex process, BIO does not believe efforts to achieve harmonization should delay the finalization of this draft guidance.