Executive Summary – The U.S. Food and Drug Administration (FDA)’s December 2024 guidance,
“Expedited Program for Serious Conditions – Accelerated Approval of Drugs and Biologics”, refines the
Accelerated Approval (AA) pathway, emphasizing timely initiation and completion of confirmatory
trials to verify clinical benefits. It stresses the need for early engagement with the FDA to determine
appropriate surrogate or intermediate endpoints and reaffirms the agency’s authority to withdraw
approvals if confirmatory trials fail or are delayed. While the guidance does not modify Priority Review
Voucher (PRV) programs, it underscores strategic alignment opportunities for sponsors pursuing AA
and PRVs. Key recommendations include designing robust trial protocols, ensuring data transparency,
and fostering collaboration with stakeholders to address patient needs. This guidance aims to balance
rapid access to innovative therapies with rigorous post-approval validation, safeguarding both public
trust and therapeutic efficacy. This article explores the updated guidance’s key points and its impact
on both the AA pathway and PRV grants.

The FDA has long utilized the AA pathway to hasten the availability of treatments for serious conditions
with unmet medical needs. This pathway allows for early approval based on surrogate or intermediate
clinical endpoints, contingent on post-approval confirmatory trials to validate clinical benefits. The
FDA’s December 2024 updated guidance offers detailed insights into enhancing the efficiency and
reliability of the AA pathway. The guidance underscores the importance of initiating confirmatory
trials promptly, preferably at the time of approval, and encourages early engagement with the FDA to
establish appropriate endpoints. While this update does not alter Priority Review Voucher (PRV)
programs, which incentivize treatments for specific conditions like rare pediatric or neglected tropical diseases, it emphasizes adherence to statutory requirements for PRV eligibility. In summary, the December 2024 guidance sharpens focus on timely trial execution and strategic endpoint selection to
optimize the AA pathway without changing the framework for PRV grants.

Updated Guidance for the AA Pathway – The FDA’s December 2024 guidance, “Expedited Program for
Serious Conditions—Accelerated Approval of Drugs and Biologics,” emphasizes the necessity for prompt initiation and completion of confirmatory trials to substantiate clinical benefits postaccelerated approval. It encourages early engagement with the FDA to determine suitable surrogate or intermediate clinical endpoints and underscores the agency’s authority to withdraw approval if confirmatory trials do not verify anticipated benefits or are not diligently pursued. This guidance aims to enhance the efficiency and reliability of the accelerated approval pathway, ensuring that patients have timely access to effective treatments for serious conditions. Key details from the FDA’s December 2024 guidance are:

1. Focus on Confirmatory Trials:
   o The guidance emphasizes that confirmatory trials should ideally be underway at the
   time of Accelerated Approval (AA) and conducted with urgency to confirm clinical
   benefit.
   o Sponsors must provide clear timelines and milestones for these trials and are
   encouraged to consider innovative trial designs that expedite completion.
2. Surrogate and Intermediate Endpoints:
   o Selecting robust surrogate or intermediate clinical endpoints is critical. The FDA
   highlights the need for endpoints that are scientifically validated and reasonably
   predictive of clinical benefit for AA.
   o Early and transparent discussions with the FDA are strongly recommended to align on
   appropriate endpoints.
3. Increased Accountability:
   o The FDA reinforces its commitment to withdrawing AA if confirmatory trials fail to
   verify the treatment’s benefits, or if trial timelines and commitments are not met.
   o This reflects an effort to ensure that the AA pathway maintains its integrity and
   delivers meaningful therapies to patients.
4. Data Transparency:
   o Sponsors must submit detailed progress updates on confirmatory trials, including
   interim data as available, ensuring continuous evaluation by the FDA.
5. Streamlined Collaboration:
   o The FDA encourages sponsors to collaborate with stakeholders, including patient
   advocacy groups, to design trials that address patient needs and generate robust
   evidence.
6. Incentives for Compliance:
   o While the guidance does not alter Priority Review Voucher (PRV) programs, adherence
   to the updated AA guidance can strengthen a sponsor’s position in pursuing additional
   incentives, including PRVs, if applicable to their product.

This detailed approach underlines the FDA’s dual goals of providing early access to innovative therapies
while safeguarding the credibility of the AA pathway through rigorous post-approval requirements.

Timely Confirmatory Trials – A cornerstone of the updated guidance is its emphasis on the timely
initiation and completion of confirmatory trials. To ensure that clinical benefits are verified without
undue delay:

• Trials at AA Approval: The FDA now strongly recommends that confirmatory trials be
  underway at the time of AA. This helps minimize the risk of prolonged uncertainty regarding
  the treatment’s real-world efficacy.
• Progress Monitoring: Sponsors are expected to provide clear timelines for trial completion
  and face increased regulatory scrutiny to ensure adherence to these commitments.

Collaboration with the FDA – Early and frequent engagement with the FDA is highlighted as critical.
Sponsors are encouraged to consult the agency regarding:

• The selection of surrogate or intermediate clinical endpoints that support AA.
• Designs for confirmatory trials that robustly validate these endpoints.

Regulatory Oversight – The guidance reinforces the FDA’s authority to withdraw accelerated approvals
if:

• Confirmatory trials fail to verify clinical benefits.
• Sponsors do not conduct confirmatory trials with sufficient rigor or timeliness. This focus on enforcement aims to maintain public trust in the AA pathway and ensure that approved therapies genuinely benefit patients.

Implications for PRV Programs – PRV programs remain unchanged under the updated AA guidance.
These vouchers are awarded under specific statutory frameworks, such as:

• Rare Pediatric Disease PRV: Incentivizing therapies for rare diseases affecting children.
• Neglected Tropical Disease PRV: Supporting treatments for conditions like malaria and leprosy.
• Medical Countermeasure PRV: Encouraging development of therapies for chemical, biological, radiological, and nuclear threats.

Implications for PRV Programs – PRV programs remain unchanged under the updated AA guidance.
These vouchers are awarded under specific statutory frameworks, such as:

• Rare Pediatric Disease PRV: Incentivizing therapies for rare diseases affecting children.
• Neglected Tropical Disease PRV: Supporting treatments for conditions like malaria and leprosy.
• Medical Countermeasure PRV: Encouraging development of therapies for chemical, biological, radiological, and nuclear threats.

However, there are indirect considerations for sponsors seeking PRVs:

1. AA Therapies and PRVs: While the AA pathway itself does not qualify a therapy for a PRV,
   sponsors can align PRV applications with AA submissions if the product addresses a relevant
   condition. For example, a drug granted AA for a rare pediatric disease could simultaneously
   qualify for a PRV.
2. Market Strategy: PRVs are valuable assets, often sold for millions of dollars. Sponsors may
   leverage PRVs to finance confirmatory trials or accelerate the development of other pipeline
   therapies.

Key Takeaways for Industry Stakeholders

1. Strategic Development Planning – Sponsors must integrate the updated AA guidance into their clinical and regulatory strategies. This includes designing confirmatory trials that meet FDA expectations and planning for early engagement to align on endpoints.
2. Effective Communication – Clear communication with regulators, investors, and other stakeholders is critical. Sponsors must transparently manage expectations regarding the risks and timelines associated with AA and confirmatory trials.
3. Compliance and Vigilance – The updated guidance underscores the need for meticulous compliance. Sponsors must proactively monitor their progress in meeting AA obligations to avoid potential regulatory actions, including withdrawal of approval.

Conclusion – The FDA’s December 2024 guidance marks an evolution in the Accelerated Approval pathway, emphasizing robust confirmatory trials and increased regulatory accountability. While it does not directly alter Priority Review Voucher programs, the guidance indirectly impacts strategic considerations for sponsors navigating both frameworks.
By prioritizing timely confirmatory trials and fostering close collaboration with the FDA, developers can
maximize the benefits of the AA pathway while ensuring compliance with its requirements.
Furthermore, aligning AA efforts with PRV opportunities may provide additional incentives and resources to support innovative therapies. As the regulatory landscape continues to evolve, staying informed and adaptable will be critical for industry stakeholders.

Download the document here.

References: These references provide a solid foundation for understanding the interplay between the FDA’s Accelerated Approval pathway and the PRV program, as well as the regulatory and financial considerations involved.

1. FDA’s Expedited Programs for Serious Conditions—Drugs and Biologics: This guidance document provides comprehensive information on the FDA’s expedited programs, including Fast Track designation, Breakthrough Therapy designation, Accelerated Approval, and Priority Review designation.
   It outlines the criteria and processes for each program, offering valuable insights into the regulatory framework.
2. FDA’s Priority Review Designation: This FDA resource explains the Priority Review designation, which aims to expedite the review process for drugs that offer significant improvements in the treatment, diagnosis, or prevention of serious conditions. It details the goals and implications of such designations.
3. FDA’s Rare Pediatric Disease Priority Review Voucher Program: This FDA page provides an overview of the Rare Pediatric Disease Priority Review Voucher Program, including eligibility criteria, the process for obtaining a voucher, and guidelines on transferability and use.
4. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review: This FDA resource outlines the various expedited programs available for drug development, detailing the criteria and benefits associated with each pathway.
5. 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.