The FDA and public access to new drugs: Appropriate levels of scrutiny in the wake of HIV, AIDS, and the diet drug debacle

Boston University Law Review

Volumn 79, Issue 1, 1999, Pages 93-150

  Salbu, Steven R ^a  

^a UNIVERSITY OF TEXAS AT AUSTIN   (United States)

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EID: 0033407848     PISSN: 00068047     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (389)

1. See Sharon Smith Holston, An Overview of International Cooperation, 52 FOOD & DRUG L.J. 197, 197 (1997) (noting that the historical mission of the FDA is "protecting consumers and promoting the public health"); Janet Woodcock, An FDA Perspective on the Drug Development Process, 52 FOOD & DRUG L.J. 145, 145 (1997) (citing the facilitation of drug development as a mission of the Agency's Center for Drug Evaluation and Research); David Woodward, The New Drug Marketing: A Consumer Protective Perspective, 51 FOOD & DRUG L.J. 637, 645 (1996) (describing the FDA's traditional mission as "ensuring that prescription drug promotional communications are truthful and do not mislead physicians or consumers").
2. See Sharon Smith Holston, An Overview of International Cooperation, 52 FOOD & DRUG L.J. 197, 197 (1997) (noting that the historical mission of the FDA is "protecting consumers and promoting the public health"); Janet Woodcock, An FDA Perspective on the Drug Development Process, 52 FOOD & DRUG L.J. 145, 145 (1997) (citing the facilitation of drug development as a mission of the Agency's Center for Drug Evaluation and Research); David Woodward, The New Drug Marketing: A Consumer Protective Perspective, 51 FOOD & DRUG L.J. 637, 645 (1996) (describing the FDA's traditional mission as "ensuring that prescription drug promotional communications are truthful and do not mislead physicians or consumers").
3. See Sharon Smith Holston, An Overview of International Cooperation, 52 FOOD & DRUG L.J. 197, 197 (1997) (noting that the historical mission of the FDA is "protecting consumers and promoting the public health"); Janet Woodcock, An FDA Perspective on the Drug Development Process, 52 FOOD & DRUG L.J. 145, 145 (1997) (citing the facilitation of drug development as a mission of the Agency's Center for Drug Evaluation and Research); David Woodward, The New Drug Marketing: A Consumer Protective Perspective, 51 FOOD & DRUG L.J. 637, 645 (1996) (describing the FDA's traditional mission as "ensuring that prescription drug promotional communications are truthful and do not mislead physicians or consumers").
4. See William M. Sage, Note, Drug Product Liability and Health Care Delivery Systems, 40 STAN. L. REV. 989, 1019 (1988).
5. See Jennifer J. Spokes, Note, Confusion in Dietary Supplement Regulation: The Sports Product Irony, 77 B.U. L. REV. 181, 184-86 (1997) (providing a broad overview of FDA regulatory functions).
6. The central focus of this Article will be on the philosophical issues underlying policy setting and regulatory activity, rather than on the particular details of specific FDA procedures. For a discussion of such procedures, see Steven R. Salbu, Regulation of Drug Treatments for HIV and AIDS: A Contractarian Model of Access, 11 YALE J. ON REG. 401, 406-18 (1994).
7. See Stuart O. Schweitzer et al., Is There a U.S. Drug Lag? The Timing of New Pharmaceutical Approvals in the G-7 Countries and Switzerland, 53 MED. CARE RES. & REV. 162, 163 (1996) (identifying hazard prevention and expedited access to new drugs as conflicting goals).
8. These objectives are irreconcilable because the tension between over-conservatism and under-conservatism, addressed in this Article, never can be eliminated. Of course, the FDA ultimately must, and does, make decisions regarding each new drug application, but these decisions are made in the shadow of unavoidable tensions implicit in determinations of the appropriate level of rigor for approval standards.
9. Although monitoring food safety is a distinct area of FDA operations, some of the issues I shall address with respect to drug safety can be applied by analogy to new food products. For example, FDA approval of the fat substitute Olestra spawned criticism that mirrors many of the concerns I express in this Article regarding the Agency's procedures for adequately protecting the public from hazardous drugs. Specifically, charges that the FDA has become too liberal in approving new products apply alike to diet drugs and Olestra. In each instance, substantial numbers of experts expressed serious reservations regarding product safety. For a discussion of the FDA advisory panel's reservations regarding the diet drug dexfenfluramine prior to approval, see infra Part III.A. For a report on the hundreds of doctors and scientists opposed to Agency approval of Olestra, see Beatrice Trum Hunter, Kessler Turns a Deaf Ear to Numerous Critics, CONSUMERS' RES. MAG., July 1996, at 12, 12-13.
10. This risk is substantial. According to one source, thirteen drugs have been recalled for safety reasons since 1980, and many others "remain on the market despite potentially fatal side effects." Nancy Shute, Pills Don't Come with a Seal of Approval: Diet Drug Recall, U.S. NEWS & WORLD REP., Sept. 29, 1997, at 74, 74. Many new drugs bear risks that are not detected until after the drugs have been approved and used by the public. See id. (noting that, by one estimation, 51% of FDA approved drugs cause major adverse effects that are not detected until after the drug has been released to and used by the general public).
11. See Henry I. Miller, Still Hazardous to Your Health: Regulatory Problems of the FDA, CONSUMERS' RES. MAG., Jan. 1998, at 10, 10 ("[T]he FDA's regulatory zeal has a dark side. The agency has constantly sought out new mandates and promulgated new requirements, regardless of the costs to patients and regulated industries.").
12. See discussion infra Part I.A for an explanation of the terms over- and under-conservatism.
13. Although I examine appetite suppressants in this Article, they are not the only widely prescribed medications recently removed from the market. For example, only a few months after the recall of the diet medications, the pharmaceutical manufacturer Hoechst Marion Roussel withdrew the very popular allergy drug Seldane from the market because researchers had observed an association between Seldane in combination with certain foods or medications and specific heart problems. See Thom Geier, So Long, Seldane, U.S. NEWS & WORLD REP., Jan. 12, 1998, at 66, 66.
14. Michael Steelman, Letter to the Editor, 277 JAMA 1201, 1201 (1997).
15. Pure Food and Drug Act of 1906, ch. 3915, 34 Stat. 768 (repealed 1938).
16. See Peter Barton Hutt, Development of Federal Law Regulating Slack Fill and Deceptive Packaging of Foods, Drugs, and Cosmetics, 42 FOOD DRUG COSM. L.J. 1, 2 (1987) (noting that "the driving force behind [the Pure Food and Drug Act] was well-publicized reports . . . about widespread adulteration of the food and drug supply").
17. See David F. Cavers, The Food, Drug and Cosmetic Act of 1938: Its Legislative History and Its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2, 20 (1939); see also HARVEY TEFF & COLIN R. MUNRO, THALIDOMIDE: THE LEGAL AFTERMATH 120-23 (1976). Although thalidomide-related birth defects in Europe have been cited as a possible impetus for the tightening of the regulatory regime in America, thalidomide itself was never approved for marketing in the United States during the 1950s and 1960s. The medication could be prescribed only abroad. See Larry Horton, Response, 81 J. NAT'L CANCER INST. 1132, 1133 (1989) (explaining that the FDA did not approve thalidomide because animal testing revealed undesirable side effects related to the drug). But see Anita Bernstein, Formed By Thalidomide: Mass Torts As a False Cure for Toxic Exposure, 97 COLUM. L. REV. 2153, 2161-63 (1997) (suggesting that "the relationship between thalidomide and drug regulation is far from direct").
18. See David F. Cavers, The Food, Drug and Cosmetic Act of 1938: Its Legislative History and Its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2, 20 (1939); see also HARVEY TEFF & COLIN R. MUNRO, THALIDOMIDE: THE LEGAL AFTERMATH 120-23 (1976). Although thalidomide-related birth defects in Europe have been cited as a possible impetus for the tightening of the regulatory regime in America, thalidomide itself was never approved for marketing in the United States during the 1950s and 1960s. The medication could be prescribed only abroad. See Larry Horton, Response, 81 J. NAT'L CANCER INST. 1132, 1133 (1989) (explaining that the FDA did not approve thalidomide because animal testing revealed undesirable side effects related to the drug). But see Anita Bernstein, Formed By Thalidomide: Mass Torts As a False Cure for Toxic Exposure, 97 COLUM. L. REV. 2153, 2161-63 (1997) (suggesting that "the relationship between thalidomide and drug regulation is far from direct").
19. See David F. Cavers, The Food, Drug and Cosmetic Act of 1938: Its Legislative History and Its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2, 20 (1939); see also HARVEY TEFF & COLIN R. MUNRO, THALIDOMIDE: THE LEGAL AFTERMATH 120-23 (1976). Although thalidomide-related birth defects in Europe have been cited as a possible impetus for the tightening of the regulatory regime in America, thalidomide itself was never approved for marketing in the United States during the 1950s and 1960s. The medication could be prescribed only abroad. See Larry Horton, Response, 81 J. NAT'L CANCER INST. 1132, 1133 (1989) (explaining that the FDA did not approve thalidomide because animal testing revealed undesirable side effects related to the drug). But see Anita Bernstein, Formed By Thalidomide: Mass Torts As a False Cure for Toxic Exposure, 97 COLUM. L. REV. 2153, 2161-63 (1997) (suggesting that "the relationship between thalidomide and drug regulation is far from direct").
20. See David F. Cavers, The Food, Drug and Cosmetic Act of 1938: Its Legislative History and Its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2, 20 (1939); see also HARVEY TEFF & COLIN R. MUNRO, THALIDOMIDE: THE LEGAL AFTERMATH 120-23 (1976). Although thalidomide-related birth defects in Europe have been cited as a possible impetus for the tightening of the regulatory regime in America, thalidomide itself was never approved for marketing in the United States during the 1950s and 1960s. The medication could be prescribed only abroad. See Larry Horton, Response, 81 J. NAT'L CANCER INST. 1132, 1133 (1989) (explaining that the FDA did not approve thalidomide because animal testing revealed undesirable side effects related to the drug). But see Anita Bernstein, Formed By Thalidomide: Mass Torts As a False Cure for Toxic Exposure, 97 COLUM. L. REV. 2153, 2161-63 (1997) (suggesting that "the relationship between thalidomide and drug regulation is far from direct").
21. See Arthur Hull Hayes, Jr., Food and Drug Regulation After 75 Years, 246 JAMA 1223, 1224 (1981).
22. The birth defects consisted of severe physical deformities that could result from the use of just one pill during the early stages of pregnancy. See Nancy Walsh D'Epiro, Thalidomide: Is It Safe This Time?, PATIENT CARE, Nov. 30, 1997, at 7, 7.
23. See Ann Saphir, Jekyll and Hyde: A New License for Thalidomide?, 89 J. NAT'L CANCER INST. 1480, 1480 (1997).
24. See infra Part III.
25. For instance, the modern consumer has unprecedented access to information through the Internet. See Nancy Ann Jeffrey, A Little Knowledge...Doctors Are Suddenly Swamped with Patients Who Think They Know a Lot More Than They Actually Do, WALL ST. J., Oct. 19, 1998, at R8 (discussing "Internet-junkie patients"). In 1997, the FDA liberalized the regulations governing drug advertising on television, further expanding patients' access to information. See Draft Guidance for Industry; Consumer-Directed Broadcast Advertisements; Availability, 62 Fed. Reg. 43,171, 43,172 (1997). As pharmaceutical companies become more aggressive and sophisticated in carrying out their newfound role as consumer marketers, this effect is likely to increase. For a discussion of the industry's efforts to develop a new approach to advertising, see Yumito Ono, Drug Marketers Learn to Craft a Slicker Pitch, WALL ST. J., Feb. 10, 1998, at B1 (noting that new guidelines allow prescription drug manufacturers to omit the lengthy disclaimers and warnings previously required in direct marketing to consumers).
26. For instance, the modern consumer has unprecedented access to information through the Internet. See Nancy Ann Jeffrey, A Little Knowledge...Doctors Are Suddenly Swamped with Patients Who Think They Know a Lot More Than They Actually Do, WALL ST. J., Oct. 19, 1998, at R8 (discussing "Internet-junkie patients"). In 1997, the FDA liberalized the regulations governing drug advertising on television, further expanding patients' access to information. See Draft Guidance for Industry; Consumer-Directed Broadcast Advertisements; Availability, 62 Fed. Reg. 43,171, 43,172 (1997). As pharmaceutical companies become more aggressive and sophisticated in carrying out their newfound role as consumer marketers, this effect is likely to increase. For a discussion of the industry's efforts to develop a new approach to advertising, see Yumito Ono, Drug Marketers Learn to Craft a Slicker Pitch, WALL ST. J., Feb. 10, 1998, at B1 (noting that new guidelines allow prescription drug manufacturers to omit the lengthy disclaimers and warnings previously required in direct marketing to consumers).
27. For instance, the modern consumer has unprecedented access to information through the Internet. See Nancy Ann Jeffrey, A Little Knowledge...Doctors Are Suddenly Swamped with Patients Who Think They Know a Lot More Than They Actually Do, WALL ST. J., Oct. 19, 1998, at R8 (discussing "Internet-junkie patients"). In 1997, the FDA liberalized the regulations governing drug advertising on television, further expanding patients' access to information. See Draft Guidance for Industry; Consumer-Directed Broadcast Advertisements; Availability, 62 Fed. Reg. 43,171, 43,172 (1997). As pharmaceutical companies become more aggressive and sophisticated in carrying out their newfound role as consumer marketers, this effect is likely to increase. For a discussion of the industry's efforts to develop a new approach to advertising, see Yumito Ono, Drug Marketers Learn to Craft a Slicker Pitch, WALL ST. J., Feb. 10, 1998, at B1 (noting that new guidelines allow prescription drug manufacturers to omit the lengthy disclaimers and warnings previously required in direct marketing to consumers).
28. For a discussion of the argument that liberalized access to drugs may dilute the pool of effective treatments and drive the costs of drugs upward, see Peter MacPherson, The FDA Just Says Yes, HOSP. & HEALTH NETWORKS, May 20, 1996, at 34, 36.
29. As companies vigorously market their products directly to patients, patients respond as the companies hope they will - by asking their doctors for specific treatments they have seen advertised on television and in print media. Although doctors have a professional obligation to exercise their best judgment in treating patients, it is reasonable to assume that some physicians will yield to patient requests and succumb to pressure in instances where they would not otherwise prescribe a given treatment. See Elyse Tanouye, Drug Ads Spur Patients To Demand More Prescriptions, WALL ST. J., Dec. 22, 1997, at B1; see also Doctors Concerned By Requests for Drug Brands Seen in TV Ads, AUSTIN AM.- STATESMAN, Jan. 7, 1998, at D1 (noting that Dr. Sidney Wolfe, Director of Health Research for the consumer activist group Public Citizen, believes that doctors are dispensing more ill-advised prescriptions due in part to advertisement-induced patient demand).
30. As companies vigorously market their products directly to patients, patients respond as the companies hope they will - by asking their doctors for specific treatments they have seen advertised on television and in print media. Although doctors have a professional obligation to exercise their best judgment in treating patients, it is reasonable to assume that some physicians will yield to patient requests and succumb to pressure in instances where they would not otherwise prescribe a given treatment. See Elyse Tanouye, Drug Ads Spur Patients To Demand More Prescriptions, WALL ST. J., Dec. 22, 1997, at B1; see also Doctors Concerned By Requests for Drug Brands Seen in TV Ads, AUSTIN AM.-STATESMAN, Jan. 7, 1998, at D1 (noting that Dr. Sidney Wolfe, Director of Health Research for the consumer activist group Public Citizen, believes that doctors are dispensing more ill-advised prescriptions due in part to advertisement-induced patient demand).
31. The FDA has been "criticized in the past as underfunded, ill-equipped, and incapable of effectively performing its public protection mandate." Gregory C. Jackson, Comment, Pharmaceutical Product Liability May Be Hazardous to Your Health: A No-Fault Alternative to Concurrent Regulation, 42 AM. U. L. REV. 199, 215-16 (1992).
32. See, e.g., Joe Graedon & Teresa Graedon, Speeding Drug Okay Could Spell Disaster, HOUS. CHRON., Jan. 10, 1998, at 8 ("As it is, far too many medications get to market before serious side effects are discovered. The current system is woefully inadequate, and 'reforming' it by reducing safeguards is shortsighted.").
33. Most of the existing regulations concerning drug approval were passed in response to injuries caused by the disasters of the 1930s and early 1960s. See Charles J. Cote et al., Is the "Therapeutic Orphan" About To Be Adopted?, 98 PEDIATRICS 118, 120 (1996) ("[M]ost of the major laws that support the FDA's role in regulating drugs have been passed in response to drug-induced adverse effects occurring in the pediatric population (ethylene glycol poisoning in 1938 and thalidomide in 1962).").
34. See Robert R. Chen et al., Vaccine Safety Datalink Project: A New Tool for Improving Vaccine Safety Monitoring in the United States, 99 PEDIATRICS 765, 766 (1997) (noting that the need to improve post-licensure monitoring of drug safety became widely recognized after the thalidomide disaster).
35. Criticism of the FDA's arguably cumbersome and overly cautious approval process focuses not only on patient access issues, but also on economic issues. For example, some commentators contend that excessive caution hurts American businesses vis-a-vis global competition, kills jobs, and contributes to the rising cost of health care. See Wayne M. Serra, Ensuring the Safety of Genotech Drugs Through Implied Warranty Theory, 23 AM. J.L. & MED. 363, 373 n.119 (1997).
36. See Li-Hsien Rin-Laures & Diane Janofsky, Note, Recent Developments Concerning the Orphan Drug Act, 4 HARV. J.L. & TECH. 269, 296 (1991); Phillip J. Witts, How the AIDS Crisis Made Drug Regulators Speed Up, N.Y. TIMES, Sept. 24, 1989, § 4, at 5 ("The average time it takes to move a drug from test tube to drug store shelves has been 7 to 10 years.").
37. See Li-Hsien Rin-Laures & Diane Janofsky, Note, Recent Developments Concerning the Orphan Drug Act, 4 HARV. J.L. & TECH. 269, 296 (1991); Phillip J. Witts, How the AIDS Crisis Made Drug Regulators Speed Up, N.Y. TIMES, Sept. 24, 1989, § 4, at 5 ("The average time it takes to move a drug from test tube to drug store shelves has been 7 to 10 years.").
38. See Carl C. Peck, Drug Development: Improving the Process, 52 FOOD & DRUG L.J. 163, 163 (1997) (criticizing the FDA's "excessive" numbers of clinical trials and the "enormous" number of observations within those trials).
39. Under federal law, clinical investigations on humans can begin only after specific data are submitted to the FDA. These data include "adequate information on the chemistry and manufacturing of the drug, controls available for the drug, and primary data tabulations from animal or human studies." 21 U.S.C.A. § 355(i)(2)(B) (West Supp. 1998).
40. See 21 C.F.R. § 312.20(a) (1998) (directing that all sponsors "shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation" using that drug).
41. See id. § 312.21 (describing the phases of testing an IND); see also infra Part II.B.1 for further discussion of these three phases. Although drugs ordinarily must go through three phases of testing to be approved by the FDA, some prospects are abandoned before all phases are completed. One analyst has estimated that only half of all drugs in phase 2 proceed to the next phase. See Erick Schonfeld, Drugs of Choice, FORTUNE, Nov. 10, 1997, at 293, 293-94 (citing Lehman Brothers analyst Tony Butler). The usual three-phase system for clinical trials can be circumvented under very limited circumstances, pursuant to AIDS era reforms. See infra Part II.B.2.b.
42. See 21 C.F.R. § 314.100(a) (1998) (describing the FDA's timeline and approval process).
43. See id. § 314.120(a)(3) (directing applicants who receive not approvable letters to "ask the agency to provide an opportunity for a hearing on whether there are grounds for denying approval").
44. See John W. Guendelsberger, The Process of New Drug Discovery and Development, 2 J. PHARMACY & L. 79, 80 (1993) (reviewing CHARLES G. SMITH, THE PROCESS OF NEW DRUG DISCOVERY AND DEVELOPMENT (1992) and arguing that FDA procedures tend to be excessively cautious, thereby substantially delaying the marketing of new drugs).
45. See John W. Guendelsberger, The Process of New Drug Discovery and Development, 2 J. PHARMACY & L. 79, 80 (1993) (reviewing CHARLES G. SMITH, THE PROCESS OF NEW DRUG DISCOVERY AND DEVELOPMENT (1992) and arguing that FDA procedures tend to be excessively cautious, thereby substantially delaying the marketing of new drugs).
46. See infra Part II.B.2 for a discussion of new procedures developed in response to AIDS activism in the 1980s and 1990s.
47. See Tanya E. Karwaki, Comment, The FDA and the Biotechnology Industry: A Symbiotic Relationship?, 71 WASH. L. REV. 821, 822 (1996).
48. For further discussion of this problem, see Paul M. Booth, FDA Implementation of Standards Developed by the International Conference on Harmonization, 52 FOOD & DRUG L.J., 203, 203 (1997) (asserting that "[r]apid worldwide introduction of new drugs is hampered by differing regulatory requirements of the agencies that approve new drugs for sale in the world's major markets"); Joseph G. Contrera, Comment, The Food and Drug Administration and the International Conference on Harmonization: How Harmonious Will International Pharmaceutical Regulations Become?, 8 ADMIN. L.J. AM. U. 927, 950 (1995) (discussing drug approval delays resulting from the lack of harmony in international drug regulations).
49. For further discussion of this problem, see Paul M. Booth, FDA Implementation of Standards Developed by the International Conference on Harmonization, 52 FOOD & DRUG L.J., 203, 203 (1997) (asserting that "[r]apid worldwide introduction of new drugs is hampered by differing regulatory requirements of the agencies that approve new drugs for sale in the world's major markets"); Joseph G. Contrera, Comment, The Food and Drug Administration and the International Conference on Harmonization: How Harmonious Will International Pharmaceutical Regulations Become?, 8 ADMIN. L.J. AM. U. 927, 950 (1995) (discussing drug approval delays resulting from the lack of harmony in international drug regulations).
50. For further discussion and analysis of this problem, see Contrera, supra note 38, at 950 (noting that inconsistent international regulatory requirements can force a new drug to undergo lengthy and costly clinical trials in each country before that nation's FDA equivalent will approve its use); Ileana Dominguez-Urban, Harmonization in the Regulation of Pharmaceutical Research and Human Rights: The Need To Think Globally, 30 CORNELL INT'L L.J. 245, 258 (1997) (discussing the duplication of effort required to comply with each nation's drug regulations).
51. See Booth, supra note 38, at 203 (describing international efforts to combat the cost and patient access problems associated with disharmonies in drug approval standards).
52. See id. (noting that the International Conference on Harmonisation was founded in 1989 for the purpose of negotiating global regulatory standards).
53. "Modern reforms" refer here to changes made during the 1980s and 1990s.
54. "Combination therapies" are often referred to as "AIDS cocktails," "protease inhibitor therapies," and "protease inhibitor cocktails." These different terms commonly denote a single set of revolutionary treatments developed during the mid 1990s.
55. The set of symptoms which were later designated AIDS were first observed clinically around 1979. See Steven R. Salbu, AIDS and Drug Pricing: In Search of a Policy, 71 WASH. U. L.Q. 691, 691 n.1 (1993).
56. See Steven R. Salbu, Should AIDS Research Be Regulated? A Manhattan Project for AIDS and Other Policy Proposals, 69 IND. L.J. 425, 425 (1994) ("While a number of drug treatments have been marketed during [the 1980s and early 1990s], . . . no effective vaccination or cure has been discovered.").
57. See Daniel Callahan, Transforming Mortality: Technology and the Allocation of Resources, 65 S. CAL. L. REV. 205, 213-14 (1991) (describing the short course of AIDS in the years immediately following its discovery, when care was limited to palliative measures rather than attempts to stem opportunistic infections).
58. See Nathan A. Adams, IV, Comment, Monkey See, Monkey Do: Imitating Japan's Industrial Policy in the United States, 31 TEX. INT'L L.J. 527, 555 (1996).
59. See id.; see also Gordon Slovut, Breaking the Brain Barrier, STAR TRIB. (Minneapolis-St. Paul), Nov. 5, 1997, at 20A.
60. See Samantha Catherine Halem, Note, At What Cost?: An Argument Against Mandatory AZT Treatment of HIV-Positive Pregnant Women, 32 HARV. C.R.-C.L. L. REV. 491, 494 (1997).
61. For further discussion of AZT as a treatment for AIDS and the research of the 1980s, see Margaret A. Fischl et al., The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double Blind, Placebo-Controlled Trial, 317 NEW ENG. J. MED. 185, 190 (1987) (noting the decreased mortality and the reduction of opportunistic infection in AIDS patients treated with AZT); see also Douglas D. Richman et al., The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double-Blind, Placebo-Controlled Trial, 317 NEW ENG. J. MED. 192, 193 (1987) (discussing the side effects of AZT).
62. For further discussion of AZT as a treatment for AIDS and the research of the 1980s, see Margaret A. Fischl et al., The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double Blind, Placebo-Controlled Trial, 317 NEW ENG. J. MED. 185, 190 (1987) (noting the decreased mortality and the reduction of opportunistic infection in AIDS patients treated with AZT); see also Douglas D. Richman et al., The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double-Blind, Placebo-Controlled Trial, 317 NEW ENG. J. MED. 192, 193 (1987) (discussing the side effects of AZT).
63. As we shall see, early treatment with AZT in isolation from other co-acting drugs was later replaced by treatments involving AZT in combination with protease inhibitors. See infra Part II.A.2.
64. See Dolores Kong, Drugs Found to Lengthen Life with AIDS-Linked Pneumonia, BOSTON GLOBE, Jan. 19, 1990, at 6 (comparing survival rates before and after the introduction of AZT for pneumocystis carinii pneumonia and other common health outcomes related to AIDS).
65. See Florence S. Antoine, Scientists Changing Therapy Outlook for AIDS Patients, 82 J. NAT'L CANCER INST. 992, 993 (1990) (noting that the dramatic success of AZT in delaying the development of AIDS led the National Institute of Allergy and Infectious Disease to extend AZT treatment to patients whose immune systems were still fairly strong in the hope that the drug might repair any existing damage).
66. Reid J. Schar, Comment, Downward Sentencing Departures for HIV-Infected Defendants: An Analysis of Current Law and a Framework for the Future, 91 Nw. U. L. REV. 1147, 1184 n.231 (1997) (quoting AMERICAN MEDICAL ASSOCIATION, HIV: EARLY INTERVENTION 12 (1994)).
67. Reid J. Schar, Comment, Downward Sentencing Departures for HIV-Infected Defendants: An Analysis of Current Law and a Framework for the Future, 91 Nw. U. L. REV. 1147, 1184 n.231 (1997) (quoting AMERICAN MEDICAL ASSOCIATION, HIV: EARLY INTERVENTION 12 (1994)).
68. See Ellen L. Luepke, Note, HIV Misdiagnosis: Negligent Infliction of Emotional Distress and the False-Positive, 81 IOWA L. REV. 1229, 1244 n.112 (1996) (noting that treatment with AZT is associated with certain side effects such as anemia).
69. See Michael Closen et al., Mandatory Premarital HIV Testing: Political Exploitation of the AIDS Epidemic, 69 TUL. L. REV. 71, 85 (1994). Before the introduction of combination therapies, the FDA stated that AZT's clinical benefits generally continue for 12 to 18 months, decreasing substantially thereafter. See James G. Dickinson, FDA Wants Viral Resistance Explored in AIDS Drugs, MED. MARKETING & MEDIA, June 1, 1993, at 10, 10.
70. See Michael Closen et al., Mandatory Premarital HIV Testing: Political Exploitation of the AIDS Epidemic, 69 TUL. L. REV. 71, 85 (1994). Before the introduction of combination therapies, the FDA stated that AZT's clinical benefits generally continue for 12 to 18 months, decreasing substantially thereafter. See James G. Dickinson, FDA Wants Viral Resistance Explored in AIDS Drugs, MED. MARKETING & MEDIA, June 1, 1993, at 10, 10.
71. Indeed, some drugs approved by the FDA have been labeled for use only by patients who fail to respond to AZT. See, e.g., Teresa Riordan, Second Major AIDS Drug Offers New Hope for AIDS Patients, REUTERS N. AM. WIRE, Oct. 10, 1991, available in LEXIS, News Library, Arcnws File (observing that the AIDS treatment DDI is specifically labeled for patients who do not respond to AZT).
72. As one investigation noted in 1996, "the benefits of zidovudine (AZT) in HIV-infected patients are small and do not last long." Delta Coordinating Committee, Delta: A Randomized Double-Blind Controlled Trial Comparing Combinations of Zidovudine Plus Didanosine or Zalcitabine with Zidovudine Alone in HIV-Infected Individuals, 348 LANCET 283, 283 (1996).
73. See Gerald H. Friedland, Early Treatment for HIV: The Time Has Come, 322 NEW ENG. J. MED. 1000, 1001 (1990) (stating that AZT treatment in asymptomatic patients "significantly delayed the progression to symptomatic illness"); Janine Sisak, Note, Confidentiality, Counseling, and Care: When Others Need To Know What Clients Need To Disclose, 65 FORDHAM L. REV. 2747, 2770 n.140 (1997) (noting that certain treatments, including AZT, may postpone the onset of symptoms if administered early in the patient's medical regimen).
74. See Gerald H. Friedland, Early Treatment for HIV: The Time Has Come, 322 NEW ENG. J. MED. 1000, 1001 (1990) (stating that AZT treatment in asymptomatic patients "significantly delayed the progression to symptomatic illness"); Janine Sisak, Note, Confidentiality, Counseling, and Care: When Others Need To Know What Clients Need To Disclose, 65 FORDHAM L. REV. 2747, 2770 n.140 (1997) (noting that certain treatments, including AZT, may postpone the onset of symptoms if administered early in the patient's medical regimen).
75. See Friedland, supra note 59, at 1001 (recommending AZT treatment for HIV-positive patients based on evidence that the medication slows the course of HIV infection and delays the onset of AIDS).
76. "Perinatal therapy" refers to therapy surrounding the birth process. In relation to HIV infection, perinatal therapy includes efforts to prevent "vertical," or mother-to-fetus/mother-to-child, transmission. For further discussion, see Michael A. Grizzi, Compelled Antiviral Treatment of HIV Positive Pregnant Women, 5 UCLA WOMEN'S L.J. 473, 476-80 (1995) (discussing the mechanics of vertical transmission and the effects ot HIV on fetuses and newborn infants).
77. See Edward M. Connor et al., Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment, 331 NEW ENG. J. MED. 1173, 1178 (1994) (reporting an association between an AZT treatment regimen administered to both the mother and newborn infant and a two thirds reduced risk of transmission).
78. Even a small dose of AZT during the last month of pregnancy seems to reduce substantially the likelihood that a child will seroconvert. See Michael Day, Brighter Future, NEW SCI., Feb. 28, 1998, at 13, 13. As a result, a larger window of time is available for medical intervention, and treatments can be relatively inexpensive. This finding has been hailed as a victory for perinatal treatment across the globe, especially in relatively poor countries. Moreover, a recent decision by the pharmaceutical company Glaxo Wellcome to slash AZT prices for mothers in developing countries will provide the benefits of late-pregnancy, limited-dose treatments to a larger population. Cf. Michael Waldholz, AZT Price Cut for Third World Mothers-to-Be, WALL ST. J., Mar. 5, 1998, at B1 (reporting that the price of the drugs, along with the lack of proper medical facilities and staff, were major obstacles to treating poor women with AIDS who live in developing countries).
79. Even a small dose of AZT during the last month of pregnancy seems to reduce substantially the likelihood that a child will seroconvert. See Michael Day, Brighter Future, NEW SCI., Feb. 28, 1998, at 13, 13. As a result, a larger window of time is available for medical intervention, and treatments can be relatively inexpensive. This finding has been hailed as a victory for perinatal treatment across the globe, especially in relatively poor countries. Moreover, a recent decision by the pharmaceutical company Glaxo Wellcome to slash AZT prices for mothers in developing countries will provide the benefits of late- pregnancy, limited-dose treatments to a larger population. Cf. Michael Waldholz, AZT Price Cut for Third World Mothers-to-Be, WALL ST. J., Mar. 5, 1998, at B1 (reporting that the price of the drugs, along with the lack of proper medical facilities and staff, were major obstacles to treating poor women with AIDS who live in developing countries).
80. See Michelle Oberman, Test Wars: Mandatory HIV Testing, Women, and Their Children, 3 U. CHI. L. SCH. ROUNDTABLE 615, 624-25 (1996) (noting that AZT is a potentially toxic drug with significant side effects).
81. See id. (conceding that some research findings suggest that AZT's side effects are relatively minor); see also Maia E. Scott, Note, Test for Pediatric AIDS: Are We Failing Our Children?, 3 VA. J. SOC. POL'Y & L. 217, 221 (1995) (noting "mild, transient neonatal anemia" as the "only significant maternal and infant adverse side effect reported" in one study of perinatal AZT therapy).
82. See Oberman, supra note 64, at 624-25 (noting that even if transmission rates are as high as 25%, the majority of children treated would not have been infected anyway).
83. See, e.g., Theresa M. McGovern, Mandatory HIV Testing and Treatment of Child-Bearing Women: An Unnatural, Illegal, and Unsound Approach, 28 COLUM. HUM. RTS. L. REV. 469, 469 (1997) ("[I]nfants who are born [HIV] positive after receiving the AZT regimen experience more rapid progression of [the] disease.").
84. See Melinda Madison, Commentary, Tragic Life or Tragic Death: Mandatory Testing of Newborns for HIV-Mothers' Rights Versus Children's Health, 18 J. LEGAL MED. 361, 364 (1997) ("If HIV-positive mothers take zidovudine (AZT) during pregnancy, then the chance of transmitting the disease to the baby is dramatically reduced.") (citation omitted).
85. The term "generalized treatment" refers here to treatment intended to retard the general onset or progression of AIDS rather than treatment aimed at alleviating specific AIDS symptoms. By the early to mid 1990s, the available treatments were AZT, DDI, DDC, and d4t. See Lois K. Perrin, Note, The Catch-22 for Persons With AIDS: To Have or Not to Have Easy Access to Experimental Therapies and Early Approval for New Drugs, 69 S. CAL. L. REV. 105, 107 n.8 (1995).
86. See Jennifer L. Rosato, The Ultimate Test of Autonomy: Should Minors Have a Right To Make Decisions Regarding Life Sustaining Treatment?, 49 RUTGERS L. REV. 1, 61 n.265 (1996) (noting that treating AIDS-associated opportunistic infections requires a "complicated trial and error approach to determine the best regimen for a particular patient").
87. See Robert Miller, HIV-Associated Respiratory Diseases, 348 LANCET 307, 308 (1996) (stating that the regimen of first choice to prevent pneumocystic carinii pneumonia is co-trimoxazole, and the second choice for treatment of this infection is nebulized pentamidine).
88. See Effective Treatment for Eye Infections in AIDS Patients, 111 PUB. HEALTH REP. 102, 102 (1996) (noting that the typical treatment regimen is twice daily infusions of these drugs for two weeks, followed by daily infusions for the rest of the patient's life).
89. See supra Part II.A.1 (describing the treatment options in the early years after AIDS was identified, when the only treatment available was AZT).
90. See Laurie Garret, Grim Statistics of AIDS Epidemic: "Staggering" Effect on Life Expectancies, NEWSDAY, Apr. 29, 1994, at A8 ("In the United States, AIDS increased the premature death rate last year [1993] by 1.5 percent. And in 1992, AIDS became the leading cause of death nationally for men aged 25-44 years.").
91. "Combination therapy" is a term commonly used to refer to the administration of a protease inhibitor and two nucleoside analogues.
92. See AIDS: Drug "Cocktails" Inhibit the Disease, Lengthen Life, ST. Louis POST-DISPATCH, Nov. 8, 1997, at 27 (reporting on research conducted in seven Swiss AIDS clinics between 1988 and 1996).
93. See Ramon A. Torres, Impact of Combination Therapy for HIV Infection on Inpatient Census, 336 NEW ENG. J. MED. 1531, 1531-32 (1997) (presenting data from a New York City hospital showing a marked drop in inpatient census that was largely attributable to the initiation of combination therapy on an outpatient basis).
94. See id. (reporting that "the average daily inpatient census [in one N.Y. hospital] of patients with AIDS peaked at 136 patients in 1994," the year before "the first protease inhibitor Saquinavir, received approval from [the FDA]").
95. See id. (stating that after the FDA approved Saquinavir in December 1995, the Agency moved quickly, approving two more protease inhibitors in February and March 1996).
96. See, e.g., Randall Osborne, Smithkline, Glaxo Wellcome in Detailed Merger Talks, BIOWORLD TODAY, Feb. 3, 1998, available in LEXIS, News Library, Allnws File (reporting the collaboration between Glaxo Wellcome and Vertex Pharmaceuticals to develop protease inhibitors); SIGA Achieves 1st Research Goal for Wyeth-Ayerst, MARKETLETTER, Feb. 16, 1998, available in LEXIS, News Library, Allnws File (noting SIGA Pharmaceutical's collaboration with Wyeth Ayerst to develop protease inhibitors); Tripos and Sepracor Announce Collaborative Effort to Investigate HIV Drugs, PR NEWSWIRE, Feb. 24, 1998, available in LEXIS, News Library, Allnws File (reporting collaboration to "enhance the discovery of improved protease inhibitor drugs").
97. See, e.g., Randall Osborne, Smithkline, Glaxo Wellcome in Detailed Merger Talks, BIOWORLD TODAY, Feb. 3, 1998, available in LEXIS, News Library, Allnws File (reporting the collaboration between Glaxo Wellcome and Vertex Pharmaceuticals to develop protease inhibitors); SIGA Achieves 1st Research Goal for Wyeth-Ayerst, MARKETLETTER, Feb. 16, 1998, available in LEXIS, News Library, Allnws File (noting SIGA Pharmaceutical's collaboration with Wyeth Ayerst to develop protease inhibitors); Tripos and Sepracor Announce Collaborative Effort to Investigate HIV Drugs, PR NEWSWIRE, Feb. 24, 1998, available in LEXIS, News Library, Allnws File (reporting collaboration to "enhance the discovery of improved protease inhibitor drugs").
98. See, e.g., Randall Osborne, Smithkline, Glaxo Wellcome in Detailed Merger Talks, BIOWORLD TODAY, Feb. 3, 1998, available in LEXIS, News Library, Allnws File (reporting the collaboration between Glaxo Wellcome and Vertex Pharmaceuticals to develop protease inhibitors); SIGA Achieves 1st Research Goal for Wyeth-Ayerst, MARKETLETTER, Feb. 16, 1998, available in LEXIS, News Library, Allnws File (noting SIGA Pharmaceutical's collaboration with Wyeth Ayerst to develop protease inhibitors); Tripos and Sepracor Announce Collaborative Effort to Investigate HIV Drugs, PR NEWSWIRE, Feb. 24, 1998, available in LEXIS, News Library, Allnws File (reporting collaboration to "enhance the discovery of improved protease inhibitor drugs").
99. See Robert Steinbrook, Battling AIDS on Many Fronts, 337 NEW ENG. J. MED. 779, 779 (1997) (finding that both better medical care and better treatments contributed to the drop in the number of deaths attributable to AIDS).
100. See AIDS Deaths Drop in U.S., MED. INDUSTRY TODAY, Feb. 4, 1998, available in LEXIS, News Library, Allnws File (citing Centers for Disease Control data).
101. See Lawrence Gostin et al., Sounding Board, National HIV Case Reporting for the United States - A Defining Moment in the History of the Epidemic, 337 NEW ENG. J. MED. 1162, 1162 (1997) (arguing that advances in AIDS treatment, including combination therapy, necessitated a comprehensive national HIV reporting system).
102. For example, combination therapy has been associated with prevention or delay of CMV retinitis. See Scott M. Whitcup et al., Therapeutic Effect of Combination Antiretroviral Therapy on Cytomegalovirus Retinitis, 277 JAMA 1519, 1519 (1997). People with AIDS who had survived devastating illness and at times believed that death was imminent have rebounded dramatically and developed new hopes of leading long and healthy lives. This wondrous prospect has brought with it an ironic challenge - how to live when one has been planning to die. Some people with AIDS made financial and personal decisions based on the presumption that death was imminent or that they would remain permanently disabled. As advancements in combination therapy prove these presumptions false, persons with AIDS must shift their perspectives back from the challenges of dying to the challenges of living. See, e.g., Randye Retkin et al., Attorneys and Social Workers Collaborating in HIV Care: Breaking New Ground, 24 FORDHAM URB. L.J. 533, 548 n.46 (1997) (noting that people with AIDS are now facing "back-to-work" issues as a result of improvements associated with combination therapy).
103. For example, combination therapy has been associated with prevention or delay of CMV retinitis. See Scott M. Whitcup et al., Therapeutic Effect of Combination Antiretroviral Therapy on Cytomegalovirus Retinitis, 277 JAMA 1519, 1519 (1997). People with AIDS who had survived devastating illness and at times believed that death was imminent have rebounded dramatically and developed new hopes of leading long and healthy lives. This wondrous prospect has brought with it an ironic challenge - how to live when one has been planning to die. Some people with AIDS made financial and personal decisions based on the presumption that death was imminent or that they would remain permanently disabled. As advancements in combination therapy prove these presumptions false, persons with AIDS must shift their perspectives back from the challenges of dying to the challenges of living. See, e.g., Randye Retkin et al., Attorneys and Social Workers Collaborating in HIV Care: Breaking New Ground, 24 FORDHAM URB. L.J. 533, 548 n.46 (1997) (noting that people with AIDS are now facing "back-to-work" issues as a result of improvements associated with combination therapy).
104. See AIDS Therapies (Hydroxyurea): New Cocktail Sends HIV Patient into Remission, AIDS WKLY. PLUS, Oct. 20, 1997, available in LEXIS, Genmed Library, Rxmega File (discussing the case of one such patient).
105. See Victoria Griffith, Breakthrough Claimed in AIDS Battle, FIN. TIMES, Oct. 15, 1997, at 4 (reporting on the results of treatment with a new protease inhibitor developed through the collaborative efforts of Glaxo Wellcome and Vertex Pharmeceuticals).
106. Pro-viral DNA is "the form that viral genes take after they are transcribed from viral RNA for integration into human DNA." For further discussion of this topic, see Joan Stephenson, The Art of "HAART": Researchers Probe the Potential and Limits of Aggressive HIV Treatments, 277 JAMA 614, 615 (1997).
107. See Richard L. Sowell, It Isn't Over Until It Is Over, 9 J. ASS'N NURSES AIDS CARE 11, 11 (1998).
108. See Dale E. Brashers, Uncertainty in Illness Across the HIV/AIDS Trajectory, 9 J. ASS'N NURSES AIDS CARE 66, 67 (1998) (associating protease inhibitors with new prognoses that reverse both the physiological and the sociological impact of HIV); New AIDS Drug Treatments Mean Many Keep on Working, AIDS WKLY. PLUS, Nov. 10, 1997, available in LEXIS, Genmed Library, Rxmega File (noting the positive effects of new HIV/AIDS drugs on patients' quality of life).
109. See Dale E. Brashers, Uncertainty in Illness Across the HIV/AIDS Trajectory, 9 J. ASS'N NURSES AIDS CARE 66, 67 (1998) (associating protease inhibitors with new prognoses that reverse both the physiological and the sociological impact of HIV); New AIDS Drug Treatments Mean Many Keep on Working, AIDS WKLY. PLUS, Nov. 10, 1997, available in LEXIS, Genmed Library, Rxmega File (noting the positive effects of new HIV/AIDS drugs on patients' quality of life).
110. See David L. Kirp, Commentary, Intelligent Policy, 2 PSYCH. PUB. POL'Y & L. 603, 605 n.3 (1996) (stating that the development of protease inhibitors was a "medical breakthrough" that "makes AIDS a chronic, not necessarily fatal disease"); Wendy E. Parmet & Daniel J. Jackson, No Longer Disabled: The Legal Impact of the New Social Construction of HIV, 23 AM. J.L. & MED. 7, 28 (1997) (explaining the transformation of AIDS in common discourse from "plague" to "chronic disease").
111. See David L. Kirp, Commentary, Intelligent Policy, 2 PSYCH. PUB. POL'Y & L. 603, 605 n.3 (1996) (stating that the development of protease inhibitors was a "medical breakthrough" that "makes AIDS a chronic, not necessarily fatal disease"); Wendy E. Parmet & Daniel J. Jackson, No Longer Disabled: The Legal Impact of the New Social Construction of HIV, 23 AM. J.L. & MED. 7, 28 (1997) (explaining the transformation of AIDS in common discourse from "plague" to "chronic disease").
112. See David A. Kessler, Remarks by the Commissioner of Food and Drugs, 52 FOOD & DRUG L.J. 1, 5 (1997) ("While . . . protease inhibitors . . . do not represent the ultimate goals that must be reached in the battle against AIDS, they do provide an entry into the next level of therapy.").
113. The "three-drug" cocktails appears ineffective in approximately half of all cases. See The Peril of AIDS Is Still with Us. TAMPA TRIB., Nov. 4, 1997, at 6.
114. See AIDS Therapy I: Triple-Cocktail Treatment Fails, HEALTH LINE, Sept. 30, 1997, available in WESTLAW, Allnews Library (citing Dr. Steven Deeks' statement that most failures occur "in patients who had tried many of the earlier AIDS medications in the past, whose immune T cells were badly depleted or who were most severely infected with HIV").
115. See Thomas H. Maugh, II, New AIDS Hope Also Brings New Challenges, L.A. TIMES, Feb. 8, 1998, at A1 ("[P]rotease inhibitors . . . produce a number of side effects, including nausea, diarrhea, headaches and other complaints. As many as 20% of HIV-positive patients fail therapy because they cannot tolerate those effects.").
116. The protease inhibitor portion of the cocktail alone can cost a patient $20,000 per year. See Gary J. Remal, Mainers Could Be First To Get "AIDS Cocktail," CENT. ME. MORN. SENTINEL, Nov. 5, 1997, at 1.
117. See David L. Wheeler, New Momentum for Research on an AIDS Vaccine, CHRON. HIGHER EDUC., Feb. 20, 1998, at A18 (noting that ninety percent of AIDS deaths occur in developing nations, where few can afford combination therapy treatment).
118. Failure to do so may harm not only the patient but also the public because "underdosing, noncompliance or partial compliance with dosing requirements may cause resistant strains of HIV to develop." Rosato, supra note 70, at 62 n.265. Although the logistical challenges of combination therapy have spawned concerns regarding effective treatment of the homeless and drug addicted, some evidence suggests that these groups can maintain complicated regimens if they receive sufficient support. See Study Shows Drug Regimen Doable, HEALTH LINE, Oct. 9, 1997, available in WESTLAW, Allnews Library ("[A] Boston group has shown that 'even the highest-risk AIDS patients . . . can swallow anywhere from 20 to 50 pills a day on a strict schedule . . . if given enough support.'").
119. See Steinbrook, supra note 81, at 779 (discussing the need for a coordinated approach to treating persons infected with HIV).
120. See Tim O'Brien, AIDS Effort Must Not Wane, Researcher Says, TIMES UNION (Albany, N.Y.), Apr. 1, 1998, at B4.
121. John Carey, A Way To Lock Out AIDS?, BUS. WK., Jan. 26, 1998, at 62.
122. Anne-christine d'Adesky, The Secret Life of HIV, OUT, Feb. 1998, at 80, 82 (quoting Johns Hopkins University immunologist Robert Siliciano).
123. See Charles Bankhead, Early Drop in Viral Load Improves Long-Term HIV Survival, DERMATOLOGY TIMES, Aug. 1, 1997, at 36, 36 (citing Dr. Marcus Conant who claims that, because HIV integrates into a person's DNA, drug treatments must be life long); Harriet A. Washington, AIDS and the High Cost of Living, EMERGE, Aug. 31, 1997, at 28, 28 (comparing protease inhibitor cocktails for persons with HIV to insulin treatment for diabetics).
124. See Charles Bankhead, Early Drop in Viral Load Improves Long-Term HIV Survival, DERMATOLOGY TIMES, Aug. 1, 1997, at 36, 36 (citing Dr. Marcus Conant who claims that, because HIV integrates into a person's DNA, drug treatments must be life long); Harriet A. Washington, AIDS and the High Cost of Living, EMERGE, Aug. 31, 1997, at 28, 28 (comparing protease inhibitor cocktails for persons with HIV to insulin treatment for diabetics).
125. See Christine Ngeo, Many AIDS Patients on "Cocktails" Regress, MOD. HEALTHCARE, Nov. 10, 1997, at 62, 62 ("[T]he AIDS virus is making a comeback in 53% of 136 HIV-infected patients [in two San Francisco hospitals] who began treatment [in March of 1996] with a combination of drugs including either Crixivan or Norvil . . . ."); see also Ross Frances, AIDS Patients Fear Pharmacy Belt Tightening, DOMINION (Wellington, Va.), Nov. 1, 1997, at 9, 9 (discussing patients' concerns that a lack of government funding could affect the range of available drugs).
126. See Christine Ngeo, Many AIDS Patients on "Cocktails" Regress, MOD. HEALTHCARE, Nov. 10, 1997, at 62, 62 ("[T]he AIDS virus is making a comeback in 53% of 136 HIV-infected patients [in two San Francisco hospitals]
127. See Slovut, supra note 48 (quoting AIDS researcher Dr. Frank Rhame) ("The problem with protease inhibitors is that the enzyme that inhibits protease appears to mutate fairly easily . . . . They might only work for two or three or four years.").
128. See id.; see also New Standard Sheds Little Light on Best Regimens, AIDS ALERT, June 1997, at 61, 61 (noting the dearth of data regarding long-term effectiveness of protease inhibitors).
129. See Immunology Molecule Blocks T-Cell Surface Receptor Needed for HIV-1 Infection, AIDS WKLY. PLUS, Nov. 3, 1997, available in LEXIS, Genmed Library, Rxmega File (reporting that in May and June 1996, scientists discovered several new receptors on the surface of immune system cells). These receptors, along with the CD4 receptor, are required for HIV-1 to enter and infect cells.
130. Id. (quoting the study's co-author, Robert W. Doms).
131. See Boost in Cell Genesys Stock Follows Report on AIDS-Fighting Therapy, BIOTECH, NEWSWATCH, Oct. 20, 1997, at 4, 4 (reporting on "bioengineered cells [that] target and kill the infected cells with the same efficiency as naturally occurring HIV-specific T-cells, from which they are made").
132. See Prophylaxis (HIV) Risk Study of "Morning-After" Drugs Begins, AIDS WKLY. PLUS, Oct. 27, 1997, available in LEXIS, Genmed Library, Rxmega File (announcing the first national study to offer people in San Francisco "morning after" AIDS cocktails).
133. See Philip J. Hilts, How the AIDS Crisis Made Regulators Speed Up, N.Y. TIMES, Sept. 24, 1989, at D5 (noting that the FDA, in an effort to expedite its drug approval procedures, now accepts data on computer disks rather than requiring hard copies and negotiates with drug companies in person rather than by mail).
134. Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, § 101, 111 Stat. 2296.
135. See supra note 30 and accompanying text.
136. See 21 C.F.R. § 312.20 (1987).
137. See id. § 312.21.
138. See id. § 312.21(a).
139. See id. § 312.21(b).
140. See id. § 312.21(c).
141. See 21 U.S.C. § 355(b)(1)(A) (1982 & Supp. IV 1986) (requiring full investigational reports as part of the pharmaceutical company's drug marketing application).
142. See 21 C.F.R. § 312.85 (1988) (describing the fourth phase of human testing, which may occur after the drug has entered the marketplace).
143. See Salbu, supra note 44, at 691 (noting the dates of the first observation and diagnosis of AIDS in the early 1980s).
144. For discussion of these groups and their efforts, see Nancy D. Polikoff, Am I My Client?: The Role Confusion of a Lawyer Activist, 31 HARV. C.R.-C.L. L. REV. 443, 445 n.5 (1996).
145. See Hilts, supra note 110 (arguing that grassroots efforts provided the necessary spur for FDA action).
146. See infra Part II.B.3 (discussing the reforms of the Modernization Act).
147. See 21 C.F.R. § 312.34(b)(1)(i)-(iv) (1988) (promulgating new regulations that allow greater access to promising drugs not yet available on the market).
148. Id.
149. See id. (describing the requirements a pharmaceutical company must fulfill to gain approval for marketing a new drug as a treatment IND).
150. See id. § 312.34(a) (noting that, in ordinary cases, a doctor may prescribe an IND during Phase 3 investigations but that, under "appropriate circumstances," the drug may be made available as early as Phase 2).
151. See id. § 312.36 (1988) (describing an appropriate "ad hoc" application as one that occurs in an "emergency situation that does not allow time for [formal] submission of an IND"). For further discussion of these expedited procedures, see Ellen C. Cooper, Changes in Normal Drug Approval Process in Response to the AIDS Crisis, 45 FOOD DRUG COSM. L.J. 329, 334-35 (1990) (providing examples of emergency situations in which physicians contacted the FDA requesting approval to treat their patients with emergency INDs).
152. See 21 C.F.R. §§ 312.80-312.82 (1988) (establishing new approval procedures to expedite the development and marketing of new drug therapies).
153. See id. § 312.80 (stating that the focus for these new therapies should be treating "persons with life-threatening and severely debilitating illnesses, especially where no satisfactory alternative therapy exists").
154. See id. § 312.82 (establishing a new procedure through which FDA reviewing officials and drug sponsors work together to create a testing protocol that will "be adequate to provide sufficient data on the drug's safety and effectiveness to support [approval] for marketing" by the end of Phase 2); see also Investigational New Drug Application, 53 Fed. Reg. 41,523, 41,523 (1988) (providing procedures "designed to expedite the development, evaluation, and marketing of new therapies").
155. See FDA Announces Interim Regulations To Speed Marketing of Promising Drugs, AIDS POL'Y & L., Nov. 2, 1988, at 1 (reporting the FDA's claim that new regulations will cut human research time by eight years in some cases). The creation of a fast track followed the FDA's decision in the mid 1980s to approve AZT without Phase 3 testing. See Julie Relihan, Note, Expediting FDA Approval of AIDS Drugs: An International Approach. B.U. INT'L L.J. 229, 240 n.87 (1995) (discussing the FDA's decision that Phase 3 testing of AZT was unduly repetitive and thus a waste of time and effort).
156. See FDA Announces Interim Regulations To Speed Marketing of Promising Drugs, AIDS POL'Y & L., Nov. 2, 1988, at 1 (reporting the FDA's claim that new regulations will cut human research time by eight years in some cases). The creation of a fast track followed the FDA's decision in the mid 1980s to approve AZT without Phase 3 testing. See Julie Relihan, Note, Expediting FDA Approval of AIDS Drugs: An International Approach. B.U. INT'L L.J. 229, 240 n.87 (1995) (discussing the FDA's decision that Phase 3 testing of AZT was unduly repetitive and thus a waste of time and effort).
157. See Patricia Kuszler, Balancing the Barriers: Exploiting and Creating Incentives To Promote Development of New Tuberculosis Treatments, 71 WASH. L. REV. 919, 960 (1996) ("This expedited process . . . could shave 3.3 years off the total regulatory phase required to bring a new drug to market.").
158. See id. at 960 n.248 (noting that the FDA approved a prostate cancer drug "in a record 3.7 months").
159. See MacPherson, supra note 21 (asserting that "rapid and efficient review and approval" accelerated the marketing of new drugs).
160. See Alicia Ault Barnett, Protease Inhibitors Fly Through FDA, 347 LANCET 678, 678 (1996) (noting FDA approval of ritonavir 72 days after the drug's sponsor applied for a license).
161. See id. (reporting that, in patients using the protease inhibitor Norvir, mortality rates dropped 40% after six months even though many patients dropped out of the study due to adverse side effects).
162. For further discussion of the idea that AIDS has been transformed from a fatal to a more manageable, non-fatal disease, see Tony Hartzel et al., AIDS Death Rate for New Patients Declines by 30%, DALLAS MORN. NEWS, Jan. 27, 1997, at 13A.
163. See supra note 52 and accompanying text (noting that treatment with AZT alone delayed AIDS deaths by an average of only seven months); see also Perrin, supra note 69, at 16 (asserting that "AIDS is almost inevitably fatal" if untreated).
164. See Richard Coorsh, FDA vs. UK Approval Time, CONSUMERS' RES. MAG., Jan. 1996, at 6, 6 (criticizing the Government Accounting Office report for falsely implying that the FDA approval process is faster than the approval procedures in the United Kingdom when "total development time" in the United States is actually two years longer than it is in the United Kingdom).
165. See Leonard Novarro, Drugs & Money, HOSP. & HEALTH NETWORKS, Aug. 5, 1997, at 54, 54.
166. Expanded Availability of Investigational New Drugs Through Parallel Track Mechanism for People With AIDS and Other HIV-Related Disease, 57 Fed. Reg. 13,250 13,250 (1992).
167. See Larry Van Dyne, Last Best Hope, WASHINGTONIAN, Sept. 1997, at 78 ("Some studies, especially those involving diseases such as cancer and AIDS, are flooded with so many volunteers that enrollment is shut off or waiting lists are established.").
168. See Expanded Availability of Investigational New Drugs Through Parallel Track Mechanism for People With AIDS and Other HIV-Related Disease, 57 Fed. Reg. at 13,256 (allowing physicians to administer "promising new drugs" without maintaining concurrent control groups, provided that a parallel controlled clinical investigation of the drug is ongoing).
169. See Expanded Availability of Investigational New Drugs Through Parallel Track Mechanism for People With AIDS and Other HIV-Related Disease, 57 Fed. Reg. at 13,258 (mandating that "[a]ll participating physicians will be required to report safety data," but recognizing that "the nature and extent of efficacy data collection may vary in different clinical settings").
170. It is important to recognize the value of all available information, and not just information that is gleaned through carefully controlled studies. Although the data collected do not result from carefully conceived experimental designs, trends evinced by the data may alert principal investigators to new directions for controlled studies and new ways of thinking about the problem they are studying.
171. See New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval, 57 Fed. Reg. 58,942, 58,942 (1992).
172. Expanded Availability of Investigational New Drugs Through Parallel Track Mechanism for People With AIDS and Other HIV-Related Disease, 57 Fed. Reg. at 13,235. For example, a surrogate marker for those who test positive for HIV could be the amount of viral agent present in their blood. See Salbu, supra note 4, at 415.
173. 21 C.F.R. § 314.510 (1993).
174. It is significant that surrogate marker evidence can be used only for drugs that treat life-threatening diseases. Because the stakes are very high for patients who are receiving these drugs, the risk of harm from experimental treatments can more easily be justified. Accordingly, the balance tips in favor of expedited access rather than sustained or increased caution. For further discussion of this issue, see Larry R. Versteegh, Science and Regulatory Rituals Associated with the Drug Development Process, 52 FOOD & DRUG L.J. 155, 157 (1997).
175. Prescription Drug User Fee Act, Pub. L. No. 102-571, § 101, 106 Stat. 4491 (1992).
176. The funds collected under the User Fee Act were earmarked "to hire more reviewers to assess applications." John Henkel, User Fees To Fund Faster Reviews, FDA CONSUMER, Oct. 1993, at 19, 19. Between 1992 and 1997, the FDA collected over $325 million in user fees. It envisioned adding 700 new reviewers and support staff to its ranks in the hope of shortening review times to twelve months for standard applications and six months for priority applications. See id. at 19-20.
177. See User Fee Act § 736, 106 Stat. at 4494.
178. See id. at 4495.
179. See id. at 4494-95.
180. See id. at 4496.
181. See id.
182. See Julie Rovner, Once Controversial U.S. FDA-Overhaul Bill Advances, 350 LANCET 1153, 1153 (1997).
183. See Jocelyn Kaiser, FDA Reform Starts Down the Track, 271 SCI. 1228, 1228 (1996) (reporting the success of the user fee program, which allowed the Agency to meet its goal of processing most new drug applications within twelve months).
184. Part II.B.3 will address public perceptions of the Act in greater detail; see also infra note 183 and accompanying text.
185. Modernization Act, Pub. L. No. 105-115, § 101, 111 Stat. 2296, 2296-2305.
186. See. e.g., Alicia Ault Barnett, PhRMA Refutes FDA Study on Drug Approval, 347 LANCET 254, 254 (1996) (noting the observation of the President of Pharmaceutical Research and Manufacturers of America that the United States leads the world in approval of AIDS drugs but lags behind the rest of the world in regard to other classes of drugs).
187. See Julie Rovner, FDA Speeds Up Some Approval Procedures, 347 LANCET 1038, 1038 (1996) (discussing the FDA's proposal for accelerating the approval of new cancer drugs and allowing some cancer patients to receive experimental drugs approved for use in other countries).
188. Id.
189. The FDA's extension of AIDS-era reforms to cancer patients is a matter of practice rather than of law. Many of the FDA's AIDS-era liberalizations logically apply to a number of terminal cancer situations. Extension of AIDS-era policies to cancer patients evinces the FDA's willingness to implement procedures that are already in place. See Rovner, supra note 163.
190. Modernization Act § 101, 111 Stat. at 2296.
191. See infra Part II.B.3.b.
192. Modernization Act § 101, 111 Stat. at 2296. Congress passed the Act only "[a]fter much debate and contention." Janet Gemignani, Finally, FDA Reform, Bus. & HEALTH, Dec. 1997, at 9, 9.
193. See Editorial, No Lumps of Coal for Those on Healthcare's Holiday A-List, MOD. HEALTHCARE, Dec. 8, 1997, at 36, 36 ("While the new law isn't a panacea, it does roll back some of the more onerous regulations and streamlines others.").
194. See President Clinton Signs; FDA-Overhaul Bill Signed into Law, MED. INDUSTRY TODAY, Nov. 24, 1997, available in LEXIS, Genmed Library, Rxmega File (describing the Modernization Act as an "overhaul [of] the FDA and its regulatory system").
195. See Modernization Act §§ 301-309, 111 Stat. at 2350-56.
196. See id. §§ 201-17, 111 Stat. at 2332-50.
197. See id. §§ 401-22, 111 Stat. at 2356-80.
198. See id. §§ 101-31, 111 Stat. at 2298-2332.
199. See Kaiser, supra note 159 (noting praise of the reforms by Pharmaceutical Research and Manufacturers of America).
200. See Mike Pezzella, BIO Expects Industry Boost from FDA Overhaul, BIOTECH. NEWSWATCH, Dec. 1, 1997, at 1, 1 (describing the Biotechnology Industry Organization's positive reaction to the Modernization Act).
201. See, e.g., Scott Hensley, Change Coming to FDA: Law Should Speed Approvals, but Critics Say It's Not Enough, MOD. HEALTHCARE, Nov. 17, 1997, at 28, 28 (noting one attorney's belief that the Act is "tinkering" rather than achieving real reform, and that the changes are modest and subject to "bureaucratic backsliding").
202. See Modernization Act § 402, 111 Stat. at 2365-67.
203. See id. § 112(a), 111 Stat. at 2309. Fast track products must be "intended for the treatment of a serious or life-threatening condition" and must demonstrate "the potential to address unmet medical needs for such a condition." Id.
204. See id. §§ 101-07, 111 Stat. at 2298-2305.
205. See 21 U.S.C. § 379h (1992).
206. FDA, The FDA Modernization Act of 1997 (visited Dec. 2, 1998) 〈http://www.fda. gov/opacom/backgrounder/modact.htm〉.
207. See Glenn Hess, The Battle for FDA Reform, CHEM. MKT. REP., Sept. 15, 1997, at FR14 (noting that tying extension of the User Fee Act to the passage of the Modernization Act's other reform proposals contributed to the Act's general appeal).
208. Modernization Act § 119, 111 Stat. at 2317-18.
209. 21 C.F.R. § 312.82 (1988).
210. See Warren R. Ross, Interactive NDAs Speed the Approval Process, MED. MARKETING & MEDIA, May 1997, at 42, 42 (suggesting that improving communication between FDA representatives and drug sponsors improves efficiency in the drug review process).
211. Modernization Act § 119, 111 Stat. at 2318.
212. Sally Lehrman, Industry Hopes Buoyed by Drugs in Line at Faster, Gentler FDA, BIOTECH. NEWSWATCH, Feb. 2, 1998, at 1.
213. Modernization Act §§ 119, 551, 111 Stat. at 2316-18, 2356-58.
214. Fen-phen Fact Sheet (visited Dec. 2, 1998) 〈http://www.citizen.org/public_citzen/ congress/fda/S.%20830-FDA/fenfaq.htm〉 [hereinafter Fact Sheet].
215. Fen-phen Fact Sheet (visited Dec. 2, 1998) 〈http://www.citizen.org/public_citzen/ congress/fda/S.%20830-FDA/fenfaq.htm〉 [hereinafter Fact Sheet].
216. See Drug Bill Would "Castrate" FDA, Consumer Group Says, MED. INDUSTRY TODAY, Aug. 11, 1997, available in LEXIS, Genmed Library, Rxmega File (defining offlabel use and reporting a consumer group's opposition to the FDA's relinquishment of control through a policy that permits off-label drug marketing).
217. See, e.g., Richard A. Samp, FDA Censorship Threatens Patient Medical Care, CONSUMERS' RES. MAG., Dec. 1994, at 16, 16 (lamenting that "[d]octors can write freely . . . on aspirin's effectiveness in preventing heart attacks, but an aspirin manufacturer cannot so much as reproduce a copy [of the doctor's article]").
218. See Richard A. Samp, FDA Faces Court-Ordered Limits to Its Powers, MED. MARKETING & MEDIA, Sept. 1997, at 50, 50 (calling for FDA officials to recognize free speech problems with policies designed to quash the dissemination of truthful information).
219. Samp, supra note 192, at 16.
220. See id. (citing the field of oncology as one in which most of the effective treatments comprise off-label uses of drugs).
221. For example, the conclusion that taking small does of aspirin daily results in a decreased risk for a first heart attack is both well known and supported by "overwhelming evidence," but this use of aspirin is considered an off-label use. Marvin M. Lipman, Office Visit: Using Approved Drugs for Unapproved Purposes, CONSUMER REP. ON HEALTH, Feb. 1998, at 10, 10 (maintaining that doctors often find suitable off-label uses well in advance of FDA approval).
222. See Lori Tripoli, The FDA Modernization Act: Whom Does It Help?, PROD. LIAB. L. & STRATEGY, Dec. 1997, at 4, 4.
223. Id.
224. Modernization Act, Pub. L. No. 105-115, § 551 (a), 111 Stat. 2296, 2357.
225. See id. § 551(a)(1)-(5), 111 Stat. at 2356-57 (enumerating approved recipients of off-label drug use information).
226. See id. § 554, 111 Stat. at 2359-61.
227. See id. § 551(b)(4)(B), 111 Stat. at 2357.
228. To qualify, a reference publication must include: information about a clinical investigation with respect to the drug . . . that would be considered to be scientifically sound by experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug . . . . Id. § 552(a)(1)(B), 111 Stat. at 2358.
229. The language of the statute authorizes dissemination of unabridged reprints or copies of "an article, peer-reviewed by experts qualified by scientific training or experience to evaluate the safety or effectiveness of the drug . . . which was published in a scientific or medical journal . . . ." Id. § 552(a)(1)(A), 111 Stat. at 2358. The article must be "about a clinical investigation with respect to the drug . . . which would be considered to be scientifically sound by . . . experts." Id.
230. See, e.g., Dr. Arnold S. Relman, On S. 830, The Senate FDA Bill (visited Dec. 2, 1998) 〈http://www.citizen.org/public_citizen/congress/fda/S.%20830-FDA/relman. htm〉.
231. Id.
232. See Tripoli, supra note 197.
233. See infra Part III.E.3 (examining the history of off-label use of two approved prescription diet drugs). These drugs were voluntarily removed from the market by their manufacturer following the escalation of off-label use and subsequent public health concerns. See id.
234. I draw this distinction between regimens "consisting of" FDA approved drugs and those "combining" FDA approved drugs to emphasize an important point: although fenfluramine and phentermine were both FDA-approved drugs during this period, treatment with the two medications in combination was an off-label use.
235. See Martha L. Elks, Appetite Suppressants as Adjuncts in the Treatment of Obesity, 42 J. FAMILY PRAC. 287, 288 (1996) (documenting the effectiveness of a number of appetite suppressant drugs, including fenfluramine, phentermine, and fenfluramine derivatives).
236. See Shute, supra note 8, at 74 (presenting the story of an overweight twenty-eight year old woman who may have suffered heart valve damage as a result of using fen-phen).
237. See Brigid Schulte, FDA Pulls Diet Drugs, ANCHORAGE DAILY NEWS, Sept. 16, 1997, at 1A (describing clinical studies and reports suggesting an association between the drugs and heart valve problems that led to the recall of fenfluramine and Redux in September 1997).
238. See id. (noting that phentermine, the "phen" in fen-phen, was not recalled). To date, only fenfluramine and dexfenfluramine (Redux) have been linked to the severe health problems that prompted the recall. See id.
239. See Douglas E. Beeman, Weight-Loss Physicians Defend the Safety of Fen-Phen, PRESS-ENTERPRISE (Riverside, Cal.), July 10, 1997, at B2 (noting that fenfluramine and phentermine, available by prescription for decades, soared in popularity in the 1990s when combined as fen-phen). Doctors began prescribing the fen-phen combination after noticing that small doses of the two drugs together reduced the side effects that often accompanied larger doses of either drug alone. See id.
240. See Proposed Rules, Schedule of Controlled Substances: Proposed Removal of Fenfluramine from the Controlled Substances Act, 62 Fed. Reg. 24,620, 24,620-22 (1997); see also Robert Kushner, The Treatment of Obesity: A Call for Prudence and Professionalism, 157 ARCHIVES INTERNAL MED. 602, 603 (1997). During the past four years, the number of new prescriptions for fentluramine increased by 6930%, and new prescriptions for phentermine increased by 442%. See id.
241. See Proposed Rules, Schedule of Controlled Substances: Proposed Removal of Fenfluramine from the Controlled Substances Act, 62 Fed. Reg. 24,620, 24,620-22 (1997); see also Robert Kushner, The Treatment of Obesity: A Call for Prudence and Professionalism, 157 ARCHIVES INTERNAL MED. 602, 603 (1997). During the past four years, the number of new prescriptions for fentluramine increased by 6930%, and new prescriptions for phentermine increased by 442%. See id.
242. Robert Lew et al., Combined Phentermine/Fenfluramine Administration Enhances Depletion of Serotonin from Central Terminal Fields, 26 SYNAPSE 36, 36 (1997).
243. See The Skinny on Redux, CONSUMER REP. ON HEALTH, Aug. 1996, at 94, 94.
244. See Mira Lessick & Joyce Keithley, Obesity: Genetic Update and Clinical Implications, 6 MEDSURG NURSING 121, 126 (1997) (discussing the variety of treatments available for helping patients overcome their obesity).
245. See Weight of Evidence Tips the Scales, 350 LANCET 867, 867 (1997) (providing a timeline of the events leading to the recall of Redux) [hereinafter Weight of Evidence].
246. See Weight of Evidence Tips the Scales, 350 LANCET 867, 867 (1997) (providing a timeline of the events leading to the recall of Redux) [hereinafter Weight of Evidence].
247. See Kathleen Kerr, FDA Sued Over Diet Drug Study: Watchdog Group Investigates Fen-Phen Safety, NEWSDAY (New York, N.Y.), Jan. 15, 1998, at A22 (referring to animal studies showing a possible association between Redux and neurological damage, suggesting a similar possibility of danger with use of the drug in humans).
248. See id. (reporting that FDA officials "decided to discard" the first advisory panel's recommendation and to adopt the second advisory panel's recommendation to approve Redux).
249. See Weight of Evidence, supra note 219, at 867. For further discussion of these risks, see infra Parts III.C-D.
250. See Weight of Evidence, supra note 219, at 867 (providing a brief history of Redux).
251. See JoAnn E. Manson & Gerald A. Faich, Pharmacotherapy for Obesity - Do the Benefits Outweigh the Risks?, 335 NEW ENG. J. MED. 659, 659 (1996) (comparing the health risks of obesity to the risks associated with PPH, a serious lung disease that may be caused by prescription appetite suppressants). The authors conclude that for every 14 PPH deaths caused by these drugs, 280 lives could be saved by preventing obesity-related deaths. See id.
252. See National Task Force on the Prevention and Treatment of Obesity, Long-Term Pharmacotherapy in the Management of Obesity, 276 JAMA 1907, 1913 (1996) (noting the absence of clinical data regarding long-term use of appetite suppressant drugs and observing that most obese patients regain lost weight upon discontinuing medication).
253. Thomas N. Tiedt, Letter to the Editor, Pharmacotherapy in the Management of Obesity, 277 JAMA 1201, 1201 (1997).
254. See Carol Potera, Fen-Phen Fallout: Back to Basics?, PHYSICIAN & SPORTS MED., Jan. 1998, at 27, 27 (urging physicians and consumers to consider the fen-phen debacle a reminder that healthy, long-term weight loss requires lifestyle changes).
255. See Michael McCarthy, Diet Pills Are Right for Few Patients, 348 LANCET 1724, 1724 (1996) (quoting clinical test conclusions from a national task force report).
256. See id.
257. See id. (reporting the observations of James Hill of the University of Colorado Health Sciences Center in Denver).
258. Ironically, the Physician's Desk Reference instructs that "Pondimin [a brand name for fenfluramine] is indicated in the management of exogenous obesity as a short-term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction." PHYSICIAN'S DESK REFERENCE § 5, at 2239 (1997). This suggests that before the recall of fenfluramine, there was a conflict between medical recommendations and long-term use of the medication. A drug recommended only for short-term use, but which must be used indefinitely to treat a long-term problem, seems in hindsight to have been doomed from the beginning. In any case, these events certainly lend credence to concerns regarding the potential harm associated with off-label uses of drugs. For further discussion of off-label uses and problems that may be associated with them, see infra Part III.E.3.
259. See Beware the Tangled Web They Weave, 278 JAMA 1, 1 (1997) (criticizing physicians for "marketing" fen-phen to consumers without any inquiry into the consumer-patient's medical history or body weight).
260. See Denise Mann, Interim Guidelines Are Issued for "Fen/Phen" Users (visited Dec. 2, 1998) 〈http://www.medtrib.com/issues/1997dec18/ob2.htm〉 (urging an estimated 50 million American consumers who used fen-phen and Redux to have echocardiograms before undergoing any surgical procedures).
261. Richard A. Knox, 2 Diet Drugs Pulled as Fears Grow, BOSTON GLOBE, Sept. 16, 1997, at A1.
262. See Mike McKee, Losing It All Over Diet Pills, RECORDER (San Francisco), Jan. 16, 1998, at 1 (quoting one lawyer's charge that some doctors prescribing fen-phen "were selling the American infatuation with the flat stomach"); The Skinny on Weight Loss, CONSUMER REP. ON HEALTH, Feb. 1998, at 1, 1 ("Many Americans, brainwashed by all the emaciated models they see, have a distorted image of a healthy physique.").
263. See Mike McKee, Losing It All Over Diet Pills, RECORDER (San Francisco), Jan. 16, 1998, at 1 (quoting one lawyer's charge that some doctors prescribing fen-phen "were selling the American infatuation with the flat stomach"); The Skinny on Weight Loss, CONSUMER REP. ON HEALTH, Feb. 1998, at 1, 1 ("Many Americans, brainwashed by all the emaciated models they see, have a distorted image of a healthy physique.").
264. According to one source, thirty billion dollars per year go toward the weight loss efforts of approximately fifty-eight million Americans. See Jeffrey Kluger, Diet in a Pill, TIME, May 26, 1997, at 70, 70.
265. See Marilyn Chase, A New Diet Drug Hits the Marketplace, with Potential Risks, WALL ST. J., Mar. 2, 1998, at B2 (comparing Meridia's risks and benefits to those of fen-phen).
266. Id.
267. Id. (quoting Timothy Seaton, medical director for endocrine and metabolic research at Knoll Pharmaceutical Company).
268. See id. (recognizing that the FDA and the drug's manufacturer may still face difficulty in trying to confine the prescription of the medication to its proper use).
269. See Lucien Abenhaim et al., Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension, 335 NEW ENG. J. MED. 609, 613-15 (1996) (observing, in a case-control study, an association between fenfluramine derivatives and increased risk of primary pulmonary hypertension). Although FDA regulators knew of this risk when they approved the drug, they determined that weight management benefits outweighed the relatively low incidence of PPH resulting from the diet drug. The incidence of PPH attributable to the drug was estimated to be between 23 and 46 cases per million users. See Robert Langreth, Diet-Fad Patient's Plight: Dashed Hopes, Ill Health, WALL ST. J., Jan. 14, 1998, at B1.
270. See Lucien Abenhaim et al., Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension, 335 NEW ENG. J. MED. 609, 613-15 (1996) (observing, in a case-control study, an association between fenfluramine derivatives and increased risk of primary pulmonary hypertension). Although FDA regulators knew of this risk when they approved the drug, they determined that weight management benefits outweighed the relatively low incidence of PPH resulting from the diet drug. The incidence of PPH attributable to the drug was estimated to be between 23 and 46 cases per million users. See Robert Langreth, Diet-Fad Patient's Plight: Dashed Hopes, Ill Health, WALL ST. J., Jan. 14, 1998, at B1.
271. Until early 1998, PPH was considered fatal. In January of 1998, findings were publicized suggesting that a Glaxo Wellcome drug, prostacyclin, can significantly extend the lives of PPH patients. See Robert Langreth, Glaxo Wellcome Drug Proves Helpful in Treating Ailment Linked to Diet Pill, WALL ST. J., Jan. 29, 1998, at B8; see also Heart Disease Fears Send Diet Pill Makers to Study, Again, MED. INDUSTRY TODAY, Aug. 27, 1997, available in LEXIS, Genmed Library, Rxmega File (reporting that marketers of fenfluramine and dexfenfluramine admitted having knowledge of a possible association between an increased risk of PPH and the use of their diet drugs and stating that the pharmaceutical companies planned to investigate this link further).
272. Until early 1998, PPH was considered fatal. In January of 1998, findings were publicized suggesting that a Glaxo Wellcome drug, prostacyclin, can significantly extend the lives of PPH patients. See Robert Langreth, Glaxo Wellcome Drug Proves Helpful in Treating Ailment Linked to Diet Pill, WALL ST. J., Jan. 29, 1998, at B8; see also Heart Disease Fears Send Diet Pill Makers to Study, Again, MED. INDUSTRY TODAY, Aug. 27, 1997, available in LEXIS, Genmed Library, Rxmega File (reporting that marketers of fenfluramine and dexfenfluramine admitted having knowledge of a possible association between an increased risk of PPH and the use of their diet drugs and stating that the pharmaceutical companies planned to investigate this link further).
273. See Weight of Evidence, supra note 219, at 867 (stating that an August 1996 report in the New England Journal of Medicine suggested an increased risk of PPH in patients using prescription weight loss drugs).
274. Other risks that were not confirmed or even studied in humans nonetheless were suspected. For example, studies on animals revealed a relationship between fenfluramine and brain serotonin neurotoxicity. Although no clinical studies were conducted to investigate this potential problem in humans prior to the recall of fen-phen, some physicians believe that such studies were necessary. See, e.g., Una D. McCann et al., Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension from Fenfluramine and Dexfenfluramine, 278 JAMA 666, 671 (1997).
275. Although a relatively small percentage of patients receiving fenfluramine or dexfenfluramine will develop PPH, the drugs do substantially increase the likelihood of developing the disease. See Michael D. Lemonick, The New Miracle Drug?, TIME, Sept. 23, 1996, at 60, 62 (citing a European study in which researchers observed that the risk of developing PPH after using fen-phen for three months increased from one or two in one million to eighteen in one million); Diet Drugs Strike Out in Weight-Loss Game, ENVTL. NUTRITION, Oct. 1997, at 3, 3 (describing a twenty-three fold increased risk of PPH from taking fen-phen or Redux for three months).
276. Although a relatively small percentage of patients receiving fenfluramine or dexfenfluramine will develop PPH, the drugs do substantially increase the likelihood of developing the disease. See Michael D. Lemonick, The New Miracle Drug?, TIME, Sept. 23, 1996, at 60, 62 (citing a European study in which researchers observed that the risk of developing PPH after using fen-phen for three months increased from one or two in one million to eighteen in one million); Diet Drugs Strike Out in Weight-Loss Game, ENVTL. NUTRITION, Oct. 1997, at 3, 3 (describing a twenty-three fold increased risk of PPH from taking fen-phen or Redux for three months).
277. See Tiedt, supra note 226, at 659 (recommending that the risk of developing PPH be viewed in the context of the benefits that appetite suppressants provide, including the prevention of premature death from obesity-related illnesses).
278. Janet Fricker, Balancing the Risks of Anti-Obesity Pills, 349 LANCET 1374, 1374 (1997) (quoting Tim Higenbottam, a British professor of respiratory medicine).
279. See Laura Johannes & Steve Stecklow, Dire Warnings About Obesity Rely on Slippery Statistic, WALL ST. J., Feb. 9. 1998, at B1 (citing the FDA and former Surgeon General C. Everett Coop).
280. J. Michael McGinnis & William H. Foege, Actual Causes of Death in the United States, 270 JAMA 2207, 2208 (1993).
281. See Johannes & Stecklow, supra note 248, at B1 (discussing a study published in JAMA in which researchers found that habits affect mortality more than body size).
282. See Susan J. Speer & Alice J. Speer, Office-Based Treatment of Adult Obesity, 25 PHYSICIAN & SPORTSMEDICINE 94, 106-07 n.27 (referring to a study by C.E. Barlow & H. W. Kohl III published under the title, Physical Fitness and Mortality in Obese Men, 21 MED. SCI. SPORTS MED. S57 (1995)).
283. See Susan J. Speer & Alice J. Speer, Office-Based Treatment of Adult Obesity, 25 PHYSICIAN & SPORTSMEDICINE 94, 106-07 n.27 (referring to a study by C.E. Barlow & H. W. Kohl III published under the title, Physical Fitness and Mortality in Obese Men, 21 MED. SCI. SPORTS MED. S57 (1995)).
284. Johannes & Stecklow, supra note 248, at B1 (quoting Lynn McAfee from the Council on Size and Weight Discrimination).
285. See Heidi M. Connolly et al., Valvular Heart Disease Associated with Fenfluramine-Phentermine, 337 NEW ENG. J. MED. 581, 581 (1997) (observing twenty-four patients after initiation of fen-phen therapy and noting "unusual valvular morphology and regurgitation in all patients," "newly documented pulmonary hypertension" among eight patients, and injury severe enough to require "cardiac surgical intervention" in five patients).
286. See Saturday Today: Dr. Louis Aronne of Cornell University's Comprehensive Weight Control Program Discusses Recommendations by the FDA for Dieters Who Took the Fen-Phen Combination To Go Have a Checkup (NBC television broadcast, Nov. 15, 1997).
287. See Heart Valve Disease and Fen-Phen: An Interview with Mayo Cardiologist Heidi Connolly (visited Dec. 2, 1998) 〈http://www.mayohealth.org/mayo/9707/htm/fen_1sb. htm〉.
288. Id. (quoting Dr. Heidi Connolly).
289. FDA Announces Withdrawal of Fenfluramine and Dexfenfluramine (visited Dec. 2, 1998) 〈http://www.fda.gov/bbs/topics/NEWS/NEWoo591.html〉.
290. Id.
291. Id.
292. The FDA asked the drugs' manufacturers, Wyeth-Ayerst Laboratories and Interneuron Pharmaceutical, to withdraw the drugs from the market. The companies complied. See Controversy Still Swirling Around Diet Drugs, MED. INDUSTRY TODAY, Nov. 10, 1997, available in LEXIS, Genmed Library, Rxmega File. The FDA generally accomplishes recalls through the voluntary actions of manufacturers, who usually cooperate. For discussion of limitations on the FDA's authority to recall dangerous or potentially dangerous products and the FDA's system of "voluntary recall" that nonetheless achieves this end, see Lars Noah, Administrative Arm-Twisting in the Shadow of Congressional Delegations of Authority, 1997 WIS. L. REV. 873, 887-91.
293. The FDA asked the drugs' manufacturers, Wyeth-Ayerst Laboratories and Interneuron Pharmaceutical, to withdraw the drugs from the market. The companies complied. See Controversy Still Swirling Around Diet Drugs, MED. INDUSTRY TODAY, Nov. 10, 1997, available in LEXIS, Genmed Library, Rxmega File. The FDA generally accomplishes recalls through the voluntary actions of manufacturers, who usually cooperate. For discussion of limitations on the FDA's authority to recall dangerous or potentially dangerous products and the FDA's system of "voluntary recall" that nonetheless achieves this end, see Lars Noah, Administrative Arm-Twisting in the Shadow of Congressional Delegations of Authority, 1997 WIS. L. REV. 873, 887-91.
294. It should be noted that shortly after the FDA sought and received voluntary removal of fenfluramine and dexfenfluramine from the market, makers of dietary supplements began advertising products as "herbal fen-phen," touting their effectiveness for weight-loss. According to the FDA, the promotion of these as substitutes for the drug combination fen-phen was false because the herbal treatment and the prescription drugs are entirely different products. The Agency further contends that the effectiveness of these herbal products is unproven and that the products carry substantial health risks of their own. See NBC Nightly News: FDA Rules So-Called Herbal Phen-Fen Unsafe (NBC television broadcast, Nov. 6, 1997). In fact, the FDA immediately informed manufacturers of "herbal fen-phen" that their activities violated federal law. Under present FDA regulations, manufacturers ordinarily need not seek approval of dietary supplements, provided that manufacturers do not make therapeutic claims regarding the effectiveness of their products. See Caroline McNeil, Potential Drug DHEA Hits Snags on Way to Clinic, 89 J. NAT'L CANCER INST. 681, 681- 82 (1997). However, when manufacturers assert medical claims about such supplements, the products are treated as new drugs and cannot be marketed without FDA approval. According to the FDA, the makers of "herbal fen-phen" marketed their product as a treatment for weight loss without receiving new drug approval, thereby violating the law. See Lauren Neergaard, Diet Supplement Maker Warned: FDA Says "Herbal Fen-Phen" Violates U.S. Law and Could Be Seized, AUSTIN AM.-STATESMAN, Nov. 7, 1997, at A21. As Acting Commissioner Michael A. Friedman noted: It is not illegal for this company to sell this product. It is illegal for this company to call this product something that is exactly like a medication and to make medical claims that it will cause weight loss and treat obesity, like the prescription products do. Sheryl Gay Stolberg, F.D.A. Warns About Herbs for Weight Loss, N.Y. TIMES, Nov. 7, 1997, at A19. In November 1997, the FDA issued a public warning that "herbal fen- phen" products were not approved by the FDA and were the source of 800 health injury reports. See FDA Issues Warning on "Herbal Fen-Phen," MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Nov. 7, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
295. It should be noted that shortly after the FDA sought and received voluntary removal of fenfluramine and dexfenfluramine from the market, makers of dietary supplements began advertising products as "herbal fen-phen," touting their effectiveness for weight-loss. According to the FDA, the promotion of these as substitutes for the drug combination fen- phen was false because the herbal treatment and the prescription drugs are entirely different products. The Agency further contends that the effectiveness of these herbal products is unproven and that the products carry substantial health risks of their own. See NBC Nightly News: FDA Rules So-Called Herbal Phen-Fen Unsafe (NBC television broadcast, Nov. 6, 1997). In fact, the FDA immediately informed manufacturers of "herbal fen-phen" that their activities violated federal law. Under present FDA regulations, manufacturers ordinarily need not seek approval of dietary supplements, provided that manufacturers do not make therapeutic claims regarding the effectiveness of their products. See Caroline McNeil, Potential Drug DHEA Hits Snags on Way to Clinic, 89 J. NAT'L CANCER INST. 681, 681-82 (1997). However, when manufacturers assert medical claims about such supplements, the products are treated as new drugs and cannot be marketed without FDA approval. According to the FDA, the makers of "herbal fen-phen" marketed their product as a treatment for weight loss without receiving new drug approval, thereby violating the law. See Lauren Neergaard, Diet Supplement Maker Warned: FDA Says "Herbal Fen-Phen" Violates U.S. Law and Could Be Seized, AUSTIN AM.-STATESMAN, Nov. 7, 1997, at A21. As Acting Commissioner Michael A. Friedman noted: It is not illegal for this company to sell this product. It is illegal for this company to call this product something that is exactly like a medication and to make medical claims that it will cause weight loss and treat obesity, like the prescription products do. Sheryl Gay Stolberg, F.D.A. Warns About Herbs for Weight Loss, N.Y. TIMES, Nov. 7, 1997, at A19. In November 1997, the FDA issued a public warning that "herbal fen- phen" products were not approved by the FDA and were the source of 800 health injury reports. See FDA Issues Warning on "Herbal Fen-Phen," MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Nov. 7, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
296. It should be noted that shortly after the FDA sought and received voluntary removal of fenfluramine and dexfenfluramine from the market, makers of dietary supplements began advertising products as "herbal fen-phen," touting their effectiveness for weight-loss. According to the FDA, the promotion of these as substitutes for the drug combination fen- phen was false because the herbal treatment and the prescription drugs are entirely different products. The Agency further contends that the effectiveness of these herbal products is unproven and that the products carry substantial health risks of their own. See NBC Nightly News: FDA Rules So-Called Herbal Phen-Fen Unsafe (NBC television broadcast, Nov. 6, 1997). In fact, the FDA immediately informed manufacturers of "herbal fen-phen" that their activities violated federal law. Under present FDA regulations, manufacturers ordinarily need not seek approval of dietary supplements, provided that manufacturers do not make therapeutic claims regarding the effectiveness of their products. See Caroline McNeil, Potential Drug DHEA Hits Snags on Way to Clinic, 89 J. NAT'L CANCER INST. 681, 681- 82 (1997). However, when manufacturers assert medical claims about such supplements, the products are treated as new drugs and cannot be marketed without FDA approval. According to the FDA, the makers of "herbal fen-phen" marketed their product as a treatment for weight loss without receiving new drug approval, thereby violating the law. See Lauren Neergaard, Diet Supplement Maker Warned: FDA Says "Herbal Fen-Phen" Violates U.S. Law and Could Be Seized, AUSTIN AM.-STATESMAN, Nov. 7, 1997, at A21. As Acting Commissioner Michael A. Friedman noted: It is not illegal for this company to sell this product. It is illegal for this company to call this product something that is exactly like a medication and to make medical claims that it will cause weight loss and treat obesity, like the prescription products do. Sheryl Gay Stolberg, F.D.A. Warns About Herbs for Weight Loss, N.Y. TIMES, Nov. 7, 1997, at A19. In November 1997, the FDA issued a public warning that "herbal fen- phen" products were not approved by the FDA and were the source of 800 health injury reports. See FDA Issues Warning on "Herbal Fen-Phen," MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Nov. 7, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
297. It should be noted that shortly after the FDA sought and received voluntary removal of fenfluramine and dexfenfluramine from the market, makers of dietary supplements began advertising products as "herbal fen-phen," touting their effectiveness for weight-loss. According to the FDA, the promotion of these as substitutes for the drug combination fen- phen was false because the herbal treatment and the prescription drugs are entirely different products. The Agency further contends that the effectiveness of these herbal products is unproven and that the products carry substantial health risks of their own. See NBC Nightly News: FDA Rules So-Called Herbal Phen-Fen Unsafe (NBC television broadcast, Nov. 6, 1997). In fact, the FDA immediately informed manufacturers of "herbal fen-phen" that their activities violated federal law. Under present FDA regulations, manufacturers ordinarily need not seek approval of dietary supplements, provided that manufacturers do not make therapeutic claims regarding the effectiveness of their products. See Caroline McNeil, Potential Drug DHEA Hits Snags on Way to Clinic, 89 J. NAT'L CANCER INST. 681, 681- 82 (1997). However, when manufacturers assert medical claims about such supplements, the products are treated as new drugs and cannot be marketed without FDA approval. According to the FDA, the makers of "herbal fen-phen" marketed their product as a treatment for weight loss without receiving new drug approval, thereby violating the law. See Lauren Neergaard, Diet Supplement Maker Warned: FDA Says "Herbal Fen-Phen" Violates U.S. Law and Could Be Seized, AUSTIN AM.-STATESMAN, Nov. 7, 1997, at A21. As Acting Commissioner Michael A. Friedman noted: It is not illegal for this company to sell this product. It is illegal for this company to call this product something that is exactly like a medication and to make medical claims that it will cause weight loss and treat obesity, like the prescription products do. Sheryl Gay Stolberg, F.D.A. Warns About Herbs for Weight Loss, N.Y. TIMES, Nov. 7, 1997, at A19. In November 1997, the FDA issued a public warning that "herbal fen-phen" products were not approved by the FDA and were the source of 800 health injury reports. See FDA Issues Warning on "Herbal Fen-Phen," MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Nov. 7, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
298. It should be noted that shortly after the FDA sought and received voluntary removal of fenfluramine and dexfenfluramine from the market, makers of dietary supplements began advertising products as "herbal fen-phen," touting their effectiveness for weight-loss. According to the FDA, the promotion of these as substitutes for the drug combination fen- phen was false because the herbal treatment and the prescription drugs are entirely different products. The Agency further contends that the effectiveness of these herbal products is unproven and that the products carry substantial health risks of their own. See NBC Nightly News: FDA Rules So-Called Herbal Phen-Fen Unsafe (NBC television broadcast, Nov. 6, 1997). In fact, the FDA immediately informed manufacturers of "herbal fen-phen" that their activities violated federal law. Under present FDA regulations, manufacturers ordinarily need not seek approval of dietary supplements, provided that manufacturers do not make therapeutic claims regarding the effectiveness of their products. See Caroline McNeil, Potential Drug DHEA Hits Snags on Way to Clinic, 89 J. NAT'L CANCER INST. 681, 681- 82 (1997). However, when manufacturers assert medical claims about such supplements, the products are treated as new drugs and cannot be marketed without FDA approval. According to the FDA, the makers of "herbal fen-phen" marketed their product as a treatment for weight loss without receiving new drug approval, thereby violating the law. See Lauren Neergaard, Diet Supplement Maker Warned: FDA Says "Herbal Fen-Phen" Violates U.S. Law and Could Be Seized, AUSTIN AM.-STATESMAN, Nov. 7, 1997, at A21. As Acting Commissioner Michael A. Friedman noted: It is not illegal for this company to sell this product. It is illegal for this company to call this product something that is exactly like a medication and to make medical claims that it will cause
299. See Alicia Ault, Anti-Obesity Drugs Recalled from Global Market, 350 LANCET 867, 867 (1997) (reporting that the FDA's recommendations came in response to the risk of heart damage associated with the recalled diet drugs).
300. U.S. DEP'T HEALTH & HUMAN SERVS., Cardiac Valvulopathy Associated with Exposure to Fenfluramine or Dexfenfluramine, 46 MORBIDITY & MORTALITY WKLY. REP. 1061, 1061 (1997).
301. See id. (issuing interim recommendations for patients who were currently taking or had taken fenfluramine and/or dexfenfluramine); see also Troubles Grow for Fat Drug Combo as More Heart Worries Emerge, BIOTECH. NEWSWATCH, Dec. 1, 1997, at 7, 7 (suggesting that fen-phen users get checkups before visiting the dentist because cleaning procedures increase the risk of heart valve infection, which can be especially deadly for patients who already suffer from valve damage).
302. See, e.g., Heather MacGregor, New Panel To Craft Mass-Tort Guidelines, 150 N.J. L.J. 692, 706 (1997) (discussing litigation initiated in New Jersey immediately following the ban of fenfluramine).
303. See Victim Compensation & Attorneys' Fees, GOV'T PRESS RELEASE, Oct. 30, 1997, available in WESTLAW, Allnews Library (reporting that lawyers began forming classes and filing class action law suits shortly after the discovery of a potential link between heart valve damage and the use of fen-phen); see also Alicia Ault, Further Phen/Fen Furore, 350 LANCET 501, 501 (discussing a class action suit filed by two Maryland women seeking compensatory and punitive damages from doctors and numerous manufacturers). While legal actions to date have been aimed primarily at drug manufacturers, suits against physicians who prescribed the diet drugs are proliferating rapidly. See Michael Prince, Fen- Phen Suits Bring in Doctors but Drug Makers Still Are Primary Targets, Bus. INS., Jan. 5, 1998, at 1, 1.
304. See Victim Compensation & Attorneys' Fees, GOV'T PRESS RELEASE, Oct. 30, 1997, available in WESTLAW, Allnews Library (reporting that lawyers began forming classes and filing class action law suits shortly after the discovery of a potential link between heart valve damage and the use of fen-phen); see also Alicia Ault, Further Phen/Fen Furore, 350 LANCET 501, 501 (discussing a class action suit filed by two Maryland women seeking compensatory and punitive damages from doctors and numerous manufacturers). While legal actions to date have been aimed primarily at drug manufacturers, suits against physicians who prescribed the diet drugs are proliferating rapidly. See Michael Prince, Fen- Phen Suits Bring in Doctors but Drug Makers Still Are Primary Targets, Bus. INS., Jan. 5, 1998, at 1, 1.
305. See Victim Compensation & Attorneys' Fees, GOV'T PRESS RELEASE, Oct. 30, 1997, available in WESTLAW, Allnews Library (reporting that lawyers began forming classes and filing class action law suits shortly after the discovery of a potential link between heart valve damage and the use of fen-phen); see also Alicia Ault, Further Phen/Fen Furore, 350 LANCET 501, 501 (discussing a class action suit filed by two Maryland women seeking compensatory and punitive damages from doctors and numerous manufacturers). While legal actions to date have been aimed primarily at drug manufacturers, suits against physicians who prescribed the diet drugs are proliferating rapidly. See Michael Prince, Fen-Phen Suits Bring in Doctors but Drug Makers Still Are Primary Targets, Bus. INS., Jan. 5, 1998, at 1, 1.
306. For example, in early 1998 a group of plaintiffs in Connecticut sued for the cost of health monitoring, including periodic tests of their brains and hearts that they claimed were necessary precautions because of their use of phen-fen before its recall. See Weight-and-See Watch, CONN. L. TRIB., Jan. 5, 1998, at News.
307. Estimates suggest that American Home Products' liability for manufacturing fenfluramine will mount to between two and nine billion dollars. See Michael Casey, Megamerger Could Mean More Drug Maker Consolidation, MED. INDUSTRY TODAY, Jan. 29, 1998, available in LEXIS, Genmed Library, Rxmega File.
308. See, e.g., Roche Pulls Xenical Application from FDA, MED. INDUSTRY TODAY, Aug. 29, 1997, available in LEXIS, Genmed Library, Rxmega File ("Stricter scrutiny of weight-loss drugs in the United States has sent Roche . . . unit back to the laboratory" to analyze further data regarding the weight loss drug Xenical before submitting it for FDA approval.).
309. For example, consider hazards that may appear only twenty or thirty years after exposure to a drug. Even if the most careful FDA testing and review procedures were to require eighteen years of intensive study and heightened scrutiny, such risks could not be detected until after the product was approved for marketing. Some products that eventually prove hazardous or even fatal are destined to slip past even the most rigorous regulatory protections.
310. See AHP Stock Falls 4 Percent Following News Reports That Heart Valve Problems Were Not Reported to FDA, MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Dec. 19, 1997, available in WESTLAW, Lawrev Library, Tp-all File (indicating that Belgian authorities and the World Health Organization had been aware of cases of heart valve damage as early as 1994).
311. Id.
312. See Ronald Rosenberg, Analysts Bullish on Interneuron Despite Diet-Drug Suits, BOSTON GLOBE, Jan. 3, 1998, at C1 (discussing American Home Products' potentially significant legal liability in the wake of the research findings and voluntary recall).
313. Accordingly, "there will inevitably be tension between the regulators and the regulated." Christine C. Vito, State Biotechnology Oversight: The Juncture of Technology, Law, and Public Policy, 45 ME. L. REV. 329, 381 (1993).
314. The concept of materiality here would be akin to the concept as it has developed with respect to subjects such as fraud. Information should be considered material, and therefore its disclosure mandated, when the information is the kind likely to affect the FDA's analysis or decision. See, e.g., United States v. Gaudin, 515 U.S. 506, 509 (1995) (defining materiality in the context of fraud against the government).
315. See Group Sues FDA To Force Agency To Release Drug Information, MED. INDUSTRY TODAY, Jan. 16, 1997, available in LEXIS, News Library, Allnws File.
316. According to Sidney Wolfe, Public Citizen's health research group director, "[t]he FDA is conspiring with the drug industry to keep this information secret instead of protecting the public interest by releasing it." Id.
317. See id. (noting that the FDA approved the diet drug on the condition that American Home Products (Wyeth-Ayerst) would conduct further studies investigating the drug's safety).
318. Testing in the pre-marketing phases is like any other clinical research: it seeks to glean information about the risk of a drug to the general population by extrapolating from observations of small samples. Because the number of participants in pre-marketing studies is fairly small, relatively rare but nonetheless significant and disturbing risks easily can escape detection during this process. It is risky to increase the sample size at this early stage in testing a new drug. Post-marketing observations of the drug's effect and research based upon such observations can be based on larger samples sizes, and therefore the chances of observing and remedying rare but serious health outcomes is increased. See generally Myron L. Marlin, Comment, Treatment INDs: A Faster Route to Drug Approval?, 39 AM. U. L. REV. 171, 180-81 (1989).
319. See Fact-Sheet, supra note 190 (arguing that the FDA's safeguards are "woefully inadequate").
320. For discussion of the Modernization Act, see supra Part II.B.3.
321. See Fact-Sheet, supra note 190 (claiming that marketing efforts could have targeted anyone who wanted to lose weight and not just the seriously obese).
322. See id. (suggesting that off-label use increased substantially after a 1992 journal article reported that a group of patients using fen-phen over an extended period of time lost more weight than they would have otherwise).
323. See Lewis J. Rubin, Relationship Between the Fen-Phen Disaster and Off-Label Drug Use (visited Dec. 2, 1998) 〈http://www.citizen.org/public_citizen/congress/fda/ S.%20830- FDA/rubin.htm〉. Dr. Rubin argues that there's nothing at all to suggest that the pharmaceutical companies and the drug manufacturers have promoted off-label use, but the fact is that off-label use was widespread and has put many people at risk for serious affects [sic]. Imagine what the impact on the health of America would have been had we allowed these pharmaceutical companies to promote these drugs for off-label use. Id.
324. See Fact-Sheet, supra note 190 (recommending that the FDA require companies to prove the safety and efficacy of a new use through clinical studies before promoting it to the public).
325. See supra notes 203-04 and accompanying text (describing statutory restrictions on the types of sources manufacturers may use when they disseminate information regarding off-label uses).
326. See supra notes 276-79 and accompanying text.
327. For discussion of the peer review system, including some of the flaws that can permit the publication of poor quality research, see Effie J. Chan, Note, The "Brave New World" of Daubert: True Peer Review, Editorial Peer Review, and Scientific Validity, 70 N.Y.U. L. REV. 100, 116-23 (1995).
328. Fact Sheet, supra note 190.
329. Modernization Act, Pub. L. No. 105-115, § 551(b)(4), 111 Stat. 2296, 2357 (requiring manufacturers to submit, 60 days prior to dissemination, a copy of the information they plan to disseminate, along with "any clinical trial information the manufacturer has relating to the safety or effectiveness of the new use, any reports of clinical experience pertinent to the safety of the new use, and a summary of such information").
330. Id. § 551(c)(1), 111 Stat. at 2358.
331. Id. § 555(a)(2). 111 Stat. at 2361.
332. See id. § 555(a)(1), 111 Stat. at 2361 (authorizing the FDA to use corrective actions to monitor manufacturers' post-marketing responsibilities).
333. See supra Parts I.A-B (describing traditional FDA approval procedures and discussing the risks of under- and over-conservatism).
334. See Fact-Sheet, supra note 190 (predicting risks to public health resulting from the Modernization Act's liberalization of drug approval and dissemination procedures).
335. The FDA has included this intuitively sensible observation in a number of its reforms, limiting liberalized access to situations in which satisfactory alternatives or therapies are lacking. See, e.g., Modernization Act § 506(a)(1), 111 Stat. at 2309 (limiting fast-track drugs to those that have the potential to address "unmet medical needs"); see also id. § 561(c)(2), 111 Stat. at 2366 (limiting treatment INDs to conditions for which "there is no comparable or satisfactory alternative therapy available").
336. The gray area is a function of many variables, including: (1) the degree of safety and effectiveness of extant treatments; (2) the conclusiveness of the evidence of safety and effectiveness; and (3) the extent of the effectiveness among members of the potential user population.
337. See supra Part II.A.1 and accompanying text (discussing the development of HIV/AIDS treatments).
338. By itself, AZT extends life expectancies by an average of approximately seven months. See supra note 52 and accompanying text; see also supra Part II.A.2 and accompanying text (discussing the introduction of protease inhibitor cocktails and the effect of this revolutionary drug treatment on the public's perception of the disease).
339. The utility of diet and exercise in weight loss across populations is debatable. While believers in the traditional diet-oriented value of willpower may contend that diet and exercise are natural and free treatments available to and effective for all, others conceptualize obesity as a "chronic disease" requiring "lifelong management and intervention." D'Ann Mabray Shippy & Karen Brooks, Drug Ban Compounds Weight-Loss Struggles, FORT WORTH STAR-TELEGRAM, Nov. 30, 1997, at 1 (quoting Texas internist Gregory Phillips).
340. Healthy Resolutions To Start the New Year Off Right: A Favorite Hobby Combined with a Balanced Diet and Exercise Can Help Prevent Disease, BUS. WIRE, Dec. 2, 1997, at 1.
341. See Patricia Long, Winning at the Losing Game, 10 HEALTH 62, 62 (1996) (addressing the "damnably difficult" challenge of losing weight and keeping it off).
342. See, e.g., Marvin E. Levin, Living Off the Fat of the Land, CLINICAL DIABETES, Mar. 1991, at 18 (citing evidence that "subjects with type II diabetes ha[ve] more difficulty losing weight than their overweight nondiabetic spouses"); see also Lee Hoffman, Eating Disorders, U.S. DEP'T HEALTH & HUMAN SERVS. PAMPHLET, Jan. 1993, available in LEXIS, Genmed Library, Rxmega File (noting special difficulty in losing weight among persons with binge eating disorders, compared to other overweight persons).
343. See, e.g., Marvin E. Levin, Living Off the Fat of the Land, CLINICAL DIABETES, Mar. 1991, at 18 (citing evidence that "subjects with type II diabetes ha[ve] more difficulty losing weight than their overweight nondiabetic spouses"); see also Lee Hoffman, Eating Disorders, U.S. DEP'T HEALTH & HUMAN SERVS. PAMPHLET, Jan. 1993, available in LEXIS, Genmed Library, Rxmega File (noting special difficulty in losing weight among persons with binge eating disorders, compared to other overweight persons).
344. See Alicia Ault, Obesity Drug Replacement, 350 LANCET 1760, 1760 (1997) (reporting the FDA's approval of the new diet drug Meridia).
345. See Pat Dooley, Dieters Have New Option: Prescription Pill Meridia, VIRGINIAN PILOT (Norfolk), Feb. 19, 1998, at A1 (noting that "Meridia is believed to be safer than Redux and fenfluramine" because the drug does not stimulate the release of additional serotonin, which may have been the cause of some of the health risks associated with fen-phen and Redux).
346. Indeed, the first FDA advisory committee recommended against approval of Meridia in September of 1996 because of the risk of elevated blood pressure. See Alicia Ault Barnett, Newest Obesity Drug Fails to Pass Muster, 348 LANCET 949, 949 (1996).
347. See CNN Talkback Live (CNN television broadcast, Nov. 25, 1997) (debating the FDA's approval of Meridia and focusing on the differences between this new drug and the recalled diet drugs fen-phen and Redux). Nonetheless, because the drug sibutramine (the scientific name for the product Meridia) is similar in its chemical properties to dexfenfluramine, the American Heart Association recommended caution in using Meridia. See American Heart Association Says New Diet Drug Similar to Redux and Pondimin, Urges Caution, MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Dec. 19, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
348. See CNN Talkback Live (CNN television broadcast, Nov. 25, 1997) (debating the FDA's approval of Meridia and focusing on the differences between this new drug and the recalled diet drugs fen-phen and Redux). Nonetheless, because the drug sibutramine (the scientific name for the product Meridia) is similar in its chemical properties to dexfenfluramine, the American Heart Association recommended caution in using Meridia. See American Heart Association Says New Diet Drug Similar to Redux and Pondimin, Urges Caution, MEALEY'S LITIG. REP.: DRUGS & MED. DEVICES, Dec. 19, 1997, available in WESTLAW, Lawrev Library, Tp-all File.
349. Any patient considering treatment weighs the cost and risk of treatment against the cost and risk of non-treatment. This model of rational patient decision-making presumes that physicians inform patients carefully and accurately of all costs, risks and potential benefits of various treatments versus non-treatment. This assumption obviously will fail in real world applications at least some of the time. It would be reasonable for the FDA to build a counterbalance into its drug approval decisions to protect the public from doctors who fail to give their patients proper notification of these risks and benefits. Ordinarily, the greater the severity of the disorder, the greater the risk and cost of non-treatment, and therefore the higher the risk and cost of treatment the patient is willing to assume. Ceteris paribus, the FDA is justified in adopting a more conservative regulatory stance on drugs for less serious disorders than on drugs for more serious disorders.
350. See Rochelle Sharp, New Antibiotic for Deadly Infection Draws Mixed Review by an FDA Panel, WALL ST. J., Feb. 20, 1998, at B6 (reporting an FDA advisory panel's reluctance to approve the new antibiotic Synercid).
351. See id. (noting that scientists were unable to perform their usual tests on the unique drug because no similar drugs existed as controls with which to compare the new drug's safety and effectiveness).
352. See id. (stating that Synercid will be used to treat patients who become infected with strains of bacteria that are not responsive to any other antibiotics).
353. The Synercid example highlights one of the potential problems with the FDA's current policy on off-label uses of drugs. According to this Article's thesis, the FDA could justify its approval of Synercid based on the deadliness and otherwise untreatable nature of a particular bacterium. However, if doctors prescribe the drug for other, non-approved uses, and if the manufacturer advertises the drug for other non-approved uses, then a potentially dangerous drug approved under relatively lax standards could be administered for less severe, treatable conditions that were not the intended targets of the relaxed standards.
354. See Market Release of Glaxo-Wellcome AIDS Drug Delayed to 1998, MED. INDUSTRY TODAY, Nov. 13, 1996, available in LEXIS, Genmed Library, Rxmega File.
355. See Marilyn Alva, Takeout Health Care: When AIDS Patients Get Better, CRAINS N.Y. BUS., Jan. 26, 1998, at 29, available in WESTLAW, Allnews Library (discussing the transformative effect of protease inhibitors on "the face of the AIDS epidemic in New York").
356. These generalizations are relative and they describe a trend rather than an absolute principle. Particularly given the limitations of protease inhibitor cocktails, great urgency remains in the effort to find new and better treatments and a cure. See supra Part II.A. However, there is less urgency than existed ten years ago. With the reduction in urgency there logically should be a corresponding increase in the FDA's scrutiny of new HIV and AIDS treatments.
357. See supra Part II.A.1 (discussing the prognosis for HIV/AIDS patients prior to the introduction of combination therapies); cf. AIDS: Experts Make Surprising Headway Against HIV, HEALTH LINE, June 17, 1996, available in WESTLAW, Allnews Library (noting that AIDS is generally considered fatal but that new combination therapies may downgrade AIDS from deadly to chronic).
358. This characterization of the risks related to obesity is not intended to understate the seriousness of associated health hazards. Researchers suggest that 300,000 deaths in the United States every year result from disorders associated with obesity. See Dr. Vernon B. Astler, Can Any Drugs Safely Suppress Appetite?, ASHEVILLE CITIZEN-TIMES (Asheville, N.C.), Nov. 10, 1997, at C2 (citing reports that estimate that as many as 300,000 Americans die each year from obesity-related illnesses). Astler further observes a relationship between obesity and conditions such as "hypertension, non-insulin diabetes mellitus, increased cholesterol, increased cardiovascular disease, osteoarthritis, depression, [and] sleep apnea." Id. But see supra notes 248-52 and accompanying text for critique of this statistic. Nonetheless, the relationship between obesity and mortality is more attenuated than the relationship between AIDS and mortality. For example, one study concluded that the mortality rate for men who exercise regularly is approximately the same whether they are overweight or not. See Allison Bell, Big Clients Want Smaller Rates: Overweight People Sometimes Find It Hard To Get Life Insurance Coverage, NAT'L UNDERWRITER LIFE & HEALTH, Nov. 10, 1997, at 7, 7 (discussing the diet and exercise research of Steven Blair of the Cooper Institute in Dallas).
359. This characterization of the risks related to obesity is not intended to understate the seriousness of associated health hazards. Researchers suggest that 300,000 deaths in the United States every year result from disorders associated with obesity. See Dr. Vernon B. Astler, Can Any Drugs Safely Suppress Appetite?, ASHEVILLE CITIZEN-TIMES (Asheville, N.C.), Nov. 10, 1997, at C2 (citing reports that estimate that as many as 300,000 Americans die each year from obesity-related illnesses). Astler further observes a relationship between obesity and conditions such as "hypertension, non-insulin diabetes mellitus, increased cholesterol, increased cardiovascular disease, osteoarthritis, depression, [and] sleep apnea." Id. But see supra notes 248-52 and accompanying text for critique of this statistic. Nonetheless, the relationship between obesity and mortality is more attenuated than the relationship between AIDS and mortality. For example, one study concluded that the mortality rate for men who exercise regularly is approximately the same whether they are overweight or not. See Allison Bell, Big Clients Want Smaller Rates: Overweight People Sometimes Find It Hard To Get Life Insurance Coverage, NAT'L UNDERWRITER LIFE & HEALTH, Nov. 10, 1997, at 7, 7 (discussing the diet and exercise research of Steven Blair of the Cooper Institute in Dallas).
360. See supra text accompanying notes 251-54 (citing research showing that fit, overweight men have substantially lower mortality rates than lean, sedentary men, a finding that suggests that obesity poses a less severe health risk than many people assume).
361. Behavior modification approaches to weight reduction include both intervention through counseling and the use of actual behavior modification devices. An example of the latter is a pager-like device called SlimSmart that alerts patients when to eat more slowly and when to stop eating. According to manufacturer studies, use of the device yields greater weight loss than dietary modifications and exercise alone. See Adaptra Corp. Announced Release of Their New Electronic Weight-Loss Product, SlimSmart, BUS. WIRE, Dec. 5, 1997, available in LEXIS, News Library, Allnws File.
362. See Jerome P. Kassirer & Marcia Angell, Editorial, Losing Weight - An Ill-Fated New Year's Resolution, 338 NEW ENG. J. MED. 52, 53 (1998) (analyzing the role of "healthful diets" and "lifelong, regular exercise" in obesity prevention).
363. See supra notes 304-07 and accompanying text (discussing the prescription diet drugs that have become available since the September 1997 recall of fen-phen and Redux).
364. The "patient monitoring" discussed in this subsection should be distinguished from the "drug monitoring" discussed in the following subsection. Although they may sound similar, they refer to distinctly different processes. Patient monitoring refers to the doctor's ability to watch patients using a specific drug and to intervene and effectively avert damage associated with any risks of the drug. Drug monitoring refers to the ability of doctors, hospitals, and pharmaceutical manufacturers to continue to test for, and remain vigilant for, signs of health risks that were not recognized during the three pre-approval phases of clinical testing. In other words, while this subsection addresses the ability to protect particular patients from health hazards by watching them carefully, the following subsection addresses the ability to continue investigating the drugs themselves after they have received FDA approval.
365. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 15 CLINICAL DIABETES 158 [hereinafter Report of Expert Committee].
366. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 15 CLINICAL DIABETES 158 [hereinafter Report of Expert Committee].
367. See id. (noting that in "type 2 diabetes" there is "a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms," such that the disease "may be present for a long period of time before diabetes is detected").
368. See id. (discussing in detailed clinical terms some of the severe manifestations of "type 1 diabetes").
369. John Carey, Rezulin: The FDA Made the Right Call, BUS. WK., Dec. 15, 1997, at 39.
370. To some extent, this is true for most diseases. However, diabetes is a disease about which generalizations are especially difficult because there is so much variation in the severity of the condition and its symptoms. Compare this example to the example of AIDS. Of course, patients with untreated AIDS also experience a variety of symptoms. Some experience more devastating manifestations than others, and some succumb more quickly than others. Nonetheless, at least to date, scientists and physicians do not distinguish between milder forms of AIDS and more pronounced forms of AIDS. While there are variations in its progression, untreated AIDS is generally viewed as fatal in all cases.
371. This form of diabetes is referred to as "insulin dependent" or "type 1" diabetes. See Report of Expert Committee, supra note 323.
372. This form of diabetes is referred to as "noninsulin dependent" or "type 2" diabetes. See id.
373. See id. (discussing the range of diabetes treatments and comparing and contrasting "type 1" and "type 2" diabetes).
374. See supra notes 323-26 and accompanying text (discussing the symptoms associated with more severe forms of diabetes).
375. See Carey, supra note 326, at 39 (arguing that the FDA correctly approved troglitazone because doctors easily can monitor their patients for signs of liver stress before any real damage occurs).
376. Id. Carey notes that troglitazone offers benefits to patients, such as fewer side effects than existing diabetes medications, and that physician monitoring can avert the risks associated with the drug. See id.
377. See supra note 119 and accompanying text (discussing regulations that give the FDA authority to require post-marketing surveillance as a condition of drug approval).
378. See E. Patrick McGuire, The Underreporting of Product-Relaled Injuries, PROD. LIAB. L. & STRATEGY, Nov. 1997, at 4, available in WESTLAW, Lawrev Library, Tp-all File (describing the mechanisms for FDA post-marketing surveillance of drugs, and explaining why many of these mechanisms may be ineffective).
379. One critic has suggested that the length of the interval period may be protracted because detection and reporting of problems with an approved drug are the responsibility of private parties and not the government. See id. Estimates suggest that two-thirds of doctors may not even be familiar with the Med-Watch adverse reaction reporting system. Accordingly, the period between first observation of a serious adverse reaction and FDA recall may be unacceptably long. See id.
380. The calculation of an interval period for a specific drug would be a daunting task, nearly impossible to achieve with any accuracy. However, by extrapolating from past experience with a similar class of drugs, a regulator could calculate an expected value or average of the length of an interval period across an entire class of similar drugs. Over the course of many new drug applications, it is likely that the average of similar drugs in the past will reflect, more or less, the average danger span in the future. Random fluctuation and systematic changes such as alterations in procedure, environment, etc., could, however render historic extrapolation an inaccurate predictor of future performance.
381. This net gain will improve if the classification of drugs becomes more precise, so that eventually, fewer and fewer drugs included in the approved class result in hazards.
382. Gregory D. Curfman, Diet Pills Redux, 337 NEW ENG. J. MED. 629, 630 (1997).
383. See id. (noting that appetite suppressants are effective only for short-term weight loss and that long-term use is not a viable option, as the risk of serious toxicity increases with duration of use).
384. See Rubin, supra note 284 (finding that the average period of diet drug use for individuals at the Mayo Clinic who developed valvular heart disease was in excess of eight months).
385. Id.
386. See Curfman, supra note 339, at 630 (arguing that appetite suppressant diet drugs should be given only to severely obese patients, for whom the health benefits outweigh the potential health risks).
387. See supra Part III.A.2 and accompanying text (discussing the FDA's controversial decision to approve dexfenfluramine after an advisory panel rejected the drug, and a subsequent panel voted 6-5 for approval).
388. Panel recommendations are considered persuasive rather than mandatory. Ordinarily the FDA gives them serious weight and deference in rendering final decisions. See Robert B. Leflar, Public Accountability and Medical Device Regulation, 2 HARV. J.L. & TECH. 1, 11-12 (1989) ("While . . . panel recommendations are not binding on the agency, in general they have been remarkably influential.").
389. See supra note 220 and accompanying text (noting that the original panel recommended rejection due to concerns regarding possible brain damage associated with the drug, and observing that FDA approvals in the face of negative panel recommendations are troubling).