KNOWLEDGE PORTAL
on innovation and access to medicines

In 2006, Ridley et al. (2006) proposed the use of PRVs to encourage the development of medicines for neglected diseases. This paper developed a list of criteria for which a PRV should be issued, estimated the value of a PRV in relation to a “potential blockbuster drug” to be higher than USD 300 million, presented the dual benefit of PRVs as increasing access to drugs that are needed in developed and developing countries, respectively, and made a cost-benefit analysis of introducing the PRV incentive (Ridley, Grabowski, and Moe 2006).

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Following support for the proposal from several members of the US Congress, the Food and Drug Administration Amendments Act (FDAAA) of 2007 introduced the PRV system in the US for the review of drug applications for neglected tropical diseases (Hamming 2013; Gaffney, Mezher, and Brennan 2018). In 2012, the Creating Hope Act of 2011 (CHA) added rare pediatric diseases to the list of PRV-eligible diseases (Hamming 2013).

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The CHA also made the PRV transferable, e.g. by sale, and revocable for failure to market the product in a timely manner; it also shortened the application notice period to ninety days from one year (Abdel-Rahman et al. 2014). The PRV was also extended to medical countermeasures for pathogens of pandemic potential in 2016 through the 21st Century Cures Act (Gaffney, Mezher, and Brennan 2018). The same legislation also extended the PRV program for rare pediatric diseases for an additional 3 years (Ekins and Wood 2016). It has been noted that the PRV mechanism has received significant political support (Ravvin 2008).

 

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FEATURES OF PRVs

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Most of the literature discuss the basic features of the PRV including (i) that the award of a PRV is granted upon a successful approval of a medicine for any of the eligible diseases or conditions, (ii) the privilege of expedited review, that is 6 months instead of the usual 10 months or so review period, of any medicine application brought by virtue of the awarded PRV, (iii) the ability to sell the awarded PRV to other entities (transferability) and (iv) the absence of or minimal direct financial costs to taxpayers with respect to the implementation of the PRV program. In order to be eligible for a PRV the tropical disease medicine application must pertain to a new chemical entity that is not yet offered for sale in the US (Berman and Radhakrishna 2017).

 

Other PRV features include: the provision permitting the list of eligible diseases to be updated (Anderson 2009), the requirement to pay user fees when claiming the PRV privilege and the corresponding amounts paid from 2011 to 2018, the proviso that the PRV does not guarantee an affirmative decision on the application nor that the decision of the review process will be issued within the target six-month period (Hamming 2013; Gaffney, Mezher, and Brennan 2018), considering that certain applications may require further clarifications or tests (Moe, Grabowski and Ridley 2009). It is noted that the user fee covers the cost for implementing the program and thus, removes the direct financial burden from the government and taxpayers (Hoffman and So 2015). Berdud, Towse and Kettler (2016), focusing on malaria research and development, argued that the PRV user fees may be steep for some entities such as small and medium enterprises or not-for-profit organizations (Berdud, Towse and Kettler 2016).

 

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EXPECTED BENEFITS

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Among the expected benefits of the PRV are an increase in R&D activities for the target diseases (Ehrenheld 2008) and accelerated access to the resulting medicines by patients in developing countries (Sonderholm 2009). Dimitri (2010) provided an economic analysis of the efficacy of PRVs and concluded that, given certain conditions, PRVs would be likely to increase R&D activities (Dimitri 2010). The proponents of the PRV also noted the direct benefits from the PRV for drug developers in the form of expedited review of their applications, or the monetary proceeds from the sale of a PRV (Moe, Grabowski and Ridley 2009). Further, PRVs are also expected to complement other drug development initiatives (Grabowski, Ridley, and Moe 2008).

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PRVs AS ISSUED AND MARKET VALUE

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Gaffney, Mezher, and Brennan (2018) listed the PRVs that were issued by the FDA from 2009 to 2018, including for which diseases and their respective status (whether they have been used, sold or remain to be used) (Gaffney, Mezher, and Brennan 2018). They compiled the known amounts for which the issued PRVs had been purchased. It was noted that, until 2015, the sales price of a PRV increased but starting in 2016 the prices decreased. Prices have ranged between USD 67 million and USD 350 million (Gaffney, Mezher, and Brennan 2018). Stefanakis et al. (2012) determined that there are 35 drugs under clinical development that would qualify under the PRV program between 2011 to 2020, yielding an estimated 1 or 2 PRVs annually (Stefanakis et al. 2012). Robertson estimated the floor price of a PRV, (upon sale to a third-party), depending on the number of PRVs awarded per year (Robertson 2016).

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Robertson et al. (2012) conducted an online survey of for-profit companies that run programs dealing with diseases covered by the PRV. The survey results indicated that the PRV is one, but not the only, factor companies consider when deciding to engage in R&D for neglected tropical diseases (Robertson et al. 2012).

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Ekins and Wood (2016) argued that the PRV is the main expected source of financial return for a small company engaged in drug R&D for rare diseases such as Sanfillipo Syndrome, which does not have a large patient base (Ekins and Wood 2016). It was also noted that the possibility of a PRV award upon approval of moxidectin for the treatment of onchocerciasis was a consideration for the Global Health Investment Fund in funding the drug’s US FDA registration by the non-profit organization Medicines Development for Global Health (Kuesel 2016).

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CRITIQUES

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Some papers have made several critiques of PRVs. Mostaghim and Kesselheim (2016) and Sinha and Kesselheim (2016) argued that the PRV program has not yet shown any quantifiable impact with respect to increasing R&D on tropical diseases. It has also been observed that a survey of drugs being developed for neglected diseases from 2000 to 2014 indicated that “[t]he proportion of neglected tropical disease drugs among all products in development decreased by 1.74% per year (95% CI, -13.86% to 12.87%) before the voucher was created and decreased by 1.73% per year (95% CI, -12.75% to 10.27%) after the voucher was created” (Jain et al. 2017).

 

Other critiques include: that the PRV system more possibly functions as a reward for organizations that already have medicines at the late stages of the development pipeline and not as an incentive for the conduct of new R&D activities on neglected disease medicines (Ravvin 2008). It is also seen as an unsustainable mechanism because it mainly relies on US patients paying indirectly for the PRV (Sonderholm 2009). Another criticism of the PRV program is that, while it may boost drug development on the eligible diseases and conditions, this does not necessarily translate into availability or affordability of the drugs to the populations in need of them (Gaffney, Mezher, and Brennan 2018; Sonderholm 2009; Kesselheim, Maggs, and Sarpatwari 2015). Kesselheim (2008) argued that the PRV is an inefficient incentive tool since research on neglected tropical diseases is usually made by small, rather than large, pharmaceutical companies having “limited drug portfolios” and who will not likely use the awarded PRV (Kesselheim 2008) (this argument was made before the PRV was revised to become transferable).

 

The question has also been raised as to whether loopholes in the legislation allow companies to obtain a PRV without having conducted any R&D. For example, Sunyoto, Potet, and Boelaert (2018) and Doshi (2014) questioned whether the company Knight Therapeutics should have received a PRV for the approval of the drug miltefosine (for treating leishmaniasis), considering that public and philanthropic actors largely funded the development of this drug, and that it had already obtained regulatory approval outside the US (Sunyoto, Potet, and Boelaert 2018; Doshi 2014). Kesselheim (2009) proposed that funding be granted directly to those entities and individuals conducting medicines research for neglected diseases instead of spending the additional amounts on medicines that obtained faster marketing approval with a PRV (Kesselheim 2009). Lexchin (2010) concluded that the PRV system, with respect to neglected diseases, may be best replaced with another incentive mechanism for R&D (Lexchin 2010). This latter view was echoed by Muthyala (2011) as to the suitability of the PRV for orphan drugs (Muthyala 2011).

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PRVs IN THE FUTURE

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Proposals for changes to improve the PRV system include: (i) the imposition of “access commitments” on the PRV awardee, (ii) requiring that the medicine eligible for PRV award be newly introduced worldwide instead of just in the United States market (Mostaghim and Kesselheim 2016), (iii) three PRVs should be awarded instead of just one to increase its “economic incentive”; (iv) that no orphan drug tax credit be granted on top of a PRV award; and (v) that the future PRV law require a waiver of patent rights over the neglected tropical disease medicine (Sonderholm 2009).

 

The adoption of the PRV system in Europe has been proposed, with the estimated value of the PRV expected to be similar to that in the US (Ridley and Sánchez 2010), but experts on orphan drug development caution that the expected benefits of adopting this program must be weighed against significant costs related to the system (Picavet, Cassiman, and Simoens 2012). PRVs have also been suggested as an incentive to develop new antibiotics for antimicrobial resistance (AMR) (Sciarretta et al. 2016).

 

The website http://www.priorityreviewvoucher.org/ provides extensive information on the PRV, and is maintained by David Ridley (one of the original proponents of the PRV).

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RESEARCH GAPS

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• Analysis regarding the extent to which PRVs increase R&D efforts over business-as-usual in targeted diseases, and whether or how it shapes R&D decision-making

• Research on the extent to which products covered by PRVs are made available, manufactured and distributed to the public, and at what price

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CITED PAPERS WITH ABSTRACTS​