FDA Extends its Rare Pediatric Disease PRV Program 

On December 27, 2020, FDA extended the Rare Pediatric Disease Priority Review Voucher Program as part of the Coronavirus Response and Relief Supplemental Consolidated Appropriations Act of 2021.

Originally set to expire in October 2020, renewal of the Rare Pediatric Disease Priority Review Voucher (PRV) Program was something drug developers and investors were thinking about even before the pandemic. Is the FDA’s Rare Pediatric Disease Priority Review Voucher Program effective? What are the benefits and limitations?

FDA Rewards Interest in Rare Pediatric Disease Treatment

Of the over 7,000 rare diseases identified the U.S., 50% affect children. Unfortunately, there isn’t much incentive for a drug developer to treat them.

Rare pediatric disease drug developers face several challenges, including a comparable lack of defined endpoints and biomarkers, a short supply of patients available to participate in trials, poorly characterized disease histories and presentations - not to mention the high cost of development for a very limited market.

To create incentives for drug development for rare pediatric diseases, Congress and the FDA developed a voucher program offering drug makers an accelerated drug approval process. The goal of the FDA’s Rare Pediatric Disease Priority Review Voucher Program (PRV) is to stimulate treatment development and expedite patient access to these treatments.

Drug companies receiving a voucher can have any drug reviewed under priority review (getting an FDA decision in six months as opposed to the standard 10 months), or they can sell the voucher to another company. Vouchers may be sold and resold an unlimited number of times.

List of Rare Pediatric Disease PRVs Awarded and Sold

Between 2014 and 2019, the FDA awarded 25 PRVs, 17 (68%) of them under the Rare Pediatric Disease Program. Drug companies have redeemed at least six of the 17 rare pediatric vouchers for priority review.

• 2014 BioMarin: Awarded for Vimizim (elosulfase alfa) to treat Morquio A syndrome. Sold to Sanofi and Regeneron for $67 million. Redeemed for approval of Praluent (alirocumab).
• 2015 United Therapeutics: Awarded for Unituxin (dinutuximab) to treat high-risk neuroblastoma. Sold to AbbVie for $350 million. Unused.
• 2015 Asklepion Pharmaceuticals: Awarded for Cholbam (cholic acid) to treat rare bile acid synthesis disorders. Transferred to Retrophin. Sold to Sanofi for $245 million. Redeemed for approval of type 2 diabetes drug.
• 2015 Wellstat Therapeutics: Awarded for Xuriden (uridine triacetate) to treat hereditary orotic aciduria. Transferred to AstraZeneca. Unused.
• 2015 Alexion Pharmaceuticals: Awarded for Strensiq (asfotase alfa) to treat hypophosphatasia. Unused.
• 2015 Alexion Pharmaceuticals: Awarded for Kanuma (sebelipase alfa) to treat lysosomal acid lipase (LAL) deficiency. Redeemed for approval of Ultomiris (Ravulizumab-Cwvz) to treat paroxysmal nocturnal hemoglobinuria (PNH).
• 2016 Sarepta Therapeutics: Awarded for Eteplirsen to treat Duchenne muscular dystrophy. Sold to Gilead for $125 million. Redeemed for approval of HIV treatment.
• 2016 Ionis Pharmaceuticals: Awarded for Spinraza (nusinersen) to treat spinal muscular atrophy (SMA). Unused.
• 2017 Marathon Pharmaceuticals: Awarded for Emflaza (deflazacort) to treat Duchenne muscular dystrophy. Unused.
• 2017 BioMarin: Awarded for Brineura (cerliponase alfa) to treat Batten disease. Sold to an undisclosed party for $125 million.
• 2017 Novartis: Awarded for Tisagenlecleucel to treat B-cell acute lymphoblastic leukemia. Unused.
• 2017 Ultragenyx Pharmaceutical: Awarded for Mepsevii to treat mucopolysaccharidosis (MPS) VII. Sold to Novartis for $130 million. Redeemed for approval of siponimod to treat secondary progressive multiple sclerosis (SPMS).
• 2017 Spark Therapeutics: Awarded for Luxturna (voretigene neparvovec-rzyl) to treat biallelic RPE65 mutation-associated retinal dystrophy. Sold to Jazz Therapeutics for $110 million. Unused.
• 2018 Ultragenyx: Awarded for Crysvita (burosumab-twza) to treat X-linked hypophosphatemia (XLH). Sold to an undisclosed party for $80.6 million.
• 2018 GW Pharma: Awarded for Epidiolex (cannabidiol) to treat Lennox-Gastaut syndrome and Dravet syndrome. Unused.
• 2018 Leadiant Bioscience Inc: Awarded for Revcovi (elapegademase-lvlr) to treat Adenosine Deaminase-Severe Combined Immunodeficiency (ADA-SCID). Unused.
• 2018 Sobi and Novimmune: Pending award for Gamifant (emapalumab-lzsg) to treat primary haemophagocytic lymphohistiocytosis (HLH).

In addition, Teva Pharmaceuticals paid $150 million for a rare pediatric PRV from an undisclosed company in 2017 and redeemed it for expedited review of their migraine med, Ajovy (fremanezumab-vfrm).

FDA Renews Rare Pediatric Disease PRV Program Another Six Years

Rare pediatric PRVs don’t expire, but the program itself was scheduled to end in October 2020. After that, only drugs designated as rare pediatric treatments and approved by October 2022 could receive a voucher.

Yet, on December 27, 2020, Congress renewed the program as part of the 2021 Coronavirus Response and Relief Supplemental Consolidated Appropriations Act. Under the current statutory sunset provisions, FDA states that after September 30, 2024 it may only award vouchers for approved rare pediatric disease product applications if sponsors have rare pediatric disease designation for the drug granted by September 30, 2024. FDA states that it may not award any rare pediatric disease priority review vouchers after September 30, 2026.

Pros and Cons of FDA’s Priority Review Voucher Program

FDA was considering renewing the program prior to the COVID-19 outbreak, weighing critics’ opinions as to whether a renewal is warranted.

One obvious complaint is that companies are using vouchers to get an expedited review for drugs for which there is little to no clinical urgency, taking FDA resources away from drugs that call for priority review. The voucher user fee ($2.46 million for 2019) helps alleviate these resource issues.

Much of the incentive to pursue rare childhood disease treatments is in the resale value of the vouchers. But with more and more vouchers being handed out each year, the resale value is dropping. In 2015, United Therapeutics sold its voucher to AbbVie for $350 million. Just three years later, Ultragenyx received a mere $80.6 million for its voucher.

And having a voucher doesn’t mean a drug will be approved. It just means you will get a decision within six months. Companies who unsuccessfully use a voucher could be out the $100 million they bought it for - plus the $2.46 million user fee.

Even with a voucher, you may not get a decision within six months. In its Draft Guidance for Industry Rare Pediatric Disease Priority Review Vouchers, the FDA states:

"Although FDA's goal is to take action on the application within six months after the 60-day filing period for an application involving a new molecular entity or within six months after the date of receipt of an application not involving a new molecular entity, this timeframe is not guaranteed.”

Some critics claim the voucher program does not provide an incentive for drug development and expedited patient access but is instead just rewarding companies who would have developed the same drug in the same time frame anyway. The voucher program does not require that the company actually sell the drug or to sell the drug at a particular price. Some critics argue that perhaps voucher holders should be required to market reasonably affordable treatments within a reasonable period of time.

Others argue that companies are getting priority review for drugs that have already been developed by other companies. Theoretically, companies who want to register drugs that are already available for purchase outside of the U.S. could be eligible for vouchers.

It is still too early to know whether the FDA’s Rare Pediatric Diseases Priority Review Voucher Program is truly granting patients expedited access to new treatments that would not be otherwise available. What we can say for certain is that rare pediatric vouchers are still a highly attractive addition to the pharmaceutical company’s portfolio, granting early exclusivity and powerful negotiation leverage.