Bioequivalence: The regulatory career of a pharmaceutical concept

Bulletin of the History of Medicine

Volumn 85, Issue 1, 2011, Pages 93-131

  Carpenter, Daniel ^a   Tobbell, Dominique A ^b  

^a HARVARD UNIVERSITY   (United States)

^b UNIVERSITY OF MINNESOTA   (United States)

Author keywords

Bioequivalence; Drug regulation; Food and drug administration; Generic drugs; Regulatory science

Indexed keywords

GENERIC DRUG;

ARTICLE; DRUG APPROVAL; DRUG CONTROL; DRUG INDUSTRY; FOOD AND DRUG ADMINISTRATION; HISTORY; HUMAN; PHARMACOKINETICS; UNITED STATES;

DRUG AND NARCOTIC CONTROL; DRUG APPROVAL; DRUG INDUSTRY; DRUGS, GENERIC; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; THERAPEUTIC EQUIVALENCY; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 79957869637     PISSN: 00075140     EISSN: None     Source Type: Journal    
DOI: 10.1353/bhm.2011.0024     Document Type: Article

References (143)

1. In the United States alone, 70 percent of the 3.4 billion prescriptions filled at pharmacies are now completed with generic drugs.
2. Allan M. Fox and Alan R. Bennett, The Legislative History of the Drug Price Competition and Patent Term Restoration Act of 1984 (Washington, D.C.: Food and Drug Law Institute, 1987);
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5. Rebecca S. Eisenberg, "The Shifting Functional Balance of Patents and Drug Regulation," Health Aff. 20, no. 5 (September/October 2001): 119-35.
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7. Stephen Skowronek, Building a New American State: The Expansion of National Administrative Capacities, 1877-1920 (New York: Cambridge University Press, 1982);
8. Daniel P. Carpenter, The Forging of Bureaucratic Autonomy: Reputations, Networks, and Policy Innovation in Executive Agencies, 1862-1928 (Princeton, N.J.: Princeton University Press, 2001).
9. Sheila Jasanoff, The Fifth Branch: Science Advisers as Policymakers (Cambridge, Mass.: Harvard University Press, 1990);
10. Philip J. Hilts, Protecting America's Health: The FDA, Business and One Hundred Years of Regulation (New York: Knopf, 2003);
11. Arthur Daemmrich, Pharmacopolitics: Drug Regulation in the United States and Germany (Chapel Hill: University of North Carolina Press, 2004);
12. Daniel Carpenter, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA (Princeton, N.J.: Princeton University Press, 2010).
13. Sally Clarke, Regulation and the Revolution in United States Farm Productivity (New York: Cambridge University Press, 1994);
14. Christian Bonah, Christophe Masutti, Anne Rasmussen, and Jonathan Simon, eds., Standards in Pharmaceutical History: Harmonizing 20th Century Drugs (Paris: Editions Glyphe, 2010);
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17. Richard Harris, The Real Voice (New York: Macmillan, 1964);
18. Richard McFadyen, Estes Kefauver and the Drug Industry (Ph.D. diss., Emory University, 1973);
19. Dominique A. Tobbell, "'Who's Winning the Human Race?' Cold War as Pharmaceutical Political Strategy," J. Hist. Med. Allied Sci. 64, no. 4 (2009): 429-73.
20. National Pharmaceutical Council, "Misconceptions about So-Called 'Generic Equivalent' Drugs" (New York: National Pharmaceutical Council, 1961), copy in Records of the U.S. Pharmacopoeial Convention (B82, F11), Wisconsin State History Society, Madison, Wis. (hereafter, USP Records).
21. Ibid., 5-6.
22. John P. Swann, "The 1941 Sulfathiazole Disaster and the Birth of Good Manufacturing Practices," PDA J. Pharmaceut. Sci. Technol. 53, no. 3 (May 1999): 148-153.
23. National Pharmaceutical Council, "Misconceptions" (n. 7), 6.
24. A. E. Slesser (assistant technical director, SK&F Labs), "The Myth of Drug Product Equivalency'" (address, Hillsboro County Medical Association meeting, June 1, 1965), copy in USP Records.
25. Ibid., 9-10.
26. Dominique A. Tobbell, "Pharmaceutical Networks: The Political Economy of Drug Development in the United States, 1945-1980" (Ph.D. diss., University of Pennsylvania, 2008), esp. 191-232.
27. Pharmaceutical Manufacturers Association (PMA), "Drugs Anonymous?" (Washington, D.C.: PMA, 1967), National Museum of American History, Parke-Davis Collection, box 1964, quotation from p. 15.
28. "Compulsory Generic Prescribing-A Peril to the Health Care System," see Senator Gaylord Nelson, "Drug Quality Standards," Cong. Rec. 113, no. 5 (1967): 5630-31.
29. On October 19, 1967, the FDA withdrew certification of generic versions of chlor-amphenicol produced by the firms McKesson Laboratories, Continental Laboratories, the Pharmusa Corporation, the Davis-Edwards Pharmacal Corporation, Rachelle Laboratories, and Westward, Inc. after laboratory tests showed Parke-Davis's Chloromycetin brand entered the bloodstream faster than its generic competitors.
30. "FDA Limits Drug to One Company," New York Times, December 22, 1967, 29;
31. FDC Reports, November 6, 1967, T&G 7.
32. "Statement of C. Joseph Stetler, President, PMA," Competitive Problems in the Drug Industry, Hearings before the Senate Select Committee on Small Business; Monopoly Subcommittee, 1967-1977 (hereafter Nelson Hearings), November 16, 1967, 1367-1400, quotation on 1367.
33. "Statement of Charles T. Silloway, President, Ciba Pharmaceutical Co.," Nelson Hearings, September 14, 1967, 896-922, quotation on 907.
34. AMA, "Generic Prescribing Doesn't Guarantee Lower Drug Costs, Chicago Survey Shows" (news release, May 26, 1967), cited in Milton Silverman and Philip R. Lee, Pills, Profits, and Politics (Berkeley: University of California Press, 1974), 147, 364n16.
35. Harry M. Marks, "Making Risks Visible: The Science & Politics of Adverse Drug Reactions," in Ways of Regulating: Therapeutic Agents between Plants, Shops and Consulting Rooms, ed. Jean-Paul Gaudillière and Völker Hess (preprint 363, Berlin: Max Planck Institute für Wissenschaftsgeschichte, 2008), 105-122;
36. Dominique A. Tobbell, "'Eroding the Physician's Control over Therapy': The Post-War Politics of the Prescription," in The American Prescription from the New Deal to the New Millennium, ed. Elizabeth Watkins and Jeremy Greene (Baltimore: Johns Hopkins University Press, forthcoming).
37. "Statement of Charles T. Silloway" (n. 17), 908;
38. Gaylord Nelson, "Therapeutic Equivalency of Drugs," Cong. Rec. 115, no. 5 (1969): 6426-28, esp. 6427.
39. Testifying in support of generic prescribing were groups representing senior citizens (e.g., "Statement of James L. Browning," Nelson Hearings, May 15, 1967, 122-27), representatives from hospitals with success using formularies of generic drugs (e.g., "Statement of Dr. Harold F. Newman," Nelson Hearings, May 17, 1967, 219-27), and representatives of municipal and state governments with experience purchasing generic drugs for their hospital and welfare programs (e.g., "Statement of Dr. James G. Haughton," Nelson Hearings, June 8, 1967, 383-97).
40. K. A. Kuiken and Carl M. Lyman, "Availability of Amino Acids in Some Foods," J. Nutr. 36 (1948): 359-68, quotation on 359.
41. D. G. Chapman, R. Crisafo, and J. A. Campbell, "The Relation between in Vitro Disintegration Time of Sugar-Coated Tablets and Physiological Availability of Sodium p-Ami-nosalicylate," J. Amer. Pharmaceut. Assoc. (Sci. Ed.) 45 (1956): 374-78;
42. J. D. Mullins and T. J. Macek, "Some Pharmaceutical Properties of Novobiocin," J. Amer. Pharmaceut. Assoc. (Sci. Ed.) 49 (1960): 245-48;
43. Gerhard Levy, "Availability of Spironolactone Given by Mouth," Lancet (October 6, 1962): 723-24.
44. D. G. Chapman, L. G. Chatten, and J. A. Campbell, "Physiological Availability of Drugs in Tablets," Can. Med. Assoc. J. 76, no. 2 (1957): 102-6, quotation on 103;
45. A.B. Morrison and J. A. Campbell, "The Relationship between Physiological Availability of Salicylates and Ribofavin and in Vitro Disintegration of Enteric Coated Tablets," J. Amer. Pharmaceut. Assoc. 49, no. 7 (1960): 473-78;
46. A.B. Morrison, C. B. Perusse, and J. A. Campbell, "The Relationship between in Vitro Disintegration Time and in Vivo Release of Vitamins from a Triple-Dose Spaced-Release Preparation," J. Pharmaceut. Sci. 51, no. 7 (1962): 623-26;
47. Denys Cook, "History of Bioavailability Testing at the Food and Drug Directorate," Revue Canadienne de Biologie 32, supplement (1973): 157-62.
48. Einar Brochmann-Hansen, "Physiological Availability of Drugs in Pharmaceutical Dosage Forms" (presented at the National Formulary Committee meeting, Washington, D.C., September 22, 1961), 1, USP Records.
49. Ibid., 1.
50. Friend to Miller, November 25, 1963;
51. Modell to Miller, November 13, 1963; notes from phone conversation (probably Miller's handwriting), n.d., USP Records.
52. Miller, "Physiological Availability and Homogeneity in U.S.P. Dosage Forms," circular 30, U.S.P. Committee of Revision, September 28, 1961, 108, USP Records.
53. Miller, Notes from "Conf. on Physiological Availability," March 28, 1963, USP Records. Beginning in the late 1960s, Wagner worked with the Bureau of Drugs under a consulting contract.
54. Office of the Secretary, U.S. Department of Health, Education, and Welfare, "Final Report of the Task Force on Prescription Drugs" (Washington, D.C., 1969), iii.
55. Ibid., 31-34, quotation on 31.
56. For discussion of the Task Force and particularly its oversight of equivalency trials.
57. Silverman and Lee, Pills, Profits, and Politics (n. 18), 151-162.
58. Governing Board, National Research Council, minutes of NRC Governing Board meeting, April 24, 1996, appendix 7.2, NAS Archives, Medical Sciences, DRB folder, Committee on Drug Efficacy Review Ad Hoc 1966.
59. Ralph G. Smith, "The Drug Efficacy Study of the NAS-NRC," November 19, 1968, NAS Archives, series 1 DES, DES of NAS-NRC, Smith R G 1968.
60. R. Keith Cannan, "The Drug Efficacy Study of the NAS-NRC: A Talk Given at the Sixth Annual Briefing in Science Council for the Advancement of Science Writing, November 11, 1968," NAS Archives, series 1 DES, Speeches on History and Work of DES by Cannan, Gilman, and Trexler, 1966-68.
61. Alfred Gilman, "Therapeutic Equivalence of Generic Drugs and Problems of Drug Formulation," appendix A, minutes, Policy Advisory Committee of the Drug Efficacy Study, no. 3, March 27, 1968, NAS Archives, series 3 DES PAC 1968, Meetings folder, 27 Mar third.
62. William B. Castle, E. B. Astwood, Maxwell Finland, and Chester S. Keefer, "White Paper on the Therapeutic Equivalence of Chemically Equivalent Drugs. Prepared by a Subcommittee of the Policy Advisory Committee, Drug Efficacy Study," J. Amer. Med. Assoc. 208, no. 7 (1969): 1171-72, quotation on 1171. The views of the subcommittee reflected those of the broader Policy Advisory Committee.
63. Ibid, 1172.
64. Dominique A. Tobbell, "Allied against Reform: Pharmaceutical Industry-Academic Physician Relations in the United States, 1945-1970," Bull. Hist. Med. 82, no. 4 (2008): 878-912.
65. "Report of the Secretary's Review Committee of the Task Force on Prescription Drugs" (Washington, D.C.: Government Printing Office, 1969), 8-9.
66. Ibid., 9.
67. G. Levy, "Bioavailability, Clinical Effectiveness, and the Public Interest," in Conference on Bioavailability of Drugs at the National Academy of Sciences, reprinted in Bioavailability of Drugs: Proceedings of the Conference on the Bioavailability of Drugs, ed. B. Brodie and W. M. Heller (Basel: S. Karger, 1972) (hereafter PCBD), pp. 29-39, quotation on 35.
68. Ibid., 33.
69. W. H. Barr, "The Use of Physical and Animal Models to Assess Bioavailability," in PCBD, 55.
70. Levy, "Bioavailability" (n. 39), 39.
71. G. Levy and E. Nelson, "USP and NF Standards, FDA Regulations and the Quality of Drugs," N.Y. State J. Med. 61 (1961): 23.
72. J. T. Dolusio (Department of Pharmacology, University of Kentucky), in PCBD, 153.
73. L. P. Chenier and G. Maner, "Perspectives in Bioavailability of Drugs. Therapeutic and Toxicological Significance," Revue Canadienne de Biologie 32, supplement (1973): 1-182.
74. Gerhard Levy, "Future of Bioavailability Studies," Revue Canadienne de Biologie 32, supplement (1973): 171-76, quotation on 175.
75. Gerhard Levy, Allen Dyer, George H. Schneller, Denys Cook, and Alan H. Conney, "Discussion," Revue Canadienne de Biologie 32, supplement (1973): 177-82, quotations on 179-81.
76. D. C. Blair, R. W. Barnes, E. L. Wildner, and W. J. Murray, "Biological Availability of Oxytetracycline HCl Capsules," J. Amer. Med. Assoc. 215 (1971): 251-54;
77. J. Lindenbaum, M. H. Mellow, M. O. Blackstone, and V. P. Butler, "Variation in Biologic Availability of Digoxin from Four Preparations," New Engl. J. Med. 285 (1971): 1344-47;
78. C. Macleod, H. Rabin, J. Ruedy, M. Caron, D. Zarowny, and R. O. Davies, "Comparative Bioavailability of Three Brands of Ampicillin," Can. Med. Assoc. J. 107, no. 3 (1972): 203-9.
79. J. Ruedy, R. O. Davies, J. Brodeur, N. A. Hinton, I. R. Innes, A. Nantel, and J. M. Parker, "Bioavailability: Report of the Special Advisory to the Health Protection Branch, DNH&W," Can. Med. Assoc. J. 109 (1973): 920-22, quotation on 920-21.
80. Vesa Manninen, John Melin, and Gottfried Härtel, "Serum-digoxin Concentrations during Treatment with Different Preparations," Lancet 298, no. 7730 (1971): 934-35, quotation on 935.
81. "Editorial: Biological Availability of Drugs," Lancet 299, no. 7741 (1972): 83.
82. Vesa Manninen, John Melin, and Pentti Reissel, "Tablet Disintegration: Possible Link with Biological Availability of Digoxin," Lancet 299, no. 7748 (1972): 490-91;
83. T. R. D. Shaw, M. R. Howard, and John Hamer, "Variation in the Biological Availability of Digoxin," Lancet 300, no. 7772 (1972): 303-7.
84. John Hamer and D. G. Grahame-Smith, "Bioavailability of Digoxin," Lancet 300, no. 7772 (1972): 325.
85. Robert N. Smith, "Generic Equivalence and Non-Equivalence of Drugs," Lancet 300, no. 7776 (1972): 528-30, quotation on 529.
86. Federal Register 34 (February 27, 1969): 2673;
87. Jerome Philip Skelly, "A History of Biopharmaceutics in the Food and Drug Administration 1968-1993," AAPS J. 12, no. 1 (March 2010): 44-50.
88. "FDA: Bio-Data Is OK Substitute for Clinical Trials on Some Drugs," Drug Trade News, February 22, 1971, 51.
89. Carpenter, Reputation and Power (n. 4), chap. 5.
90. "FDA: Bio-Data" (n. 55), 51.
91. Ibid.
92. Memorandum from Walter Sloboda to Heino Trees (Division of Cardiopulmonary and Renal Drug Products), September 18, 1970, DF 505.8 (AF 30-841), RG 88, National Archives.
93. Edwards, "Welcome Address" to Conference on Bioavailability of Drugs at the National Academy of Sciences, reprinted in PCBD, 12.
94. Bennett, Legislative History (n. 2), iii.
95. Carpenter, Reputation and Power (n. 4), chap. 3.
96. FDC Reports, December 19, 1973, pp. A1-A7, quotation on A6.
97. "Statement of C. Joseph Stetler," Examination of the Pharmaceutical Industry, 1973-1974. Hearings before the Subcommittee on Health, Committee on Labor and Public Welfare, U.S. Senate, 93rd Congress, 1st and 2nd Sessions (hereafter the Kennedy Hearings), December 19, 1973, 336-63, quotation on 336.
98. Ibid., 337.
99. "Clinical Equivalency Proof for Military Drug Purchase," FDC Reports, May 1, 1967;
100. Max Feinberg, "How We Seek Quality in Competitive Drug Procurement," Pharmacy Times, December 1973, 36-41.
101. "Statement of C. Joseph Stetler" (n. 62), 337.
102. Tobbell, "Pharmaceutical Networks" (n. 13), esp. 96-134;
103. Tobbell, "Who's Winning?" (n. 6);
104. Tobbell, "Allied against Reform" (n. 36).
105. E. W. Kenworthy, "Doctor Suggests Drug Men Denied Him Post in FDA," New York Times, August 26, 1969, 1.
106. Gina B. Kolata, "Large Drug Firms Fight Generic Substitution," Science 206 (November 30, 1979): 1054-56, quotation on 1054.
107. In the early 1970s, clinical pharmacologists Louis Lasagna and William Wardell argued that as a direct result of the 1962 Drug Amendments the U.S. pharmaceutical industry had made significantly fewer pharmaceutical innovations and as a result the public's health was suffering.
108. Louis Lasagna and William M. Wardell, Regulation and Drug Development (Washington, D.C.: American Enterprise Institute for Public Policy Research, 1975).
109. Arthur A. Daemmrich, "Invisible Monuments and the Costs of Pharmaceutical Regulation: Twenty-Five Years of Drug Lag Debate," Pharm. Hist. 45 (2003): 3-17.
110. Edward Kennedy, Opening Statement, Brand Names and Generic Drugs, 1974. Kennedy Hearings, July 22, 1974, 1.
111. Drug Bioequivalence Study Panel, U.S. Office of Technology Assessment, Drug Bio-equivalence" (Washington, D.C.: Office of Technology Assessment, 1974), 1-78, quotations on 1, 2. (Online copy at http://www.fas.org/ota/reports/7401.pdf.)
112. Ibid., 32.
113. Ibid., 53.
114. Ibid., 51-54.
115. Ibid., 22.
116. Ibid., 23.
117. Ibid., 22-23.
118. Ibid., 55.
119. Goodman to Alfred G. Gilman, Jr., December 31, 1974, "No info available re a 1975 European Pharmacopoeia. The bioavailability (plasma conc.) area is pre-empted by FDA, not USP, for the present," Louis Goodman Papers, Alfred G. Gilman folder, Marriott University Library, University of Utah, Salt Lake City.
120. Sharon Anderson and Walter W. Hauck, "Consideration of Individual Bioequiva-lence," J. Pharmacokinetics Pharmacodynamics 18, no. 3 (June 1990): 259-73, esp. 260, 268.
121. Victor Smolen, "Bioavailability and Pharmacokinetic Analysis of Drug Responding Systems," Annu. Rev. Pharmacol. Toxicol. 18 (1978): 495-522.
122. Skelly, "History of Biopharmaceutics" (n. 54), 47.
123. Federal Register 38 (January 22, 1974): 885;
124. Federal Register 40 (June 20, 1975): 26164;
125. Federal Register 42 (January 7, 1977): 1624;
126. Federal Register 42 (August 23, 1977): 4231.
127. Robert Spencer, "Bioequivalence/Bioavailability-The FDA's Plans," Food, Drug Cosmetic Law J. 31 (1976): 32-38;
128. Bernard Cabana, "Bioavailability/Bioequivalence," Food, Drug Cosmetic Law J. 32 (1977): 512-26;
129. James T. Dolusio, "A Defnition of Bioequivalence/ Bioavailability and a Historical Perspective," Food, Drug Cosmetic Law J. 32 (1977): 506-11.
130. Mossinghoff, "Overview" (n. 2), 187.
131. Fox and Bennett, Legislative History (n. 2), 2, 213.
132. Ibid., 23;
133. Roger L. Nation and Lloyd N. Sansom, "Bioequivalence Requirements for Generic Products," Pharmacol. Therap. 62 (1994): 41-55.
134. On the spread of other FDA-originated concepts and regulations around the modern pharmaceutical world, including twentieth-century India and its regulation of Ayurvedic medicines.
135. Carpenter, Reputation and Power (n. 4), chap. 11.
136. Mossinghoff, "Overview" (n. 2), 189.
137. Anderson and Hauck, "Consideration of Individual Bioequivalence" (n. 80), 266-67;
138. Bernard E. Cabana, "Assessment of 75/75 Rule: FDA Viewpoint," J. Pharmaceut. Sci. 72 (1983): 98-99.
139. The 80/20 standard owed much to Canadian regulatory writings (see discussion on p. 115). It is likely, however, that the widespread acceptance of this standard in the global pharmaceutical world was facilitated by the FDA's 1978 rules and the 1984 statute as well as the work of the FDA statistician.
140. Mossinghoff, "Overview" (n. 2), 190.
141. Leslie Alderman, "Patient Money: Not All Drugs Are the Same After All," New York Times, December 18, 2009, http://www.nytimes.com/2009/12/19/health/19patient.html?ref=health (accessed December 23, 2009).
142. Wayne H. Maleski (counsel to CVS Caremark), Arent Fox LLP, to FDA, division of Dockets Management, October 19, 2007, Re FDA docket number 2007N-0382, "Comments Regarding 180-Day Generic Drug Exclusivity for Ramipril Capsules," docket number 2007N-0382, FDA.
143. In the middle 1990s, the FDA's drug reviewing divisions considered issues of bioavail-ability for Merck's Fosamax (alendronate) for Paget's disease. Here the comparison was not between a pioneer and a generic molecule but between two pioneer molecules, namely alendronate and etidronate (Didronel, manufactured by Procter & Gamble). "Fosamax is Effective in Paget's Regardless of Disease Severity and Previous Piphosphonate Treatment; Shows Greater Efficacy Than Etidronate," F-D-C Reports, Pharmaceutical Approvals Monthly, July 1996, 27.