Priority review

Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program is a program that grants a voucher for priority review to a drug developer as an incentive to develop treatments for disease indications with limited profitability.

Priority review vouchers are currently earned by pharmaceutical companies for the development and approval of drugs treating neglected tropical diseases, rare pediatric diseases, and "medical countermeasures" for terrorism. The voucher can be used for future drugs that could have wider indications for use, but the company is required to pay a fee (approximately $2.8 million) to use the voucher.

When seeking approval for a drug, manufacturers can apply to the FDA for priority review. This is granted when a drug is intended to treat a serious condition and would "provide a significant improvement in safety or effectiveness" over currently available treatments.^[1] A priority review voucher can be used when a drug does not fit these requirements, but the company wishes to expedite the review process.^[2]

In 2007, Title XI of the Food and Drug Administration Amendments Act of 2007 created the priority review voucher program for neglected tropical diseases. This was extended in 2012 by the Food and Drug Administration Safety and Innovation Act to include rare pediatric diseases. The act built upon the tropical disease system and made amendments including a shorter notification to the FDA before exercising a voucher, a designation system so that early in the drug development cycle sponsors may use the possibility of earning a voucher in their valuation of their company, a requirement of a marketing plan and reporting of marketing, and indefinite transferability of the voucher. In 2016, medical countermeasures were added to the program.^{[citation needed]}

Priority review

Prior to approval, each drug marketed in the United States must go through a detailed FDA review process. In 1992, under the Prescription Drug User Fee Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – standard review and priority review.

A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. The 2002 amendments to PDUFA set a goal that a standard review of a new drug application be accomplished within a ten-month time frame. The FDA goal for completing a priority review is six months. Priority review status can apply both to drugs that are used to treat serious diseases and to drugs for less serious illnesses.

The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment. Such advances can be demonstrated by, for example: evidence of increased effectiveness in treatment, prevention, or diagnosis of disease; elimination or substantial reduction of a treatment-limiting drug reaction; documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or evidence of safety and effectiveness in a new subpopulation, such as children.

A request for Priority Review must be made by the drug company. It does not affect the length of the clinical trial period. FDA determines within 45 days of the drug company's request whether a priority or standard review designation will be assigned. Designation of a drug as "priority" does not alter the scientific/medical standard for approval or the quality of evidence necessary. Safety requirements for a priority review are equal to that of a standard review.

The amendment can be found on page 150 of the Food and Drug Administration Amendments Act of 2007.^[3]

Priority review voucher program

The statute authorizes the FDA to award a priority review voucher to the sponsor (manufacturer) of a newly approved drug or biologic that targets a neglected tropical disease or a rare pediatric disease. The provision applies to New Drug Applications (NDAs), Biological License Applications (BLAs) and 505(b)(2) applications. The voucher, which is transferable and can be sold, entitles the bearer to a priority review for another product.

Under current Prescription Drug User Fee Act targets, the FDA aims to complete and act upon reviews of priority drugs within six months instead of the standard ten-month review period. Actual FDA review timelines, however, can be longer than the target PDUFA review periods, particularly for new products that haven't previously been approved for any indications. Economists at Duke University, who published on this concept in 2006, estimated that priority review can cut the FDA review process from an average of 18 months down to six months, shortening by as much as a full year the time it takes for the company's drug to reach the market.^[4]

An intangible benefit of the voucher is the value created for a company if the faster review provides them "first mover advantage," allowing the voucher holder's product to be introduced ahead of a similar, competing product. By taking advantage of existing market forces, patients in the developing world can have faster access to lifesaving products that may not otherwise be developed. And sponsors of neglected disease drugs can be rewarded for their innovations^[5]

Sponsors must inform the FDA of their intention to use a priority review voucher 90 days before submission. Before the Adding Ebola to the FDA Priority Review Voucher Program Act in 2014, this requirement was 365 days, which was a hindrance to the process of speedy review, as companies do not typically determine when drugs will be submitted until the results of safety studies are available.^[2]

Companies may also sell vouchers to other drug companies. Thus far, priority review vouchers have sold for $50–350 million.

Cost

Companies that use the voucher will be required to pay a supplemental priority review user fee to ensure that the FDA can recoup the costs incurred by the agency for the faster review, in addition to the fee for standard review of drugs. The additional user fee also aims to ensure that the new program will not slow the progress of other products awaiting FDA review. The cost has decreased dramatically from over $5 million in 2012.^[6] For the fiscal year 2018, this fee is $2.8 million.^[7]

Uses of the priority review program

As of 2017, fourteen priority review vouchers have been awarded, four for tropical diseases, and ten for rare pediatric diseases. The first priority review voucher was awarded in 2009 to Novartis for its approval of Coartem. The next voucher was not awarded until 2012.^[2][8]

Vouchers have been awarded for the following:

Program	Drug	Indication	Company	Year
Tropical disease	Coartem	Malaria	Novartis
Tropical disease	Sirturo	Multi-drug-resistant tuberculosis	Janssen Pharmaceutica
Rare pediatric disease	Vimizim	Morquio syndrome	BioMarin Pharmaceutical
Tropical disease	Impavido	Leishmaniasis	Knight Therapeutics
Rare pediatric	Unituxin	Neuroblastoma	United Therapeutics
Rare pediatric	Cholbam	Zellweger syndrome	Asklepion Pharmaceuticals
Rare pediatric	Xuriden	Orotic aciduria	Wellstat Therapeutics
Rare pediatric	Strensiq	Hypophosphatasia	Alexion Pharmaceuticals
Rare pediatric	Kanuma	Lysosomal acid lipase deficiency	Alexion
Tropical disease	Vaxchora	Cholera prevention	PaxVax
Rare pediatric	Exondys 51	Duchenne muscular dystrophy	Sarepta Therapeutics
Rare pediatric	Spinraza	Spinal muscular atrophy	Ionis Pharmaceuticals
Rare pediatric	Emflaza	Duchenne muscular dystrophy	Marathon Pharmaceuticals
Rare pediatric	Brineura	Batten disease	BioMarin Pharmaceutical
Tropical disease	benznidazole	Chagas disease	ChemoResearch
Rare pediatric	Kymriah	B-ALL	Novartis
Rare pediatric	Mepsevii	Mucopolysaccharidosis type VII	Ultragenyx
Rare pediatric	Luxturna	RPE65-mutated retinal dystrophy	Spark Therapeutics
Rare pediatric[9]	Crysvita	X-linked hypophosphatemia	Ultragenyx	2020
Tropical disease	Moxidectin	Onchocerciasis	Medicines Development for Global Health
Rare pediatric	Epidiolex	Lennox-Gastaut syndrome	GW Pharmaceuticals
Material threat countermeasure	Tpoxx	Smallpox	SIGA Technologies
Tropical disease	Krintafel	Malaria	GlaxoSmithKline
Rare pediatric	Revcovi	Adenosine deaminase-SCID	Leadiant Biosciences
Rare pediatric	Gamifant	Haemophagocytic lymphohistiocytosis	Novimmune
Tropical disease	Egaten	Fascioliasis	Novartis
Rare pediatric	Symdeko	F508del cystic fibrosis	Vertex Pharmaceuticals
Tropical disease[10]	Dengvaxia	Dengue	Sanofi
Rare pediatric[11]	Zolgensma	Spinal muscular atrophy	AveXis
Tropical disease[12]	Pretomanid	Tuberculosis	TB Alliance
Material threat countermeasure[13]	Jynneos	Smallpox	Bavarian Nordic
Rare pediatric[14]	Trikafta	Cystic fibrosis	Vertex Pharmaceuticals
Tropical disease[15]	Ervebo	Ebola	Merck & Co.
	Capmatinib[16]	MET exon 14 skipping mutated non-small cell lung cancer	Novartis
	KTE-X19[16]	Mantle cell lymphoma	Kite Pharma
	Selpercatinib[16]	RET fusion-positive non-small cell lung cancer	Eli Lilly
	elantamab mafodotin[16]	Multiple myeloma	GlaxoSmithKline
	Cedazuridine and decitabine[16]	Chronic myelomonocytic leukemia	Astex Pharmaceuticals
Rare pediatric[17]	Vyondys 53	Duchenne muscular dystrophy	Sarepta Therapeutics	2020
Rare pediatric[18]	Oxlumo	Primary hyperoxaluria type 1	Alnylam Pharmaceuticals	2020
Rare pediatric[19]	Rethymic	Congenital athymia	Enzyvant Therapeutics	2021

Extensions

Extension to rare pediatric diseases

In 2012, President Obama signed into law the FDA Safety and Innovation Act which includes Section 908, the "Rare Pediatric Disease Priority Review Voucher Incentive Program".^[20] Section 529 extends the voucher program to rare pediatric diseases, but only on a trial basis. After the third voucher is awarded, the Comptroller General of the United States is to conduct a study on the effectiveness of the pediatric priority review voucher program.^{[citation needed]}

The pediatric voucher program includes changes to the voucher program. First, the pediatric treatment developer can ask the FDA in advance for an indication of whether the disease qualifies as a rare, pediatric disease.^{[citation needed]}

The awardee must market the drug within 365 days of approval, or the voucher may be revoked. Within five years of approval, the manufacturer must submit a report containing information on the estimated population in the United States suffering from the rare pediatric disease, the estimated demand in the United States for such rare pediatric disease product, and the actual amount of such rare pediatric disease product distributed in the United States.^[21]

The Advancing Hope Act of 2016 reauthorized the program until December 31, 2016 and instructed the GAO to compile a report on the effectiveness of the program.^[22]

Extension to ebola virus

In December 2014, the Senate approved a bill that would add the Ebola virus to the Priority Review Voucher List.^[23] The bill, S. 2917—Adding Ebola to the FDA Priority Review Voucher Program Act, was introduced by Senator Tom Harkin on November 12, 2014. President Obama signed it on December 16, and it became Public Law 113-233.^[24] Forty-five Senators cosponsored the bill (26 Democrats and 19 Republicans).^[25] This act also eliminated the differences between tropical disease and pediatric disease vouchers, but allowing both to be sold an unlimited number of times and be used after a 90-day notification period to the FDA.

On a technical level, S. 2917 added "Filoviruses" to the priority review list. The Ebola virus is a type of Filovirus. According to the Congressional Budget Office, enactment of the law does not have an effect on the federal budget.^[26]

Extension for medical countermeasures

The Senate's Medical Countermeasure Innovation Act of 2016 proposed adding a new category of drugs to the priority review voucher program. In 2016, it was confirmed that the approval of drugs for medical countermeasures would be eligible to earn a priority review voucher. Medical countermeasures are drugs to "prevent or treat harm from a biological, chemical, radiological or nuclear agent identified as a material threat".^[27]

Proposed adoption by European Medicines Agency

Writing in The Lancet, David Ridley and Alfonso Calles Sánchez proposed extending the voucher to the European Union. The proposed EU voucher would provide priority regulatory review through the European Medicines Agency, as well as accelerated pricing and reimbursement decisions by EU member states.^[28]

Secondary market

Because Priority Review Vouchers (PRVs) may be sold, a secondary market for the vouchers has emerged, and their value has increased, although the market for the vouchers is limited.^[29] Companies use the sale of PRVs to recoup expenses undertaken for drug research and development.^[29] A 2015 Wall Street Journal article raised concerns about the sale of these vouchers, given that they "require the FDA to shorten its decision deadline to six months from the standard 10 months—potentially giving companies an extra four months' worth of sales," but also noted that a voucher is not a guarantee of FDA approval for a drug.^[30]

In 2014, Regeneron Pharmaceuticals and Sanofi purchased a PRV that BioMarin had won for a recent rare disease drug approval for $67.5 million; the voucher cut four months off the regulatory review time for alirocumab and was part of their strategy to beat Amgen to market with the first approval of a PCSK9 inhibitor.^[30][31][32] In 2015, Retrophin sold a PRV to Sanofi for around $245 million, and later the same year, United Therapeutics Corp. sold a PRV for a drug for a rare pediatric disease to AbbVie Inc. for $350 million.^[33] In 2016–2018, the value of a voucher ranged from $125 million to $200 million, down from its peak in 2015.^[34]

Diseases targeted

The eligible tropical diseases include the following:^[3][35]

• Blinding trachoma
• Buruli ulcer
• Chagas disease (added in 2015)
• Cholera
• Chikungunya virus disease (added in 2018 final order)
• Cryptococcal meningitis (added in 2018 final order)
• Dengue/dengue haemorrhagic fever
• Dracunculiasis (guinea-worm disease)
• Fascioliasis
• Filovirus diseases (including Ebola virus disease) (added in 2014 by Pub. L. 113-233, amended by Pub. L. 114-146)
• Human African trypanosomiasis
• Lassa fever (added in 2018 final order)
• Leishmaniasis
• Leprosy
• Lymphatic filariasis
• Malaria
• Neurocysticercosis (added in 2015)
• Onchocerciasis
• Rabies (added in 2018 final order)
• Schistosomiasis
• Soil-transmitted helminthiasis
• Tuberculosis
• Yaws
• Zika virus disease (added in 2016 by Pub. L. 114-146)
• Any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by order of the Secretary.

Pediatric rare diseases are any disease that primarily affects people under the age of 18 and affects 200,000 or fewer people in the United States. Medical countermeasures are drugs to be used "in the event of a public health emergency stemming from a terrorist attack with a biological, chemical, or radiological/nuclear material, a naturally occurring emerging disease, or a natural disaster."^{[citation needed]}

Limitations

Critics have claimed a number of issues with the priority review program. First, the priority review voucher might be too small or too large to encourage drug development. It may be too small because tropical diseases with incredible burdens can be presumed to merit more resources. This is likely not the case for pediatric rare diseases, some drugs are developed for pediatric use through expansion of adult drug research for similar conditions. The priority review voucher might be too large, if it rewards research which would have been done anyway, or research with low value.^{[citation needed]}

The priority review voucher may tax FDA resources. To mitigate this, use of the priority review voucher includes an extra fee paid by manufacturers to the FDA and requires that voucher bearers provide FDA with 90 days' notice before using a voucher.^{[citation needed]}

Critics of the FDA allege that priority review might not be safe. Priority review should not, however, be confused with accelerated approval or fast track designation. Priority review does not omit safety or efficacy studies or require approval within a given time frame. It sets a target of 6 rather than 10 months for FDA review. Nevertheless, a study in 2008 claimed that new molecular entities approved in the two months before the first review deadlines showed a higher rate of postmarketing safety problems than drugs approved at other times.^[36] Nardinelli and colleagues (2008) of the FDA, however, wrote that they were not able to replicate the findings and that the findings might be driven by HIV-AIDS therapies.^[37] Following the Nardinelli piece, Carpenter acknowledged several errors in their data set and demonstrated errors in the FDA's and Nardinelli's data; Carpenter and colleagues report that the original associations between last-minute approvals and safety problems hold.^[37]

There have also been complaints that the priority review voucher encourages innovation, but does not pay for access to existing therapies. Funding from governments or foundations might be needed to purchase treatments for poor people. Aidan Hollis of the University of Calgary has commented that the proposal does not address "the access problem, but helps to increase incentives through creating distortions in markets in developed countries". This is entirely a separate issue from the promotion of research intended by the priority review program.^{[citation needed]}

News and reaction

According to Bill Gates,^[38]

"Some of the highest-leverage work that government can do is to set policy and disburse funds in ways that create market incentives for business activity that improves the lives of the poor. Under a law signed by President Bush last year, any drug company that develops a new treatment for a neglected disease like malaria or TB can get priority review from the Food and Drug Administration for another product they've made. If you develop a new drug for malaria, your profitable cholesterol-lowering drug could go on the market a year earlier. This priority review could be worth hundreds of millions of dollars."

— Bill Gates at the World Economic Forum in Davos in 2008.

See also

• FDA Fast Track Development Program
• Breakthrough therapy

References

1. "Expedited Programs for Serious Conditions––Drugs and Biologics" (PDF). Food and Drug Administration. April 10, 2019.
2. "Regulatory Affairs Professionals Society | RAPS". Retrieved December 14, 2023.
3. "H.R. 3580" (PDF). Food and Drug Administration.
4. Ridley DB, Grabowski HG, Moe JL (2006). "Developing drugs for developing countries". Health Aff (Millwood). 25 (2): 313–24. doi:10.1377/hlthaff.25.2.313. hdl:10161/7017. PMID 16522573.
5. "Archived copy" (PDF). Archived from the original (PDF) on September 10, 2008. Retrieved March 21, 2008.{{cite web}}: CS1 maint: archived copy as title (link)
6. "Priority Review Voucher Fees to Decline in FY 2017".
7. "Fee for Using a Rare Pediatric Disease Priority Review Voucher in Fiscal Year 2017". September 30, 2016.
8. "Issuance of Priority Review Voucher; Rare Pediatric Disease Product". Federal Register. December 13, 2018. Retrieved March 28, 2019.
9. "FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia". U.S. Food and Drug Administration. March 24, 2020. Retrieved October 8, 2021.
10. "First FDA-approved vaccine for the prevention of dengue disease in endemic regions". U.S. Food and Drug Administration (FDA) (Press release). May 1, 2019. Retrieved November 17, 2019.
11. "FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality". U.S. Food and Drug Administration (FDA) (Press release). May 24, 2019. Retrieved November 17, 2019.
12. "FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs". U.S. Food and Drug Administration (FDA) (Press release). August 14, 2019. Retrieved November 17, 2019.
13. "FDA approves first live, non-replicating vaccine to prevent smallpox and monkeypox". U.S. Food and Drug Administration (FDA) (Press release). September 24, 2019. Retrieved November 17, 2019.
14. "FDA approves new breakthrough therapy for cystic fibrosis". U.S. Food and Drug Administration (FDA) (Press release). October 21, 2019. Retrieved November 17, 2019.
15. "First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response". U.S. Food and Drug Administration (FDA). December 19, 2019. Archived from the original on December 20, 2019. Retrieved December 19, 2019.
16. "FDA Speeds Up Examination of 5 Drugs with Priority Review". BioSpace. Retrieved November 6, 2020.
17. "FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation". U.S. Food and Drug Administration. March 24, 2020. Retrieved October 8, 2021.
18. "FDA Approves First Drug to Treat Rare Metabolic Disorder". U.S. Food and Drug Administration (Press release). November 23, 2020. Retrieved October 8, 2021.
19. "FDA Approves Innovative Treatment for Pediatric Patients with Congenital Athymia". U.S. Food and Drug Administration (FDA) (Press release). October 8, 2021. Retrieved October 8, 2021.
20. "Section 529 Rare Pediatric Disease Priority Review Voucher Incentive Program, Public Law 112-144" (PDF). Public Law. July 9, 2012. Retrieved November 19, 2015.
21. "Public Law 112-144". gpo.gov. Retrieved December 14, 2023.
22. Casey, Robert (September 30, 2016). "Text - S.1878 - 114th Congress (2015-2016): Advancing Hope Act of 2016".
23. Daw, Daniel (December 5, 2014). "Senators praise passage of faster Ebola review by FDA". BioPrepWatch. Chicago, Illinois. Retrieved March 23, 2015.
24. "Summary: S.2917 — 113th Congress (2013-2014)". Congress.gov. Washington, D.C.: U.S. Library of Congress. December 16, 2014. Retrieved March 23, 2015.
25. "Cosponsors: S.2917 — 113th Congress (2013-2014)". Congress.gov. U.S. Library of Congress. December 16, 2014. Retrieved March 23, 2015.
26. "S. 2917, Adding Ebola to the FDA Priority Review Voucher Program Act; Cost Estimate". Congressional Budget Office. November 25, 2014. Retrieved March 23, 2015.
27. "Senators Propose New Exclusivity Voucher, Priority Review Voucher Programs".
28. Ridley DB, Sánchez AC (September 2010). "Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases". Lancet. 376 (9744): 922–7. doi:10.1016/S0140-6736(10)60669-1. PMID 20833303. S2CID 34391520.
29. Andrew S. Robertson (May 2016). "Preserving an Incentive for Global Health R&D: The Priority Review Voucher Secondary Market". American Journal of Law & Medicine. 42 (2–3): 524–542. doi:10.1177/0098858816658278. PMID 29086641. S2CID 3985989.
30. Loftus, Peter (November 1, 2015). "Drug Makers Buy Pricey Vouchers to Speed Products to Market". Wall Street Journal. Retrieved November 19, 2015.
31. John Carroll (July 30, 2014), "Sanofi, Regeneron pay $67M for a shortcut in the blockbuster PCSK9 race with Amgen", FierceBiotech
32. Ron Winslow; Joseph Walker (July 30, 2014), "Drug Firms Buy $67.5 Million Voucher to Speed FDA Review", Wall Street Journal
33. Chelsey Dulaney, United Therapeutics Sells Priority-Review Voucher to AbbVie for $350 Million, Wall Street Journal (August 19, 2015).
34. Conor Hale, Jazz grabs Spark's priority review voucher for $110M, Fierce Biotech (April 30, 2018).
35. "Tropical Disease Priority Review Voucher Program". U.S. Food and Drug Administration (FDA). August 23, 2018. Archived from the original on December 20, 2019. Retrieved December 19, 2019. This article incorporates text from this source, which is in the public domain.
36. Carpenter D, Zucker EJ, Avorn J (March 2008). "Drug-review deadlines and safety problems". N. Engl. J. Med. 358 (13): 1354–61. doi:10.1056/NEJMsa0706341. PMID 18367738.
37. Nardinelli C, Lanthier M, Temple R (July 2008). "Drug-review deadlines and safety problems". N. Engl. J. Med. 359 (1): 95–6, author reply 96–8. doi:10.1056/NEJMc086158. PMID 18596282. S2CID 205041656.
38. "Bill Gates - Bill & Melinda Gates Foundation". Microsoft.

External links

• Priority review voucher page published by one of the Duke authors of the voucher
• "FDA to aid tropical disease research" at the Financial Times in 2008
• Optional Rewards for New Drugs for Developing Countries, a critique from the WHO's Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)
• SEC. 524. (21 USC §360n) Text of the amendment
• Rare Pediatric Disease Priority Review Vouchers from the U.S. Food and Drug Administration (FDA), 2019