As pharmaceutical consultants engaged in the compilation and submission of marketing applications, we are frequently called upon by our clients to address all or part of their BPCA and PREA needs. This paper is meant to serve as a review and primer for anyone at the Pre-IND stage or who is confronted with the need for help with an iPSP, including a waiver or deferral request.
What are BPCA and PREA?
BPCA stands for Best Pharmaceuticals for Children Act. PREA is the Pediatric Research Equity Act. Together, these two legislative acts play a primary role in governing pediatric drug studies and pediatric drug and biologic labeling. See FD&C Act: section 505A (BPCA) and section 505B (PREA). Each was made permanent in the 2012 Food and Drug Safety and Innovation Act (FDASIA). The background stories of both PREA and BPCA date back to at least 1979 when FDA first issued a rule requiring pediatric indications, if any, to be contained within drug labeling (“Indications and Usage” and “Dosage and Administration” sections). The 1979 rule did not have the intended effect of encouraging drug sponsors to conduct pediatric studies, or of appropriately labeling products for children. In 1994, FDA announced two new initiatives, marking the beginning of the contemporary history of both BPCA and PREA. That history is included as Appendix 1 of this paper and is excerpted from recent guidance.
PREA/BPCA Similarities and Differences
PREA requires that sponsors study their products in pediatric patients under certain circumstances. Known as pediatric assessments, when such studies are required, they must be conducted using the same drug and indication for which they were approved in adults. BPCA, on the other hand, provides incentive for sponsors to conduct FDA-requested pediatric studies by granting six additional months of marketing exclusivity; and facilitates FDA requests for studies that cannot be required under PREA.
It is useful to think of BPCA as the pediatric carrot and PREA as the pediatric stick, with the shared goals of developing new pediatric data/drug labeling to encourage appropriate pharmacotherapy in pediatric populations. Here are a few of the differences and similarities according to FDA’s “CDER World”:
- PREA studies are mandatory; BPCA studies are voluntary.
- PREA requires studies only on indication(s) under review; BPCA studies relate to an entire moiety and may include unapproved and different indications.
- Studies for orphan indications are exempt from PREA; however, written requests may be issued for orphan indications under BPCA.
- PREA and BPCA cover drugs and biologics.
- PREA/BPCA pediatric studies must be labeled.
BPCA essentially provides an avenue for FDA to request pediatric assessments (including either or both clinical and non-clinical studies) via a written request (WR). FDA is authorized to request assessments on both approved and unapproved pediatric indications. For example, “if valproic acid or divalproex sodium is submitted for a new approval to treat seizures in adults, the PREA requirement would be to submit for a new approval to treat seizures in children or the same indication. However, under BPCA, FDA can request studies for migraine, migraine prophylaxis, and for the treatment of mania since the drug also treats those indications.” In addition, FDA may submit a WR for pediatric assessment based on a public health need, e.g. when a product is being used off-label in pediatric populations.
Except for orphan drugs, PREA requirements apply to NDAs and BLAs for new active ingredients, indications, dosage forms, dosing regimens, or routes of administration. Sponsors must submit, as part of the application, pediatric assessments including data adequate to gauge the safety and effectiveness of the medicinal product for each indication and relevant pediatric subpopulation. Pediatric assessments serve the dual purposes of assessing safety and effectiveness of claimed pediatric indications, as well as determining adequate dosage and administration for those pediatric claims in which the product has been proven to be safe and effective. Because studies must utilize an appropriate formulation for each tested age group, the sponsor may be required to develop and test a new formulation. There is no requirement that the studies demonstrate safety and efficacy for any pediatric use. Indeed, pediatric studies have yielded important negative findings resulting in warnings that products are not safe and should not be administered in certain pediatric settings.
The Initial Pediatric Study Plan or iPSP
Before pediatric assessments are conducted, the FD&C Act requires the sponsor to submit an iPSP to include “’(i) an outline of the pediatric study or studies that the sponsor plans to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach); (ii) any request for a deferral, partial waiver, or waiver… if applicable, along with any supporting information; and (iii) other information specified in the regulations’ promulgated by the FDA… In certain situations, it may be premature to include a detailed outline of a planned pediatric study (or studies) because additional data are needed (e.g., efficacy, safety, potential endpoints). In such cases, the outline of the pediatric studies should include a brief explanation for not including more detailed information.” Marketing applications and/or supplements should not be submitted until agreement has been reached on the iPSP. It should be noted that the iPSP doesn’t lose the “i” and become the PSP until the marketing application for the product is approved. Sponsors may amend iPSPs at any time prior to approval of the marketing application.
When PREA was made permanent under FDASIA in 2012, a provision was included that required sponsors to submit an iPSP early in the development process. Because the purpose of the iPSP is to facilitate sponsor/FDA recognition of, and planning for, needed pediatric studies, the Pre-IND stage is the optimal time for work on the iPSP to begin. However, FDA provides specific development timelines as follows:
A sponsor must submit the iPSP before the date on which the sponsor submits the required assessments and not later than 60 calendar days after the date of the end-of-phase 2 meeting. In the absence of an end-of-phase 2 meeting, the sponsor should submit the iPSP as early as practicable but before the initiation of any phase 3 studies, or any combined phase 2 and phase 3 studies, of the drug that is the subject of the iPSP. If a phase 3 study, or a combined phase 2 and phase 3 study, will not be conducted, the sponsor should submit the iPSP no later than 210 calendar days before it submits a marketing application or supplement. A sponsor should submit the iPSP to its IND for the drug. In cases when there is no active IND for the drug, but the sponsor expects upon submission of the IND that the initial studies would include a phase 3 study, the iPSP should be submitted as a pre-IND submission. In this situation, the FDA encourages sponsors to schedule a pre-IND meeting before submission of the iPSP, and, as stated above, the sponsor should submit the iPSP before the initiation of any phase 3 studies or combined phase 2 and phase 3 studies.
After an iPSP is submitted by the sponsor, the FDA has 90 days to review the iPSP and provide comments to the sponsor. A second 90-day review period is initiated after the sponsor has received these comments. By the end of this second 90-day review period, the sponsor must submit an agreed iPSP. The FDA then has 30 days to review and issue correspondence confirming agreement, or issue correspondence stating that the FDA does not agree. If the FDA does not agree, the iPSP is considered a non-agreed iPSP (see section VIII., Non-Agreed Initial Pediatric Study Plans). The total length for review of an iPSP is 210 days.
Deferral/Waiver of Pediatric Assessments
FDA may waive, partially waive or defer pediatric studies. FDA decisions are not finalized until the subject marketing application is approved. Information contained in an agreed upon iPSP, which precedes pediatric assessments, if any, is considered in FDA’s review of requests for waiver and/or deferral as part of the application review process. Hence, the iPSP is required regardless of the perceived necessity of pediatric assessments. While final decisions as to waivers and deferrals are not formalized until approval, FDA does provide feedback on these requests during review of the marketing application.
Deferral of Pediatric Assessment Requirements
FDA may on its own initiative, or based on sponsor request, defer pediatric assessment submission(s) until a certain time after approval. Reasons for deferral may include that “the drug or biologic is ready for approval for use by adults before pediatric studies are complete; additional safety or effectiveness data should be collected before pediatric studies are initiated; or another appropriate reason exists.”
Requesting a Deferral
Deferral requests must include certification of the grounds for deferral to FDA, description of planned or ongoing studies, proof that the studies are or will be conducted, schedule for completing the studies and annual reporting of progress.
Waiver of Pediatric Assessment Requirements
As with deferrals, FDA may on its own initiative, or based on sponsor request, fully or partially waive the pediatric assessment requirement for all or specific pediatric age groups. It should be noted that if FDA grants a waiver based on evidence that a drug or biologic would be ineffective or unsafe in pediatric populations, that labeling for the product must reflect those findings.
Criteria for full waivers include that studies are impossible or highly impractical to conduct, evidence exists that strongly suggests the product would be ineffective or unsafe in all pediatric age groups, the product does not envisage meaningful benefit over existing therapies or is otherwise not likely to be used in significant numbers by pediatric patients of any age. The criteria for partial waivers are like those for full waivers, except that partial waivers may be granted if the sponsor cannot produce a pediatric formulation for that age group. Such a waiver would only cover only the pediatric groups requiring that formulation.
Requesting a Waiver
To request a waiver, FDA recommends that the sponsor provide: Product name, applicant name, indication, age group(s) in waiver request, statutory reason(s) for waiver (including reference to the applicable statutes), evidence that the request is consistent with the statutory reason(s) for waiver and applicant certification.
PDG can help you write your iPSP, interface with FDA, write your pediatric protocols and/or request a waiver or deferral of required pediatric assessments.
About the Authors
Charles Jaap is Vice-President of Operations and Business Development for PDG®, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices.
Mikel Alberdi, MPH, RAC is Director of Regulatory Affairs/New Product Development for PDG®. He has over 15 years of regulatory affairs experience, with expertise in facilitating FDA meetings and compiling NDA, 505(b)(2), and ANDA submissions.
The opinions and statements in this paper are solely those of Charles Jaap and Mikel Alberdi and do not necessarily reflect those of PDG®.
Contemporary History of BPCA and PREA, Excerpted from Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry DRAFT GUIDANCE, March 2016.
Over the last 2 decades, the FDA has worked to address the problem of inadequate testing of drugs in pediatric populations and inadequate pediatric use information in drug and biological product labeling. In 1994, the FDA published a final rule that required manufacturers of marketed drugs to survey existing data and determine whether those data were sufficient to support adding pediatric use information to the drug’s labeling. However, the 1994 rule did not impose a general requirement that manufacturers carry out studies when existing information was not sufficient to support adding pediatric use information. This initial attempt to encourage sponsors to submit pediatric studies and plans to sufficiently inform use of drugs in pediatric patients was not successful in achieving adequate labeling for most drugs and biological products regarding use in the pediatric subpopulation, and product labeling frequently failed to provide directions for safe and effective use in pediatric patients.
To address this continued problem, the Food and Drug Administration Modernization Act of 1997 was signed into law and contained provisions that established incentives for conducting pediatric studies on drugs for which exclusivity or patent protection exists. Also, on December 2, 1998, the FDA published a regulation known as the pediatric rule. This rule partially addressed the lack of pediatric use information by requiring manufacturers of certain new and marketed drugs and biologics to conduct studies to provide sufficient data and information to support directions for pediatric use for the claimed indications. The pediatric rule also stated that the FDA would provide sponsors with its best judgment on whether pediatric studies will be required and whether their submission will be deferred until after approval. This input was given by the FDA at the end-of-phase 1 meeting, for drugs and biologics for life-threatening diseases, and at the end-of-phase 2 meeting, for other drugs, as described in other FDA regulations.
The pediatric rule also stated that sponsors should submit, at least 1 month in advance of the end-of-phase 2 meeting, certain background information, including a proposed timeline for protocol finalization, enrollment, completion, and data analysis, or, in the alternative, information to support a planned request for waiver or deferral. However, on October 17, 2002, the U.S. District Court for the District of Columbia held that the FDA had exceeded its statutory authority when issuing the pediatric rule and the court suspended the rule’s implementation and enjoined its enforcement.
Congress subsequently passed PREA, which was signed into law on December 3, 2003. Many of the provisions described under the pediatric rule were adopted under PREA. Under PREA as originally enacted and under its reauthorization under the Food and Drug Administration Amendments Act of 2007, a proposed timeline and plan for the submission of pediatric studies were not required to be submitted during the investigational new drug application (IND) phase of drug development. Under FDASIA, signed into law on July 9, 2012, for the first time PREA includes a provision that requires sponsors planning to submit an application for a drug subject to PREA to submit an iPSP early in the development process. The intent of the iPSP is to identify needed pediatric studies early in development and begin planning for these studies. The timing and content of the submission of an iPSP are described below. FDASIA requires the FDA to promulgate regulations and issue guidance to implement these and other provisions. The FDA is issuing this guidance and intends to publish a proposed regulation consistent with FDASIA.