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Potential Interactions of the Orphan Drug Act and Pharmacogenomics: A Flood of Orphan Drugs and Abuses?

Published online by Cambridge University Press:  06 January 2021

David Loughnot
David Loughnot*
Affiliation:
Molecular and Cell Biology (emphasis in Genetics), University of California at Berkeley; Boston University School of Law
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Extract

To overcome the unattractiveness of small markets, the United States government provides financial aid and incentives for drug manufacturers to create cures for rare diseases under the Orphan Drug Act (“the Act”). Recent research integrating genetic information and pharmacology holds promise for creating more effective drugs targeted at smaller populations than ever before. In the near future, it seems that a flood of new drugs targeted at small disease populations could take advantage of the government benefits under the Act. Drug applicants will include true orphan drugs along with “Trojan” applicants that seek to co-opt the benefits for drugs that should not qualify as orphans. Currently, the FDA appears ill prepared to discern between the two types of applicants and prevent abuse of the system.

In 1983, the federal government passed the Act. Congress designed the Act and subsequent modifications to provide incentives for companies to bring drugs for rare diseases to market.

Type
Article
Information
American Journal of Law & Medicine , Volume 31 , Issue 2-3 , June 2005 , pp. 365 - 380
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2005

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References

1 Orphan Drug Act, Pub. L. No. 97-414, 96 Stat. 2049 (1982) (codified as amended as 21 U.S.C. §§ 360aa-360ee (1994), 26 U.S.C. § 45C (Supp. II 1994), 42 U.S.C. § 236 (1994)).

2 21 U.S.C. §§ 360aa-360ee.

3 Duffield Rohde, David, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 131 (2000)Google Scholar.

4 Thomas Maeder, The Orphan Drug Backlash, SCIENTIFIC AMERICAN, May 2003, at 83.

5 Id.

6 Id.

7 Office of Science, DOE, Human Genome Project Information, at http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml (last updated Oct. 27, 2004).

8 Ann Biznak, Barbara, How Pharmacogenomics Will Impact the Federal Regulation of Clinical Trials and the New Drug Approval Process, 58 Food & Drug L.J. 103, 103 (2003)Google Scholar.

9 Office of Science, DOE, Human Genome Information: Pharmacogenomics, at http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml (last updated July 9, 2004). A patient's genetic code often influences any potential reactions to treatment. For example, genetics largely determines an individual's allergies to certain medications and the rate at which that individual metabolizes a drug. Id.

10 See, e.g., Evans, William E. & Relling, Mary V., Moving Towards Individualized Medicine with Pharmacogenomics, 429 Nature 464, 466 (2004)CrossRefGoogle ScholarPubMed (mentioning the genetic screen employed to identify patients with a high risk of abacivir hypersensitivity).

11 See Office of Science, supra note 9 (commenting on the promise of pharmacogenomics to customize drugs even on an individual level).

12 21 U.S.C. §§ 360aa-360ee (1994).

13 Pulsinelli, Gary A., The Orphan Drug Act: What's Right With It, 15 Santa Clara Computer & High Tech. L.J. 299, 332-36 (May 1999)Google Scholar.

14 Id.

15 Id. at 336.

16 FDA, GUIDANCE FOR INDUSTRY: PHARMACOGENOMIC DATA SUBMISSIONS (2003), available at http://www.fda.gov/cder/guidance/5900dft.pdf.

17 Pulsinelli, supra note 13, at 303.

18 See Rohde, supra note 3, at n.39 (discussing the increasing cost of clinical trials for drug manufacturers).

19 Id. at 126.

20 See Haffner, Marlene E. & Kelsey, John V., Evaluation of Orphan Products by the U.S. Food and Drug Administration, 8 Int’L J. Tech. Assessment Health Care 647, 647-48 (1992)CrossRefGoogle ScholarPubMed. Dr. Haffner is the Director of the Office of Orphan Products Development within the FDA.

21 21 U.S.C. §§ 360aa-360ee (1994).

22 Health Promotion and Disease Prevention Amendments of 1984, Pub. L. No. 98-551, 98 Stat. 2815 (1984).

23 Orphan Drug Amendments of 1985, Pub. L. No. 99-91, 99 Stat. 387 (1985).

24 Orphan Drug Amendments of 1988, Pub. L. No. 100-290, 102 Stat. 90 (1988).

25 See Haffner & Kelsey, supra note 20, at 647-48.

26 Maeder, supra note 4, at 83.

27 Id.

28 Haffner, Marlene E., Orphan Products – Ten Years Later and Then Some, 49 Food Drug Cosm. L.J. 593, 601 (1994)Google Scholar.

For the 70 drugs approved by the FDA in 1993, approval time averaged 33.1 months; the approval time for orphan drugs in that year averaged 12.8 months. Non-orphan NMEs were approved in 25.58 months, compared to 12.4 months for orphan drugs that were NMEs. These approval times are significantly different, and significantly shorter, than in previous years, when the range of difference was only six to seven months less for orphans than for non-orphans.

Id.

29 ROBIN J. STRONGIN, NATIONAL HEALTH POLICY FORUM, HATCH-WAXMAN, GENERICS, AND PATENTS: BALANCING PRESCRIPTION DRUG INNOVATION, COMPETITION, AND AFFORDABILITY 5 (2002), available at http://www.nhpf.org/pdfs_bp/BP_HatchWaxman_6-02.pdf.

30 21 U.S.C. § 360cc(a)(2) (1994).

31 Haffner, supra note 28.

32 See Haffner & Kelsey, supra note 20, at 601.

33 26 U.S.C. § 45C (2000) (excluding from the tax credit any expenses which are funded via grant).

34 See Cann, Wesley A. Jr.,,Symposium: Corporate and Legal Implications of Re-Pricing Medicines in Developing Nations: Article: On the Relationship Between Intellectual Property Rights and the Need of Less-Developed Countries for Access to Pharmaceuticals: Creating a Legal Duty to Supply under a Theory of Progressive Global Constitutionalism, 25 U. Pa. J. Int’L Econ. L. 755, 791 (2004)Google Scholar (stating that it currently costs over $800 million to bring a new drug to market. While that figure includes costs unassociated with clinical trials, the cost of clinical trials is a substantial portion of drug development, and a 50% credit would still amount to millions of dollars).

35 21 U.S.C. § 360ee(a) (2000).

36 FDA, Frequently Asked Questions Regarding the OOPD Grant Program, at http://www.fda.gov/orphan/grants/faq.htm (last visited Nov. 26, 2004).

37 21 U.S.C. § 360ee(c) (2000) (section c amended in 2002 by Pub. L. 107-281 § 3 to increase annual funding available to $25 million for 2003 though 2006).

38 See 21 U.S.C. § 360cc (1994).

39 See Bohrer, Robert A. & Prince, John T., A Tale of Two Proteins: The FDA's Uncertain Interpretation of the Orphan Drug Act, 12 Harv. J.L. & Tech. 365, 371-72 (1999)Google Scholar (finding that while the “market protection is narrow,” it can be “essentially as effective as patent protection”).

40 Maeder, supra note 4, at 83. Two other exceptions exist to the market exclusivity provision. The first is if the sponsor company cannot supply enough of the drug to satisfy market demand. See U.S.C § 360cc(b)(1) (1994). The second is when the sponsor company agrees to approval of another application. See U.S.C § 360cc(b)(2) (1994).

41 Pulsinelli, supra note 13, at 311 (explaining that the market exclusivity provision “was originally intended to compensate for a lack of patent protection”).

42 21 U.S.C. § 360cc(a)(2) (1994).

43 STRONGIN, supra note 29, at 5.

44 Id.

45 Maeder, supra note 4, at 87.

46 Id.

47 Id.

48 Id.

49 Id. at 83.

50 Id. at 81.

51 FDA, LIST OF ALL ORPHAN PRODUCT DESIGNATIONS AND APPROVALS 45 (Feb. 19, 2004) available at http://www.fda.gov/orphan/designat/alldes.rtf.

52 Id.

53 Id.; see also Amgen, History of Epogen, at http://www.epogen.com/professional/about/epogen_history.jsp (last visited Oct. 15, 2004).

54 Pulsinelli, supra note 13, at 321.

55 See Maeder, supra note 4, at 82 (explaining that Epogen and Procrit, an almost identical drug, shared the market and generated over five billion dollars revenue annually for their respective manufacturers).

56 Id. at 87.

57 Pulsinelli, supra note 13, at 321-22.

58 Ass’n of Am. Physicians & Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204, 206 (D.D.C. 2002).

59 Id.

60 Id.

61 Chris Adams & Alison Young, FDA Oversight of Off-Label’ Drug Use Wanes, KNIGHT RIDDER NEWSPAPERS, Nov. 4, 2003, at http://www.realcities.com/mld/krwashington/news/special_packages/riskyrx/7152542.htm.

62 See generally Pulsinelli, supra note 13; Maeder, supra note 4. Both authors acknowledge the contention from critics that highly profitable drugs abuse the privileges awarded under the Act.

63 Pulsinelli, supra note 13, at 324-35.

64 E.g., S. Rep. No. 102-358, at 4 (1992) (1992 WL 193619).

65 Rohde, supra note 3, at n.39.

66 See Noah, Lars, The Coming Pharmacogenomics Revolution: Tailoring Drugs to Fit Patients’ Genetic Profiles, 43 Jurimetrics J. 1, 5 (2002)Google ScholarPubMed (“[P]hysicians frequently must try different medications at different dosages until they find the one that seems to work best in a particular patient.”).

67 See id. at 5-7 (describing a “trial and error” method employed by physicians which allows them to determine the correct drug and dosage for an individual patient based on outward signals such as adverse reactions).

68 See Maeder, supra note 4, at 87 (pointing out that five of the ten best-selling biotech drugs in the world in 2001 were originally approved as orphan drugs and another three were approved for orphan indications).

69 AMA, Pharmacogenomics, at http://www.ama-assn.org/ama/pub/category/2306.html (last updated Apr. 25, 2003).

70 See Soo-Jin Lee, Sandra et al., The Meanings of “Race” in the New Genomics: Implications for Health Disparities Research, 1 Yale J. Health Pol’Y L. & Ethics 33, 36 (2001)Google Scholar (observing that many believe the sequenced human genome and related technology will help create the field of pharmacogenomics).

71 See Evans & Relling, supra note 10, at 464-65 (mentioning many polymorphisms in genes which affect the metabolism and transportation of drugs); but see Phillips, Kathryn A. et al., Potential Role of Pharmacogenomics in Reducing Adverse Drug Reactions, 286 JAMA 2270, 2275 (2001)CrossRefGoogle ScholarPubMed (“The link between [adverse drug reactions] and genetic variability is complex, and our findings do not imply a causal relationship or that [adverse drug reaction] incidence would necessarily be reduced if drug selection and dosing were based on genetic variability.”)

72 See CNN, Tailor-Made Drugs Step Closer to Reality: FDA Urges More Research on Drug- Gene Interaction (Nov. 3, 2003), available at http://www.cnn.com/2003/HEALTH/11/03/tailoring.drugs.ap/index.html (describing pharmacogenomic research into p450, a family of drug metabolizing enzymes).

73 Id.

74 Marc Wortman, Medicine Gets Personal, TECHNOLOGY REVIEW, Jan.-Feb. 2001, at 72.

75 Id.

76 Id.

77 Id.; see also Noble, Holcomb B., Concern Grows Over Reactions to Lyme Shots, N.Y. TIMES, Nov. 21, 2000Google Scholar, at F1.

78 Epogen, Procrit, and HGH (human growth hormone) are all examples of blockbuster drugs whose parent companies utilized (whether intentionally or not) the “salami slicing” methodology. See generally Maeder, supra note 4.

79 21 U.S.C. § 360bb(a)(2) (1994).

80 Maeder, supra note 4, at 81-82 (“Epogen proved useful for other … purposes: restoring red blood cells in people suffering from bone marrow suppression as a result of taking AIDS drugs or cancer chemotherapy, and reducing the need for transfusions in surgery patients.”)

81 Id. at 84 (showing that annual worldwide sales of epoetin alfa reached $5.88 billion in 2001).

82 Id. at 81. Epogen and Procrit are the epoetin alfa products of Amgen and Ortho Biotech, respectively.

83 See Evans & Relling, supra note 10, at 465 (discussing mutations in “pathways” and “networks” of genes that lead to different conditions).

84 If each genetic variation affected a different step in the pathway, it seems that a strong argument could be made that each mutation gives rise to a medically plausible subset of the disease.

85 Pulsinelli, supra note 13, at 322.

86 Id.

87 Orphan Drug Regulations, 57 Fed. Reg. 62,076, 62,081 (Dec. 29, 1992) (to be codified at 21 C.F.R. pt. 316).

88 Orphan Drug Act, Pub. L. No 97-414, 96 Stat. 2049 (1982) (codified and amended at 21 U.S.C. §§ 360aa-360ee (1994)).

89 Pulsinelli, supra note 13, at 307.

90 See id. (stating that “[t]he response to the 1983 Orphan Drug Act was underwhelming”).

91 Health Promotion and Disease Prevention Amendments of 1984, § 4(a)-(b), Pub. L. No. 98- 551, 98 Stat. 2815 (1984).

92 See supra Part II(B).

93 Evans & Relling, supra note 10, at 466.

94 Pamisyl is an example of an orphan drug designed to treat a subgroup of victims of a common disease who are intolerant to the drug created for the majority of the population. Pamisyl's designated indication is to treat mild to moderate ulcerative colitis in patients intolerant to sulfasalazine. The FDA has not granted market approval for Pamisyl as of February 19, 2003. FDA, supra note 51.

95 See Policy of Eligibility of Drugs for Orphan Designation, 51 Fed. Reg. 4505, 4505 (1986).

96 See Bohrer & Prince, supra note 39, at 384 (asserting that “before the development of recombinant proteins by the biotechnology industry … smaller, simpler structures provided the basis for most drugs”).

97 Id.

98 See id. at 387-98 (examining some earlier litigation arising from conflicts over the definition of “same” and “different” under the Act).

99 Id. at 392; see also Orphan Drug Regulations, 57 Fed. Reg. at 62,077 (rejecting the proposal that FDA adopt an “active moiety” standard of “sameness” for macromolecules under the Act).

100 Bohrer & Prince, supra note 39, at 392.

101 Orphan Drug Regulations, 57 Fed. Reg. at 62,078.

102 FDA Orphan Drug General Provision, 21 C.F.R. §316.3(b)(3) (1999).

103 Bohrer & Prince, supra note 39, at 392.

104 See supra Part II(B).

105 See Noah, supra note 66, at 12 (describing pharmaceutical companies as seeking out possible subgroups that will respond most favorably and with least side effects to a tested treatment).

106 Pulsinelli, supra note 13, at 332-36

107 Id. at 333-36.

108 Id. at 310 (“[Market exclusivity] is the most significant incentive …”); see also Maeder, supra note 4, at 83 (“The seven-year market exclusivity clause has been key to the effectiveness of the [A]ct.”).

109 Pulsinelli, supra note 13, at 332-36.

110 Id. at 334.

111 Id.

112 Id.

113 Id.

114 Id. at 334-35.

115 Id. at 323.

116 See id. (mentioning that the proposals call for monitoring the size of the disease population rather than total prescriptions or sales).

117 Pulsinelli, supra note 13, at 335.

118 See, e.g., 136 Cong. Rec. H6194 (daily ed. July 31, 1990) (allowing companies to recover twice the development costs plus a 25 percent profit before the tax goes into effect); 137 Cong. Rec. H7777 (daily ed. Oct. 10, 1991) (calling for a tax once the development costs had been recovered).

119 Id.

120 Pulsinelli, supra note 13, at 336.

121 Rin-Laures, Li-Hsien & Janofsky, Diane, Recent Developments Concerning the Orphan Drug Act, 4 Harv. J.L. & Tech. 269, 285 (1991)Google Scholar.

122 See Washington Legal Found. v. Henney, 202 F.3d 331, 336 (D.C. Cir. 2000) (holding the FDA may not prevent drug manufacturers from educating doctors about off-label uses of their products).

123 Beck, James M. & Azari, Elizabeth D., FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53 Food & Drug L.J. 71, 72 (1998)Google ScholarPubMed.

124 FDA, supra note 16.

125 Orphan Drug Regulations, 57 Fed. Reg. at 62,081.

126 See Maeder, supra note 4, at 84-85 (describing the numerous orphan drugs created by biotechnology companies and the growth of that industry incident with the success of several orphan drugs).

127 The current regulations were proposed in January 1991, less than four months after the start of the Human Genome Project. Orphan Drug Regulations, 56 Fed. Reg. 3338 (Jan. 29, 1991) (to be codified at 21 C.F.R. pt. 316).