Debate Over the Priority Review Voucher

March 17, 2017
The FDA serves as the gatekeeper of pharmaceutical innovation in the United States, ensuring the efficacy and safety of drugs through careful regulatory supervision. Founded in 1906 with the passage of the Pure Food and Drugs Act, the FDA is responsible for guaranteeing the integrity of America’s food and pharmaceutical industries. Succeeding legislation, from the Hatch-Waxman Act to the FDA Modernization Act, have enshrined the modern-day regulatory pathway a drug must successfully navigate in order to be taken to market. [1]

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The process begins with the submission of an Investigational New Drug (IND) application. The drug must then make it through three phases of clinical trials, with the trial data summarized in a New Drug Application (NDA). [2] It can take over twelve years for a drug to complete the IND-NDA pipeline, delaying consumer access to potentially life-saving drugs for a decade or more.

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The need to expedite the drug approval process led to the proposal of a priority review voucher system in March 2006 by David Ridley, Henry Grabowski, and Jeffery Moe of Duke University. They articulated a legislative framework in which pharmaceutical companies seeking approval for a neglected or rare tropical disease could receive a voucher for priority review, shortening the typical review period by four months for any drug of the company’s choice. This framework became law in 2007 as a provision of the FDA Amendments Act, and it has since evolved to include rare pediatric diseases with the Creating Hope Act of 2012. [3]

In recent years, the efficacy of the priority review voucher has come into question by the FDA, which perceives the voucher system to be inefficient and flawed. On the other hand, consumer advocacy groups and the pharmaceutical industry continue to champion the priority review voucher as essential to promoting drug discovery in rare tropical and pediatric diseases.

Support for the Priority Review Voucher

One of the major arguments in favor of priority review is the temporal imperative of disease. Many patients cannot afford to wait years for the approval of a potentially life-saving drug or treatment; the drug review process could prove fatal for these individuals. Consumer advocacy groups like Kids v. Cancer are at the helm of this crusade. Nancy Goodman, the executive director of Kids v. Cancer, established the foundation after her ten-year old son died from a rare pediatric brain cancer.[4]

Support for the priority drug review voucher amongst pharmaceutical companies is also predicated on the promise of better financial performance. Expedited approval saves companies hundreds of millions of dollars in expenses pertaining to staffing and compliance during the regulatory pipeline.[5] Additionally, because priority review shortens the timeline for approval, companies can take their drugs to market faster. This shortened review period takes on even greater significance considering the fixed patent timeline. Pharmaceutical companies file for patent protection for their molecules before beginning the regulatory process; the countdown to patent expiration begins before firms even have the opportunity to begin making profit. As such, by reducing the regulatory period by four months, a firm’s drug enjoys an additional period of market exclusivity before patent expiry, allowing pharmaceutical companies to recoup their R&D costs before the arrival of generic competitors. [6] Once a company submits a treatment for a tropical or pediatric disease for FDA approval, the company is eligible to receive a priority review voucher, which can be used to expedite the approval process for any drug of the company’s choice. As such, companies are incentivized to create needed drugs for rare tropical and pediatric diseases, which can allow them to shorten the approval process for another of their promising drugs. Bill Gates, who has come out in support of the priority review voucher, voices this idea quite succinctly: “If you develop a new drug for malaria, your profitable cholesterol-lowering drug could go on the market a year earlier.” For now, this incentive remains largely theoretical, as it can take a decade or longer to develop a drug. New treatments catalyzed by the voucher system will not be evident for several more years. [7]

The priority review voucher system has inspired extensive congressional support, passing both the House and Senate in 2007 with a near unanimous vote. The system has been so popular among lawmakers for primarily two reasons. First, the granting of vouchers has no budgetary implications; Congress does not need to allocate additional funding or grants for drug discovery. Another, comparatively cynical, reason is the fact that passing the priority review system allows congressmen to say they’re taking action to address unmet tropical and pediatric diseases without proposing more comprehensive legislation to alleviate R&D costs in the pharmaceutical industry. [8]

Opposition to the Priority Review Voucher

The chief opponent of the priority drug review voucher is the FDA itself. Considering that Congress promulgated the priority review system with minimal FDA oversight, the Department holds serious reservations about the efficacy of priority review in its current form.

First, no requirement exists mandating that treatments up for priority review be novel. Essentially, companies can be awarded vouchers for drugs that have been approved and sold in international markets, but not yet in the United States. For example, Novartis was awarded the first priority review voucher in 2009 for its combination malaria drug. While it was a treatment targeting a tropical disease, the drug had already been licensed and in active use outside the United States for almost a decade prior. Essentially, firms can take already developed drugs for tropical or pediatric diseases in international markets and submit them for approval in the U.S. to receive a review voucher, a perversion of the program’s motivation to encourage new drug development. [9]

Additionally, pharmaceutical companies do not need to guarantee that their drugs will be sold at affordable prices. Because the priority review system lacks the means to establish and enforce price controls, firms can be granted vouchers for drugs that may not be accessible to patients. Janssen, for example, was awarded a voucher for Sirturo, a treatment for multidrug resistant tuberculosis. However, it has been reported that Sirturo is prohibitively priced in many international markets, reducing access to this potentially life-saving drug. [10] Indeed, this prohibitive pricing undermines the temporal imperative of disease, one of the key purposes of the priority review system. What is the purpose of a voucher system to accelerate drug development if patients at the end of the pipeline can’t afford the needed treatment? <a href="" target="_blank">Source</a>Source

To receive a priority review voucher, a company needs only to submit a drug for a pediatric or tropical disease for FDA approval; there is no stipulation that the drug had to be developed by the company itself. This oversight, along with the ability to transfer a priority review voucher to another firm, has created a shadow market around the voucher system. Knight Pharmaceuticals, for instance, received a voucher for Impavido, a drug it acquired which treats leishmaniosis, a rare infectious disease transmitted by sandflies. Knight played no role in the development process, as R&D was conducted by the World Health Organization in collaboration with public and private partners. However, because its drug fulfilled the necessary requirement of treating a tropical disease, Knight was able to receive a priority review voucher after spending $10 million to get Impavido through the approval process. However, the company’s true intent for the drug was revealed when it sold its priority review voucher to Gilead Sciences for $125 million, netting Knight Pharmaceuticals a $115 million profit. [11] Knight isn’t alone in the market for priority review vouchers, as Askelepion Pharmaceuticals, BioMarin, and United Therapeutics have all sold their vouchers for a combined $662 million. [12]

Perhaps most fundamentally, the FDA opposes the priority review system for its inherent impact on the Department’s mission. Redeeming a voucher limits  the FDA’s autonomy, forcing it to prioritize a drug which may not combat a key health issue per its existing prioritization process. Indeed, FDA officials believe that the program has “adversely [affected] the agency’s ability to set its public health priorities by requiring FDA to provide priority reviews of new drug applications that would not otherwise qualify if they do not treat a serious condition or provide a significant improvement in safety or effectiveness.” Moreover, by shortening the approval pipeline from ten to six months, the FDA has expressed concerns that this window is insufficient to guarantee drug safety, given these tight timelines are already straining agency resources. While drug companies must pay a fee of around $2 million to redeem a voucher, the FDA argues that there is insufficient time to use the money to hire and train additional, long-term employees for accelerated reviews. [13]

What’s next?

The priority review voucher system for rare tropical and pediatric diseases was reauthorized by Congress in December 2016 with the 21st Century Cures Act, extending the program’s lifeline to October 1st, 2020. [14] While priority review will continue for another four years, questions remain about the effectiveness of the voucher system, as the Government Accountability Office’s March 2016 study was inconclusive, finding that “insufficient time has elapsed to determine whether the 3 year-old program has been effective.” [15] Additionally, there have even been complaints that the voucher system isn’t providing sufficient incentive for drug makers to begin early-stage research, considering the uncertainties and exorbitant cost of R&D.

With discussion circulating in Congress about adding generic drugs to the priority review voucher, the FDA’s concerns with the program will once again be raised. [16] It appears that, without undermining the basis of the program, Congress might assuage the FDA’s concerns by either provide additional funding for the FDA to hire more permanent staff for expedited review or increase the existing fee to redeem a voucher. Additionally, amending the voucher system to include stipulations on pricing and a requirement that firms partake in some aspect of the drug’s development seem to be stipulations that will further ensure the voucher system fulfills its stated mission: to promote the discovery of novel treatments for patients suffering from rare pediatric and tropical diseases.