Executive Summary – A pediatric drug can qualify for a Priority Review Voucher (PRV) upon FDA
approval, even without receiving a Rare Pediatric Disease Designation (RPDD). While RPDD is a
common route to PRV eligibility, it is not the only pathway. This article outlines the criteria for PRV
eligibility, emphasizing the need for a designation for a rare pediatric disease, separate from RPDD. It
also highlights the benefits of RPDD, including pathway guidance and potential priority review, and
explores alternative routes for pediatric drugs to secure a PRV. Understanding these nuances is
essential for drug developers and sponsors in the rare pediatric disease space to navigate the regulatory
process effectively.

The FDA’s Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) program incentivizes the
development of treatments for serious pediatric conditions by offering PRVs to eligible drugs, which
allow manufacturers to expedite the review of a future drug application. A common question is
whether a pediatric drug can qualify for a PRV without receiving a Rare Pediatric Disease Designation
(RPDD). The short answer is yes – while RPDD offers certain advantages, it is not a strict requirement
for PRV eligibility. As long as the drug is approved through a New Drug Application (NDA) or Biologics
License Application (BLA), it can still qualify for a PRV, regardless of its RPDD status. This article discusses
the PRV eligibility criteria, the role of RPDD in the review process, and alternative pathways for pediatric
drugs that may still meet PRV requirements upon FDA approval.

1. Eligibility Criteria for PRV – To qualify for a PRV, the drug must be designated for a rare pediatric
   disease, which is defined as a disease that affects fewer than 200,000 individuals in the U.S. If a drug
   treats a pediatric condition that qualifies as a rare disease but does not receive RPDD, it may still be
   eligible for a PRV upon approval. The primary requirements include:

• Rare Pediatric Disease Designation: While RPDD is helpful, it is not a mandatory criterion for
  PRV eligibility. A drug may still qualify if it targets a rare pediatric disease—one affecting fewer
  than 200,000 people in the U.S.
• New Drug or Biologics License Application Approval: The drug must gain FDA approval under
  a New Drug Application (NDA) or a Biologics License Application (BLA), as only new, approved
  drugs are considered eligible for PRVs.
• First-to-Market Innovation: PRV-eligible drugs must provide a novel treatment, targeting an
  unmet pediatric medical need without overlapping significantly with previously approved
  therapies for the same indication.
  Case Study: bluebird bio’s recent experience with its Sickle Cell Disease therapy, Lyfgenia, illustrates the FDA’s stringent criteria for awarding a Priority Review Voucher (PRV). Although Lyfgenia received RPDD in 2020, the FDA declined to grant a PRV upon its approval, citing that the therapy included an active ingredient previously approved in Zynteglo (betibeglogene autotemcel) in 2022. Under sections 351(a) and 351(k) of the Public Health Service Act, the FDA clarified that to qualify for a PRV, the biologic must contain a novel active ingredient that has not been approved in prior applications (December 8, 2023 Approval Letter – LYFGENIA). This outcome was unexpected, as bluebird bio had entered a $103 million advance agreement with Novartis on October 30, 2023, to sell the anticipated PRV upon Lyfgenia’s approval (bluebird bio Enters into Advance Agreement to Sell Priority Review Voucher, if Granted, for $103 Million). The decision highlights the FDA’s emphasis on first-to-market innovation, demonstrating the importance of developing treatments with previously unapproved active ingredients to meet PRV eligibility.

2. Benefits of RPDD and the Path to PRV – RPDD offers several advantages for pediatric drug
   development, including an increased likelihood of securing a PRV upon approval and access to other
   expedited review benefits. When granted early, RPDD can provide clearer regulatory guidance, helping sponsors align their development programs with FDA expectations for pediatric efficacy and safety.
   Yet, while beneficial, RPDD is not essential for PRV eligibility. A drug targeting a rare pediatric disease
   may qualify for a PRV if it aligns with the FDA’s criteria for addressing unmet pediatric needs and secures marketing approval, even without an RPDD. However, achieving RPDD can improve a drug’s review pathway and likelihood of priority review, which can be beneficial for sponsors seeking accelerated approval timelines.
3. Other Designations and PRV Eligibility – In addition to RPDD, other FDA designations, such as
   Orphan Drug Designation (for rare diseases) or Breakthrough Therapy Designation, can also influence the review process and impact potential PRV eligibility. These designations can support and expedite the development of pediatric drugs, enhancing the likelihood of qualifying for a PRV:

• Orphan Drug Designation (ODD): This designation, granted to drugs for rare diseases
  regardless of age group, can help secure regulatory incentives such as tax credits and market
  exclusivity. An ODD, when combined with a pediatric indication, may strengthen a drug’s case
  for PRV eligibility, even if RPDD is absent.
• Breakthrough Therapy Designation (BTD): For drugs addressing a serious or life-threatening
  condition, BTD can offer accelerated development and review support, potentially expediting
  the path to a PRV-eligible approval.
• Fast Track and Priority Review Designations: These expedite the FDA’s review process and may
  support the rapid availability of innovative treatments, though neither guarantees PRV
  eligibility.
  

Each of these designations offers unique benefits that can complement RPDD and contribute to overall
PRV eligibility, especially for sponsors pursuing approvals for novel pediatric therapies.

4. Consulting with FDA Early for Strategic Guidance – It is crucial for sponsors to thoroughly review
   the FDA’s guidelines and consider consulting with FDA representatives early in the drug development process to understand how their specific drug candidate may align with PRV eligibility requirements.
   Given the complexity of regulatory pathways, engaging with the FDA early—through Pre-IND meetings or RPDD requests—can provide valuable insights into whether a pediatric drug qualifies for a PRV. These discussions can help clarify the nuanced differences between RPDD and PRV eligibility, as each program involves distinct criteria and levels of scrutiny. While RPDD assesses the potential to address unmet pediatric needs, PRV eligibility hinges on factors such as novelty, disease rarity, and demonstrated efficacy upon approval. Consulting the FDA early allows sponsors to refine their development plans and ensure they meet the necessary regulatory standards for both programs.
   The FDA’s input can be especially helpful in clarifying the nuanced distinctions between RPDD and PRV eligibility, as these reviews, though related, apply different levels of scrutiny to determine a drug’s fit for each program. For example, while RPDD may indicate a drug’s potential to address an unmet pediatric need, PRV eligibility depends on satisfying criteria related to novelty, disease rarity, and confirmed efficacy upon approval.

Conclusion – A pediatric drug can qualify for a PRV upon FDA approval even without receiving an RPDD,
as long as it meets the FDA’s eligibility criteria for treating a rare pediatric disease. While RPDD offers
benefits like expedited reviews and regulatory guidance, it is not a strict requirement for obtaining a PRV. Other designations, such as Orphan Drug or Breakthrough Therapy, can also play a significant role
in supporting the drug’s development and review. Early engagement with the FDA is essential for
sponsors to navigate the regulatory landscape and ensure their drug meets the PRV eligibility criteria.
This flexibility in PRV eligibility encourages the development of innovative therapies for pediatric
diseases, supporting the FDA’s broader mission to address unmet medical needs. By consulting the FDA
early and thoroughly documenting how their drug aligns with PRV requirements, sponsors can
maximize their chances of success in the complex regulatory process.

Kindly download the document here.

References – These references provide valuable insights into the FDA’s approach to orphan drug and
rare pediatric disease designations, with a particular focus on financial and regulatory incentives that
support the development of novel therapies.

1. Successfully Navigating Food and Drug Administration Orphan Drug and Rare Pediatric Disease
   Designations for AAV9-hPCCA Gene Therapy: The National Institutes of Health Platform Vector Gene Therapy Experience – PMC. This reference discusses a successful case of FDA designations for pediatric therapies, illustrating how RPDD and other designations facilitate regulatory processes for novel treatments.
2. FDA Lifecycle Management Mayer Brown Webinar Orphan Drug Exclusivity – March 16, 2023. The
   webinar provides insights into exclusivity and orphan drug pathways that impact PRV eligibility and
   highlights regulatory strategies to enhance review efficiencies for rare diseases.
3. Roberta Szydlo – FDA Office of Orphan Products Development: Financial Incentives for CDER Medical Products. Roberta Szydlo’s work highlights FDA financial incentives that encourage the development of novel therapies, including those targeting rare pediatric diseases.
4. Navigating the Rare Pediatric Disease Priority Review Voucher Program Ahead of September 2024 – Scendea. This resource examines the PRV program, providing up-to-date guidance on navigating the RPD PRV pathway, recent updates, and its impact on pediatric drug development.
5. FDA Guidance – Rare Pediatric Disease Priority Review Vouchers. This FDA guidance document clarifies the requirements and processes for PRV eligibility under the Rare Pediatric Disease program, assisting developers in aligning with regulatory expectations.
6. PRV Market Insights and Strategic Implications: Please contact the authors.

Authors
Dr. Nana Mainoo, PharmD, MA
Chief Executive Officer at Cleracs Consulting
Email: nkmainoo@cleracs.com
With over 16 years of experience in the healthcare industry, Nana has held key roles at Pfizer and Komodo Health and co-founded Medsfinder, a healthtech platform. As CEO of Cleracs Consulting, he specializes in regulatory strategy, focusing on orphan drug regulatory affairs. Nana holds a Doctor of Pharmacy from Nova Southeastern University, a Master of Arts from IE Business School, and certificates in Health Leadership and Finance from INSEAD and Cornell University, respectively, along with a Bachelor of Pharmacy from KNUST.

Christian Girard, MiM
Co-Founder at The PRV Fund Project
Email: christian@prv.fund
Christian is a co-founder of The PRV Fund, an initiative focused on providing non-dilutive funding to early-stage biotech companies developing treatments for rare pediatric-onset disorders. Christian has over 30 years professional background marked by his commitment to advancing rare pediatric disease drug development, from lab bench to approval. His involvement in this sector highlights his dedication to supporting innovative therapies aimed at improving the lives of children with rare diseases. He is a graduate of ESCP Europe, an European business school.

Dr. Jean Chatellier, PhD
Partner, EVP & Managing Director at KYBORA
Email: jean@kybora.com Jean is a Partner and EVP at KYBORA, a global advisory firm specializing in M&A, licensing, fundraising, and strategic advisory services in biopharma. He contributed to the divestiture of Bayer’s PRV to argenx for $98M [1]. With over 24 years of experience, he has held key leadership roles, including CBO at Besins Healthcare and pivotal
positions at Avadel Pharmaceuticals, Micromet (now Amgen), and Crucell (now J&J). He was the founding CEO of Avidis (now Osivax) and has worked with Nobel laureates during his postdoctoral research. Jean holds a PhD in Biochemistry and Molecular Biology and has led significant industry partnerships and transactions throughout his career.

[1] On November 2020, argenx enters into agreement to acquire Priority Review Voucher https://www.globenewswire.com/newsrelease/2020/11/23/2131371/0/en/argenx-Enters-Into-Agreement-To-Acquire-Priority-Review-Voucher.html