Potential pathways for abbreviated approval of generic biologics under existing law and proposed reforms to the law

Food and Drug Law Journal

Volumn 62, Issue 1, 2007, Pages 77-137

  Dinh, Tam Q ^a  

^a FOLEY AND LARDNER LLP   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL PRODUCT; GENERIC DRUG;

BIOTECHNOLOGY; CONSUMER; DRUG APPROVAL; DRUG COST; DRUG EFFICACY; DRUG INDUSTRY; DRUG LABELING; DRUG LEGISLATION; DRUG MARKETING; DRUG SAFETY; FOOD AND DRUG ADMINISTRATION; PRESCRIPTION; REVIEW;

BIOLOGICAL AVAILABILITY; BIOLOGICAL PRODUCTS; DRUG APPROVAL; DRUG INDUSTRY; DRUGS, GENERIC; DRUGS, INVESTIGATIONAL; HUMANS; INVESTIGATIONAL NEW DRUG APPLICATION; LEGISLATION, DRUG; MARKETING OF HEALTH SERVICES; PATENTS; TIME FACTORS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 33947265301     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (126)

1. FDCA, Pub. L. No. 75-717, ch. 675, 52 Stat. 1040 (June 25,1938) (codified as amended at 21 U.S.C. §§ 301 to 399 (2002)).
2. PHSA, Pub. L. No. 78-410, ch. 373, 58 Stat. 682 (July 1, 1944) (codified as amended at 42 U.S.C. §§ 201 et seq. (2005)).
3. For a list of the world's 10 best-selling biological therapeutics in 2003, see Yves Mamou, L'Amerique se construit un quasi-monopole dans les biotechnologies, Le Monde (Apr. 22,2005), available at http://www.lemonde.fr (last visited Apr. 22, 2005).
4. In 2003, the U.S. had 1,830 biotech companies investing 16.4 billion euros in R&D, and the European Union (EU) had 1,975 biotech firms spending 5.9 billion euros on R&D. Id.
5. Biologics represent about one-quarter to one-third of the total therapeutics in development. Pharmaceutical Research and Manufacturers of America (PhRMA), Issues and Questions on Biologics-Can There Be Abbreviated Applications, "Generics" or "Follow-on" Products?, at 3 (Oct. 11, 2001) [hereinafter Issues on Biologics], available at http://www.europabio.org/ documents/QA-Pharma.doc (last visited Jan. 2, 2006);
6. Selena Class, Biogenerics: Waiting for the Green Light, IMS Health (Oct. 28, 2004), available at http://www.ims-global.com/insight/ news_story/0410/news_story_041027a.htm (last visited Jan. 2, 2006).
7. In 2004, over 400 biopharmaceuticals were in development worldwide. Mamou, supra note 3.
8. In 2001, there were 78 approved biologics in the U.S. PhRMA, Issues on Biologics, supra note 5, at 3.
9. Globally, 190 therapeutic biologics were on the market in 2004. Mamou, supra note 3. Forty percent of new medicines marketed around the world are now biologics.
10. Id.
11. America's healthcare crisis: Desperate measures, THE ECONOMIST (Jan. 28, 2006), at 24.
12. Id. at 25.
13. Nilay D. Shah et al., Projecting Future Drug Expenditures-2003, 60 AM. J. HEALTH-SYST. PHARM. 137, 137 (2003).
14. Id. at 137-138.
15. The drugs industry: An overdose of bad news, THE ECONOMIST (Mar. 19, 2005), at 74 (Fig. 1).
16. For a comprehensive list of marketed biologics, see David M. Dudzinski, Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-based Therapeutics and Monoclonal Antibodies, 60 FOOD & DRUG L.J. 143, 243 (appendix A) (2005).
17. Gregory N Mandel, The Generic Biologics Debate: Industry's Unintended Admission that Biotech Patents Fail Enablement, unpublished manuscript shared by the author, at 4 (2006).
18. Marc Kaufman, Clinical Trials of Drugs Fewer, Study Says; Report Also Notes Decline in Number of Principal Investigators in U.S., WASH. POST (May 4, 2005), at A2.
19. Shah, supra note 9, at 138, 140.
20. Geeta Anand, As Biotech Drug Prices Surge, U.S. Is Hunting for a Solution, WALL ST. J. (Dec. 28, 2005), at A1.
21. Shah, supra note 9, at 138, 140 (Table 2).
22. See, e.g., Amy Kapczynski et al., Addressing Global Health Inequities: An Open Licensing Approach for University Innovations, 20 BERKELEY TECH. L.J. 1031, 1114 n.288 (2005). Many therapeutic biologics cost more than $10K a year.
23. FDA Looks at Biogeneric Issue, but Action Unlikely in Near Term, SPECIALTY PHARMACY NEWS (Nov. 10, 2004), available at http://www.aishealth.com/DrugCosts/specialty/SPNFDABiogeneric. html (last visited Jan. 2, 2006).
24. Less expensive biologics may cost several thousand dollars annually, while the most expensive ones cost several hundred thousand dollars a year. Anand, supra note 16.
25. BioPortfolio, The Biogenerics Threat Looms Large, http://www.bioportfolio.com/news/datamonitor_27.htm (last visited Jan. 2, 2006). In the U.S., Epogen (erythropoietin-α (EPO)) came off patent in 2004, and Novolin (insulin), Protropin (somatrem), and Activase (alteplase) in 2005.
26. SPECIALTY PHARMACY NEWS, supra note 18. Neupogen (granulocyte colony stimulating factor (G-CSF)) will lose patent protection in 2006.
27. Id. The patents on Humulin (insulin), Avonex (interferon β-1a), and Humatrope (somatropin) have already expired.
28. Id.
29. Dudzinski, supra note 12, at 183. It is estimated that generic biologics would lower the cost of biologics by 20-30 percent.
30. Marc Kaufman, Biotech Drugs' Generic Future Debated: Medications Are Hard to Afford-But May Also Be Hard to Copy, WASH. POST (Feb. 10, 2005), at A1.
31. The HWA is formally called the Drug Price Competition and Patent Term Restoration Act of 1984. Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified as amended at 21 U.S.C. § 355 and 35 U.S.C. §§ 156, 271, and 282).
32. 57 Fed. Reg. 17950, 17951 (Apr. 28, 1992).
33. The "Bolar exemption" allows a firm "to make, use, ... or sell ... a patented invention [during the patent term] ... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use or sale of drugs or veterinary biological products." 35 U.S.C. § 271(e)(1) (2004).
34. The U.S. Supreme Court has ruled that the Bolar exemption applies to any type of patented, the FDA-regulated product that is eligible for patent term extension under the HWA (specifically, 35 U.S.C. § 156). Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 664 (1990).
35. Moreover, the Court has held that the Bolar exemption protects preclinical or clinical research that may reasonably generate information relevant to FDA premarket approval process. Merck KGaA v. Integra LifeSciences I, Ltd., 125 S.Ct. 2372, 2382-84 (2005). The Bolar exemption was designed to permit a generic company to test its generic drug in comparison with the patented pioneer drug during the patent term so that the generic drug would be ready for marketing upon expiration of the patent.
36. FDCA §§ 505(b)(2) and (j) correspond to 21 U.S.C. §§ 355(b)(2) and (j), respectively. A new drug approved by FDA for marketing is published (listed) in FDA's Orange Book.
37. According to a study in 2001, the average cost of developing a new drug was $802 million. Tufts Center for the Study of Drug Development (TCSDD), Backgrounder: A Methodology for Counting Costs for Pharmaceutical R&D (Nov. 2001), available at http://csdd.tufts.edu/NewsEvents/ RecentNews. asp?newsid=5 (last visited Mar. 24, 2005).
38. A new drug averages seven years in clinical trials. TCSDD, Impact Report: Analysis and Insight into Critical Drug Development Issues (Nov./Dec. 2005), available at http://csdd.tufts.edu/InfoServices/ ImpactReportPDFs/ImpactReportSummaryNovDec2005.pdf (last visited Feb. 16, 2006).
39. According to PhRMA, on average clinical trials of a new drug last six years and cost $390 million based on a total R&D cost of $802 million. PhRMA, Pharmaceutical Industry Profile 2005, at 4-5 (Fig. 1.3) (2005), available at http://www.phrma.org/publications/publications// 2005-03-17.1143.pdf (last visited Mar. 24, 2005).
40. For a summary of the three phases of clinical trials, see id. at 4.
41. Paul F. Fehlner et al., Can "Hatch-Waxman" for Generic Biologics Work? Despite Complexities, Expedited Approval for Biotech Drugs Is Possible, 6/3/02 NAT'L L. J. C4 (2002);
42. Kapczynski et al., supra note 18, at 1114n.288.
43. A mechanism for the approval of "similar biological medicinal products" took effect in the EU in late 2004. Class, supra note 5. An application must contain "a full characterization of the molecule as 'biosimilar'" to the pioneer biologic.
44. SPECIALTY PHARMACY NEWS, supra note 18. To show biosimilarity, the sponsor must conduct a clinical study involving a specified number of patients (e.g., 500 patients for EPO).
45. Id. A product approved as "biosimilar" to a pioneer biologic is technically not a "generic" because it cannot be directly substituted for the pioneer as a therapeutic equivalent, but must compete against the pioneer based on its own merit as a therapeutic alternative, a situation akin to a "me-too" drug.
46. Id.
47. See, e.g., Bruce N. Kuhlik, The Assault on Pharmaceutical Intellectual Property, 71 U. CHI. L. REV. 93, 105 (2004) ("The [HWA] does not apply to [biologics licensed under the PHSA], and there is no other mechanism available for abbreviated biologics license applications.").
48. The terms "pioneer" and "innovator" will be used interchangeably, and "pioneer" or "innovator" product will be synonymous with "brand-name" product. The term "pioneers" or "innovators" normally refers to research-based pharmaceutical or biotech companies that develop and market the first therapeutic product of its kind in a particular structural or therapeutic class.
49. 42 U.S.C. § 262(i) (2005) (corresponding to PHSA § 351(i)).
50. Dudzinski, supra note 12, at 180. In an immunogenic response, the body produces antibodies targeting the agent causing the response (see Part III.A).
51. Id at 181.
52. Id.
53. Definitions, 21 C.F.R. § 600.3(h)(5)(i)-(iii) (2004).
54. Edward L. Korwek, Human Biological Drug Regulation: Past, Present, and Beyond the Year 2000, 50 FOOD & DRUG L.J. 123, 143 (1995).
55. FDCA § 201(g)(1) (2002) (corresponding to 21 U.S.C. § 321(g)(1)).
56. Gary E. Gamerman, Regulation of Biologics Manufacturing: Questioning the Premise, 49 FOOD & DRUG L.J. 213, 228 (1994). Gamerman nicely summarizes the (confusing) regulation of biologics by CDER or CBER as either "drugs" or "biological products," respectively.
57. Id.
58. Lisa Raines, Biotechnology and Patent Term Extension Issues, 54 FOOD & DRUG L.J. 237, 239 (1999).
59. FDA, Intercenter Agreement Between the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research (Oct. 25, 1991) [hereinafter 1991 intercenter agreement], available at http://www.fda.gov/oc/ombudsman/drug-bio.htm (last visited Jan. 2, 2006).
60. See also 56 Fed. Reg. 58754, 58754-60 (Nov. 21, 1991).
61. Wayne H. Matelski, Generic Biologics: Outline of Legal and Regulatory Issues, 760 PLI/Pat 291, 297 (2003) (citing the 1991 intercenter agreement).
62. Press Release, Dept. of Health and Human Services, FDA to Consolidate Review Responsibilities for New Pharmaceutical Products (Sept. 6, 2002) [hereinafter 2002 FDA press release], available at http://www.fda.gov/ bbs/topics/NEWS/2002/NEW00834.html (last visited Jan. 9, 2006).
63. 68 Fed. Reg. 38067, 38068 (Notice) (June 26, 2003). For example, CDER was given responsibility to review the applications of "proteins intended for therapeutic use that are extracted from animals or microorganisms."
64. Matelski, supra note 39, at 297 (quoting Memorandum from Murray M. Lumpkin and Theresa M. Mullin to FDA Staff (Oct. 28, 2002)).
65. FDA, FDA Completes Final Phase of Planning for Consolidation of Certain Products from CBER to CDER (Mar. 17, 2003), available at http://www.fda.gov/bbs/topics/NEWS/2003/NEW00880. html (last visited Jan. 14, 2006).
66. 2002 FDA press release, supra note 40.
67. Raines, supra note 37, at 239;
68. see also Korwek, supra note 34, at 149.
69. Raines, supra note 37, at 239;
70. Korwek, supra note 34, at 143 (hormones are not classified as "biological products" under 21 C.F.R. § 600.3(h)(5)(ii));
71. Matelski, supra note 39, at 296 (listing examples of hormone products approved as "drugs" in n.5);
72. John C. Petricciani, Reinventing the Biologics Approval Process, 51 FOOD & DRUG L.J. 139, 140 (1996) (noting that "[i]n most other countries antibiotics and hormones are regulated as biologicals" rather than as drugs).
73. The CDER has jurisdiction over hormones, antibiotics, and certain inhibitors made by fungi or bacteria despite their biological origin. 1991 intercenter agreement, supra note 38.
74. Raines, supra note 37, at 239. A "therapeutic serum" (a "biological product") is prepared from blood by removing clotting components and blood cells.
75. C.F.R. § 600.3(h)(2) (2004).
76. Raines, supra note 37, at 239.
77. 21 C.F.R. § 600.3(a)(1)-(4) (2002).
78. 58 Fed. Reg. 53248 (1993).
79. Korwek, supra note 34, at 147-148
80. (citing 58 Fed. Reg. at 53250).
81. 42 U.S.C. § 262(a)(1)(A) (2005);
82. C.F.R. § 610.4 (2003). "From 1944 to 1997, the [PHSA] required approval of both an Establishment License Application [ELA] and a Product License Application [PLA] for each [biological] product."
83. Matelski, supra note 39, at 294. The FDA Modernization Act of 1997 (FDAMA) amended the PHSA to require approval of a single application-a BLA, which essentially combined the ELA and the PLA.
84. Id. at 295.
85. 42 U.S.C. § 262(a)(2)(C)(i)(I)-(II) (2005).
86. 45 Fed. Reg. 73922, 73922 (1980) (licensure of a biologic requires that it be "tested to ensure that it is safe, pure, potent and effective");
87. Korwek, supra note 34, at 129 (citing 21 C.F.R. § 601.25). "Purity" presumably pertains more to "safety" than to "potency"/"efficacy" to the extent that impurities may cause side effects. Purity would affect potency/efficacy if impurities interfere with the intended action of the active agent.
88. Legally, "potency" means "the specific ability or capacity of the product ... to effect a given result," while " effectiveness" requires a "reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product... will serve a clinically significant function" in addressing a human disease or condition. 21 C.F.R. §§ 600.3(s), 601.25(d)(2) (2003). For purposes of this paper, the terms "potency" and "efficacy" or "effectiveness" will be used interchangeably.
89. 21 C.F.R. § 601.2(a) (2005).
90. 21 C.F.R. §§ 314.125(b)(6) (for drugs) and 601.25(d)(2) (for biologics) (both referring to "controlled clinical investigations" defined in § 314.126) (2003).
91. 21 C.F.R. § 312.2(a) (2003) (stating that an IND for clinical investigations is required for biologics under the PHSA as well as for drugs under FDCA § 505);
92. Id. § 312.3(b) (defining an "investigational new drug" as a "new drug, antibiotic drug, or biological drug that is used in a clinical investigation").
93. 42 U.S.C. § 262(c) (2005).
94. See, e.g., Kuhlik, supra note 27, at 105 ("The Hatch-Waxman Act does not apply to [biologics licensed under the PHSA], and there is no other mechanism available for abbreviated [BLAs].").
95. 21 C.F.R. § 601.2(a) (2005). Back in 1974, FDA declared that premarket licensing of every biological product requires new clinical evidence of its safety and efficacy, "regardless whether other versions of the same product are already marketed or standards for the product have been adopted by rulemaking," because "all biological products are to some extent different and thus must be separately proven safe, pure, potent and effective."
96. Fed. Reg. 44602, 44641 (1974).
97. See, e.g., Kuhlik, supra note 27, at 105 ("the approval of generic biologic[s] must be supported by a full data package, without reliance on the innovator's safety and effectiveness data").
98. 42 U.S.C. § 262(j) (2005).
99. A biologic with an approved BLA does not need an approved application under the FDCA. Id. § 262(j). A pioneer probably would rather have its biologic "drug"be approved under the FDCA than the PHSA because while it may qualify for a patent term extension via either route, only the FDCA offers non-patent-based marketing exclusivities like the three-year new clinical study exclusivity and the five-year new molecular entity exclusivity. Moreover, the pioneer probably would not worry too much about a generic of its listed drug being approved under § 505(j) or 505(b)(2), for FDA has not shown much resolve to do so.
100. As used in this paper, the term "abbreviated approval" is distinct from FDA procedures for "expedited approval" of certain drugs. For example, FDA has a "fast track" procedure for "expedit[ing] the review of [a new drug that] is intended for the treatment of a serious or life-threatening condition and [that] demonstrates the potential to address unmet medical needs for such a condition." FDCA § 506(a)(1) (2002).
101. If FDA approves an NDA under § 505(b)(1) or (b)(2), it publishes (lists) the new drug and any patents claiming certain aspects (including use) of the drug in the Orange Book (formally called Approved Drug Products with Therapeutic Equivalence Evaluations).
102. C.F.R. §§ 314.3(b), 314.92(b) (2005).
103. A generic drug approved under an ANDA may also be listed in the Orange Book. Id. § 314.3(b) .
104. In this paper, the term "NDA" will refer to § 505(b)(1), not also to § 505(b)(2), unless noted otherwise.
105. FDCA § 505(b)(1)(A) (2004) (FDCA § 505 corresponds to 21 U.S.C. § 355).
106. 21 C.F.R. § 314.50(d) (2005).
107. 35 Fed. Reg. 7,250 (Regulations Describing Scientific Content of Adequate and Well-Controlled Clinical Investigations) (May 8, 1970).
108. "CBER and CDER have the same [scientific and legal] requirements and standards for assessing the safety and efficacy of medical products" as well as their "quality and manufacturing." PhRMA, Issues on Biologics, supra note 5, at 4.
109. FDCA § 505(b)(1)(C)-(D) (2004).
110. FDA, Consolidated response to citizen petitions from Pfizer/Pharmacia, BIO and TorPharm [hereinafter 2003 FDA response to petitions], at 7, 9, 14 (Oct. 14, 2003), available at http://www.fda. gov/ohrms/dockets/dailys/03/ oct03/l02303/01p-0323-pdn0001-vol1.pdf (last visited Jan. 2, 2006);
111. H.R. REP. NO. 98-857, pt. 1, 98th Cong., 2d Sess., at 14-15 (June 21, 1984).
112. Bioequivalence is determined in Phase I-like clinical investigation in humans.
113. FDCA § 505(j)(2)(A) (2004);
114. FDA response to petitions, supra note 72, at 33. If the ANDA applicant establishes pharmaceutical equivalence and bioequivalence, FDA cannot require it to provide additional preclinical or clinical evidence of safety or effectiveness.
115. FDCA § 505(j)(2)(A) (2004);
116. FDA response to petitions, supra note 72, at 7.
117. FDCA §§ 505(j)(2)(A)(i), (ii)(II), (iii), (v)(2004);
118. C.F.R. §§ 314.92(a)(1), 320.1(c) (2003);
119. FDA response to petitions, supra note 72, at 33. A "pharmaceutically equivalent" drug need not have the same inactive ingredients as a listed drug. 2003 FDA response to petitions,
120. id.
121. An "active ingredient" is any "component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals." 21 C.F.R. § 60.3(b)(2) (2002). An "active moiety" is defined as "the molecule or ion ... responsible for the physiological or pharmacological action of the drug substance."
122. Id. § 314.108(a). Different salts or prodrugs (e.g., esters) of the same active moiety are deemed different active ingredients.
123. Id. 320.1(c);
124. Fed. Reg. 2932, 2937-38 (1979).
125. FDCA § 505(j)(8)(B)(i) (2004). Bioequivalence essentially means that the two drugs are bioavailable to the same extent.
126. Id. § 505(j)(8)(A)(i). Under FDA policy, bioequivalence is demonstrated if the rate and extent of absorption of the active ingredient for a drug are within ±20% of those for the listed drug.