Bourgeois, Florence Tanya

Hwang, Thomas J

JAMA Pediatrics

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New Regulatory Paradigms for InnovativeDrugs to Treat Pediatric DiseasesThe Harvard community has made thisarticle openly available.  Please share  howthis access benefits you. Your story mattersCitation Hwang, Thomas J., and Florence T. Bourgeois. 2014. “NewRegulatory Paradigms for Innovative Drugs to Treat PediatricDiseases.” JAMA Pediatrics 168 (10) (October 1): 879. doi:10.1001/jamapediatrics.2014.904.Published Version 10.1001/jamapediatrics.2014.904Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:33974339Terms of Use This article was downloaded from Harvard University’s DASHrepository, and is made available under the terms and conditionsapplicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAPNew Regulatory Paradigms for Innovative Drugs to Treat Pediatric DiseasesThomas J. Hwang, AB andFaculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts; and The Blackstone Group, London, England.Florence T. Bourgeois, MD,MPHDivision of Emergency Medicine, Boston Children’s Hospital, Boston, Massachusetts; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.The development of safe and effective pediatric drugs continues to fall short.1 The paucity of new therapies is particularly stark for rare diseases, which disproportionately affect children and collectively affect an estimated 25 million people in the United States and 30 million in Europe.2 Since the 1980s, US policymakers have enacted a range of policies to stimulate drug development for rare diseases, defined as those affecting fewer than 200 000 individuals in the United States. The most notable policy is the 1983 Orphan Drug Act, which grants 7 years of marketing exclusivity as well as subsidies and tax credits to pharmaceutical companies bringing a drug for a rare disease to market. While the Orphan Drug Act has been credited with stimulating product development for rare diseases, only one-quarter of orphan drugs were approved explicitly for pediatric indications between 2000 and 2009.3To incentivize the development of novel therapeutics for children, US Congress established the Rare Pediatric Disease Priority Review Voucher (PRV) program, passed as part of the Food and Drug Administration (FDA) Safety and Innovation Act. To qualify for the program, the new drug or biologic must be indicated to treat a rare pediatric disease, defined as a disease that either affects fewer than 200 000 individuals primarily aged 0 to 18 years in the United States or affects more than 200 000 individuals aged 0 to 18 years of age but for which there is no reasonable expectation that the cost of developing and making the drug available will be recovered from sales in the United States. Once approved, the sponsor of the drug is issued a voucher that can be freely transferred or sold and entitles the holder to a priority FDA review of any new drug or biologic application, with the expedited review accelerating market entry by up to 6 months.There are a number of important differences between the pediatric PRV program and the Orphan Drug Act, with more stringent requirements applying to the PRV program (Table).4 For example, to gain pediatric PRV approval, the rare pediatric disease product cannot contain an active ingredient (or an ester or salt of the active ingredient) of a previously Corresponding Author: Thomas J. Hwang, AB, 40 Berkeley Square, London W1J 5AL, England (tjhwang@post.harvard.edu). Conflict of Interest Disclosures: None reported.HHS Public AccessAuthor manuscriptJAMA Pediatr. Author manuscript; available in PMC 2016 February 04.Published in final edited form as:JAMA Pediatr. 2014 October ; 168(10): 879–880. doi:10.1001/jamapediatrics.2014.904.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptapproved agent. In addition, the FDA can revoke the pediatric PRV if the product for which the voucher was awarded is not marketed within a year of approval. The program is also subject to a sunset provision, which will be effective 1 year after the first 3 vouchers are granted unless the program is reauthorized by Congress.Owing to its novelty and limited track record, there are important unanswered questions about the pediatric PRV program. As the FDA develops final guidance for the industry and as policymakers and clinicians review emerging evidence from drugs approved through this new pathway, it is critical to consider the impact of the program in light of several key factors. First, manufacturers can qualify for the pediatric PRV even if their product is intended to treat a nonrare condition, as long as there is no reasonable a priori expectation of recouping costs. However, the statute is silent on whether the FDA can withdraw a pediatric PRV if the patient population is later found to be larger than the threshold. A claw-back provision has precedent in pharmaceutical regulation and could ensure that products receiving PRV designation are truly intended to treat unmet medical needs. For example, in the Humanitarian Device Exemption Program—the device analogue to the orphan drug program—the FDA withdrew marketing authorization in 2006 for 2 devices treating a condition later determined to be significantly larger than the statutory limit for a rare disease.5Second, the accessibility of these new therapeutics to patients remains a source of controversy. On February 14, 2014, the FDA approved the first drug through the pediatric PRV program, elosulfase alfa (Vimizim; BioMarin Pharmaceutical), an enzyme replacement therapy for the treatment of mucopolysaccaridosis IV, or Morquio A syndrome, which affects approximately 800 individuals in the United States and has no existing treatment options. The company subsequently announced that the annual net cost of therapy is expected to be $380 000 per patient after spending approximately $300 million on the development program.6 Based on equity research analyst estimates, gross revenues from the drug are projected to surpass this investment within just 3 years, raising questions about whether participation in the program should be contingent on certain limitations to the costs passed on to patients. Companies should ensure that access programs reach patients who cannot afford treatment, either because of insufficient or lack of insurance coverage.Finally, policymakers should revisit the program as the sunset provision approaches with a view toward continuing programs that maximize innovation, benefit vulnerable populations, and minimize costs to taxpayers and public payers. There may be valuable lessons from other pharmaceutical incentive programs for the PRV program. For example, in 2007, a similar voucher program was established to award priority review vouchers for manufacturers developing drugs for neglected tropical diseases. Although there were some initial concerns that the tropical disease PRV would be misused to bring inadequately reviewed drugs more quickly to market,7 only 1 drug has been submitted for approval through this pathway, by Novartis for canakinumab in 2011, which did not ultimately lead to the drug’s approval. As the pediatric PRV program attracts greater attention, it will be important to test whether and how the PRV influences the research and development priorities of companies and the approval of other drugs.Hwang and Bourgeois Page 2JAMA Pediatr. Author manuscript; available in PMC 2016 February 04.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptThe creation of the pediatric PRV program and the recent approval of the first drug via this mechanism mark a new chapter in regulatory efforts to address and correct the significant unmet medical needs of diseases affecting children. Close monitoring of the program’s implementation and impact should serve to guide refinements in future renewals and ensure that the program meets its intended purpose of rewarding innovation and increased availability of safe and effective therapies for underserved populations and conditions.REFERENCES1. Adamson PC. Unintended consequences of regulatory initiatives in childhood cancer drug development. JAMA Pediatr. 2013; 167(10):886–887. [PubMed: 23938865] 2. Bavisetty S, Grody WW, Yazdani S. Emergence of pediatric rare diseases: review of present policies and opportunities for improvement. Rare Dis. 2013; 1:e23579. [PubMed: 25002987] 3. Thorat C, Xu K, Freeman SN, et al. What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis. Pediatrics. 2012; 129(3):516–521. [PubMed: 22371464] 4. Connor E, Cure P. “Creating hope” and other incentives for drug development for children. Sci Transl Med. 2011; 3(66) cm1. 5. Hwang TJ, Kesselheim AS, Bourgeois FT. Postmarketing trials and pediatric device approvals. Pediatrics. 2014; 133(5):e1197–e1202. [PubMed: 24733871] 6. BioMarin Pharmaceutical Inc. Investor Presentation at: the J.P. Morgan Healthcare Conference; January 16, 2014; San Francisco, CA. 7. Kesselheim AS. Priority review vouchers: an inefficient and dangerous way to promote neglected-disease drug development. Clin Pharmacol Ther. 2009; 85(6):573–575. [PubMed: 19451908] Hwang and Bourgeois Page 3JAMA Pediatr. Author manuscript; available in PMC 2016 February 04.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptHwang and Bourgeois Page 4TableKey Federal Incentives for the Development of Pediatric DrugsIncentive ProgramIncentiveYearEnactedKey ProvisionsNoveltyWithdrawalProgram DurationPediatric PriorityReview VoucherTransferablevoucher forpriority reviewof any drug2012Must be novel,defined as notcontaining an activeingredient (or anester or salt of theactive ingredient) ofa previouslyapproved agentCan be revoked if theproduct for which thevoucher was awardedis not marketedwithin a year ofapprovalNo furthervouchers can beawarded after thelast day of the 1-yperiod that beginson the date thatthe third voucheris grantedBestPharmaceuticals forChildren Act6 mo ofadditionalmarketingexclusivitya2002Applies to productswith patent life orexclusivityremainingNo specificwithdrawal provisionExtendedindefinitely underthe FDA Safety andInnovation Act of2012Orphan Drug Act7 y of additionalmarketingexclusivity, taxcredits, andclinical researchsubsidies1983No specific noveltyrequirementCan only be revoked ifthe request for orphandrug designationcontained untrueinformation; cannotbe revoked if theprevalence of thedisease exceeds200 000 after thedesignation is grantedIndefinite durationAbbreviation: FDA, Food and Drug Administration.aThe 6 additional months of marketing exclusivity for sponsors conducting pediatric clinical trials were first codified under Section 505A of the US Food and Drug Administration Modernization Act of 1997 and later extended in the Best Pharmaceuticals for Children Act of 2002.JAMA Pediatr. Author manuscript; available in PMC 2016 February 04.

New Regulatory Paradigms for Innovative Drugs to Treat Pediatric Diseases

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New Regulatory Paradigms for Innovative Drugs to Treat Pediatric Diseases

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