Rare Diseases: Too Early to Gauge Effectiveness of FDA's Pediatric Voucher Program
Published: 2016-03-02T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Almost 7,000 rare diseases, most of which are serious or life-threatening, affect more than 25 million Americans. About half of all rare diseases affect children, and few of these diseases have viable treatments. To encourage the development of drugs to treat or prevent rare pediatric diseases, the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 authorized FDA to award a priority review voucher to a drug sponsor upon approval of that sponsor's drug to treat a rare pediatric disease. A drug sponsor can later redeem the voucher when submitting another new drug application to treat any disease or condition in adults or children, or sell or transfer the voucher to another sponsor. A voucher entitles a sponsor to a 6-month priority review by FDA rather than the 10-month standard review.
FDASIA included a provision for GAO to study the pediatric voucher program. GAO examined what is known about the effectiveness of the program in encouraging the development of drugs to prevent or treat certain rare pediatric diseases. GAO reviewed relevant laws and documentation related to the program and its management, and identified drug sponsors who were awarded vouchers, the diseases their drugs were approved to treat, and whether the vouchers were redeemed, sold, or transferred. GAO also interviewed FDA officials, drug sponsors, patient advocacy groups, and organizations representing physicians and children's hospitals, among others.
section_title: What GAO Found
paragraphs: It is too early to gauge whether the Food and Drug Administration's (FDA) pediatric voucher program has stimulated the development of drugs to treat or prevent rare pediatric diseases. Given that the typical drug development process often exceeds a decade, insufficient time has elapsed to determine whether the 3 year-old program has been effective. Any drug sponsors motivated by the program to attempt to develop a drug for a rare pediatric disease may be many years from submitting new drug applications—which contain scientific and clinical data about safety and effectiveness—to FDA for review.
As of December 31, 2015, there have been 11 requests for a pediatric voucher. Of these, six have been awarded, two denied, and three remain under review. The six drugs for which vouchers were awarded were in development prior to the program's implementation and these drugs helped fulfill unmet medical needs. One drug is indicated to treat a rare pediatric cancer, and the other five drugs treat rare metabolic diseases affecting children. No other drugs had been previously approved by FDA for these conditions. Four of the six awarded pediatric vouchers have been sold to other drug sponsors for prices ranging from $67.5 million to $350 million. One of the six vouchers awarded has been redeemed and was used to obtain a priority review of a new drug application for a drug to treat adults with high cholesterol. FDA approved this new drug application in July 2015.
FDA officials stated that, while they strongly support the goal of incentivizing drug development for rare pediatric diseases, they have seen no evidence that the program is effective. The program's authorization, as amended, is set to terminate October 1, 2016, and FDA officials said they do not support the program's continuation. They expressed concern that the program adversely affects 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. Additionally, FDA officials said that the additional workload from the program strains the agency's resources. However, other stakeholders provided generally positive feedback on the program. For example, drug sponsors that sold these vouchers said they plan to reinvest portions of the proceeds they received into additional research on rare pediatric diseases, although there is no requirement to do so. Patient advocacy groups told GAO that the program could lead to the development of needed drugs.
We provided a draft of this report for comment to the Department of Health and Human Services (HHS). HHS provided technical comments, which we incorporated as appropriate.

section_title: Letter
paragraphs: Rare diseases are diseases that affect fewer than 200,000 people in the  United States. However, they pose a serious health concern as  approximately 7,000 rare diseases affect more than 25 million Americans,  according to the National Institutes of Health (NIH). Almost half of these  diseases affect children. The onset of a rare disease can be devastating  for patients and their families. Most of these diseases are serious,  disabling, and life-threatening, yet little may be known about them,  making it difficult to diagnose a patient correctly. Even once a patient is  diagnosed, many rare diseases do not have viable treatment options.  Individuals with a rare disease can experience shortened life expectancy  or decreased quality of life. Finding effective treatments for these  diseases is important but challenging, and developing such treatments  specifically for children adds to that challenge.
Over the years, a number of laws have been enacted to improve the  availability of drugs for patients with rare diseases and for children,  including the Orphan Drug Act, the Pediatric Research Equity Act of  2003, and the Best Pharmaceuticals for Children Act. Most recently, in  2012, the Food and Drug Administration Safety and Innovation Act  (FDASIA) authorized a new program to encourage the development of  new drugs for rare pediatric diseases. Through this program, the sponsor  of a new drug application that is approved by the Food and Drug  Administration (FDA) may be eligible to receive a voucher entitling it to  later receive a 6-month priority review for another of its new drug  applications for a drug to treat any disease or condition in adults or  children, rather than the typical 10-month standard review. The voucher  may also be transferred or sold to another drug sponsor, who may then  redeem it. The potential for additional revenue that comes from  marketing a drug approximately 4 months sooner—or the proceeds that  may come from selling the voucher to another drug sponsor—could  incentivize sponsors to develop drugs that prevent or treat rare pediatric  diseases.
FDASIA included a provision that we study the effectiveness of the rare  pediatric disease priority review voucher program. This report examines  what is known about the effectiveness of the pediatric voucher program in  encouraging the development of drugs to prevent or treat certain rare  pediatric diseases.
To perform our work, we examined relevant laws, policies, FDA guidance,  and other documentation related to the pediatric voucher program and its  management, including FDASIA’s provisions, FDA’s draft guidance for  industry on pediatric vouchers, and FDA’s report on developing drugs for  rare pediatric diseases and its strategic plan for accelerating drug  development for them. Additionally, we obtained information from FDA  about the number of requests FDA has received for pediatric vouchers  and related requests for rare pediatric disease designations, which are  usually a precursor to receiving a voucher and which a drug sponsor may  request any time during the drug development process. In addition, we  reviewed information from FDA related to the new drug applications for  which vouchers were awarded. We identified drug sponsors that were  awarded these vouchers and the diseases their drugs were approved to  treat, as well as the status of the vouchers once awarded—that is,  whether they had been sold, transferred, or redeemed. We reviewed the  medical literature and information from NIH, patient advocacy groups, and  physicians to learn about the rare pediatric diseases for which these  drugs had been developed, including how patients with these diseases  are currently treated.
We interviewed FDA officials to supplement our understanding of the  pediatric voucher program, and FDA and NIH officials to supplement our  understanding of the diseases for which vouchers were awarded. We also  spoke with 9 of the 10 drug sponsors that were awarded, purchased, or  otherwise received or redeemed a voucher. Among other things, we  discussed their perspectives on the program, including the extent to  which they believed the program acted as an incentive for drug sponsors  to encourage the development of drugs for rare pediatric diseases.  Additionally, we spoke with six patient advocacy groups associated with  the rare pediatric diseases for which a voucher was awarded, and with  several organizations representing the pharmaceutical industry, the  insurance industry, and other interested organizations and individuals.  (See app. I for a complete list of those we interviewed.)
We conducted this performance audit from July 2015 to March 2016 in  accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings based on our audit objectives. We believe that the evidence  obtained provides a reasonable basis for our findings and conclusions  based on our audit objectives.
subsections: section_title: Background
subsections: section_title: Rare Pediatric Diseases and Drug Development Challenges
paragraphs: 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.
section_title: FDA and the Pediatric Voucher Program
paragraphs: 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.
section_title: Too Early to Gauge if Pediatric Voucher Program Stimulates Drug Development
subsections: section_title: Drugs for Which Vouchers Were Awarded Were in Development Prior to the Program’s Implementation, though They Helped Fulfill Unmet Medical Need
paragraphs: 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. According to FDA, the drug  demonstrated increased life expectancy in a clinical trial among  children who were diagnosed as infants.
Officials from both NIH and FDA agree that these drugs are meaningful  for patients with the rare pediatric diseases as the drugs may, for  example, increase life expectancy, alleviate certain symptoms, or  otherwise improve quality of life. Similarly, patient advocacy groups and  physicians said that these drugs provide important new treatment for  patients and improve survival rates and symptoms. (See app. II for a  summary about each of these diseases based on information available  from NIH, patient advocacy groups, and physicians familiar with these  diseases.)
As of December 31, 2015, four of the six pediatric vouchers—for Vimizim,  Unituxin, Cholbam, and Xuriden—have been sold or transferred to other  drug sponsors. Sale prices of the pediatric vouchers have ranged from  $67.5 million to $350 million. The other two awarded vouchers—for  Strensiq and Kanuma—remain held by the original sponsor. Only the  voucher awarded for Vimizim has been redeemed. It was used to  expedite the review of Praluent, a new drug to treat adults with high  cholesterol. See table 1 for more detailed information about the status of  these vouchers.
section_title: FDA Does Not Believe the Pediatric Voucher Program Effectively Stimulates Drug Development and Opposes Its Reauthorization
paragraphs: FDA officials expressed concern about the pediatric voucher program,  and do not support its continuation after its current authorization expires  October 1, 2016. In written responses to our questions, FDA officials  reported that they have seen no evidence that the program has  encouraged increased development of drugs for rare pediatric diseases.  The agency also indicated that while it strongly supports the goal of the  program—incentivizing the development of drugs for rare pediatric  diseases—it has not seen evidence that the program has yet been  effective in achieving this goal. Instead, 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. FDA  specifically cited its authority to provide an additional 6 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.
In addition to sharing its views regarding the program’s effectiveness in  incentivizing drug development, FDA cited concerns about what it  considers to be the significant adverse impact of the program on the  agency’s ability to determine its public health priorities. According to FDA,  the program interferes with its ability to set priorities on the basis of public  health needs by requiring FDA to provide priority reviews of new drug  applications that would not otherwise qualify, based on the merits of those  applications. The agency noted that an application for a drug will receive  priority review designation if it is for a drug that treats a serious condition  and, if approved, would provide a significant improvement in safety or  effectiveness. However, FDA anticipates that sponsors will seek to  redeem their vouchers for new drug applications that would otherwise  receive a standard 10-month review for more prevalent conditions that  already have available treatments. Such applications may be for drugs to  treat diseases or conditions such as elevated blood pressure, high  cholesterol, obesity, or diabetes and other drugs with substantial market  potential. FDA explained that, in effect, the program allows sponsors to  “purchase” a priority review at the expense of other important public  health work in FDA’s portfolio, which undermines FDA’s public health  mission and the morale of its professional review staff.
According to FDA, the pediatric voucher program also places a  substantial strain on its workload. First, the agency explained that  performing a priority review on a drug that would otherwise merit a  standard review requires the agency to conduct significant work in a  compressed timeframe. FDA pointed out that, while patients and  providers are willing to accept a greater risk for a drug that fulfills an  unmet medical need, there is a different benefit risk balance that must be  considered when assessing drugs for more prevalent conditions that may  be used in millions of patients. A new drug application qualifying for a  standard review is typically accompanied by very large data sets,  reflective of the study of thousands of patients to support substantial  evidence of the drug’s effectiveness and to provide the safety data  required to demonstrate that its benefits outweigh its risks. As a result, 6- month priority reviews of applications that would otherwise receive a 10- month standard review require FDA to conduct work in 4 months less  time. 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. 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.
Second, FDA indicated that the pediatric voucher program hinders its  ability to effectively manage its own workload. FDA pointed out that it is  organized into separate review divisions with specific areas of expertise  and that it cannot quickly train new staff. There is not a pool of review  staff that can be moved from one review division to another review  division on an ad hoc basis to complete priority reviews for the application  based on the rare pediatric review vouchers. According to FDA, it cannot  predict which review divisions will need additional staff to complete the  additional priority reviews, making anticipatory hiring infeasible. Although  FDA receives a special user fee from a drug sponsor when the sponsor  redeems a voucher, in addition to the regular user fee that accompanies a  new drug application, the agency noted that FDASIA did not authorize  resources beyond the user fees—funding or staff—to administer the  program, including determining rare pediatric disease designations. FDA  noted that there is a disconnect in the timing of its collection of the  additional user fee and the time it takes the agency to hire, orient, and  train additional reviewers to assist with the additional reviews.  Furthermore, the additional user fee is a one-time payment and does not  provide the funding needed to sustain the longer-term employment of  additional staff hired to assist with conducting the priority review. While  the additional user fee is intended to compensate for FDA’s increased  workload related to redemption of the vouchers, FDA noted that the  funding mechanism does not provide the agency the resources required  to review the particular voucher priority application. FDA told us that, if the  number of pediatric vouchers awarded and redeemed continues to  increase, the agency’s ability to meet its public health mission and other  commitments will be adversely affected, including monitoring postmarket  safety, engaging with patient and stakeholder groups, and advising drug  sponsors on their development programs, including those focused on  pediatric drugs.
Third, in a discussion with FDA, officials said that the pediatric voucher  program has also significantly increased its workload due to its need to  respond to requests for rare pediatric disease designations, often within  60 days, and the complexity involved in making such determinations.  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. As a result, FDA must work with the drug sponsor to determine  what types of information are acceptable to support such an assertion.
section_title: Drug Sponsors, Advocacy Groups, and Other Organizations Generally Support the Pediatric Voucher Program
paragraphs: Feedback from stakeholders about the pediatric voucher program 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. Drug sponsors  largely favor the program; one sponsor and half of the patient advocacy  groups with whom we spoke pointed to the sales of and prices for the  vouchers as evidence that demand for the vouchers exists. Most  sponsors also noted that each sale provides cash infusions for drug  sponsors who were initially awarded—and later sold—the vouchers. Four  of five sponsors that were awarded or transferred and later sold vouchers  told us that they plan to reinvest a portion of the proceeds they received  into additional research and development of drugs to treat other rare  pediatric diseases. However, 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.
Patient advocacy groups also generally favor the program. For example,  one group we spoke to said that the program has stimulated a transfer of  cash from larger drug sponsors to smaller ones through the sales of the  vouchers, and that these smaller drug sponsors may reinvest a portion of  the proceeds to continue developing drugs for rare pediatric diseases. A  few groups also indicated that the program could lead to the development  of much-needed pediatric drugs without costing the government  resources. Most told us that they believe the program incentivizes drug  development. 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.
Although sponsors and patient advocacy groups were generally positive  about the voucher program, some also expressed concerns related to the  uncertain future of the program and FDA’s interpretation of what diseases  are considered rare pediatric diseases, concerns also expressed by  organizations representing physicians and the health insurance industry.  For example, some of the sponsors, patient advocacy groups, and other  organizations that we contacted said that the FDASIA provision providing  for termination of FDA’s authority to award pediatric vouchers one year  after the award of the third voucher under the program (March 2016)  created ambiguity for industry that therefore diminishes the program’s  appeal. Specifically, two drug sponsors told us that they are concerned  about pursuing lengthy and costly drug development for rare pediatric  diseases in order to obtain a voucher that may be unavailable by the time  they are ready to submit new drug applications to FDA. To enhance the  program’s effectiveness, most drug sponsors and many patient advocacy  groups said that they believe the program should be reauthorized for a  longer period of time, or even permanently. Additionally, a drug sponsor  and a few patient advocacy groups told us that, in their view, FDA’s  interpretation of the definition of a rare pediatric disease is too narrow.  Some said that as a result, certain rare diseases, such as sickle cell  disease and some pediatric cancers, are not eligible for a pediatric  voucher because more than 50 percent of afflicted children survive to  adulthood. One patient advocacy group indicated that such an exclusion  effectively penalizes all patients with these diseases because a majority  of them live past 18 years, although the onset of the disease occurs  during childhood. They told us that they believe such diseases should be  included in FDA’s definition. When asked about how the agency  determined its definition of a rare pediatric disease, FDA officials pointed  out that a vast majority of rare diseases are diagnosed in childhood— given this, products for all rare diseases diagnosed at that time would be  eligible for a voucher. However, since children were to be the intended  population for pediatric voucher program per FDASIA, FDA officials noted  that, by law, the definition applies to those diseases that primarily affect  children 18 years and younger.
Several drug sponsors and a patient advocacy group raised some  concerns about the program but were uncertain about how to address  them. For example, certain drug sponsors and the patient advocacy  group suggested that there might be an optimal number of vouchers to be  awarded to maximize their value to industry and their incentivizing effect.  The patient advocacy group suggested that awarding too many vouchers  would cause their value to plummet. 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.
Finally, feedback from organizations representing physicians, health  insurers, and children’s hospitals about the pediatric voucher program  was varied. While two of these organizations generally favored the  program, all told us that there was insufficient information to judge the  program’s overall effectiveness or that it was simply too soon to tell. One  organization shared FDA’s concerns about potential unintended  consequences, such as the diversion of resources from other agency  priorities. Feedback from the academic community was also varied. One  academic told us that the voucher program has been consistent with his  expectations and echoed what a few patient advocacy groups said—that  the program could be a stimulant for developing drugs for rare pediatric  diseases at little cost to the federal government. In contrast, another  academic said it was difficult to determine whether the program  stimulated research since only a few years have elapsed since the  program was implemented. He indicated, similar to FDA’s concern, that  the program could instead lead to unintended consequences. For  example, this academic suggested that the program could strain FDA  resources, commoditize its approval process, and result in the granting of  a priority review to a drug that is neither novel nor fulfills an unmet  medical need. He also proposed that, if the pediatric voucher program is  reauthorized it could be improved by delaying the awarding of the  vouchers until several years after the drugs’ approval. This would allow  more time to assess whether patients have actually benefitted from the  drugs, and are able to access the drugs, before the voucher is awarded.
section_title: Agency Comments
paragraphs: We provided a draft of this report for comment to HHS. HHS provided  technical comments, which we incorporated as appropriate.
We are sending copies of this report to the appropriate congressional  committees and the Secretary of Health and Human Services. In addition,  the report is available at no charge on the GAO website at  http://www.gao.gov.
If you or your staff have any questions about this report, please contact  me at (202) 512-7114 or crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on  the last page of this report. GAO staff who made key contributions to this  report are listed in appendix III.
section_title: Appendix I: List of Organizations and Individuals Interviewed
subsections: section_title: Federal agencies
section_title: Drug sponsors
section_title: Drug sponsor associations
section_title: Patient advocacy groups
section_title: Other organizations or individuals
paragraphs: 1. American Academy of Pediatrics 2. Children's Hospital Association 3. America’s Health Insurance Plans 4. Jerry Vockley, MD., Ph.D.
Professor of Pediatrics and Human Genetics University of Pittsburgh 5. Dr. David Ridley Duke University The Fuqua School of Business Faculty Director of the Health Sector Management Program 6.  Aaron S. Kesselheim, M.D., J.D., M.P.H.
section_title: Appendix II: Information about the Rare Pediatric Diseases That Can Be Treated by Newly Approved Drugs for Which Pediatric Vouchers Were Awarded
paragraphs: Pediatric patients affected by seven diseases that previously had no  approved treatment may now benefit from six newly-approved drugs for  which pediatric vouchers were awarded. We have summarized  information about each of these diseases obtained from the National  Institutes of Health’s Genetics Home Reference, patient advocacy  groups, and physicians familiar with these conditions.
subsections: section_title: Mucopolysaccharidosis Type IVA
paragraphs: Mucopolysaccharidosis type IVA, also known as Morquio A Syndrome, is  a rare, progressive, hereditary disease that mainly affects the skeleton  and can lead to paralysis and early death. Genetic mutations reduce or  eliminate the activity of certain enzymes that are involved in the  breakdown of large sugar molecules, resulting in the accumulation of  such molecules to toxic levels in many tissues and organs, particularly in  the bones, causing deformities. Affected individuals typically demonstrate  signs of the disease during early childhood, including skeletal  abnormalities such as knock knees, short stature, and abnormalities of  the chest, hips, ribs, spine, and wrists. Other symptoms may include  vision loss; hearing loss; frequent upper respiratory infections; thin tooth  enamel and multiple cavities; heart valve abnormalities; and a mildly- enlarged liver. Morquio A Syndrome does not affect intelligence.
Although the exact prevalence of Morquio A Syndrome is unknown, it is  estimated that the broader condition—Mucopolysaccharidosis type IV— occurs in approximately 1 in every 200,000 to 300,000 individuals. The  life expectancy of individuals with Morquio A Syndrome depends on the  severity of symptoms, with the most severely affected patients surviving  only until late childhood or adolescence. Individuals with milder forms of  the disorder may live into adulthood, although their life expectancy may  be reduced.
Vimizim (elosulfase alfa), is the first FDA-approved drug for the treatment  of Morquio A Syndrome. No other FDA-approved therapies exist for  treatment of this disease.
section_title: High-Risk Neuroblastoma
paragraphs: Neuroblastoma, a type of pediatric cancer that occurs when immature  nerve cells become abnormal and multiply uncontrollably, most often  occurs in children before age 5 and rarely occurs in adults. Most  commonly, a tumor forms in the adrenal gland located above each kidney  and can spread to other parts of the body such as the bones, liver, or  skin. Tumors also commonly grow in the nerve tissue in the abdomen,  chest, neck, or pelvis. Individuals with neuroblastoma may exhibit  symptoms such as fever, irritability, pain, tiredness, diarrhea, loss of  appetite, and weight loss. Some symptoms may be location-specific, such  as a tumor in the abdomen causing abdominal swelling; a tumor in the  chest causing difficulty breathing; and a tumor metastasizing to the bone  causing bone pain, bruises, and pale skin.
Neuroblastoma occurs in approximately 1 in every 100,000 children and  is diagnosed in about 650 children each year in the United States. It is the  most common cancer in infants younger than 1 year. Only 40 to 50  percent of children with high-risk neuroblastoma live at least 5 years after  diagnosis.
Unituxin (dinutuximab) is the first FDA-approved drug for the treatment of  high-risk neuroblastoma. There are currently other FDA-approved drugs  for neuroblastoma (specifically, Cyclophosphamide, Vincasar PFS, and  Doxorubicin Hydrochloride); however, none of these were approved  specifically for the treatment of patients with high-risk neuroblastoma.
section_title: Bile Acid Synthesis Disorders
paragraphs: Bile acid synthesis disorders are a group of rare metabolic disorders  characterized by impaired production and release of a digestive fluid,  called bile, from liver cells. People with bile acid synthesis disorders  cannot produce bile acids, which are a component of bile that stimulate  bile flow and help it absorb fats and fat-soluble vitamins, such as vitamins  A, D, E, and K. Consequently, an abnormal form of bile is produced. The  failure to produce normal or functional bile acids results in the  accumulation of abnormal bile acids and other substances that normally  would be broken down within the body, leading to deterioration of certain  organ systems. Symptoms may include interruption or suppression of the  flow of bile from the liver, fat-soluble vitamin malabsorption, progressive  neurological disease, and liver disease.
Bile acid synthesis disorders are estimated to occur in between 1 to 9  individuals in every 1,000,000 births. If left untreated, the disorders may  lead to cirrhosis of the liver and death in childhood.
Cholbam (cholic acid) is the first FDA-approved drug for the treatment of  bile acid synthesis disorders due to single enzyme defects. No other  FDA-approved therapies exist for these disorders.
section_title: Peroxisomal Disorders
paragraphs: Peroxisomal disorders are a group of metabolic disorders, including those  in the Zellweger spectrum. These systemic diseases, which affect  multiple organs and may have neurological manifestations, present as  rare autosomal recessive disorders with impairment of production and  release of digestive fluid, called bile, from liver cells. Bile is used during  digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D,  E, and K. Individuals with the most severe forms of this disease develop  symptoms of the condition as newborns, and experience weak muscle  tone, feeding problems, hearing and vision loss, and seizures. They may  also develop life-threatening problems in other organs and tissues, such  as the liver, heart, and kidneys, and may have skeletal abnormalities.  Affected individuals have distinctive facial features, including a flattened  face and broad nasal bridge. Individuals with less-severe forms of the  disease may not develop signs of the disease until late infancy or early  childhood. They may have many of the same features as those patients  with severe cases; however, their conditions typically progress more  slowly. Children with these less-severe conditions often exhibit  developmental delays and intellectual disability.
Zellweger spectrum disorders (a subset of peroxisomal disorders) are  estimated to occur in approximately 1 in every 50,000 individuals.  Peroxisomal disorders encompass a spectrum of disorders, which means  the life expectancy of a patient depends on the severity of his or her  disease. Patients diagnosed with the most severe form typically do not  live beyond 1 year. Children with less severe forms generally live until 10  years of age, although there have been cases reported of children living  longer.
Cholbam (cholic acid) is the first FDA-approved drug for the treatment of  peroxisomal disorders (including Zellweger spectrum disorders). No other  FDA-approved therapies exist for these disorders.
section_title: Hereditary Orotic Aciduria
paragraphs: Hereditary orotic aciduria is an extremely rare, potentially life-threatening,  genetic disorder in which patients cannot produce adequate amounts of  uridine, a component of ribonucleic acid that is involved in the synthesis  of protein in the body. Patients with inadequate amount of uridine can  suffer from blood abnormalities, failure to thrive, a range of developmental  delays, and episodes of crystal formation in the urine leading to  obstruction of the ureter (a tube that carries urine from the kidneys to the  bladder), causing urine to back up into the kidney, making it swell.
Hereditary orotic aciduria is extremely rare, with only four known patients  with this disease in the United States, and an estimated 20 worldwide.  Left untreated, the disease can contribute to early mortality.
Xuriden (uridine triacetate) is the first FDA-approved drug for the  treatment of hereditary orotic aciduria. No other FDA-approved therapies  exist for this disease.
section_title: Hypophosphatasia
paragraphs: Hypophosphatasia is a rare, genetic, progressive, metabolic disease in  which patients experience devastating effects on multiple systems of the  body, leading to severe physical disability and life-threatening  complications. With a spectrum of symptoms and severity, the disease is  characterized by defective bone mineralization and softening of the  bones. Though forms of hypophosphatasia may appear in childhood or  adulthood, the most severe forms tend to occur before birth and in early  infancy. Affected newborns exhibit short limbs, an abnormally-shaped  chest, and soft skull bones. Additional complications in infancy include  poor feeding, a failure to gain weight, respiratory problems, and high  levels of calcium in the blood that may lead to kidney problems. Early loss  of primary (baby) teeth is one of the first signs of the condition in children.  Affected children may have short stature with bowed legs or knock knees,  enlarged wrist and ankle joints, and an abnormal skull shape. Afflicted  individuals may exhibit delayed development with traditional milestones  such as sitting, crawling, or walking.
Severe forms of hypophosphatasia are estimated to occur in  approximately 1 in every 100,000 births. Milder cases, such as those that  appear in childhood or adulthood, may occur more frequently. The life  expectancy of a patient depends on which form of hypophosphatasia  (perinatal, infantile, juvenile, or adult) he or she has. The life expectancy  of those with the most severe form, perinatal hypophosphatasia, is  measured only in days or weeks.
Strensiq (asfotase alfa) is the first FDA-approved drug for the treatment of  perinatal, infantile, and juvenile-onset hypophosphatasia. No other FDA- approved therapies exist for this disease.
section_title: Lysosomal Acid Lipase Deficiency
paragraphs: Lysosomal acid lipase deficiency is an inherited spectrum condition in  which affected individuals are unable to properly breakdown and use fats  and cholesterol in the body. The condition ranges from the infantile-onset  form (Wolman disease) to later-onset forms (known as cholesteryl ester  storage disease). In affected individuals, harmful amounts of fats may  accumulate in areas such as the spleen, liver, bone marrow, and small  intestine. Chronic liver disease can develop, along with accumulation of  fatty deposits in the arteries. The deposits may eventually block the  arteries, which may increase the chance of having a heart attack or  stroke. The symptoms of lysosomal acid lipase deficiency are highly  variable. Individuals in which onset occurs later in life may experience  mild symptoms that are undiagnosed until late adulthood, while those with  early onset of the disease may have liver dysfunction in early childhood.  Infants with Wolman disease may demonstrate an enlarged liver and  spleen, poor weight gain, low muscle tone, jaundice, vomiting, diarrhea,  developmental delay, anemia, and poor absorption of nutrients from food.
Wolman disease is estimated to occur in 1 in 350,000 newborns. Children  affected by Wolman disease develop severe malnutrition and generally  do not survive past early childhood. Comparatively, about 50 individuals  affected by cholesteryl ester storage disease have been reported  worldwide, and the lifespan of these individuals depends on the severity  of the associated complications.
Kanuma (sebelipase alfa) is the first FDA-approved drug for the treatment  of lysosomal acid lipase deficiency. No other FDA-approved therapies  exist for this disease.
section_title: Appendix III: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Staff Acknowledgments
paragraphs: In addition to the contact named above, Geri Redican-Bigott, Assistant  Director; George Bogart; Muriel Brown; Kaitlin Coffey; Jesse S. Elrod; and  Cathleen Hamann made key contributions to this report.