Navigating the Rare Pediatric Disease Priority Review Voucher Program Ahead of September 2024
Author:
Iheoma Anosike
Senior Consultant
Introduction.
The rare pediatric disease priority review voucher (RPD PRV) program was introduced by the US Food and Drug Administration (FDA) in 2012 with the aim of incentivizing drug development for new medicines targeting rare pediatric diseases. The program may be used alone or in combination with other incentive programs available for rare diseases and pediatric populations.
Under the RPD PRV program, Sponsors who receive an approval for a drug or biological product for a rare pediatric disease may qualify for a voucher that can be redeemed to receive priority review for a subsequent application. Sponsors also have the option of transferring the voucher to a different Sponsor.
This paper provides useful information relating to the rare pediatric disease designation (RPDD) and RPD PRV program, with important considerations for Sponsors ahead of the upcoming 30 September 2024 sunset date.
Rare Pediatric Disease Designation.
What is a Rare Pediatric Disease Designation?
The RPDD is available for therapeutic and diagnostic small molecule and biological products under development for the treatment or prevention of rare childhood diseases. Throughout this paper, unless specified, the term ‘drug’ will refer to both therapeutic and diagnostic products. By definition, a rare pediatric disease must be a serious or life-threatening condition with serious or life-threatening manifestations primarily affecting individuals from birth to the age of 18 years. In addition, the disease must not affect more than 200,000 persons in the US. If more than 200,000 persons are affected, there must be a reasonable expectation that the cost of developing the drug will not be recovered from sales of the drug in the US. It should be noted that prevalence estimates for diagnostic drugs must be based on the number of persons of all ages to whom the drug will be administered to in the US annually.
Rare Pediatric Disease Designations and Rare Pediatric Disease Priority Review Vouchers
A RPDD is not a pre-requisite for obtaining a RPD PRV (please see section ‘Requesting a Rare Pediatric Disease Priority Review Voucher’ for more information). However, the FDA strongly recommends that Sponsors request a RPDD if a RPD PRV request is planned to be submitted at the time of filing the New Drug Application (NDA) / Biologics License Application (BLA).
Under the current sunset provisions in place for the RPD PRV program at the time of publishing this paper, the FDA will not award a RPD PRV after 30 September 2024 unless the application is approved by 30 September 2026 and is for a drug that was designated for a rare pediatric disease by 30 September 2024. Obtaining a RPDD ahead of the sunset date would allow Sponsors who are interested in requesting a RPD PRV within the next two years, to remain eligible to do so. In addition, Sponsors who have been awarded a RPDD will not need to submit an amended prevalence estimate at the time of the RPD PRV request.
Requesting a Rare Pediatric Disease Designation
Requests for a RPDD should be submitted ‘at the same time as’ an orphan drug designation (ODD) request or an application for fast-track designation (FTD) for the same drug. The FDA will consider the requests as submitted at the same time if the applications are received by the FDA within two weeks of each other. Sponsors should indicate in the RPDD request whether or not it is requesting ODD or FTD at the same time as the RPDD request. The FDA will accept cross-references to information presented in an ODD request if the RPDD request is submitted concurrently or shortly after the ODD request. This approach will aid in expediting the preparation of a potential RPDD request.
The submission of a RPDD request at a different time to an ODD or FTD application is also acceptable, however, Sponsors should note that the 60 day review period for the RPDD request does not apply in such situations (refer to section ‘Rare Pediatric Disease Designation Request Review Timelines’ for further information).
A RPDD request should include details on the Sponsor, a description of the rare pediatric disease for which the serious and life-threatening manifestations primarily affect children, information on the product including supportive data to demonstrate that the drug may be effective in treating or preventing the disease, and a justification that the drug will be used for a rare condition based on the prevalence of the affected patient population or the number of persons whom the drug will be administered to in the US.
Requests for the RPDD must be submitted before the Sponsor’s filing of a marketing application for the drug. Applications for RPDD are emailed to orphan@fda.hhs.gov or can be sent by mail to the FDA’s Office of Orphan Products Development.
Rare Pediatric Disease Designation Request Review Timelines
Following submission of a request for RPDD, the FDA will decide on the request no later than 60 days from receipt of the application. This review period is only applicable for RPDD requests submitted with an additional designation request (e.g. ODD or FTD). The FDA will aim to respond to RPDD requests submitted alone in a timely manner, however the statutory 60 day response timeline does not apply.
Following review of the RPDD request, the FDA will provide one of the following responses:
Deficiency letter requesting for further information.
Approval of the RPDD request and denial of the designation of the potential marketing application as a rare pediatric disease product application.
A denial for the potential marketing application will be issued if at the time of the RPDD request, it appears that the application will fail to meet at least one of the criteria required to be considered a rare pediatric disease product application (refer to section ‘Requesting a Rare Pediatric Disease Priority Review Voucher’ for further details). Sponsors who have been denied the designation for the potential marketing application may still request for a RPD PRV in the eventual NDA/BLA submission.
Approval of the RPDD request and conditional designation of the potential marketing application as a rare pediatric disease product application.
Following approval of the eventual NDA/BLA submission, the FDA will confirm whether the marketing application is a rare pediatric disease product application and if a RPD PRV will be awarded.
Denial of the RPDD request and denial of the designation of the potential marketing application as a rare pediatric disease product application.
Even if a Sponsor is denied a RPDD, the Sponsor may still request for a RPD PRV at the time of NDA/BLA submission.
Although RPDDs are not publicly disclosed, since the inception of the RPD PRV program through 31 December 2022, there were 569 RPD designations, with 38 RPD PRVs awarded from 2014 to 20221.
Whilst the FDA will endeavour to respond to RPDD requests within the applicable timelines, due to limited resources available to review such requests and the likely surge in submitted requests ahead of the 30 September 2024 sunset date, meeting the review timelines may not always be feasible. If the FDA is unable to grant a request for RPDD by 30 September 2024, a marketing application for that drug cannot be eligible for a RPD PRV under the current provisions of the law.
Rare Pediatric Disease Priority Review Vouchers.
What is a Rare Pediatric Disease Priority Review Voucher?
Under section 529(a)(2) of the Federal Food, Drug, and Cosmetic (FD&C) Act, a RPD PRV is a voucher that the FDA issues to a Sponsor of a rare pediatric disease product application at the time of the marketing application approval. This voucher entitles the holder to designate a single human drug application submitted under section 505(b)(1) of the FD&C Act or section 351 of the Public Health Service (PHS) Act as qualifying for a priority review and therefore regulatory review within 6 months of receipt of the application, instead of the standard 10 month review period. Such subsequent human applications would not have to meet the usual requirements for a priority review but would have to be submitted after the approval of the rare pediatric disease product application.
Requesting a Rare Pediatric Disease Priority Review Voucher
To apply for a RPD PRV, Sponsors must include a request for the voucher in the original NDA/BLA submission. To be awarded the voucher, the NDA/BLA must be a rare pediatric disease product application.
To be classed as a rare pediatric disease product application, the following criteria must be met (as defined in Section 529(a)(4) of the FD&C Act):
The application must be a human drug application for a drug or biological product.
The application must be submitted under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) or Section 351(a) of the Public Health Service Act.
The indication must be for the prevention or treatment of a rare pediatric disease.
The drug or biological product must not contain an active moiety or active ingredient hat has previously been approved in any other application under Section 505(b)(1), 505(b)(2) or 505(j) of the Federal Food, Drug, and Cosmetic Act (for a small molecule drug) or under section 351(a) or 351(k) of the Public Health Service Act.
The application must be approved by the FDA.
The FDA must deem the application eligible for priority review.
The application must rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.
The application must not seek approval for an adult indication in the application.
Although Sponsors are not required to have been awarded a RPDD in order to receive a RPD PRV, it is advisable to obtain a RPDD in advance to facilitate the preperation of the RPD PRV request. Furthermore, after 30 September 2024, a RPD PRV may only be awarded if the drug has been awarded a RPDD (no later than 30 September 2024) and the NDA/BLA is approved by 30 September 2026.
The RPD PRV request should be prominently marked “Rare Pediatric Disease Priority Review Voucher Request” and be included or referenced in a cover letter at the time of NDA/BLA filing. The request for a voucher should describe how the application meets the eligibility criteria outlined in Section 529(a)(4) of the FD&C Act for a rare pediatric disease product application. Sponsors who have received a RPDD for the drug should include the designation letter with the voucher request and need not re-analyze the prevalence estimates at the time of the marketing application submission; cross-references to the information in the designation request will be sufficient. If the designation request has been denied or withdrawn, the voucher request should include new prevalence estimates as of the time of NDA/BLA submission.
The priority voucher is issued at the time of marketing application approval and designates a single human drug application submitted under Section 505(b)(1) of the FD&C Act or Section 351 of the PHS Act as qualifying for priority review. This subsequent application would not be limited to drugs for rare pediatric diseases.
Using a Rare Pediatric Disease Priority Review Voucher
The Sponsor redeeming the voucher must notify the FDA of its intent to submit an application with a RPD PRV, at least 90 days before submission of the NDA/BLA and also must include the intended submission date. Upon submitting this notification to FDA, the sponsor is obligated to pay the priority review user fee. This fee is not subject to waivers, exemptions, reductions or refunds.
The Sponsor of a rare pediatric disease drug receiving a priority review voucher may transfer (including by sale) the voucher to another Sponsor. The voucher may be further transferred any number of times before the voucher is used, as long as the Sponsor making the transfer has not yet submitted the application. The reported purchase prices of RPD PRVs to third parties has been estimated to average approximately $100 million (USD), with a range of $67.5 million to $350 million (USD)1. Each person to whom a voucher is transferred must notify the FDA of the change of voucher ownership within 30 days after the transfer. The notification must include a letter from the previous owner to the current owner and a letter from the current owner to the previous owner, each acknowledging the transfer. Any sponsor redeeming a voucher should include these transfer letters in the application submitted to FDA.
Sponsors of the approved rare pediatric disease product application should note the annual requirement to submit a report to the FDA, for each of the first four post-approval years.
The report must provide the following information:
The estimated population in the US with the rare pediatric disease for which the product was approved (both the entire population and the population aged 0 through 18 years).
The estimated demand in the US for the product.
The actual amount of product distributed in the US.
Sponsors should submit such reports to the review division or office within CDER or CBER that reviewed the NDA/BLA for the rare pediatric disease product.
The report should be prominently marked ‘Rare Pediatric Disease Product Post-Approval Report’. Sponsors should also note that under section 529(e)(1), the FDA may revoke a priority review voucher if the rare pediatric disease drug for which the voucher was awarded is not marketed in the U.S. within 1 year following the date of approval.