A rare pediatric disease, as defined by statute, is one that primarily affects children 18 years and younger and generally affects fewer than 200,000 individuals in the United States. Some diseases affect less than a handful of children, while others affect many more. In many cases, no FDA-approved therapy exists for the treatment of the disease. Drug development is inherently challenging, and developing drugs to treat rare pediatric diseases adds layers of complexity. The drug development process in general is time-consuming and costly for drug sponsors. The drug industry estimates that, on average, a sponsor spends over a decade developing a drug at an average cost of $2.6 billion. The industry also reports that the percentage of drugs that enter clinical trials and that are eventually approved by FDA as safe and efficacious is less than 12 percent. Many more drugs will fail and prove to be either unsafe or ineffective at the earlier, preclinical stage. Developing drugs to treat rare pediatric diseases is even more challenging for several reasons. By definition, the number of patients affected by any individual rare disease is small, making it difficult to understand a disease’s progression and to design studies for potential new drugs. For example, FDA has pointed out that this challenge is further compounded in drug development for children, as they represent a smaller percentage of the overall population, which makes it difficult to identify and recruit sufficient numbers of patients to include in studies. The agency further notes that conducting these studies is difficult because the manifestation and progression of the same rare disease can vary by patient. There can also be different sub- types of a single disease, which can further reduce the number of patients to study. Further, there are relatively few researchers who are knowledgeable about a particular rare disease, which makes designing studies challenging. In addition, according to drug sponsors, there may be a greater incentive for them to focus on developing drugs for large patient populations that produce higher returns on investment than drugs for smaller patient populations that may generate less revenue. As a result of these challenges and others, drug sponsors may be hesitant to attempt to develop drugs to treat rare pediatric diseases. FDA, an agency within the Department of Health and Human Services (HHS), is responsible for overseeing the safety and efficacy of drugs sold in the United States. This responsibility includes the implementation of the pediatric voucher program, as provided for in FDASIA. FDA may award a drug sponsor a voucher upon approval of that sponsor’s new drug application for a rare pediatric disease. Specifically, the drug must be for the prevention or treatment of a rare disease that primarily affects children 18 or under. The application may include the same indication for use in adults with the same rare pediatric disease, but it cannot include a different adult indication. Other criteria must also be met in order to receive a voucher. For example, the drug must not contain an active ingredient that has been previously approved by FDA in another drug application, and the drug must be eligible for priority review. New drug applications that FDA determines not to qualify for a priority review, and which therefore receive a standard review, are ineligible to receive a pediatric priority review voucher. If a drug meets the eligibility criteria, the drug sponsor should include a request for a pediatric voucher in its new drug application, including supporting documentation demonstrating how the application meets the eligibility criteria for a pediatric voucher. Alternatively, if a drug sponsor does not submit a request for a pediatric voucher, but FDA determines that the sponsor may be eligible to receive one, FDA notifies the drug sponsor of its possible eligibility. Once FDA receives a sponsor’s new drug application and pediatric voucher request, it reviews the information and considers whether it should be approved. If FDA approves the drug application, it includes its decision regarding whether to award a pediatric voucher in its approval letter. In making this decision, FDA determines whether the drug sponsor has met all of the eligibility criteria for a pediatric voucher, which includes determining that the drug is for a rare pediatric disease as well as reviewing the clinical data examining the drug’s use in a pediatric population included in the drug application. Once a drug sponsor is awarded a voucher, it can later be redeemed by that sponsor with the submission of another new drug application for a drug to treat any disease or condition in adults or children, making the sponsor automatically eligible for a 6-month priority review. The original drug sponsor also has the option of selling or transferring the voucher to a new drug sponsor, who may then choose to use the voucher or similarly sell or transfer it. The voucher may be transferred any number of times before it is used. When the sponsor who possesses the voucher ultimately decides to redeem it, the sponsor must notify FDA at least 90 days in advance of submitting the new drug application. The sponsor redeeming the voucher must also pay any other required user fees. Figure 1 provides a general overview of the pediatric voucher program. Before submitting a new drug application, a sponsor may also request a rare pediatric disease designation for a drug that is still in development. This designation was established as part of the pediatric voucher program in 2012. In its designation request, a sponsor is to include information about, among other things, the drug and the rare pediatric disease for which the drug is being investigated, and the basis for concluding that the disease is rare and primarily affects children. FDA reviews the provided information and generally informs a drug sponsor of its designation decision within 60 days of receiving the request. FDA encourages drug sponsors to request such a designation in order for the agency to have the necessary information to evaluate a drug’s pediatric voucher eligibility and to ensure that drug sponsors have an adequate opportunity to provide this information before requesting a voucher. However, requesting such designation is not required in order to receive a rare pediatric disease voucher. If a rare pediatric disease designation is not requested prior to a drug sponsor submitting its new drug application, FDA officials may determine through their reviews of a new drug application and discussions with a drug sponsor that a certain drug may be eligible for a voucher. FDA officials will ask the drug sponsor to submit the necessary information to demonstrate that the drug is for a rare pediatric disease as, according to FDA, that information is generally not included in a new drug application. Given that the typical drug development process often exceeds a decade, insufficient time has elapsed to gauge whether the 3-year-old pediatric voucher program has been effective at encouraging the development of drugs for rare pediatric diseases. We found that each of the drugs awarded pediatric vouchers were in development prior to the voucher program’s implementation. 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. Although it is too early to gauge whether the program stimulates drug development, a potential indication of sponsor interest in the program may be reflected by the number of requests that have been submitted for a pediatric voucher or a rare pediatric disease designation. We examined how many requests for pediatric vouchers and rare pediatric disease designation were submitted to FDA and how many of these vouchers were awarded and designations were granted. As of December 31, 2015, there have been 11 requests for a pediatric voucher. Of these, 6 have been awarded, 2 denied, and 3 are 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. 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. Since the pediatric voucher program and designation were established, through December 31, 2015, there have been 52 rare pediatric disease designations requested and 29 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. Alternatively, these designations could be for drugs that were being studied before FDASIA was enacted and thus are farther along in the development process. According to FDA, the agency does not track which stage of development a drug is in when a request for this designation is submitted. The six drugs for which pediatric vouchers were awarded helped fulfill an unmet medical need. Specifically, these six drugs were the first drugs approved by FDA to treat the seven rare pediatric diseases for which they are indicated. No other drugs had been previously approved for these diseases. Vimizim, sponsored by BioMarin Pharmaceutical, treats children with Mucopolysaccharidosis Type IVA, a rare inherited metabolic disorder resulting from an enzyme deficiency. According to FDA and NIH, the drug significantly improves patients’ ability to walk. Unituxin, sponsored by United Therapeutics, is intended to help patients with high-risk neuroblastoma, a rare pediatric cancer, and, according to FDA, improves the overall survival rates of affected children. Cholbam, sponsored by Asklepion Pharmaceuticals, is considered by relevant patient advocacy groups to be an effective and important therapy for children with some bile acid synthesis disorders and some peroxisomal disorders, both of which are metabolic disorders. Xuriden, sponsored by Wellstat Therapeutics, allows certain children with hereditary orotic aciduria—an extremely rare, genetic metabolic disorder—to live life unimpeded by the disease as long as they continue treatment, according to FDA. Strensiq, sponsored by Alexion Pharmaceuticals, is for use by children suffering from hypophosphatasia, a genetic, rare metabolic disorder. FDA and physicians reported that the drug increased survival rates and alleviated symptoms among children in clinical trials. Kanuma, also sponsored by Alexion Pharmaceuticals, is for use by patients with lysosomal acid lipase deficiency, a rare, genetic, progressive metabolic disorder.