More time is needed to gauge whether FDA's rare pediatric disease priority review voucher program has actually encouraged the development of new treatments, the Government Accountability Office believes.

FDA, however, isn't interested in giving the incentive program any more time to try to prove itself.

"FDA officials expressed concern about the pediatric voucher program, and do not support its continuation after its current authorization expires in Oct. 1, 2016," GAO said in a March 2 report.

In FDA's eyes, the program has adversely impacted the ability to set its public health priorities and effectively manage its workload. The need to respond to requests for rare pediatric disease designation within 60 days also has increased the workload of staff.

FDA "had to curtail or defer other important work with the first redemption of a pediatric voucher for Praluent" – GAO Report

Although FDA officials strongly support the program's goal of incentivizing development of drugs for rare pediatric disease, the agency sees no evidence yet that the program has accomplished this objective, GAO said.

The report suggests FDA favors an incentive program that would have far less impact on its workload.

"The agency suggested that companies may consider that other incentives, such as provision of an additional period of 'market exclusivity,' may be more effective at incentivizing drug development than the priority review vouchers," GAO said.

"FDA specifically cited its authority to provide an additional six months of market exclusivity for FDA-requested pediatric studies in products that may produce health benefits in the pediatric population – known as pediatric exclusivity – as providing an effective incentive to drug sponsors."

Although the jury is still out on the success of the voucher program in incentivizing drug development for rare pediatric diseases, one thing is clear: Any congressional reauthorization of the program will necessarily take place over FDA's objections, albeit with the strong backing of patient advocacy groups and industry.

Popular But Imperiled

Established in the FDA Safety and Innovation Act of 2012, the rare pediatric disease voucher program was largely modeled after an earlier program aimed at incentivizing the development of tropical disease treatments.

Sponsors of products designated as a treatment for a rare pediatric diseases can, upon NDA or BLA approval, secure a voucher for a priority review of another product that would not otherwise qualify for the shorter review. The voucher may be redeemed by the sponsor of the rare pediatric disease treatment, or sold or transferred to another company for redemption.

To date, six products have qualified for a priority review voucher upon approval, with the most recent being Alexion Pharmaceuticals Inc.'s Kanuma (sebelipase alfa), approved Dec. 8 for treatment of lysosomal acid lipase deficiency ([A#14151208002]).

Four of the six vouchers awarded under the program have been sold or transferred to other sponsors in deals ranging from $67.5m to $350m. Only one of these vouchers has been redeemed. Sanofi and Regeneron Pharmaceuticals Inc. used a voucher purchased from BioMarin Pharmaceutical Inc. to secure a priority review of their PCSK9 inhibitor Praluent (alirocumab), which was approved in July ([A#00151221013]).

The rare pediatric disease voucher program was due to sunset in March 2016, but the omnibus appropriations bill passed by Congress in December extended it until Sept. 30 ([A#14151216002]).

The 21^st Century Cures bill that passed the House in July would reauthorize the pediatric voucher program through December 2018.

On March 9, the Senate Health, Education, Labor and Pensions Committee is expected to consider legislation that would permanently reauthorize the program ([A#00160125014]).

FDASIA included a provision for GAO to study the effectiveness of the program following award of the third voucher. In developing its report, GAO interviewed FDA officials, drug sponsors who received or redeemed priority review vouchers, patient advocacy groups and organizations representing physicians and children’s hospitals, among others.

Too Soon To Tell

The oversight agency said it is too early to determine whether the voucher program has stimulated drug development for rare pediatric diseases.

Each of the six drugs awarded vouchers was in development prior to the implementation of the program, the report notes. Given the length of time inherent in the typical drug development process, "any sponsors motivated by this relatively new program to attempt to develop drugs for such diseases would likely be years away from submitting their new drug applications to FDA," GAO said.

However, the number of requests for a priority review voucher under the program and for rare pediatric disease designation may be an early indicator of interest by drug developers, the report states.

As of Dec. 31, there were 11 requests for a pediatric voucher. Of these, six were awarded, two were denied, and three were still under review.

"The fact that the sponsors of these drugs took the steps to request vouchers and demonstrate their eligibility – either on their own initiative or in response to FDA’s suggestion – suggests interest in the program," GAO said.

"Similarly, taking steps to demonstrate that their drugs are intended to treat rare pediatric diseases and requesting such designations also indicates that these sponsors are considering applying for a pediatric voucher."

Through Dec. 31 there have been 52 requests for rare pediatric disease designation, 29 of which were granted.

"Because requests for a rare pediatric disease designation can be submitted at any time in the drug development process prior to submitting a new drug application, these designations could be for drugs that, for example, are in early stages of development and were pursued specifically in response to the program," GAO said.

"Alternatively, these designations could be for drugs that were being studied before FDASIA was enacted and thus are farther along in the development process," GAO said. The report notes that FDA does not track the development stage during which a designation request is submitted.

FDA Still Doesn't Like It …

FDA officials have previously expressed reservations about the priority review voucher programs, asserting that granting a speedier review for a product that otherwise would qualify for a standard review is not consistent with the agency's usual approach to determining its priorities Also see "Priority Review Vouchers: Buyers Beware!" - Pink Sheet, 14 October, 2015..

Such concerns are reiterated in the GAO report, which uses the term "significant adverse impact" to describe FDA's view of the program's effect on agency operations.

By allowing sponsors to purchase a priority review voucher, at the expense of other important public health work in FDA's portfolio, "undermines FDA's public health mission and the morale of its professional review staff," the report states.

The program also places "substantial strain" on the agency's workload because it must conduct significant review work in a compressed timeframe when a voucher is redeemed, according to the report.

"FDA noted that, in order to meet the required shortened timeframe for review, staff must divert attention from other important work or management must assign more reviewers to review an application," GAO said. "FDA noted that it confronted this challenge and had to curtail or defer other important work with the first redemption of a pediatric voucher for Praluent."

Although applicants must pay an additional user fee when redeeming a voucher, there is a disconnect in the timing of fee collection and the time it takes the agency to hire and train additional reviewers to assist with such reviews, the report notes.

Furthermore, responding to requests for rare pediatric disease designation has proven to be a burden in and of itself.

"Determining whether to designate a drug as one for a rare pediatric disease is challenging; FDA officials told us that the vast majority of initial requests for such designation have not included adequate information to demonstrate that the disease primarily affects children 18 years and younger," GAO said.

"As a result, FDA must work with the drug sponsor to determine what types of information are acceptable to support such an assertion."

The head of FDA's Office of Orphan Product Development made a similar observation in a recent interview ([A#00160222011]).

Despite agency misgivings about the program, FDA has encouraged a sponsor to seek a voucher in at least one instance ([A#00150914016]).

… But Sponsors And Advocacy Groups Do

GAO said feedback about the voucher program from different stakeholders varied "but has been generally positive, with nearly all drug sponsors and patient advocacy groups we spoke with saying that the program could potentially motivate further research in rare pediatric diseases."

Four of five sponsors that were awarded or transferred and later sold vouchers said they planned to reinvest a portion of the proceeds into additional research and development of drugs to treat other rare pediatric diseases, GAO said, noting "there is no requirement that sponsors must use the proceeds in this way"

"A few sponsors said that the program will be a factor in future business decisions and most said that it will likely encourage the development of drugs for treating rare pediatric diseases if it is reauthorized," the report states.

The program got a generally favorable review from patient advocacy groups. "Most told us that they believe the program incentivizes drug development," GAO said. "A few groups told us that, since the creation of the program, they have spoken with several drug sponsors interested in discussing the extent to which their drugs in development might be able to treat the patients that these groups represent."

Sponsors and advocacy groups did raise concerns, however, with regard to how FDA defines a rare pediatric disease and the program's sunset provisions.

Some drug sponsors and one advocacy group suggested "there might be an optimal number of vouchers to be awarded to maximize their value to industry and their incentivizing effect," GAO said. "However, most of them were uncertain about what the optimum quantity of awarded vouchers should be."

"In addition, similar to a concern raised by FDA, one drug sponsor told us that it was concerned that incentivizing development of drugs for rare pediatric diseases could potentially lead to unintended consequences, such as diverting attention from mass-market diseases such as diabetes," the report states.

Review Voucher Program For Rare Pediatric Diseases Should Not Be Reauthorized, FDA Says

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