Priority review vouchers (PRVs), which are fast-becoming a powerful incentive for drug companies, were originally based on a publication (Ridley et al. 2006) from a group at Fuqua School of Business at Duke University in NC. The idea behind PRVs was that developers of treatments for neglected infectious diseases (and later, rare pediatric diseases) would receive a voucher that could later be used with a product of their choice to shorten review times by up to 1 year or sold or transferred to another developer, thus incentivizing development of these much needed therapeutics. The voucher also would benefit consumers both in developing and developed countries, speeding access to highly valued treatments and providing a win-win for both developers and consumers.

Tropical Disease Vouchers

PRVs for tropical diseases became law in 2007 (FDA Amendments Act of 2007, PDUFA IV). To be eligible for a PRV, a drug or vaccine must satisfy at least 4 criteria:

1. Treat one of following 17 diseases (list may be extended by the Secretary of HHS):
   

   Blinding trachoma	Leprosy
   Buruli Ulcer	Lymphatic filariasis
   Cholera	Malaria
   Dengue	Onchocerciasis
   Dracunculiasis	Schistosomiasis
   Fascioliasis	Soil transmitted helminthiasis
   Filoviruses (including Ebola)	Tuberculosis
   Human African trypanosomiasis	Yaws
   Leishmaniasis

2. Be a new drug application (NDA) (additional details on this point in Vouchers and 505(b)(2) Submissions)
3. Be a new molecular or chemical entity (NME or NCE)
4. Offer major advances in treatment or provide treatment where no adequate therapy exists (ie, qualify for priority review)

Details on the parameters for use of these vouchers can be found in the 2008 procedural guidance on tropical disease PRVs or here. In order to account for the cost of the expedited review and to prevent tying up FDA resources, an additional user fee must be paid by manufacturers to FDA when the voucher is used ($2,562,000 in fiscal year 2015) and FDA must be notified 90 days prior to submission.

Rare Pediatric Disease Vouchers

In 2012, FDASIA (PDUFA V) expanded the law on PRVs to include rare pediatric diseases on a trial basis. Notably, this pilot program is set to expire one year after the third pediatric voucher is awarded, which occurred recently (17 March 2015; see Table 1). Rare pediatric diseases are defined by FDA as diseases that primary affect individuals age birth to 18 years (interpreted in the FDA guidance on rare pediatric vouchers as greater than 50% of those affected in US in the 0 – 18 years age range) and affects fewer than 200,000 persons in the US (or a disease that affects larger numbers of individuals for which there is no reasonable expectation that the costs of developing the drug can be recovered from US sales). For vaccines, diagnostic drugs, and preventative drugs, prevalence estimates should be based upon the number of individuals in the US that would receive the drug annually.

To qualify for a rare pediatric disease PRV, a drug or biological product must meet criteria similar to those of the tropical PRVs, as follows:

1. Used for the prevention or treatment of a rare pediatric disease
2. Submitted under Section 505(b)(1) [or 505(b)(2)] of the FD&C Act
3. Categorized as an NCE or NME
4. Qualify for priority review
5. Approval for an adult indication must not be sought in the original rare pediatric disease product application
6. Application must rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population

Details on the parameters for use of these vouchers can be found in the 2014 procedural guidance on rare pediatric disease PRVs or here. As with tropical disease vouchers, the manufacturer must submit an additional user fee ($2,562,000 in fiscal year 2015) and notify FDA 90 days prior to submission.

Voucher Recipients

Since 2007, only 6 companies have received PRVs, 3 for tropical and 3 for rare pediatric diseases (Table 1). The awarding of the third rare pediatric disease PRV initiates a one-year countdown clock (per Sec 908 of FDASIA, which adds Section 529(b)(5) to the FD&C Act), after which FDA may no longer award any additional rare pediatric disease PRVs unless Congress enacts legislative changes. It is likely that Congress would act to approve an extension of the rare pediatric disease voucher program, considering the success of the program thus far. Rare pediatric disease PRVs have only been available since 2012, while tropical disease PRVs were passed into law in 2007, and the same number of each has been awarded. Additionally, it reasonable to believe that public support of extending the rare pediatric disorder PRVs could pressure Congress to act, as many rare diseases have gained wider attention in recent years due to social media campaigns.

Table 1     Recipients and Status of Priority Review Vouchers

Year Awarded	Disease	Drug Name	Company	Comments	Status
2009	Malaria	Coartem® (artemether/ lumefantrine)	Novartis	First voucher awarded (Tropical)	Used (Novartis)a
2012	Tuberculosis	Sirturo® (bedaquiline)	Janssen (JNJ)	First TB drug approved by FDA in decades (Tropical)	Unused
2014	Morquio A syndrome	Vimizim® (elosulfase alfa)	BioMarin	First rare pediatric disease voucher awarded	Sold ($67.5 million)b
2014	Leishmaniasis	Impavido® (miltefosine)	Knight	For patients with visceral, muscosal, and cutaneous Leishmaniasis (Tropical)	Sold ($125 million)c
2015	High-risk neuroblastoma	Unituxin® (dinutuximab)	United Therapeutics	Rare pediatric	Unused
2015	Rare bile acid synthesis disorders	Cholbam®	Asklepion Pharmaceuticalsd	Rare pediatric	Unused
aVoucher was used unsuccessfully by Novartis for Ilaris (canakinumab), which was deemed not approvable for the proposed indication of gouty arthritisb Sold to Sanofi/Regeneronc Sold to Gilead d To be transferred to Retrophin Inc., as part of a deal predicated upon approval of Cholbam.

The number of tropical disease vouchers is unlimited, they are fully transferable, and interestingly, their transferability is also unlimited. Theoretically, a company that purchases a voucher could also sell that voucher, although this situation has not yet occurred.

Only 6 vouchers have been awarded, with varying fates. Novartis was awarded the first tropical disease PRV in 2009 for Coartem^® (artemether/lumefantrine) tablets under the 505(b)(1) pathway. Novartis then redeemed the voucher for priority review of their supplemental Biologics License Application (sBLA) for Ilaris (canakinumab) for the treatment of gouty arthritis attacks. Unfortunately for Novartis, they paid the high PRV redemption price of $4,582,000 for Fiscal Year 2011 and were denied initial approval. In July 2014, BioMarin sold its rare pediatric disease voucher for $67.5 million to Sanofi/Regeneron, who redeemed the PRV in January 2015 for their PCSK9 inhibitor cholesterol-lowering drug (alirocumab). Priority review potentially could provide a leg-up in the ongoing race with Amgen’s competing PCSK9 inhibitor (evolocumab). This new class of drugs are expected to be expensive with an annual market of $3 billion each, highlighting the potential value of the PRVs.

One other tropical disease voucher, originally awarded to Knight Therapeutics, was sold in November 2014 for $125 million to Gilead, nearly twice that paid for BioMarin’s rare pediatric disease voucher. Gilead has a large pipeline, so it is not yet clear what their plan for the voucher is.

As a result of the recent approval of Cholbam for the treatment of rare bile acid synthesis disorders, Retrophin Inc. will exercise its right to acquire all worldwide rights to the treatment from Asklepion Pharmaceuticals, LLC for a one-time cash payment of $27 million and 661,278 Retrophin shares along with up to $37 million in cumulative sales milestones as well as tiered royalties based on future net sales of Cholbam. As part of the deal, the rare pediatric disease PRV awarded to Asklepion will be transferred to Retrophin.

Vouchers and 505(b)(2) Submissions

Of the 6 products receiving PRVs, one was approved via the 505(b)(2) regulatory pathway. Cholbam^® (cholic acid) capsules is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs) and adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat soluble vitamin absorption. Asklepion Pharmaceuticals was awarded a rare pediatric disease priority review voucher, as this treatment is the first approved for patients with these rare diseases. Cholbam is an interesting example of a rare pediatric disease PRV recipient for two reasons. First, it is the third rare pediatric disease PRV that has been granted, thereby starting the one-year clock until March 2016, after which no additional rare pediatric disease vouchers will be granted unless Congress takes action. Cholbam, as a 505(b)(2), is also the first instance of a 505(b)(2) product being granted a voucher. This is interesting, as both the 2008 procedural guidance on tropical disease PRVs and the 2014 procedural guidance on rare pediatric disease PRVs state that only applications submitted under Section 505(b)(1) of the FD&C Act are eligible to receive a voucher (and only 505(b)(1) applications can redeem a voucher). However, the more recent guidance on rare pediatric diseases further specifies in the footnotes that because 505(b)(2) NDAs are submitted under Section 505(b)(1), all references to NDAs submitted under Section 505(b)(1) include 505(b)(2) applications. It will be interesting to see if this is applied consistently across different divisions at FDA, particularly with the (possible) ending of the rare pediatric disease voucher program.

Stay tuned for further updates on whether these PVRs can be used successfully to gain market advantage over competitors and how high the prices will go.