Research and development (R&D) is lengthy and costly. It takes more than a decade and costs around $2.6 billion to bring a new drug to the market (2013 US dollars) [1].

Failure in R&D is common; for example, the overall probability that a drug entering clinical testing ends up being approved by the US FDA is estimated to be 11.8% [1]. Failure rates nonetheless vary across drug development phases and are estimated at around 45.9% for phase I, 43.5% for phase II, and 10.6% for phase III/regulatory review [1].

Given the costly and risky nature of R&D, pharmaceutical companies have an interest in investing in diseases with a large and stable market in high-income countries (HICs). Consequently, infectious diseases that are mostly prevalent in low-income countries (LICs), such as leishmaniasis, sleeping sickness, dengue fever and Chagas disease, have not historically attracted much interest.

These diseases mainly affect the world’s poorest populations with a purchasing power that is not high enough to generate a return on investment for the pharmaceutical industry. Moreover, for some of these diseases, the market is small and distributed in very concentrated and specific regions of the world, often with low ability-to-pay for therapeutic products. As a result, these diseases are labeled as ‘neglected diseases’.

Between September 1999 and December 2011, 118,634 trials were registered in the US National Institutes of Health (NIH) registry (ClinicalTrials.gov), but only 1541 (1%) were for neglected diseases [2]. While neglected diseases account for 12% of the global health burden, their share of R&D activity barely reaches 1%.

To address this unmet need, the US congress established the priority review voucher (PRV) program in September 2007. The PRV was initially designed for tropical diseases but was expanded to include rare pediatric conditions in 2012 and medical countermeasures in 2016.Footnote 1

The rationale behind the PRV was to reward the development of successful products for one of the eligible diseases, by awarding the products’ manufacturers/sponsors a voucher that reduces the duration of a product review by the FDA from the usual 10 months to 6 months [3]. The voucher thus grants faster review and can be used for any product of the PRV holder’s choice, either for an earlier market launch or during earlier R&D phases. Alternatively, the voucher can be sold to a third party. Thus far, prices of PRVs have ranged from $67.5 million in 2014 to $338 million in 2015 [4].

The PRV is said to lead to a ‘win-win’ situation, with the social welfare gains to patients both in LICs and HICs and the net gains to manufacturers being greater than the cost of FDA review incurred by the government [5,6,7]. This being said, the cost borne by the FDA is not to be neglected. The PRV program is said to hinder the ability of the FDA to predict its own workload and to divert staff attention from other important work to meet the required shortened timeframe for review [8].

The policy has specific eligibility requirements that touch upon diseases, registries, and product types. For tropical diseases, the PRV policy includes a specific list of eligible diseases (see Fig. 1). The policy was implemented in a staggered way; most tropical diseases became eligible as of September 2007, while a few became eligible in 2014, 2015, 2016, and 2018. The voucher can only be awarded to products (drugs, vaccines, and devices) for one of the eligible diseases and for which previous trials, other than phase I trials, were registered in the US registry (ClinicalTrials.gov) within 21 days of enrolling the first patient in the trial.

Source: Our elaboration on US FDA data [24]. PRV priority review voucher

Eligible diseases of the priority review voucher program. Most diseases became eligible for the PRV when the policy was implemented in 2007. Few additional diseases were added to the eligible list later on, in 2014, 2015, 2016 and 2018.

Eligible products are products that demonstrate their non-inferiority to existing products and contain no active ingredient that has been approved in any other application (although combination products with at least one new active moiety are eligible).

Accordingly, translating these requirements to trial activity, eligible trials are trials other than phase I that (1) demonstrate the non-inferiority of the tested product; (2) are interventional; and (3) are registered on ClinicalTrials.gov within 21 days of enrolling the first patient but after the program start date (27 September 2007). Trials registered on or before that date are also considered eligible if they were still ongoing as of 26 December 2007. For diseases eligible in 2014, 2015, and 2016, trials should have been initiated after their date of eligibility.

Lastly, the program has faced structural changes since its implementation, in 2011 and 2014. Since 2011, a fee has to be paid to the FDA to compensate for the incurred added cost of conducting a priority review, which varies annually—from $2.32 million in 2014 up to $5.28 million in 2012 [9]. Before 2014, companies that were granted (or bought) the voucher and wanted to use it had to notify the FDA 365 days in advance, but as this was limiting the usefulness of the voucher, it was changed to a 90-day notice period. In that same year, it was decided that the voucher could be sold an unlimited number of times as opposed to once.

More than a decade after its implementation, it is unknown if the supposed benefits of the PRV have materialized. As of 2019, 31 PRVs have been awarded, of which 11 were awarded for tropical diseases (Table 1) [4].

The PRV has been criticized for rewarding products already in use/licensed outside the US and/or manufacturers that purchased the license but who were not involved in the R&D process [10]. The PRV has also been criticized for rewarding products that would have been developed had the program not been implemented. This assertion is based on the idea that a potential 4-month early entry to the market is not sufficient to incentivize pharmaceutical companies to invest in risky projects for neglected diseases. The word ‘potential’ is important for two reasons: (1) R&D may not lead to successful product development and to access to the voucher; and (2) a voucher does not guarantee an earlier market launch since the FDA can decide to reject a product on which it conducted a priority review (e.g. the case of Novartis for its biological licensing application for canakinumab) [3]. Additionally, the voucher’s uncertainty is not only limited to its use but also extends to its sale; its market price has fluctuated significantly since the first voucher was sold in 2011, with a general depreciation since 2017 to around 100 million US dollars. Selling the voucher rather than using it may appear more appealing to smaller pharmaceutical companies that do not have a blockbuster candidate in their pipeline on which to use the voucher.

Until now, evidence of the PRV’s impact is limited. Only three studies—two for tropical diseases and one for rare pediatric conditions—have evaluated the PRV, but with research design and data limitations that limit the extent to which causal inferences can be made [11,12,13] (for more details refer to Online Resource 1 in the Electronic Supplementary Material [ESM]).

Therefore, the objective of this study was to assess whether the PRV has successfully incentivized R&D for the intended tropical diseases that would have not taken place in its absence. We built on previous studies by employing a difference-in-difference-in-differences approach. As the policy targets specific diseases (Fig. 1) from a specific regulatory body/trial registry (i.e. the FDA/ClinicalTrials.gov), we defined two control groups: the diseases that are not targeted by the PRV (non-eligible diseases) and the registries that are not affected by the PRV (any registries other than ClinicalTrials.gov that are members of the WHO International Clinical Trials Registry Platform [ICTPR]; (see Online Resource 2 in the ESM).