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Expansion of the Priority Review Voucher Program Under the 21st Century Cures Act: Implications for Innovation and Public Health

Published online by Cambridge University Press:  06 January 2021

Michael S. Sinha ,
Nina Jain ,
Thomas Hwang  and
Aaron S. Kesselheim
Michael S. Sinha
Affiliation:
Program On Regulation, Therapeutics, And Law (“PORTAL”), Brigham Women's Hospital and Harvard Medical School, Boston, MA
Nina Jain
Affiliation:
Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Thomas Hwang
Affiliation:
PORTAL, Brigham and Women's Hospital, Boston, MA
Aaron S. Kesselheim
Affiliation:
Harvard Medical School and Director, PORTAL, Brigham and Women's Hospital, Boston, MA
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Extract

The U.S. federal government awards a priority review voucher (“PRV”) to a pharmaceutical manufacturer after the Food and Drug Administration (“FDA”) approves a product for one of a list of voucher-eligible indications. The voucher, which can be transferred or sold, allows the company to accelerate the review timeline of another product for any indication. The PRV program was proposed in 2006 as an incentive for research and development for neglected diseases, such as dengue and leishmaniasis.

Neglected tropical diseases (“NTDs”) predominantly affect the world’s poorest populations and are associated with significant morbidity and mortality. Despite their global public health importance, neglected diseases were estimated to account for less than 1% of pharmaceutical research and development expenditures. The voucher program was intended to address this gap between investment and disease burden: “[t]he major obstacle to stimulating the R&D of new medicines for neglected diseases is lowincome nations' inability to pay for such medicines.” The voucher would provide an additional financial incentive to fund clinical development of these products without requiring additional appropriations from Congress.

Type
Articles
Information
American Journal of Law & Medicine , Volume 44 , Issue 2-3: Symposium - The 21st Century Cures Act: A Cure for the 21st Century? , May 2018 , pp. 329 - 341
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2018

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References

1 21 U.S.C. § 360n(b)(1) (2018).

2 Id. § (b)(2).

3 Stefanakis, Rianna et al., Analysis of Neglected Tropical Disease Drug and Vaccine Development Pipelines to Predict Issuance of FDA Priority Review Vouchers Over the Next Decade, 6 PLoS Neglected Tropical Diseases 1 (2012)CrossRefGoogle ScholarPubMed.

4 Ridley, David B., Developing Drugs for Developing Countries, 25 Health Aff. 313 (2006)CrossRefGoogle ScholarPubMed [hereinafter Ridley et al., Developing Drugs].

5 The proposal intended to reward sponsors for innovation in neglected disease, a disease category with overlapping definitions among global health practitioners. Id. Per Ridley and colleagues' definition, whether a disease is neglected is contingent on its relative burden in developing and developed countries. Id. at 317. Under this reasoning, HIV/AIDS does not qualify as a neglected disease because this condition affects many in developed countries, giving pharmaceutical companies financial motivation to identify novel HIV/AIDS treatments. Malaria, on the other hand, would be considered neglected because the overwhelming majority of cases occur in developing countries, limiting the profit potential of novel antimalarials. In contrast, the World Health Organization (“WHO”) takes into account the availability of donor funding for a disease and does not include malaria on its list of NTDs, likely because funding to combat malaria is more widely available than support for other conditions on the WHO list. See Neglected Tropical Diseases, WHO, http://www.who.int/neglected_diseases/diseases/en [https://perma.cc/4ZHC-R8MN].

6 World Health Org., Neglected Tropical Diseases: Hidden Successes, Emerging Opportunities 3 (2006), http://apps.who.int/iris/bitstream/10665/69367/1/WHO_CDS_NTD_2006.2_eng.pdf.

7 Henry G. Grabowski et al., Encouraging Innovative Treatment of Neglected Diseases through Priority Review Vouchers, in Prescribing Cultures and Pharmaceutical Policy in the Asia-Pacific 347, 348 (Karen Eggleston ed., 2009).

8 Ridley et al., Developing Drugs, supra note 4, at 313.

9 Id. at 315.

10 Id. at 319.

11 Brownback, Senator Sam, Letter to the Editor, Eliminating Neglected Diseases: Impact of Published Paper, 5 Health Aff. 1509, 1509 (2007)CrossRefGoogle Scholar.

12 Id.; see also Elias Mossialos et al., Policies and Incentives for Promoting Innovation in Antibiotic Research, London Sch. of Econ. & Political Sci, 111 (2009), http://www.lse.ac.uk/LSEHealthAndSocialCare/impacts/LSEHealthNews/News%20Attachments/Policies%20and%20incentives%20report.pdf (describing proposals for US-based patent extensions of between 6 months and 2 years and EU-based patent extensions of up to 5 years).

13 21 U.S.C. § 360bbb-4a(a)(3) (2018).

14 Id. § 360n(a)(4)(A)(i).

15 Id. § 360n(a)(2). There may be uncertainty with regard to developing drugs for diseases that have yet to be officially added to the qualifying list by Congress. For instance, Middle East Respiratory Syndrome is being considered for PRV eligibility, but has yet to be formally designated as a voucher-eligible indication. See generally H.R. Res. 6033, 114th Cong. (2016) (noting that the Secretary of Health and Human Services has discretion to approve vouchers for indications not listed in the statute).

16 21 U.S.C. § 360n(a)(3)(A)-(R). In addition to the conditions listed, the statute also covers any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, as designated by the Secretary of Health and Human Services. See id. § 360n(a)(3)(S).

17 U.S. Food & Drug Admin., Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics 25 (2014), https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf.

18 Hwang, Thomas J., The FDA's Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016, 318 JAMA 2137, 2137 (2017)CrossRefGoogle Scholar [hereinafter Hwang et al., Expedited Programs and Clinical Development Times].

19 See Stefanakis et al., supra note 3, at 1.

20 Ridley et al., Developing Drugs, supra note 4, at 315.

21 Strengthening Public Health Emergency Response Act of 2015: Hearing Before the H. Subcomm. on Health, 114th Cong. 28-38 (2016) (statement of Michael Mair, Director of Strategic Operations, Office of Counterterrorism and Emerging Threats, U.S. Food & Drug Admin.).

22 The rare pediatric PRV program was initially set to sunset one year after the first three vouchers were awarded. The program was reauthorized in the 21st Century Cures Act until 2020. 21st Century Cures Act, Pub. L. No. 114-255, § 3013, 130 Stat. 1093 (2016).

23 Id.

24 See Alexander Gaffney et al., Regulatory Explainer: Everything You Need to Know About FDA's Priority Review Vouchers, Reg. Focus (Dec. 17, 2017), https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2017/12/regulatory-explainer-everything-you-need-to-know-about-fda%E2%80%99s-priority-review-vouchers.

25 Id.

26 Expert Working Group, World Health Org., Research and Development 75 (2010), http://www.who.int/phi/documents/RDFinancingEN.pdf?ua=1; see also Consultative Expert Working Group on Research and Development, World Health Org., Research and Development to Meet Health Needs in Developing Countries: Strengthening Global Financing and Coordination 60 (2012), http://www.who.int/phi/CEWG_Report_5_April_2012.pdf?ua=1.

27 Letter from Dr. Atul Malhotra, President, American Thoracic Society et al., to The Honorable Lamar Alexander, Chairman, Committee on Health, Education, Labor and Pensions and The Honorable Patty Murray, Ranking Member, Committee on Health, Education, Labor and Pensions (Nov. 17, 2015), http://www.doctorswithoutborders.org/sites/usa/files/joint_open_prv_letter_to_help_committee_web.pdf.

28 Kesselheim, Aaron S., Experience with the Priority Review Voucher Program for Drug Development, 16 JAMA 1687, 1687 (2015)CrossRefGoogle Scholar.

29 Id.

30 Id.

31 Id.

32 Malhotra et al., supra note 27.

33 Ridley et al., Developing Drugs, supra note 4, at 313.

34 Kesselheim et al., supra note 28, at 1687.

35 Andrew Pollack, Martin Shkreli's Latest Plan to Sharply Raise Drug Price Prompts Outcry, N.Y. Times (Dec. 11, 2015), https://www.nytimes.com/2015/12/12/business/martin-shkrelis-latest-plan-to-sharply-raise-drug-price-prompts-outcry.html [hereinafter Pollack, Martin Shkreli's Latest Plan]. Mr. Shkreli was indicted and removed as CEO prior to the voucher award for benznidazole. See Andrew Pollack, Martin Shkreli is Removed as C.E.O. from Another Company, KaloBios, N.Y. Times (Dec. 21, 2015), https://www.nytimes.com/2015/12/22/business/martin-shkreli-kalobios-pharmaceuticals-turing.html.

36 The transaction value for Retrophin's acquisition of a PRV for cholic acid (Cholbam) from Asklepion Pharmaceuticals ($36 million) includes the one-time cash ($25 million) and stock payment (valued at $9 million at the time of the agreement) but excludes additional payments and royalties that Asklepion may receive based on future sales of the drug.

37 21 U.S.C. § 360bbb-4a (2016).

38 Alex Philippidis, The High Cost of Rare Disease Drugs, GEN (Mar. 4, 2014), https://www.genengnews.com/gen-exclusives/the-high-cost-of-rare-disease-drugs/77900055 [https://perma.cc/K623-Z5D3].

39 Burgart, Alyssa M., Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy, 172 JAMA Pediatrics 188, 188 (2017)CrossRefGoogle Scholar.

40 Ridley, David B., Efficacy of the Priority Review Voucher Program, 315 JAMA 1659, 1660 (2016)CrossRefGoogle ScholarPubMed.

41 Press Release, PATH, Clarus, and the Global Health Investment Fund Announce an Innovative $25 Million Financing Arrangement to Improve Treatment of Intestinal Worms, Affecting More Than 1 Billion People Worldwide (Jan. 31, 2017), http://www.path.org/news/press-room/797/ [https://perma.cc/YW6G-LZJZ].

42 Id.

43 Jain, Nina et al., Association of the Priority Review Voucher with Neglected Tropical Disease Drug and Vaccine Development, 318 JAMA 388, 388 (2017)CrossRefGoogle ScholarPubMed.

44 U.S. Gov't Accountability Off., GAO-16-319, Rare Diseases: Too Early to Gauge Effectiveness of FDA's Pediatric Voucher Program 14 (2016).

45 Id.

46 Id. at 1-2.

47 21 U.S.C. § 360bbb-4a(a)(3) (2016).

48 Id. § 360bbb-4a(a)(4)(A)(i)-(ii).

49 Id. § 360bbb-4a(a)(4)(D).

50 Id. § 360bbb-4a(b)(1).

51 Id. § 360bbb-4a(b)(2).

52 See U.S. Food & Drug Admin., Material Threat Medical Countermeasure Priority Review Vouchers: Draft Guidance for Industry 4 (2018), https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-gen/documents/document/ucm592548.pdf.

53 Id.

54 Id.

55 U.S. Dep't of Health & Human Servs., 2017-2018 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan 8 (Dec. 2017), https://www.phe.gov/Preparedness/mcm/phemce/Documents/2017-phemce-sip.pdf.

56 In addition, the PHEMCE lists pandemic influenza, chlorine, and phosgene as high-profile threats, although whether they are considered material threats and eligible for the PRV is unclear. See Pandemic Influenza Medical Countermeasures—Amendment, 80 Fed. Reg. 76,506, 76,506 (Dec. 9, 2015).

57 Milne, Christopher et al., Market Watch: Landscape for Medical Countermeasure Development, 16 Nature Reviews Drug Discovery 448, 449 (2017)CrossRefGoogle ScholarPubMed.

58 See Biomedical Advanced Research and Development Authority, U.S. Dep't of Health & Human Servs., https://www.medicalcountermeasures.gov/barda.aspx [https://perma.cc/5K6R-KP9F].

59 See AdisInsight, http://adisinsight.springer.com/ [https://perma.cc/V5E8-NM44]. Data first extracted on December 10, 2017 and updated on January 1, 2018.

60 See id.

61 Hwang, Thomas J., Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results, 176 JAMA Internal Med. 1826, 1827 (2016)CrossRefGoogle ScholarPubMed; Hwang, Thomas J., Effect of US Food and Drug Administration's Cardiovascular Safety Guidance on Diabetes Drug Development, 102 Clinical Pharmacology & Therapeutics 290, 294 (2017)CrossRefGoogle ScholarPubMed.

62 Lincker, Helene et al., Regulatory Watch: Where Do New Medicines Originate From in the EU?, 13 Nature 92, 92 (2014)Google ScholarPubMed.

63 World Health Org., Antibacterial Agents in Clinical Development 43 n.3 (2017), http://www.who.int/medicines/news/2017/IAU_AntibacterialAgentsClinicalDevelopment_webfinal_2017_09_19.pdf.

64 See AdisInsight, http://adisinsight.springer.com/ [https://perma.cc/V5E8-NM44]. An additional 45 products were identified under clinical testing for pandemic influenza. Id.

65 Percentages may not total to 100 due to rounding.

66 Refers to products that are currently under FDA review or that have been approved in other countries but not in the United States.

67 Small and medium-size companies are defined as those with annual gross revenues less than $1 billion as of January 2018.

68 See Ridley, David B., The Commercial Market for Priority Review Vouchers, 35 Health Aff. 776, 776 (2016)CrossRefGoogle ScholarPubMed.

69 See id. at 781.

70 Hwang et al., Expedited Programs and Clinical Development Times, supra note 18, at 2137.

71 Ridley et al., Developing Drugs, supra note 4, at 315.

72 Darrow, Jonathan J., Speed, Safety, and Industry Funding—From PDUFA I to PDUFA VI, 337 N. Eng. J. Med. 2278, 2280 (2017)Google Scholar.

73 See Ed Silverman, Congress Should Fix the Priority Review Voucher Program: MSF's Rius Explains, Wall St. J. (Dec 3, 2014, 10:43 AM), https://blogs.wsj.com/pharmalot/2014/12/03/congress-should-fix-the-priority-review-voucher-program-msfs-ruis-explains/.

74 See id.

75 See U.S. Gov't Accountability Off., supra note 44 at 14.

76 Kesselheim et al., supra note 28, at 1688.

77 Ridley et al., Developing Drugs, supra note 4, at 317.

78 See, e.g., Pollack, Martin Shkreli's Latest Plan, supra note 35.

79 See generally Downing, Nicholas S., Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010, 317 JAMA 1854, 1863 (2017)CrossRefGoogle ScholarPubMed.

80 See Mostaghim, Sana R., Safety Related Label Changes for New Drugs After Approval in the US through Expedited Regulatory Pathways: Retrospective Cohort Study, 358 BMJ 1, 4 (2017)Google ScholarPubMed.

81 Blume-Kohout, Margaret E., Does Targeted, Disease-Specific Public Research Funding Influence Pharmaceutical Innovation?, 31 J. Pol'y Analysis & Mgmt. 641, 654-55 (2012)Google ScholarPubMed.

82 Medical Countermeasures Initiative (MCMi), U.S. Food & Drug Admin., https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/default.htm [https://perma.cc/6G5Z-3P9Z] (last updated Feb. 28, 2018).