One in 10 Americans is affected by rare diseases—more than half of which are children—and approximately 95% of the more than 7,000 rare diseases have no available treatments.
To advance the development of rare disease treatments, the Food and Drug Administration (FDA) Office of Orphan Products Development, OOPD, grants orphan drug and rare pediatric disease designations to eligible products for the prevention, diagnosis, and treatment of rare diseases or conditions that affect fewer than 200,000 individuals in the United States.
Additionally, the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) provide four expedited program and approval pathways— priority review voucher, fast track designation, breakthrough therapy designation, and accelerated approval—to facilitate and expedite the development and review of drugs to address the unmet medical need in the treatment of serious and life-threatening conditions.
Because most rare diseases are serious or life-threatening, with a high unmet medical need, most qualify for at least one expedited program.
In this blog, we will discuss the key features of the four expedited programs: rare pediatric disease priority review voucher, fast track designation, breakthrough therapy designation, and accelerated approval.
Rare Pediatric Disease Priority Review Voucher
A priority review voucher is awarded to a sponsor if it develops a drug for a rare pediatric disease, and the drug is approved. The priority review voucher allows a sponsor to expedite the FDA review of a future drug. The priority review voucher indicates that the FDA will aim to act on a marketing application within 6 months of receipt, rather than the typical 10 months. A sponsor may sell the voucher to other drug developers to the expedite review of another drug.
Among the recent rare pediatric disease priority review vouchers sales was Boston based Rhythm Pharmaceuticals’ $100 million dollar sale of its priority review voucher to Alexion Pharmaceuticals after the FDA had approved Rhythm’s drug, Imcivree, in pediatric patients with obesity. Should Alexion use this voucher for one of its programs, then its FDA marketing application review process would be expedited by months—ultimately shortening the drug’s time to market and adding a few extra months of sales for the company.
Sponsors interested in rare pediatric disease priority review vouchers should note that, on December 27, 2020, the Rare Pediatric Disease Priority Review Voucher Program was extended as part of the 2021 Coronavirus Response and Relief Supplemental Consolidated Appropriations Act. “Under the current statutory sunset provisions, after September 30, 2024, FDA may only award a voucher for an approved rare pediatric disease product application if the sponsor has rare pediatric disease designation for the drug, and that designation was granted by September 30, 2024. After September 30, 2026, FDA may not award any rare pediatric disease priority review vouchers.”
Fast Track Designation
Fast track designations are intended to expedite the development of drugs for serious conditions with an unmet need. Seriousness is usually based on factors such as day-to-day functioning, survival, and likelihood that the condition may worsen or progress to a more serious condition if left untreated. An unmet need refers to providing a therapy where none exists or providing therapy potentially better than available therapy.
Minimum data required for fast-track designations are preclinical efficacy data in a validated animal model of the disease.
The designation request may be submitted at the time of IND submission or anytime during drug development, but, ideally, no later than the Pre-Biologics License (PreBLA) or Pre-New Drug Application (PreNDA) meeting. Requests for fast-track designation are submitted as amendments to an open investigational new drug application (IND), and the FDA determines fast track designation within 60 calendar days of receipt of the request.
Sponsors receiving designation are eligible for more frequent meetings with the FDA to discuss their drug development plan, more frequent written communication with the Agency, and eligibility for rolling review of their BLA or NDA—which means that sponsors may submit completed sections of their BLA or NDA for FDA review, rather than submitting when the entire application is complete.
Breakthrough Therapy Designation
Breakthrough therapy designations are intended to expedite the development of drugs for serious conditions, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.
Unlike fast-track designations, investigational drugs require preliminary clinical evidence to obtain breakthrough therapy status.
Breakthrough therapy designations may be submitted at the time of the IND submission or any time before marketing approval, but, ideally, before the End‐of‐Phase 2 meeting. The FDA’s response may be expected within 60 calendar days of receipt of the request.
Sponsors receiving designation have the same benefits as fast track, but with more intensive guidance and greater organizational commitment from the Agency.
Sponsors should note that the FDA may later rescind breakthrough therapy designation status if the drug no longer meets the designation criteria.
The accelerated approval pathway is intended to expedite the development and approval of drugs:
- For a serious condition
- That generally provide a meaningful advantage over available therapies; and demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is reasonably likely to predict clinical benefit.
Drugs granted accelerated approval must conduct postmarketing confirmatory trials to verify and describe the anticipated clinical benefit. Sponsors should also discuss the confirmatory trials, and there should be agreement with FDA on the design and conduct to support confirmation of clinical benefit. Typically, the confirmatory trial should already be underway at the time of the request for accelerated approval
The FDA may withdraw approval of a drug or indication approved under the accelerated approval pathway.
Benefits of Expedited Programs
For drugs under at least one expedited program (ie, priority review, fast track, breakthrough therapy, accelerated approval), the duration of clinical development from IND to FDA approval was 0.9 years shorter than drugs not under any expedited program. Development timelines for drugs with fast-track designation were reduced by approximately 1 year versus 8 years.
The greatest advantage was evident in drugs that received breakthrough therapy designation in which development timelines were reduced from 8 years to 4.8 years.
For questions on FDA Expedited Program Designations to Support Rare Disease Drug Developments, or regulatory strategy in general, request a meeting with Dr. Clarke here.
By: Christine Clarke PhD, Senior Medical Writer
Learn more about orphan drug, rare pediatric disease, and expedited program designations by watching our full webinar on the subject here.
Additional information on the FDA’s Expedited Program Designation may be found in the Guidance for Industry, Expedited Programs for Serious Conditions—Drugs and Biologics and Rare Pediatric Disease Priority Review Vouchers Guidance for Industry
1 RDD-FAQ-2019.pdf (rarediseases.org)
2 Rare Pediatric Disease (RPD) Designation and Voucher Programs | FDA
3 Newly acquired Alexion pays $100M for Rhythm’s speedy review voucher | FierceBiotech
4 Cox EM, Edmund AV, Kratz E, Lockwood SH, Shankar A. Regulatory Affairs 101: Introduction to
Expedited Regulatory Pathways. Clin Transl Sci. 2020;13(3):451-461.
5 Expedited Programs for Serious Conditions––Drugs and Biologics | FDA