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Priority Review Voucher

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Overview

The priority review voucher (PRV) was based on a 2006 paper (Ridley et al. 2006) and became law in 2007. Under the law, a developer of a treatment for a neglected or rare pediatric disease receives a voucher for priority review from the FDA to be used with a product of its choice or sold to another developer.

Priority review means that the FDA aims to render a decision in 6 months. In contrast, the FDA aims to complete a standard review in about 10 months, and it often takes even longer. The median difference in recent years was about 7 months (Grabowski et al. 2009).

The PRV is intended to reduce two types of inefficiency. First, the PRV speeds approval of potential blockbuster therapies in the US, getting US patients access to these treatments more quickly. Second, the PRV motivates more treatments for neglected diseases.

By moving one drug to faster review, there is the potential to slow other drugs. To provide FDA with more resources and mitigate this cost, the PRV holder must pay the FDA an additional user fee ($2,727,000 in fiscal year 2016).

The PRV is transferable.

Impact

Because of the voucher program, investors are more willing to provide funding to entrepreneurs working on drugs for neglected diseases. For example, NanoViricides was developing drugs for viruses that have large sales potential in markets such as the United States, such as HIV-AIDS and flu. They are now developing a drug for dengue because of the voucher incentive. According to Dr. Eugene Seymour, CEO of NanoViricides,

"After learning of the priority review voucher (PRV) program, I pushed my company to initiate development of a drug for dengue/dengue hemorrhagic fever, then the only viral disease on the FDA eligibility list for a PRV. The drug, built on our NanoViricides platform, has since undergone initial testing... I’ve had serious discussions with many different entities, including the head of the dengue branch of the US Centers for Disease Control who has pledged clinical trial support as well as a large Foundation in South America who would like to pursue discussions regarding distribution of the drug after it’s approved in the US. None of this would have happened had there not been a PRV program in place" (Email correspondence with Dr. Seymour, November 2015).

Likewise, the Global Health Investment Fund announced that it is providing $10 million to non-profit drug developer Medicines Development of Australia to complete registration of moxidectin, a drug for river blindness. Because river blindness does not affect people in rich countries, moxidectin had been languishing on the shelf of a drug manufacturer. If it is approved, then it can help speed the eradication of river blindness. Furthermore, if the drug is approved and wins a priority review voucher from the Food and Drug Administration, the Fund will share in some of the rewards from sale of the voucher. The fund can then use some of the returns to re-invest in global health. According to Mark Sullivan, the CEO:

"Medicines Development for Global Health's ability to attract the finances required to complete the final stages of moxidectin's development was a direct result of the value of the voucher. Even then, the risk/benefit debate diminished only once two commercial voucher transactions had taken place and the theoretical market value had become a confirmed value. Without this mechanism, moxidectin would have been a missed opportunity for global health" (Email correspondence with Mr. Sullivan, January 2016).

BIO Ventures for Global Health (BVGH) reports on the pipelines for treatments for neglected diseases such as Ebola, malaria, river blindness, and tuberculosis. For example, there are several late-stage clinical trials for tuberculosis drugs and vaccines that could be eligible for vouchers. One of the companies developing a tuberculosis drug and pursuing a voucher is Sequella.

Eligibility

To be eligible for a PRV, the drug or vaccine must satisfy the following criteria.

  1. Treat one of the following diseases:
    • Blinding trachoma
    • Buruli Ulcer
    • Chagas (added in 2015 by FDA)
    • Cholera
    • Dengue
    • Dracunculiasis
    • Fascioliasis
    • Filoviruses (including Ebola) (added in 2014 through legislation)
    • Human African trypanosomiasis
    • Leishmaniasis
    • Leprosy
    • Lymphatic filariasis
    • Malaria
    • Neurocysticercosis (added in 2015 by FDA)
    • Onchocerciasis
    • Schistosomiasis
    • Soil transmitted helminthiasis
    • Tuberculosis
    • Yaws
    • Zika (added in 2016 through legislation)
    • A rare pediatric disease (added in 2012 through legislation)
  2. Contain no active ingredient (including any ester or salt of the active ingredient) that has been approved in any other FDA application.
  3. Offer major advances in treatment, or provide treatment where no adequate therapy exists, thus earning priority review on its own merit. (In other words, to win a bonus priority review, the treatment must first get its own priority review).
Some drugs for these diseases are available in other countries, but are not registered in the United States, and thus might be eligible for vouchers. Some have called on Congress to make drugs ineligible for the voucher, if the drug has been available outside the United States for more than 3 years. See "Extension to Rare Pediatric" below for eligibility for a pediatric vouchers.

Recipients

 YearDiseaseDrugCompanyCommentsStatus

1)2009MalariaCoartem (artemether/lumefantrine)NovartisThe first voucher awardedUsed by Novartis
2)2012TuberculosisSirturo (bedaquiline)Janssen (JNJ)The first TB drug approved by FDA in decades
3)2014Morquio A syndromeVimizim (elosulfase alfa)BioMarinThe first voucher for a rare pediatric disease Sold for $67.5 million
4)2014LeishmaniasisImpavido (miltefosine)KnightFor patients with visceral, mucosal and cutaneous Leishmaniasis Sold for $125 million
5)2015High-risk neuroblastomaUnituxin (dinutuximab)United TherapeuticsFor a type of cancer that most often occurs in young childrenSold for $350 million
6)2015Rare bile acid synthesis disordersCholbamAsklepionFDA press releaseSold for $245 million
7)2015Hereditary orotic aciduriaXuridenWellstatFDA press release
8)2015HypophosphatasiaStrensiq (asfotase alfa)AlexionFDA press release
9)2015Lysosomal acid lipase (LAL) deficiencyKanuma (sebelipase alfa)AlexionFDA press release
10)2016CholeraVaxchoraPaxVaxFDA press release

Value

The price of the voucher will depend on supply and demand. On the demand side, the PRV's value derives from three factors: shifting sales earlier, longer effective patent life due to earlier entry, and competitive benefits from earlier entry relative to competitors. Top-selling treatments can yield billions in sales each year, so being approved months earlier can be worth hundreds of millions of dollars to the PRV holder (Ridley et al. 2006; Grabowski et al. 2009). The value of the voucher will depend on the drug's therapeutic class (Noor 2009).

About half of the blockbuster drugs in the 1990s received a standard review, and thus could have benefited from a PRV. There are typically about three blockbusters per year with standard review.

On the supply side, researchers at BioVentures for Global Health estimate that over the next decade, 3.5 vouchers could be awarded per year. They forecast that the next voucher could be awarded as early as 2013, possibly for a drug to treat river blindness. They forecast that the distribution across years will not be smooth with most of the vouchers awarded in the latter half of the decade.

In 2014, BioMarin sold its voucher for $67.5 million to Sanofi/Regeneron and Knight sold its voucher for $125 million to Gilead. In 2015, Retrophin sold a voucher to Sanofi for $245 million and United Therapeutics sold a voucher to AbbVie for $350 million.

In July 2015, Amgen's cholesterol drug Repatha was approved in Europe, 2 months ahead of Sanofi/Regeneron's Praluent. But in the US, the order was reversed with Praluent a month ahead of Repatha, because Sanofi/Regeneron used a priority review voucher. Read more at Fierce Pharma.

Expiration

Priority review vouchers do not expire. Furthermore, the priority review voucher program for neglected diseases (enacted in 2007) does not sunset. However, the program for rare, pediatric diseases (enacted in 2012) expired in spring 2016 (one year after the FDA awarded the third pediatric voucher). Congress extended the pediatric program until fall 2016. If Congress does not renew the pediatric voucher program in fall 2016, then FDA will stop awarding vouchers for rare, pediatric diseases. Members of Congress seem to like the voucher program (although also seeing scope for improvement), as evidenced by votes to extend the program to additional diseases, which suggests that Congress will probably renew the program.

History

David Ridley, Henry Grabowski, and Jeff Moe proposed the voucher in a paper published in 2006. David presented the idea at several conferences, including the June 2004 meeting of the Drug Information Association, the January 2005 meeting of the American Economic Association, and the July 2005 meeting of the International Health Economics Association. In 2006, the voucher proposal was the lead article in Health Affairs. After Health Affairs published the paper, David was invited to present the idea at the National Press Club on March 7, 2006. After the press conference, Laura Blinkhorn (a reporter for Congressional Quarterly) told David that Senator Brownback (R-KS) would be interested. David and Jeff met with Senator Brownback and his staff (including Melanie Benning). Senator Brown (D-OH) and others joined Senator Brownback in sponsoring the bill. In a later issue of Health Affairs, Senator Brownback wrote, "After reading their proposal in Health Affairs, I met with Ridley and colleagues to discuss the idea further, and I subsequently drafted an amendment... Indeed, their idea is the heart of my Elimination of Neglected Diseases (END) amendment" (Brownback 2007).

In 2008, Bill Gates speaking at the World Economic Forum in Davos in 2008, said "But 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" (transcript, video, video excerpt).

Extension to Europe

Writing in The Lancet, David Ridley and Alfonso Calles Sanchez proposed extending the voucher to the European Union (Ridley and Calles Sanchez 2010). 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.

Extension to Patents

Inspired by the priority review voucher, in 2012 the United States Patent and Trademark Office (USPTO) launched a pilot program called "Patents for Humanity" to encourage businesses to apply their patented technology to addressing humanitarian challenges. Winners receive a voucher with which they may (1) move a patent re-examination proceeding to the front of the queue; (2) move a patent appeal case in front of the Board of Patent Appeals and Interferences to the front of the queue; or (3) accelerate the examination of a patent with the goal of a final decision on the application within twelve months. Application categories include medical technology, food & nutrition, clean technology, and information technology. In 2013, the USPTO awarded ten acceleration certificates.

Extension to Rare Pediatric Diseases

In 2012, the U.S. President signed into law the FDA Safety and Innovation Act which includes Section 908 the "Rare Pediatric Disease Priority Review Voucher Incentive Program". The act extends the voucher program to rare pediatric diseases on a trial basis.

In 2014, the U.S. President signed into law the Adding Ebola to the FDA Priority Review Voucher Program Act which makes (1) adds filoviruses (including Ebola) to the list of eligible diseases, (2) allows multiple transfers of the voucher, and (3) reduces the notification period for FDA from one year to 90 days.

To be eligible for a pediatric PRV, the drug or biological product must

  • be novel
    • contain no active ingredient that has been previously approved by FDA
    • qualify for priority review (in addition to the bonus priority review)
  • treat a rare pediatric disease
    • rely on clinical data from studies examining a pediatric population and dosages of the drug intended for that population
    • not seek approval for an adult indication in the original rare pediatric disease product application
Tropical Rare Pediatric
Legislative authority FDAAA (2007) (PDUFA IV) FDASIA (2012) (PDUFA V)
Voucher winner Number of vouchers to be issued Unlimited Pilot expires one year after third pediatric voucher awarded
Eligibility 17 neglected diseases (may be extended by Secretary of HHS) Rare, pediatric diseases (may ask FDA in advance for an indication of whether disease qualifies as a rare, pediatric disease)
Obligations for voucher winner None (other than public pressure) Winner must market drug within a year and report to FDA about use of drug within five years
Voucher user Notification 90 days prior to voucher redemption
Transferability Unlimited
Additional user fee $2,727,000 in fiscal year 2016
Voucher expiration date None

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