Suitability of expanding the priority review voucher into rare disease drug development

KEYWORDS:

• Priority review voucher
• tropical diseases
• rare pediatric diseases
• drug development

Some diseases may not attract private investment to develop treatments under natural market conditions. This is perhaps because they do not affect enough patients in settings with the resources that are needed to make the drug development investment profitable. The priority review voucher (PRV) was conceived to address this type of problem by creating a cross-subsidization incentive. PRVs are awarded to drug sponsors for earning approval for a therapy treating a selected disease and provide the opportunity to receive expedited regulatory review of different, potentially more profitable drugs. The profits offered by the other drug are intended to incentivize investment in research for the disease that might not have otherwise attracted attention. A PRV model was first described in 2006 [1], and in 2007, it was enacted into US law [2] to encourage new therapies for certain neglected tropical diseases that preferentially affect patients in resource-poor settings around the world.

The PRV as a policy tool has grown in popularity. In 2012, Congress made new drugs treating rare pediatric diseases eligible to earn PRVs. Since then, treatments for Chagas, Ebola, and Zika have also been added. There have been calls for policymakers to include additional potential pandemic agents before they develop into major threats [3]. Other diseases currently being actively considered in 2016 include medical countermeasure treatments and treatments for neonatal diseases [4]. By mid-2016, 10 vouchers have been awarded, with 4 for neglected disease and 6 for rare pediatric disease drugs; four have been used and four have been sold for prices ranging from $67.5M to $350M USD [5].

Should the PRV have been expanded to rare pediatric diseases, and should the PRV be applied to rare diseases more broadly? There are over 6000 different types of rare diseases, affecting about 6–8% of the US population [6]. Many would benefit greatly from increased private investment in treatments. But there are fundamental shortcomings with the PRV mechanism that make it a poor fit for this purpose.

The PRV has not yet had any measurable effect on research priorities related to tropical diseases [7]. Others have offered anecdotes about the PRV’s utility and note that it will take time to realize the full benefits because of drug development’s long time horizons [8]. We believe that strong evidence from real-world experience that the program is working as intended should be required before considering further expansion. After close to a decade of operation, stories of patients receiving products in clinical trials for which development was initiated because of the voucher incentive should begin to emerge.

Such evidence will be important because there are, unfortunately, already examples demonstrating how the present mechanism design is vulnerable to misuse [9]. The current mechanism has allowed old drugs that have been widely used for decades outside the US to earn a voucher without any additional meaningful research and development – a true windfall for the sponsoring manufacturer. Such was the case for the first voucher, awarded for artemether–lumefantrine (Coartem) [5]. There is also no requirement for access and distribution commitments by sponsors after a PRV-eligible product is approved [10].

These shortcomings could be addressed by adjusting the PRV eligibility requirements. For example, awarding a voucher could be made conditional on access commitments from the pharmaceutical company, and the new-to-the-US registration requirement could be broadened so that it is new-to-anywhere. At minimum, these design flaws should be addressed before continuing the application of the PRV to rare pediatric diseases, let alone expanding the PRV program to other rare diseases.

Even if aspects of the voucher’s implementation are improved, there will still be inherent problems with the PRV program. The fundamental idea involves linking an essential government public health function – namely the regulatory review of investigational drugs – with a way of generating monetary value for private companies. The Food and Drug Administration (FDA) has been publicly critical of the PRV mechanism. In a recent governmental performance audit, FDA officials contended that the PRV program fundamentally interferes with the agency’s ability to set priorities based on public health needs and warned about the adverse effects of voucher implementation [11]. When describing the kind of drugs that are likely to have a PRV applied, FDA’s Director of the Office of New Drugs stated that imposing a 6-month review ‘is very challenging and has the adverse impact of requiring managers and reviewers to refocus time and resources away from other important public health work, such as reviewing other applications for potentially much more serious conditions or drafting of guidance documents on issues related to drug development’ [7]. The limited variability of voucher use also strains the FDA’s permanent reviewer staffing model [11].

Additional resources (via the voucher-specific user fee and one-time allocations to FDA from Congress) have been pointed to as a potential solution to FDA’s concerns, as has the notion that more vouchers would reduce FDA’s workload variability and ostensibly improve planning [12]. Unfortunately, more money per drug will not change the institutional hiring and organizational parameters that ultimately shape FDA’s review capabilities. These options also do not address FDA’s fundamental critique, which is about the potential public health trade-off of using non-public health reasons to force the accelerated review of a dossier. This risk must be assessed and carefully understood so long as the PRV is in use.

The nature of the PRV incentive inherently discourages expanding the program because the value per voucher can be expected to fall as the quantity of issued vouchers increases. One of the PRV’s original architects recently modeled that if one voucher was issued per year, the expected price would be $129–234M USD, while issuing five vouchers per year would drop the expected price to only $25–39M for each voucher [13]. This sensitivity has significant repercussions for the strength of incentive and risks undermining the entire enterprise. The number of PRVs awarded in recent years for rare pediatric disease PRVs – the development of all of which were initiated before the 2012 expansion – may already diminish the value of the program.

It is worth remembering that numerous existing incentives are already available for drugs for rare diseases. In the US, the Orphan Drug Act offers research grants, tax credits, waived FDA fees, and 7-year marketing exclusivity. An analysis of the total value of orphan-designated drugs and non-orphan-designated drugs over the last 2 decades found a significant revenue opportunity in orphan-designated drug products resulting from high pricing, increased market share, longer exclusivity period, and rapid uptake [14]. Therefore, orphan-designated drugs – which by definition include all rare pediatric disorders in America – often have a high rate of return on investment, as well as lower development costs related to fewer clinical trial participants and shorter clinical trials [15].

Expert opinion

Of course, nearly all rare diseases can benefit from additional attention by the scientific community. The PRV is alluring in this situation because it offers a potentially lucrative incentive for investment in such areas without requiring direct government budget outlays. However, the incentive as currently structured remains open to misuse; there are fundamental challenges with its implementation, and expansion will inevitably reduce the monetary value per voucher. For these reasons, we suggest reconsidering the application of the PRV to rare pediatric diseases and recommend against considering whether more rare diseases could benefit from being made eligible to earn PRVs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work is supported by the Laura and John Arnold Foundation, a grant from the Greenwall Faculty Scholars in Bioethics, The Engelberg Foundation, and an Ignition Award from the Harvard Program in Therapeutic Science.