Executive Summary – The FDA’s “not same active moiety” principle plays a key role in evaluating eligibility for Rare Pediatric Disease Designation (RPDD) and Priority Review Vouchers (PRV), with different levels of scrutiny applied at each stage. While RPDD primarily assesses whether a drug addresses a rare pediatric condition and shows potential efficacy, it does not rigorously evaluate the uniqueness of the active moiety against approved drugs. The PRV review, conducted at the time of marketing approval, thoroughly examines whether the drug’s active moiety is novel, ensuring that PRVs incentivize truly innovative treatments. For instance, Argenica Therapeutics’ compounds ARG-006 and ARG-007, both designated for hypoxic-ischemic encephalopathy (HIE), may only receive separate PRVs if they prove distinct in active moiety during FDA’s PRV assessment. This structured approach ensures that PRVs reward novel therapies, supporting the FDA’s mission to advance treatments for rare pediatric diseases by fostering true innovation. By law, for a drug to qualify for RPDD, its active ingredient, including any ester or salt of the active ingredient, must not have been previously approved under Sections 505(b)(1), 505(b)(2), or 505(j) of the FD&C Act, or Sections 351(a) or 351(k) of the Public Health Service Act.
The FDA’s evaluation of the “not same active moiety” principle is pivotal in determining eligibility for RPDD and PRV awards. These two stages differ in their focus and the timing of their assessments, leading to potential misunderstandings about the conditions required for each. This article will clarify how the FDA applies this principle at both stages and the implications it has for drug sponsors seeking to advance treatments for rare pediatric conditions.
The Role of RPDD in Addressing Rare Pediatric Needs – The Rare Pediatric Disease Designation (RPDD) is a regulatory incentive granted by the FDA to encourage the development of treatments for rare diseases that primarily affect individuals aged from birth to 18 years. When the FDA evaluates a candidate for RPDD, the main criteria include whether the treatment addresses a rare pediatric disease and if there is a strong scientific basis for potential efficacy. The FDA also considers whether the disease is serious or life-threatening.
The RPDD process involves some consideration of whether the drug is the “same” as a previously approved drug. For small molecules, this refers to a previously approved active moiety. For macromolecules, it involves structural features. However, the primary intent of the RPDD is to identify promising therapies addressing unmet pediatric needs rather than rigorously enforcing the “not same active moiety” principle. However, the law explicitly requires that the active ingredient (including esters or salts) must not have been previously approved under Sections 505(b)(1), 505(b)(2), or 505(j) of the FD&C Act, or Sections 351(a) or 351(k) of the Public Health Service Act.
PRV Evaluation and the “not same active moiety” Principle – The PRV assessment takes place later, during the drug’s marketing approval process. Here, the “not same active moiety” principle becomes a crucial factor. This stage involves a stringent review to confirm that the drug or biological product does not contain an active moiety identical to that of any previously approved treatments. This requirement ensures that the PRV program only rewards genuinely novel treatments, maintaining the program’s focus on incentivizing innovation in rare pediatric diseases. At this stage, the scrutiny for determining ‘sameness’ is equivalent to the standard applied for RPDD eligibility, ensuring that only unique active moieties receive PRVs.
To qualify for a PRV, a drug must:
1. Have a novel active moiety distinct from any previously approved drugs.
2. Receive approval under a New Drug Application (NDA) or Biologics License Application (BLA).
3. Satisfy other eligibility criteria, such as being submitted after the Creating Hope Act’s enactment and not having previously been awarded a PRV under other provisions.
This “not same active moiety” principle in the PRV review provides an extra layer of scrutiny to ensure the uniqueness and novelty of the treatment. For example, if two similar therapies with RPDD for the same rare pediatric indication are reviewed for market authorization, only one PRV may be issued if the FDA determines they share the same active moiety. If they can substantiate structural differences or fulfill requirements for clinical superiority, both may qualify for separate PRVs.
Case Study: Argenica Therapeutics and Hypoxic-Ischemic Encephalopathy – A recent example that demonstrates these principles involves Argenica Therapeutics’ investigational therapies, ARG-006 and ARG-007. Both compounds received RPDD status for targeting hypoxic-ischemic encephalopathy (HIE). ARG-006 is preparing for Phase 1 trials, expected to start in 2024, while ARG-007 has recently completed Phase 1, showing safety and tolerability, and has entered a Phase 2 trial focusing on efficacy in acute ischemic stroke.
If one or both of these therapies eventually receive market approval, the FDA will assess PRV eligibility based on the “not same active moiety” criterion, which could determine whether each drug qualifies for a distinct PRV. Although RPDD helps propel drugs addressing rare pediatric diseases through development, it does not assure a PRV, nor does it exclude one. This two-tiered review structure enables the FDA to rigorously assess the unique qualities of each candidate at different points, safeguarding the PRV program’s role in driving true innovation. This includes verifying that neither compound contains an active ingredient or derivative previously approved under the specified sections of the FD&C Act and Public Health Service Act.
Practical Implications for Sponsors – Understanding the nuances of RPDD and PRV eligibility can help drug developers strategically navigate the FDA’s regulatory pathways:
1. RPDD Requirements: Emphasize the unmet need for rare pediatric conditions and provide a strong scientific basis for potential effectiveness, focusing less on active moiety distinctions.
2. PRV Requirements: Prepare a robust case for the novelty of the drug’s active moiety when seeking marketing approval. For compounds that are structurally similar to existing therapies, demonstrate meaningful structural or clinical superiority to strengthen eligibility for multiple PRVs.
Conclusion – The FDA’s “not same active moiety” principle is central to determining eligibility for Rare Pediatric Disease Designation (RPDD) and Priority Review Vouchers (PRV), applying different levels of scrutiny at each phase. While RPDD focuses on whether a drug addresses a rare pediatric need and has scientific rationale, it does not rigorously assess the uniqueness of the active moiety at that stage. It is important to note that RPDD is not awarded to drugs that have already been approved by the FDA, emphasizing the need for novel treatments that fill critical gaps in pediatric care. In contrast, during the PRV review at marketing approval, the FDA thoroughly examines whether the active moiety is novel, thus rewarding only truly innovative treatments. This two-step approach allows multiple drugs Page 3 of 4
targeting the same condition to achieve RPDD status but applies a higher standard for PRV eligibility based on active moiety uniqueness. As a result, the FDA balances the need to foster development in rare pediatric therapies with the goal of rewarding genuine innovation, thereby supporting its mission to advance groundbreaking treatments for critical unmet pediatric needs. This structured process provides drug developers with a clear regulatory pathway while ensuring that the PRV program remains aligned with incentivizing true pharmaceutical advancements. While RPDD focuses on scientific and clinical potential for addressing rare pediatric needs, it does not allow designation for drugs containing active ingredients previously approved under Sections 505(b)(1), 505(b)(2), 505(j), 351(a), or 351(k). PRV assessments similarly enforce this requirement to maintain the program’s integrity and reward true innovation.
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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. The NIH’s work on AAV9-hPCCA gene therapy offers a case study in navigating FDA designations (Reference 1), while webinars from Mayer Brown (References 2 and 5) detail lifecycle management and exclusivity strategies, including pediatric incentives. Roberta Szydlo from the FDA and Scendea’s guidance (References 3 and 4) outline key financial motivations and recent developments in the PRV program, respectively. The FDA’s recent approvals for Argenica’s therapies (Reference 6) and official guidance on PRVs (Reference 7) underscore the FDA’s commitment to fostering innovation in rare pediatric diseases by awarding vouchers for groundbreaking treatments.
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/news-release/2020/11/23/2131371/0/en/argenx-Enters-Into-Agreement-To-Acquire-Priority-Review-Voucher.html
