Balancing the barriers: Exploiting and creating incentives to promote development of new tuberculosis treatments

Washington Law Review

Volumn 71, Issue 4, 1996, Pages 919-967

  Kuszler, Patricia C ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

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EID: 0346158831     PISSN: 00430617     EISSN: None     Source Type: Journal    
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References (333)

1. K K Tan, Tuberculosis - Fighting a Losing Battle?, 36 Sing. Med. J. 209, 211 (1995).
2. Tuberculosis was the leading cause of death in 19th century America, killing one in five persons. Sheila M. Rothman, Living in the Shadow of Death - Tuberculosis and the Social Experience of Illness in American History 2 (1994).
3. Although other plagues such as the bubonic "Black" plague and the 1918 flu epidemic have produced similar devastation, they lasted only a short period of time and then were eradicated or burned themselves out. Laurie Garrett, The Coming Plague - Newly Emerging Diseases in a World out of Balance 157-58, 238-39 (1994) Unlike these plagues, tuberculosis has remained an ongoing public health threat for several centuries. Id. at 240-41.
4. See Charles Marwick, Do Worldwide Outbreaks Mean Tuberculosis Again Becomes 'Captain of All These Men of Death'?, 267 JAMA 1174 (1992);
5. Phyllida Brown, A Disease that is alive and kicking; tuberculosis returns to industrialized nations, World Health, July 1993, at 4.
6. See Alan B. Bloch et al., Nationwide Survey of Drug-Resistant Tuberculosis in the United States, 271 JAMA 665 (1994);
7. Thomas R. Frieden et al., The Emergence of Drug-Resistant Tuberculosis in New York City, 328 New Eng. J. Med. 521, 524 (1993);
8. Kent A. Sepkowitz et al., Trends in the Susceptibility of Tuberculosis in New York City, 1987-1991, 18 Clinical Infectious Diseases 755 (1994).
9. Every year there are eight million new cases of tuberculosis and three million deaths caused by tuberculosis. The disease accounts for 6.7% of all deaths in the developing world, 18.5% of all deaths in adults aged 15 to 59 years, and 26% of avoidable adult deaths. John Porter et al., The challenge is international, World Health, July 1993, at 10. Currently TB kills more people worldwide than any other infection, including AIDS and malaria. See Brown, supra note 3. It is estimated that TB will claim 30 million lives during the coming decade; over 95% of these will occur in the developing world, but industrialized nations will also experience dramatic increases in TB disease and death.
10. Dale I. Morse, Directly Observed Therapy for Tuberculosis: Spend Now or Pay Later, 312 Brit. Med. J. 719, 719-20 (1996);
11. Hiroshi Nakajima, Tuberculosis: A Global Emergency, World Health, July 1993, at 3.
12. Mario C. Raviglione et al., Global Epidemiology of Tuberculosis: Morbidity and Mortality of a Worldwide Epidemic, 273 JAMA 220, 220 (1994).
13. The term "white plague" refers to the pallor of the patient afflicted with tuberculosis. The term was popularized by Rene and Jean Dubos, in their history of tuberculosis in the 19th and early 20th centuries. See Rene & Jean Dubos, The White Plague - Tuberculosis, Man and Society (1952). For other renditions of TB's historical impact,
14. see Barbara Bates, Bargaining for Life - A Social History of Tuberculosis, 1876-1938 (1992); Rothman, supra note 2;
15. and F.B. Smith, The Retreat of Tuberculosis 1950-1950 (1988).
16. Joan Stephenson, Health at Home Means Watching the Global Village, 273 JAMA 1648 (1995). In 1993, the World Health Organization (WHO) declared TB to be a global health emergency, a designation that had never before been applied to any single disease. Tuberculosis is now considered the greatest single threat to the world's public health. See id.;
17. Lee B. Reichman, How To Ensure the Continued Resurgence of Tuberculosis, 347 Lancet 175 (1996).
18. The development of drug resistance is due to inadequate or incomplete treatment of the traditional strain of tuberculosis. Although public health clinicians in the mid-20th century had at their disposal sanitaria and enforceable public health laws, both of these diminished in the latter part of the century. As a result, adherence to treatment plans eroded. Patients became less likely to complete their treatment regimens. In addition, physicians became less familiar with tuberculosis and its pathogenesis as the disease decreased in incidence; thus the medical profession became less effective at administering adequate therapy. Michael D. Iseman, Evolution of Drug-Resistant Tuberculosis: A Tale of Two Species, 91 Proc. Nat'l Acad. Sci. U.S. 2428 (1994).
19. "We have turned a disease that was completely preventable and curable into one that is neither." Dr. Lee B. Reichman, President, Am. Lung Ass'n, quoted in Michael Specter, Neglected for Years, TB Is Back with Strains That Are Deadlier, N.Y. Times, Oct. 11, 1992, at A1.
20. This phenomenon is not unique to TB, but applies to virtually all infectious diseases. Microbes are vested with high intrinsic mutability and rapid replication. As such, they present a constantly-evolving adversary. See Joshua Lederberg, Infectious Diseases - a Threat to Global Health and Security, 476 JAMA 417 (1996).
21. In the 1960s and 1970s, only one to two percent of tuberculosis strains evidenced resistance to existing drugs, and the resistance was limited to only one of the available drugs. The propensity for drug resistance has risen steadily. In 1992, 33% of tuberculosis strains found in New York City patients were resistant to at least one drug; 19% were resistant to two or more drugs. In developing nations, drug resistant strains are present in over 30% of cases. Iseman, supra note 9, at 2428. Others report even higher incidences of drug resistance. See Marwick, supra note 3. By 1991-92, one strain of tuberculosis (the "W-strain"), appearing initially in New York City, had developed resistance to every available drug and had a 50% mortality rate. Laurie Garrett, The Return of Infectious Disease, Foreign Aff., Jan.-Feb. 1996, at 66.
22. For example, HIV patients are extremely susceptible and vulnerable to MDR forms of tuberculosis: "[I]n fact, the HIV-positive are 40 times more likely to contract and develop tuberculosis that those who are HIV negative." Rosemary G. Reilly, Combating the Tuberculosis Epidemic: The Legality of Coercive Measures, 27 Colum. J.L. & Soc. Probs. 101, 104 (1993).
23. See Nakajima, supra note 5. Asia illustrates the tuberculosis epidemic at its worst; notably, HIV is also prevalent in developing Asian nations. It is estimated that nearly half the Asian population is infected with TB. The death rate for patients dually infected with TB and HIV is doubling every three to five years. See U.S. Dep't of Health & Human Servs., Tuberculosis. HIV Coepidemic to Multiply Sevenfold in Asia, Pub. Health Rep., Jan.-Feb. 1995, at 108.
24. The tuberculosis epidemic, like most other infectious disease epidemics, is rooted in "conditions of social despair inflicted by one class of human beings upon another." Garrett, supra note 2, at 214 (citing Dubos & Dubos, supra note 7).
25. For example, the bones of 3000-year-old Egyptian mummies show signs of tuberculosis; similarly, bony deformities associated with TB are represented in statuary dating back to 4000 B.C. Dubos & Dubos, supra note 7, at 5.
26. J. Arthur Myers, Captain of All These Men of Death - Tuberculosis Historical Highlights 11 (1977).
27. See id. at 12-17. Hippocrates and the physicians that followed him believed that good nutrition and exposure to healthful air were critical to prevention and treatment of the disease; as a result climatic changes and relocation to the mountains or seaside were recommended.
28. Id. at 34. These tubercle lesions are the result of the baccilli's destruction of normal lung tissue and replacement with small collections of necrotic matter. See l Kurt J. Isselbacher et al., Harrison's Principles of Internal Medicine 711-12 (13th ed. 1994).
29. Dubos & Dubos, supra note 7, at 210.
30. Smith, supra note 7, at 1. Nevertheless, as Smith documents, "Tuberculosis respected rank." Although the rich were as vulnerable to tuberculosis exposure as the poor, those with financial and social resources fared better in escaping active infection and in availing themselves of earlier access to treatment. Id. at 10.
31. Dubos & Dubos, supra note 7, at 101, 210.
32. Tuberculosis results from chronic infections with Mycobacterium tuberculosis; the bacteria infects tissues of the lung, bone, and other organs, resulting in the formation of granulomas - areas of inflammation and decay. See Isselbacher et al., supra note 17, at 711-12. Mycobacterium tuberculosis is one of more than 30 members of the genus Mycobacterium. Other member of the genus also infect humans, notably, Mycobacterium leprae, the microbe responsible for leprosy. See id. at 710.
33. The public health efforts to improve living conditions were tremendously successful. Numerous infectious diseases, including cholera and typhoid, lost their status as mass killers as a result of improved sanitation and public health education. See generally John Duffy, The Sanitarians: A History of American Public Health (1990);
34. John Duffy, A History of Public Health in New York City (1968); Garrett, supra note 2.
35. By 1900, the mortality rate from tuberculosis had dropped to half of what it had been in the middle of the 19th century, both in Europe and in the United States. Dubos & Dubos, supra note 7, at 186; Smith, supra note 7, at 236-37. How much of this decline was due to improved living conditions and how much was due to the periodic waning that is characteristic of infectious diseases is unknown.
36. Sylvia N. Tesh, Miasma and "Social factors" in Disease Causality: Lessons From the Nineteenth Century, 20 J. Health Pol. Pol'y & L. 1001, 1004 (1995). Tesh notes that a second factor fueling the change in public health strategy was the political ideology of the time. The public health concentration upon sanitary reform and improved living conditions went hand-in-hand with the economic liberalism of the time. As this political theory lost vitality, the public support for the sanitation effort waned, and support for more aggressive public health actions in the form of quarantines and other coerced treatments gained strength. Id. at 1005.
37. Myers, supra note 15, at 59; Barren H. Lerner, New York City's Tuberculosis Control Efforts: The Historical Limitations on the "War on Consumption," 83 Am. J. Pub. Health 758, 758-59 (1993).
38. Lerner, supra note 25, at 758-59.
39. In fact, the medical profession bitterly opposed the Biggs plan and sought to enjoin its implementation by proposing a series of bills to the State Legislature that would strip the Board of Health of any authority in dealing with tuberculosis as an infectious disease. Myers, supra note 15, at 59. The basis for their opposition was manifold: some adhered to the "anticontagionist" philosophy which held that genetically predisposed individuals contracted tuberculosis by exposure to harmful "miasmas"; others alleged that the mandatory reporting required them to breach a patient confidence. Lerner, supra note 25, at 758-59.
40. Myers, supra note 15, at 59.
41. Dubos & Dubos, supra note 7, at 211. Nearly 40 states have laws addressing control of tuberculosis, most of which were drafted around the rum of the century and are similar to the New York City model. See Lawrence O. Gostin, Controlling the Resurgent Tuberculosis Epidemic: A 50-State Survey of TB Statutes and Proposals for Reform, 269 JAMA 255 (1993);
42. Karen H. Rothenberg & Elizabeth C. Lovoy, Something Old, Something New: The Challenge of Tuberculosis Control in the Age of AIDS, 42 Buff. L. Rev. 715, 743 (1994).
43. Gostin, supra note 29, at 255.
44. See Kathryn Render, Tuberculosis Chapters: A Model for Future AIDS Legislation?, 32 St. Louis U. L.J. 1145, 1149-56 (1988). For a state-by-state breakdown of specific provisions applicable to public health powers, see Gostin, supra note 29, at 256-57.
45. See Render, supra note 31, at 1157. A recent survey of state laws revealed that 19 states provide for emergency detention for reasons of health. Nine of these vest the authority for such detention solely in the discretion of a health officer; eight require a court order, and four provide for detention in the context of commitment. The criteria for detention range from failure to comply with counseling suggestions to being deemed a public health threat. See Gostin, supra note 29, at 258.
46. The European model of treatment was based on the theory that stress and complicated urban life impeded recovery from tuberculosis. In this model, patients were institutionalized in healthcare facilities and given the opportunity to rest, receive a nutritious diet, and breathe healthy, preferably cold, mountain or sea air. Sanitaria flourished throughout Europe; in the United States, the premier sanitarium was at Saranac Lake in the Adirondacks. See Dubos & Dubos, supra note 7, at 176-78.
47. This support coincided with a shift in the perception of who would be the caretaker of the sick. Whereas in the previous century, the caretakers were the family and friends of the patient, the twentieth century saw this role increasingly assumed by physicians, nurses, clergy, and other caretaking professions. Bates, supra note 7, at 329.
48. Id. at 331.
49. Lerner, supra note 25, at 760.
50. Poor sanitation and crowded living conditions provided an ideal environment for the spread of tuberculosis. See Dubos & Dubos, supra note 7, at 202.
51. See Bates, supra note 7, at 329-31.
52. See Myers, supra note 15, at 36-37.
53. Instead of the non-virulent BCG vaccine, the infants were vaccinated with live human tuberculosis bacilli. See Dubos & Dubos, supra note 7, at 122-23, 160-62.
54. See id. at 162. BCG later was found to be somewhat effective in immunizing against tuberculosis. However, the immunizing effects of BCG are extremely variable and inconsistent; its efficacy as a vaccine remains inconclusive to this day. See infra part IV and accompanying notes.
55. Dr. Waksman faced innumerable difficulties in getting the new drug tested and used as treatment. He was not a medical doctor, but a soil bacteriologist; this hindered the acceptance of his research, even though the results were dramatic. As a result the drug was not distributed until 1947. Smith, supra note 7, at 246.
56. Id.
57. Rifampin is the second most important anti-tuberculosis drug, after isoniazid. As in the case of isoniazid, liver dysfunction is a adverse side effect. See Isselbacher et al., supra note 17, at 706. It is substantially more expensive than isoniazid.
58. Lerner, supra note 25, at 760.
59. Smith, supra note 7, at 247.
60. Id.
61. Bates, supra note 7, at 339-40.
62. See, e.g., Lerner, supra note 25, at 761 (discussing situation in New York City).
63. This optimism was not confined to tuberculosis. The post-World War II world believed that the antibiotics, antimalarials, and vaccines that had been developed had indeed effected a "health transition" and that infectious diseases were no longer a major threat to mankind. This view was supported by the successful eradication of smallpox. Unfortunately, the much lauded "health transition" was founded on two false assumptions: that bacteria and other microbes were immutable and unchanging and that outbreaks of disease could be sequestered. See Garrett, supra note 10.
64. For example, targeted federal funding for tuberculosis projects gave way to nonspecific "block grants" that gave the states and local government discretion as to how the funds were used. See Reichman, supra note 8, at 176.
65. Lerner, supra note 25, at 762. For example, the National Tuberculosis Association renamed itself the National Tuberculosis and Respiratory Disease Association in 1968. Id.
66. Smith, supra, note 7, at 247. This misconception died hard. Throughout the 1970s and 1980s, many public health authorities, including the U.S. Office of the Surgeon General, continued to predict that, like smallpox, tuberculosis would be eradicated from the globe. In fact, during the Bush Administration, the Centers for Disease Control assured state governments that fiscal commitments dedicated to TB could be decreased because the threat was so diminished. Garrett, supra note 10.
67. Jonathan Weiner, The Beak of the Finch: A Story of Evolution in Our Time 261 (1994).
68. Smith, supra note 7, at 247.
69. Compliance presented problems for New York City's public health efforts even at the turn of the century; the noncompliant "rounders" were detained and incarcerated in healthcare facilities, but generally were released while still infected. The availability of antibiotics did not erase the noncompliance problem. New York City municipal hospitals were able to discharge 9000 tuberculosis patients between 1950 and 1954; approximately one-third of these left against medical advice and presumably before they had been rendered non-infectious. In addition, audits of outpatient therapy revealed that noncompliance was common; in 1979, only 53% of cases followed by the New York City Health Department had completed the full courses of outpatient treatment for tuberculosis. Lerner, supra note 25, at 761.
70. This was particularly marked in New York, where 9.6% of new, never-treated patients had drug resistant strains, compared to a national average of 6.9%. The fact that these patients with newly diagnosed TB had a resistant strain indicated that such resistant tuberculosis bacilli could be transmitted directly and was not necessarily the product of prior inadequate treatment. As a result, any individual, regardless of prior history of TB, may contract virulent MDR-TB. Lerner, supra note 25, at 762.
71. Lerner, supra note 25, at 762.
72. See id.; see also Karen Glanz & Haiou Yang, Communicating about Risk of Infectious Diseases, 275 JAMA 253 (1996) (discussing role of media in informing and awakening public as to perils of infectious diseases including tuberculosis).
73. See Consuelo Beck-Sague et al., Hospital Outbreak of Multidrug-Resistant Mycobacterium Tuberculosis Infections: Factors in Transmission to Staff and HIV-Infected Patients, 268 JAMA 1280 (1992);
74. Charles L. Daley et al., An Outbreak of Tuberculosis with Accelerated Progression Among Persons Infected with the Human Immunodeficiency Virus, 326 New Eng. J. Med. 231 (1992);
75. Maria de Lourdes Garcia Garcia et al., Epidemiology of AIDS and Tuberculosis, 29 Bull. Pan Am. Health Org. 37 (1995).
76. See Stephen Luby et al., A Nosocomial Outbreak of Mycobacterium Tuberculosis, J. Fam. Prac., July, 1994, at 21;
77. Michele L. Pearson et al., Nosocomial Transmission of Multidrug-Resistant Mycobacterium Tuberculosis: A Risk to Patients and Health Care Workers. 117 Annals Internal Med. 191 (1992);
78. Sarah E. Valway et al., Multidrug-Resistant Tuberculosis in the New York State Prison System. 1990-1991, 170 J. Infectious Diseases 151 (1994);
79. see also Ruth E. Brown et al., Health-Care Expenditures for Tuberculosis in the United States, 155 Archives Internal Med. 1595 (1995).
80. See Keith Brudney & J. Dobkin, Resurgent Tuberculosis in New York City: Human Immunodeficiency Virus, Homelessness, and the Decline of Tuberculosis Control Programs, 144 Am. Rev. Respiratory Diseases 745 (1991);
81. Centers for Disease Control, Crack Cocaine Use Among Persons with Tuberculosis - Contra Costa County, California, 1987-1990, 40 Morbidity & Mortality Wkly. Rep. 485, 485-87 (1991). The risk of tuberculosis in substance abusers is undoubtedly linked to their higher risk of HIV, or incipient HIV, and homelessness. Rothenberg & Lovoy, supra note 29, at 723. The risk is further magnified by the fact that these patients frequently are unaware of their increased susceptibility to tuberculosis.
82. Salynn Boyles, At-Risk Populations IVDUs Need More Information about TB, TB Wkly., July 31, 1995, available in WESTLAW, 1995 WL 10089953.
83. One such immunosuppressed group is the homeless, who frequently fall through the cracks of TB treatment and develop MDR-TB. See Rebecca Voelker, New Push to Control Drug-Resistant TB. Am. Med. News, Jan. 20, 1992, at 3. Another group frequently prone to increased risk on the basis of immunosuppression is the chronically ill elderly.
84. See Centers for Disease Control, Prevention and Control of Tuberculosis in Facilities Providing Long Term Care in the Elderly, 39 (RR-10) Morbidity & Mortality Wkly. Rep. 7 (1990).
85. See The World as a Hot Zone: New and Re-Emerging Diseases, Vaccine Wkly., Mar. 20, 1995, available in WESTLAW, 1995 WL 10090736, at *4.
86. Iseman, supra note 9, at 2429.
87. Id.
88. For example, one study of 25 patients with MDR-TB who were not HIV positive found that only eight of them had a history of inadequate treatment for tuberculosis and nine of them had known exposures to MDR-TB patients as Healthcare workers (eight) or fellow patients (one). Three of the remaining patients were residents of a homeless shelter. However, four patients had no previously established risk factors for tuberculosis. See Edward E. Telzak et al., Multidrug Resistant Tuberculosis in Patients without HIV Infection, 333 New Eng. J. Med. 907, 909-10 (1995).
89. See Centers for Disease Control, Outbreak of Multidrug Resistant Tuberculosis - Texas, California and Pennsylvania, 264 JAMA 173 (1990) (reporting outbreaks of MDR-TB, each traced back to index patients and perpetuated by their contacts);
90. U.S. Reports TB Outbreak Killed 29 of 32 Patients, Chi. Trib., July 14, 1993, at C7 (reporting outbreak of drug resistant TB in New York hospital).
91. See Iseman, supra note 9, at 2429; Rise of Drug-Resistant Tuberculosis Alarms Thai Doctors, Agence France-Presse, June 30, 1995, available in WESTLAW, 1995 WL 7823493.
92. Centers for Disease Control, Exposure of Passengers and Flight Crew to Mycobacterium Tuberculosis on Commercial Aircraft, 1992-1995, 273 JAMA 911 (1995);
93. Cynthia R. Driver et al., Transmission of Mycobacterium Tuberculosis Associated with Air Travel, 272 JAMA 1031 (1994).
94. California School Becomes Notorious for Epidemic of TB, N.Y. Times, July 18, 1994, at A1.
95. Reichman, supra note 8.
96. See Josephine Gittler, Controlling Resurgent Tuberculosis: Public Health Agencies, Public Policy and the Law. 19 J. Health Pol. Pol'y & L. 107, 124 (1994).
97. The tuberculin test consists of an intradermal injection of a purified protein derived from tuberculosis cultures that is usually injected into the skin of the forearm. If the injection produces a significant inflammatory reaction after two days, the test is positive for tuberculosis infection. Isselbacher et al., supra note 17, at 714-15.
98. See id. at 714. Until very recently, the research underlying the diagnosis of tuberculosis was several decades old and unaffected by newer biotechnologic techniques. The vast majority of diagnoses are still derived using these time-consuming methods. Brown, supra note 3. Recently available techniques have improved the length of time for MDR-TB diagnosis to about three weeks. Lawrence O. Gostin, Tuberculosis and the Power of the State: Toward the Development of Rational Standards for the Review of Compulsory Public Health Powers, 2 U. Chi. L. Sch. Roundtable 219, 229 (1995). Even at three weeks, however, there is an appreciable risk of the patient failing to follow through or otherwise being lost to follow-up.
99. See Gostin, supra note 75, at 249.
100. Id.
101. See Gittler, supra note 73, at 116. For example, one group typically screened are persons working in the healthcare industry. Such healthcare workers will be predisposed to agree to screening programs by virtue of their medical knowledge and the fact that it is a requirement for employment in their profession.
102. For example, in the United States, approximately 20% of the population is uninsured. See Laurie Abraham, Tough Times Ahead, 14 Bus. & Health 59 (1996).
103. See Frederick Schmitt, 67M in U.S. Had Lapse in Health Cover, Nat'l Underwriter Life & Health-Fin. Servs. Edition, July 8, 1996, at 2. Elsewhere in the world, particularly in developing nations, healthcare services may be inaccessible or non-existent.
104. These patients frequently are unreliable as a result of their substance abuse disorders, underlying mental illness, and lack of options for transportation to and communication with healthcare facilities and providers. Such a patient might have a tuberculin test placed, but not return for the follow-up reading of the results; likewise if the test is positive, the patient might not appear for the radiographic and laboratory studies. With several stages necessary for the diagnostic process, many at-risk patients never attain diagnosis, let alone treatment of their tuberculosis. See Stephen E. Weis et al., The Effect of Directly Observed Therapy in the Rates of Drug Resistance in Tuberculosis, 330 New Eng. J. Med. 1179 (1994).
105. Among the vulnerable populations are racial and ethnic minorities; they comprise 70% of TB patients. In fact, there is some research data that indicates that certain minorities may be genetically more susceptible to tuberculosis. However, it is more likely that the increased susceptibility is due to a variety of social, economic, behavioral, and biologic factors. See The NHLBI Working Group, Respiratory Diseases Disproportionately Affecting Minorities, 108 Chest 1380 (1995). These vulnerable patients frequently reside in a crowded, substandard living situation that is ideal for easy transmission of tuberculosis. Rothenberg & Lovoy, supra note 29, at 722. Moreover, these are the very populations that lack adequate insurance coverage for healthcare service. Similarly, the homebound elderly person, who may live in a lower socioeconomic neighborhood, be immunologically compromised as a result of age and chronic illness, and be well enough to shop and ambulate in the immediate neighborhood (where TB is prevalent), may face transportation and financial barriers in obtaining routine non-emergency health care.
106. Rothenberg & Lovoy, supra note 29, at 722.
107. See Isselbacher et al., supra note 17, at 715.
108. Anergy is the incapacity of the patient to mount a reaction to the tuberculin test despite the fact the tuberculosis is indeed present. Approximately one-third of patients with new tuberculosis exhibit anergy upon tuberculin testing. Anergy is associated with immunocompromised states. Elderly patients, children, and infants frequently exhibit anergy as do patients suffering from chronic illness. See id. at 715.
109. See id.
110. See Iseman, supra note 9, at 2429; Telzak, supra note 67, at 907.
111. For example, in Asia, where the tuberculosis epidemic is most severe, most Asian governments have not undertaken significant public health efforts. See U.S. Dep't of Health & Human Servs., supra note 12, at 108.
112. Such chemoprophylaxis is prescribed when the patient tests positive with a tuberculin test, but otherwise tests negative for tuberculosis. Chemoprophylaxis is indicated for all patients under the age of 35 and for patients belonging to risk groups who demonstrate a positive tuberculin test. Isselbacher et al., supra note 17, at 717.
113. There are a number of drug regimens that effectively treat tuberculosis; all contain a minimum of two drugs, usually rifampin and isoniazid. The usual course of treatment requires the patient to take these two medications for six to twelve months. Additional or different drugs are required when there is a need to shorten the course of treatment, when the patient is at risk for MDR-TB, when the patient is afflicted with HIV, renal failure, or other maladies that affect response to the drugs, or is pregnant. Id. at 716.
114. Side effects of first-line drugs include hepatitis, peripheral neuropathies, fever, and flu-like symptoms. Unfortunately the liver toxicity and hepatitis associated with isoniazid and similar drugs is a particularly common side effect in Asians; approximately 30% of Asian patients develop this adverse effect, making treatment in the TB-endemic areas of Asia even more difficult. See id. Deafness and renal impairment are associated with streptomycin and most of the second-line drugs. Other deleterious side effects may also occur, but are less common. Id. at 715.
115. Patients frequently fail to finish their treatment program. Default rates as high as 40% to 60% are not uncommon; rarely is the default rate less than 15%. Most of the defaults occur within the first six months of therapy. As a result, more intensive short-course regimens have been developed in the hopes that patients will be more likely to complete the course. See id. at 716. Psychiatric disease, alcoholism, drug addiction and other substance abuse, and homelessness are all positively correlated with noncompliance. Age, sex, religion, education, race, and socioeconomic status are not positively correlated with compliance. See Weis, supra note 80.
116. When a patient has a recurrence of tuberculosis, after having failed to adhere to their past treatment regimen, the likelihood of the recurrence being due to drug resistant tuberculosis is about two chances in three. Isselbacher et al., supra note 17, at 717.
117. Five major drugs are available to treat TB: they are streptomycin (the first anti-TB drug, discovered in 1944 by Waksman), isoniazid (INH, a 1912 drug rediscovered in the 1950s and found to be effective against TB), ethambutol (1950s), pyrazinimide (PZA, developed in the 1960s), and rifampin (1972). Tuberculosis strains frequently have developed resistance to two or more of these drugs. There are also several second-line drugs, including para-amino-salicylic acid, ethionamide, cycloserine, capreomycin, kanamycin and amikacin, thioacetazone, rifabutin, and quinolones; tuberculosis has developed resistance to these drugs as well. See Isselbacher et al., supra note 17, at 715.
118. Marian Goble et al., Treatment of 171 Patients with Pulmonary Tuberculosis Resistant to Isoniazid and Rifampin, 328 New Eng. J. Med. 527, 530 (1993). The more drugs the patient is resistant to, the higher the mortality rate.
119. Sriram Prasad Tripathy, Multidrug-resistant Tuberculosis, World Health, July-Aug. 1993, at 19.
120. Although DOT has become part of the vernacular associated with the current TB epidemic, its origins date back to the late 1940s and early 1950s, where it was used successfully by British researchers to treat patients in Africa, Asia, and London. It also demonstrated successful results when it was implemented on a small scale in the United States during the same era. See Ronald Bayer & David Wilkinson, Directly Observed Therapy for Tuberculosis: History of an Idea, 345 Lancet 1545 (1995). However, DOT was believed to be too costly and labor intensive for widespread use, until desperation caused New York and other urban U.S. cities to try DOT programs. See Morse, supra note 5, at 719.
121. This visitation may take place at the residence, workplace, or other agreed-upon site (shelter, school, food bank, etc.). Successful DOT program are flexible, seeking out the TB patients in tent cities, approaching those working the streets, and offering incentives of food to encourage compliance. See Scott Winokur, Traveling With the TB Trolley. S.F. Examiner, Sept. 14, 1993, at A19.
122. Rothenberg & Lovoy, supra note 29, at 727.
123. A DOT public health worker who prevents even two hospitalizations justifies the cost of the worker's salary. Seven hundred patients can be treated in a DOT program for what it would cost to hospitalize just one patient with MDR-TB. See Morse, supra note 5, at 719.
124. Rothenberg & Lovoy, supra note 29, at 728.
125. In the United States, approximately 15% of patients are involved in DOT programs. Id. at 727. However, as noted infra note 126 and accompanying text, 97% of patients with tuberculosis are located in the developing world, where intensive DOT programs are not feasible.
126. See Morse, supra note 5, at 719.
127. Id.
128. See Winokur, supra note 96.
129. In 1993, 29.6% of reported tuberculosis cases in the United States occurred in persons born outside the United States; overall foreign-born persons account for 60% of the increase in tuberculosis cases from 1986 to 1993. See Raviglione, supra note 6, at 223.
130. For example, one study documented that 89% of patients being treated in a Harlem treatment program were ultimately lost in follow-up. See Brudney & Dobkin, supra note 62, at 747.
131. See Gostin, supra note 29, at 255, 257-58.
132. Id. at 255.
133. See generally Lisa A. Vincler & Deborah L. Gordon, Legislative Reform of Washington's Tuberculosis Law: The Tension Between Due Process and Protecting the Public Health, 71 Wash. L. Rev. 989 (1996). For a discussion of due process issues arising in the context of existing TB control laws and proposals for reform, see Gostin, supra note 29 and Gostin, supra note 75.
134. See infra part III.C.2.
135. See supra notes 37-49 and accompanying text.
136. Rothenberg & Lovoy, supra note 29, at 728.
137. See Russell C. Coile, Jr, Assessing Healthcare Market Trends and Capital Needs: 1996-2000, Healthcare Fin. Mgmt., Aug. 1, 1995;
138. Price Colman, State Hospitals Continue to Shrink: Outpatient Increases Show Growing Trend Toward Managed Care, Rocky Mtn. News (Denver), June 8, 1995, at 51A.
139. See generally Coile, supra note 112; Michael S. Jacobs, When Antitrust Fails: Public Health, Public Hospitals, and Public Values, 71 Wash. L. Rev. 899 (1996).
140. Public health infrastructure has been defined as: "individuals and institutions that, when working effectively together, promote and protect the health of people. The public health system in America consists of the strategies, facilities, the material resources and, above all, the human resources committed to transforming our national health." William L. Roper et al., Strengthening the Public Health System,107 Pub. Health Rep. 609 (1992).
141. See Lederberg, supra note 9; Philip R. Lee, The Evolution of Public Health, 272 JAMA 1315 (1994). The complacency that fostered this deterioration has also contributed to lack of compliance with medication programs and abuse and overuse of antibiotics. Lederberg, supra note 9; See also Brudney & Dobkin, supra note 62, at 748.
142. Alfred Sommer, Whither Public Health, 110 Pub. Health Rep. 57 (1995). Many of the problems that have been embraced by the public health movement are deeply rooted in societal determinants, for which successful intervention is undefined. This results in precious resources being devoted to problems which cannot be resolved at the expense of problems which might be alleviated. Id.
143. Worldwide disease surveillance is inadequate and deteriorating; this is largely due to a lack of a public health infrastructure to underpin such an endeavor. In most cases, although the public health infrastructure can respond to a short-term emergency crisis, it cannot sustain the vigilant effort that is required for a long-term global threat such as tuberculosis. See generally Charles Marwick, Effective Response to Emerging Diseases Called An Essential Priority Worldwide, 273 JAMA 189 (1995).
144. For a discussion of how such a reconstruction could be effected in the age of healthcare reform, see Philip R. Lee & Kathleen E. Toomey, Epidemiology in Public Health in the Era of Health Care Reform, 109 Pub. Health Rep. 1 (1994).
145. See also Kristine Gebbie, Rebuilding a Public Health Infrastructure, 21 J.L. Med. & Ethics 368 (1993);
146. Margaret A. Hamburg, Rebuilding the Public Health Infrastructure: The Challenge of Tuberculosis Control in New York City, 21 J.L. Med. & Ethics 352 (1993);
147. Stephen C. Joseph, New York City, Tuberculosis, and the Public Health Infrastructure, 21 J.L. Med. & Ethics 372 (1993); Roper et al., supra note 114.
148. TB is predicted to be responsible for 30 million deaths worldwide in the coming decade. See Nakajima, supra note 5.
149. See Siege Relief, Am. Med. News, Jan 8, 1996, at 35. However, some postulate that unless the public health system survives and strengthens to the point that it is able to effectively work with private healthcare efforts, the private healthcare financing and delivery system will be overwhelmed with illnesses and injuries caused by public health problems they are powerless to control.
150. See generally Edward L. Baker et al., Health Reform and the Health of the Public: Forging Community Health Partnerships, 272 JAMA 1276 (1994).
151. See Earl S. Hershfield, Prevention in the Developed World, 346 Lancet 813 (1995).
152. All industrialized nations with the exception of the United States and South Africa have universal healthcare systems providing care for their populations. Note, however, that several of the systems, notably that in the United Kingdom, have recently sought to privatize certain segments of health-care services.
153. Christina Kent, A Long-Neglected System Strains to Respond to a Rising Threat, Am. Med. News, Jan. 8, 1996, at 9.
154. See Reichman, supra note 8, at 175.
155. See Ronald J. Waldman, Public Health Surveillance on the World Health Agenda, Speech delivered at International Symposium on Public Health Surveillance, in 41 Morbidity & Mortality Wkly. Rep. 201 (1992) (describing information and system needs for world health surveillance).
156. But see Lawrence O. Gostin et al., The Public Health Information Infrastructure: A National Review of the Law on Health Information Privacy, 275 JAMA 1921 (1996) (discussing confidentiality and privacy concerns of enhanced informational systems).
157. More than one-fifth of the 5.6 billion people in the world live in extreme poverty, almost a third of the world's children are undernourished, and half the global population lacks access to medications. See WHO Widening Gaps Between Rich and Poor Pose Global Health Threat, Vaccine Wkly., May 1, 1995, available in WESTLAW, 1995 WL 10090893, at *I; see also Brown, supra note 3.
158. Weiner, supra note 54, at 261.
159. The role of travel and migration in the spread of tuberculosis has been appreciated since the turn of the century. With the invention of the locomotive, rail travel brought tuberculosis to many areas in which tuberculosis had been rare. Moreover, these new frontier areas frequently were unable and unwilling to accept the chronically ill tuberculosis patient who stepped off the train. See Rothman, supra note 7, at 190-91.
160. See Lederberg, supra note 9.
161. One of the greatest potential causes of infectious disease epidemics, including tuberculosis, is the development of the third world and the urbanization of industrialized nations. As persons from rural areas devoid of an infectious disease are exposed to urban areas rife with risk, the disease is able to spread geographically. See International (North and South America) Spread of Infectious Disease Continues, AIDS Wkly. Plus, June 3, 1996, available in WESTLAW, 1996 WL 2093337. From 1950 to 1990, the world's urban population increased from 29% to 45% of the planet's population. Concerned about the public health implications of this movement into cities, the World Health Organization has urged nations to offer incentives to their citizenry to deter such migration.
162. Phil Gunby, 1992 Could Be Pivotal Year in Efforts to Improve Health of People Everywhere, 267 JAMA 15 (1992).
163. See Garrett, supra note 10; see also Mitchell L. Cohen, Epidemiology of Drug Resistance: implications for a Post-Antimicrobial Era, 257 Science 1050 (1992).
164. See Garrett, supra note 10.
165. See Lederberg, supra note 9; Working Group on Emerging & Re-emerging Infectious Diseases, National Science & Technology Council, Infectious Disease - A Global Health Threat (last modified Nov. 7, 1996) 〈http://www.whitehouse.gov/WH/EOP/OSTP/CISET/html/ciset.html〉.
166. See Lederberg, supra note 9. Surveillance for infectious disease at airport entry ranges from grossly inadequate to biologically irrational to non-existent. Infectious diseases may not be symptomatic or evident for days, weeks, or months after entry. See Garrett, supra note 10. In the case of TB, a patient would have to exhibit significant signs of active disease to be detected given that rapid testing for the tuberculosis is unavailable.
167. See Garrett, supra note 10.
168. Immigration from developing nations increases the risk of MDR-TB. The immigrant may have received inadequate treatment prior to leaving the native country and may be incubating drug resistant TB. The immigrant is likely to settle in an urban area, often in a enclave of other recent immigrants who might harbor tuberculosis. In addition, the new immigrant may lack access to health care in his or her new home and allow the disease to progress before seeking treatment. See Alan B. Bloch et al., Preventing Multidrug Tuberculosis, 275 JAMA 487 (1996); Garrett, supra note 10. In the United States, for instance, foreign-born patients are markedly more prone to be diagnosed with tuberculosis.
169. U.S. Dep't of Health & Human Servs., Tuberculosis Morbidity - United States, 1994, 44 Morbidity & Mortality Wkly. Rep. 387, 395 (1995). In New York, where the TB epidemic is strongly identified with the incidence of HIV and substance abuse, one-third of the patients are foreign born. In other areas of the United States, TB primarily affects immigrant populations. Similarly, in other industrialized nations, more than half of new TB cases are found among foreign-born persons.
170. WHO Urges Making Directly-Observed Therapy the Priority in Global Tuberculosis Control; Praises New York as Model to Stop TB Epidemic, U.S. Newswire, Mar. 20, 1995.
171. See Sana Loue, Immigrants, Immigration Law, and Tuberculosis, 71 Wash. L. Rev. 969, 979-85 (1996).
172. See id.; Stephenson, supra note 8, at 1648.
173. See Stephenson, supra note 8.
174. Nakajima, supra note 5.
175. Id.
176. 197 U.S. 11 (1905). In Jacobsen, the Supreme Court held that a Massachusetts man had to comply with a mandatory smallpox vaccination law, despite the fact that it infringed upon his individual liberty rights. The Court reasoned that individual liberty rights may be curtailed under the police powers of a state when the health and safety of the general citizenry are at risk. Id. at 26-27.
177. See Gittler, supra note 73, at 124.
178. See Gostin, supra note 29, at 257-59; Rothenberg & Lovoy, supra note 29, at 733-37.
179. Rothenberg & Lovoy, supra note 29, at 733.
180. For a detailed analysis of the interplay between individual rights to substantive and procedural due process in the context of prevention and treatment of tuberculosis, see Gostin, supra note 75.
181. See Reilly, supra note 11, at 140-41.
182. Brown, supra note 61, at 1595.
183. Id.
184. Id.
185. In the United States, there were 24,361 cases of active tuberculosis in 1994; a year later, as a result of conscientious renewed public health efforts in cities like New York, the number decreased to just under 23,000. See Thomas R. Frieden et al., Tuberculosis in New York City - Turning the Tide, 333 New Eng. J. Med. 229 (1995);
186. TB's Resurgence Calls for New Drugs, Seattle Post-Intelligencer, Mar. 26, 1996, at A6.
187. See Lederberg, supra note 9. And these are not the best of times; like many other nations, the United States faces an ever more constrained budget. Id.
188. Many developing countries tend to refrain from using rifampin, a more expensive drug, if possible. Often, they instead use thiacetazone, a cheap but less effective anti-TB drug that also has a propensity for fatal adverse reactions when administered to AIDS patients. In addition, because developing countries are heavily dependent upon donor drug supplies from pharmaceutical companies or other nations, they may have little control over the content and quantity of their supply of anti-tuberculosis drugs. See Alwyn Mwinga, Treatment in Developing Countries, 346 Lancet 812 (1995); Brown supra note 3. Obviously this presents significant problems in Asia, where risk of hepatic toxicity from isoniazid is high and access to rifampin limited; the net result is that developing nations may find themselves deprived of both first-line drugs. See supra note 90.
189. Rothenberg & Lovoy, supra note 29, at 728.
190. See supra notes 97-102 and accompanying text
191. See Morse, supra note 5, at 719.
192. See Fighting TB-U.S. Must Join Global Health Effort, Dallas Morning News, Dec. 29, 1993, at 18A.
193. Moreover, in relative terms, the amount of currently allocated aid is woefully inadequate when compared to other medical problems of the developing world. For example, in contrast to the $16 million allotted to TB in 1990, $77 million was devoted to treatment of leprosy, a disease which claimed only 2000 lives that year. Id.
194. Tan, supra note 1, at 211.
195. See Richard J. O'Brien. WHO's Role in Tuberculosis Research, World Health, July 1993, at 13.
196. Five major first-line drugs are available to treat TB; several second-line, less effective drugs may also be used. See supra notes 89-90, 93 and accompanying text.
197. Reichman, supra note 8, at 175.
198. These drugs, Rifater, and Rifamate, contain two or more anti-tuberculosis drugs in one capsule. They offer dosing advantages over multiple single agents. See id; Thomas Moulding et al., Fixed-dose Combinations of Antituberculous Medications to Prevent Drug Resistance, 122 Archives Internal Med. 951, 951 (1995).
199. See WHO Accuses Industry of Indifference to TB Dilemma, Pharmaceutical Bus. News, Mar. 27, 1996, at 14.
200. At the time, this was thought to be due to a myriad of factors, not the least of which were the technical limitations of the time. See Dubos & Dubos, supra note 7, at 163.
201. See generally supra notes 40-41 and accompanying text.
202. See supra notes 40-41 and accompanying text. A recent review of the literature indicated that BCG significantly reduces the risk of TB, but that there is insufficient information to determine its efficacy, especially as related to age of vaccination. Graham A. Colditz et al., Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature, 271 JAMA 698 (1994). Perhaps the greatest problem with BCG is the incredibly variable protection it provides-ranging from zero to 80%. In seeking to clarify its efficacy, one study found that the effectiveness of the vaccine appears to be affected by geography, sunlight, temperature, manufacturing and storage conditions, and genetic factors.
203. P.E.M. Fine, Variation in Protection by BCG: Implications of and for Heterologous Immunity, 346 Lancet 1339 (1995).
204. See Daniel J. DeNoon, New Strategies Revolutionize Vaccinology, Vaccine Wkly., Nov. 13, 1995.
205. M. Harboes, Novel Developments: Vaccines against Tuberculosis, Vaccine Wkly., Apr. 1, 1996.
206. See Joseph H. Bates, Tuberculosis Chemotherapy: The Need for New Antituberculosis Drugs is Urgent, 151 Am. J. Respiratory Critical Care Med. 942, 943 (1995). Note however, that several trials are ongoing with respect to new versions of existing drugs and combinations of existing drugs to decrease the length and absolute number of doses to effect cure. See Reichman, supra note 8, at 175.
207. Many historians have commented upon the strange association between tuberculosis and intellectual and creative activities, citing its more famous victims as examples: Voltaire, Keats, Shelley, Robert Louis Stevenson, and Saint Francis of Asissi. See generally Lewis J. Moorman, Tuberculosis and Genius (1940).
208. In the United States, 29.6% of tuberculosis cases occur in persons bom outside the United States. Raviglione, supra note 6, at 223. Foreign-born persons are increasingly viewed as outsiders regardless of their immigration status, as is illustrated by the recent legislative proposals to limit government benefits and other entitlements available to legal immigrants. Bruce B. Auster et al., A Blizzard of Bills from Congress: Will Welfare Reform Worsen Life for the Poor?, U.S. News & World Rep., Aug. 12, 1996, at 25;
209. Faye Fiore, Welfare Reform Increases Health Risks, Experts Warn, L.A. Times, Aug. 24, 1996, at A12;
210. Janice Somerville, AMA: Maintain Health Care for Legal Immigrants, Am. Med. News, July 17, 1995, at 5.
211. There is some evidence that tuberculosis undermines developing nations' efforts to build more functional economies in that it strikes potential workers before or in their most productive years. U.S. Newswire, supra note 136.
212. Lederberg, supra note 9; see also WHO Accuses Industry of Indifference to TB Dilemma, supra note 164.
213. See Kent, supra note 123.
214. See Lederberg, supra note 9.
215. See generally Rosemarie Kanusky, Pharmaceutical Harmonization: Standardizing Regulations among the United States, the European Economic Community, and Japan, 16 Hous. J. Int'l L. 665 (1994).
216. See generally id.
217. Federal News Service, Hearing of the Oversight and Investigations Subcomm. of the House Commerce Comm., Feb. 29, 1996, available in WESTLAW, 1996 WL 5509259, at *146 (comments by Chair of Subcomm., Rep. Joe Barton).
218. Carolyn Lochhead, "Deadly Over-Caution"/FDA Assailed for Slow Testing of New Drugs, S.F. Chron., Oct. 26, 1992, at A1.
219. 21 U.S.C. §§ 301-393 (1996). The 1938 Food, Drug and Cosmetics (FD&C) Act superseded the Food and Drug Act of 1906, expanding the scope of product regulation dramatically. The 1938 Act imposed requirements upon drug manufacturers to file a new drug application before they marketed their products to the public. A series of amendments have modified and further expanded the scope of the 1938 Act, usually enacted in response to the expanding frontiers of science. These range from amendments added in 1941 to address a new biologic, insulin, to the Prescription Drug User and Generic Drug Enforcement Acts of 1992. Throughout its long history, the FDA has focused on regulating food and drug manufacturing to ensure safety and effectiveness. See Alan H. Kaplan, Fifty Years of Drug Amendments Revisited: In Easy-to-Swallow Capsule Form, 50 Food & Drug L.J. 179 (1995).
220. 42 U.S.C. § 262 (1994). Curiously, the statutory provisions governing biologies like vaccines actually predate the 1906 Food and Drug Act. Congress took action to regulate such biologies in 1902 after a number of highly publicized deaths resulted from contaminated smallpox vaccine. Despite the early legislative action and statutory authority, regulation of biologies was largely unenforced until the 1950s. Gary E. Gamerman, Regulation of Biologics Manufacturing: Questioning the Premise, 49 Food & Drug L.J. 213 (1994).
221. 21 U.S.C. § 360 (1994).
222. For discussion of the relationship and interplay between the FD&C Act and the PHS Act provisions, see Edward L. Korwek, Human Biological Drug Regulation: Past, Present, and Beyond the Year 2000, 50 Food & Drug L.J. 123 (1995). Korwek notes that biologies products are simultaneously either biologies and drugs or biologics and devices under existing law. Thus, the major distinction is whether or not the contemplated product is a biologic; if so, it will be susceptible to two sets of regulatory requirements. Id. at 128. Another layer of complication is that within the regulatory bureaucracy, separate regulatory centers deal with different FDA products. Drugs are evaluated by the Center for Drug Evaluation and Research (CDER) and biologies by the Center for Biologics Evaluation and Research (CBER). See Gamerman, supra note 182, at 213-16.
223. The delays and time required in the current process are inextricably linked with cost. Industry experts report that taking the average drug from laboratory to market costs $400 million and requires 15 years. Moreover, they estimate that 90% of the average cost is secondary to the regulatory delays. See Julie C. Relihan, Expediting FDA Approval of AIDS Drugs: An International Approach, 13 B.U. Int'l L.J. 229, 237 (1995).
224. Elizabeth M. Rutherford, The FDA and "Privatization" - The Drug Approval Process, 50 Food & Drug L.J. 203, 212 (1995);
225. Tanya E. Karwaki, Comment, The FDA and the Biotechnology Industry: A Symbiotic Relationship?, 71 Wash. L. Rev. 821, 828 (1996).
226. John Patrick Dillman, Prescription Drug Approval and Terminal Diseases: Desperate Times Require Desperate Measures, 44 Vand. L. Rev. 925, 929 (1991); Relihan, supra note 185, at 237.
227. The United States, European Community nations, and Japan generate 90% of all pharmaceutical research and constitute 75% of the market Kanusky, supra note 177, at 667.
228. Reichman, supra note 8, at 175.
229. Such "profitable" conditions are suffered by a higher quotient of the adequately insured populations of the world; the majority of tuberculosis patients, on the other hand, are poor, powerless, and uninsured.
230. Reichman, supra note 8, at 175.
231. Since then, WHO reportedly has received permission to study this drug for treatment of TB in Europe. WHO continues to complain bitterly about the pharmaceutical industry's apparent disinterest in developing new therapies to combat TB. Moreover, it argues that given the enormous market for the current TB drugs, the prices could and should be lowered. WHO Accuses Industry of Indifference to TB Dilemma, supra note 164.
232. See generally Kanusky, supra note 177; Christina Kent, Controversial FDA Overhaul Advances in Congress, Am. Med. News, Apr. 22, 1996, at 3.
233. Until recently, the length of the patent term was 17 years. However, as of June 8, 1995, the patent term length was increased to 20 years. See 35 U.S.C. § 154 (1996).
234. See 35 U.S.C. §§ 155-156 (1996) (detailing conditions pertaining to such extensions). Despite the extensions, critics argue that they fail to adequately address the problems faced by manufacturers. Jonathan L. Mezrich, The Patentability and Patent Term Extension of Lifesaving Drugs: A Deadly Mistake, 6 J.L. & Health 111, 116-17 (1991-92).
235. Janice M. Hogan, Revamping the Orphan Drug Act: Potential Impact on the World Pharmaceutical Market, 26 L. & Pol'y Int'l Bus. 523, 525-27 (1995). The length of the approval process proved to be a barrier in responding to new disease challenges, as became glaringly evident with the AIDS epidemic. In fact, a 1981 congressional survey revealed that 80% of drugs considered "public service" drugs were the result of serendipitous discoveries, rather than from research targeted to a specific disease.
236. Peter S. Arno et al., Rare Diseases, Drug Development, and AIDS: The Impact of the Orphan Drug Act, 73 Milbank Q. 231, 233 (1995).
237. Veronica Henry, Problems with Pharmaceutical Regulation in the United States: Drug Lag and Orphan Drugs, 14 J. Legal Med. 617, 637-39 (1993); Relihan, supra note 185, at 245-49.
238. See Kanusky, supra note 177, at 676-84.
239. See id. at 684-87. Although the perception is that foreign regulations are much less arduous and time-consuming than the U.S. process, in reality the differences are slight. For example, a new product in the United States typically takes 12 years to develop and costs $231 million to market while a new product in a European Community nation takes 12-14 years to develop and costs S220 million to market. See id. at 682-83.
240. Indeed, even within the European Community, member states subject pharmaceutical products to separate regulation. Id. at 680.
241. Randall B. Keiser, Deja Vu All Over Again? The National Childhood Vaccine Injury Compensation Act of 1986, 47 Food & Drug L.J. 15, 16 (1992);
242. see also Philip M. Boffey, Experts Warn of 'Precarious' Vaccine Supplies, N.Y. Times, July 30, 1985, at C10.
243. See Subcomm. on Health & the Env't of the House Comm. on Energy & Commerce, 99th Cong., 2d Sess., Childhood Immunizations 86 (Comm. Print 1986).
244. Id. at 70-71.
245. See Carolyn H. Asbury, The Orphan Drug Act: The First 7 Years, 265 JAMA 893 (1991).
246. Ronald Podraza, The FDA's Response to AIDS: Paradigm Shift in New Drug Policy?, 48 Food & Drug L.J. 351, 352-54 (1993). There was widespread perception that the FDA attitude towards AIDS and AIDS patients was "obstructionist, insensitive, inflexible and otherwise cruelly oblivious of their plight." Id.
247. See id. at 363.
248. See Reichman, supra note 8, at 175-77.
249. See supra notes 196-204 and accompanying text.
250. See Asbury, supra note 204, at 893; Donna Brown Grossman, The Orphan Drug Act: Adoption or Foster Care?, 39 Food Drug Cosmetic L.J. 128 (1984); Hogan, supra note 196, at 525.
251. See Henry, supra note 197, at 629.
252. 21 U.S.C. §§ 360aa-360ee (1994).
253. See 26 U.S.C. § 28(a) (1996). This tax credit was available only for expenses incurred through the end of 1994.26 U.S.C. § 28(e) (1996).
254. 21 U.S.C. § 360aa.
255. 21 U.S.C. § 360cc.
256. A second drug can be approved for the same indication when the first manufacturer is unable to produce the drug in adequate quantities, when the second company obtains the consent of the first to enter the market, when the first chooses to exit the market, or when the second newer orphan drug is proven to be superior to the initial drug for the treatment indications. Hogan, supra note 196, at 529.
257. 21 U.S.C. § 360bb(a)(2).
258. 21 U.S.C. § 360bb(a)(2).
259. 21 U.S.C. § 360ee.
260. Cystic fibrosis is a hereditary disorder characterized by pancreatic dysfunction and chronic progressive respiratory disease; patients frequently succumb as young adults.
261. This hereditary enzyme deficiency presents in several different forms, ranging from a devastating infantile form to a milder adult form. The adult form of the disease is characterized by disorders of blood and clotting, pulmonary disease, and liver dysfunction; more severe forms of the disease impair the neurologic system. Care and treatment of patients with Gaucher's disease has changed materially with the development of a replacement enzyme, marketed as Ceredase, which was developed as an orphan drug.
262. Hogan, supra note 196, at 530; see also Arno et al., supra note 196, at 232.
263. Patients with this type of deficiency have a dysfunction of the pituitary gland, a small gland in the brain. The pituitary is responsible for triggering the release of a variety of hormone necessary for normal life, including reproductive hormones, thyroid hormones, and growth hormone. The latter is responsible for normal growth; if it is lacking, it must be supplemented to assure normal height and maintain certain-other metabolic parameters within normal range.
264. Hogan, supra note 196, at 530.
265. Id. at 531.
266. Use of insurance health plans and Medicaid plans for coverage of such expensive drugs has far-reaching implications. If the patient is a member of a small health plan the cost of the premium for the coverage may increase dramatically as the small group's subscribers offset the cost of this extreme expense. See id. at 531-32. Similarly if the patient is covered under a state Medicaid plan, this single patient may use so many financial resources that many other worthy Medicaid patients are foreclosed from eligibility.
267. Id. at 533; see also Arno et al., supra note 196, at 237.
268. For example, a new drug, D-Nase, developed by Genentech for cystic fibrosis (CF) may have orphan status on the basis of its use for CF, but it also may be effective against more common afflictions, like bronchitis and pneumonia - afflictions likely to be widespread in developed nations. See Hogan, supra note 196, at 533.
269. See id.; Arno et al., supra note 196, at 240. "Off-label" use means that the drug is used for an indication not authorized by the descriptive label approved by the FDA. For a more in depth discussion of off-label use of drugs and the scientific, ethical, and economic implications of this practice, see Richard M. Cooper, Unapproved Uses of Drugs: An Analysis and Some Proposals, 49 Food & Drug L.J. 533 (1994).
270. See Hogan, supra note 196, at 535-36.
271. TB 's Resurgence Calls for New Drugs, supra note 151. Note, however, that these promising statistics are not found elsewhere in the world, particularly in the developing world where 97% of tuberculosis occurs. This will make continued success of public health efforts in industrialized nations ever more susceptible to erosion.
272. Hogan, supra note 196, at 537.
273. Id. at 537-38.
274. See International Prescription Drug Prices: Hearing Before the Subcomm. on Health and the Env't of House Comm. on Energy and Commerce, 103d Cong., 1st Sess. (1993).
275. Hogan, supra note 196, at 548.
276. See supra notes 220-232 and accompanying text.
277. The cost of a typical orphan drug can be shared among only a finite number of patients around the world. Cost sharing is further permuted by the fact that many countries limit the price that can be charged for pharmaceutical products in their countries. As a result, the cost-shifting burden on the U.S. patient is multiplied. Unlike most orphan drugs that are dedicated to rare orphan diseases afflicting a small number of patients new TB drugs would treat disease, that, although relatively rare in the United States, is rampant elsewhere in the world. Thus, given the great volume of patients, the cost shifting burden is unlikely to be as severely disproportionate, and may even be negligible.
278. Sheila R. Shulman & Jeffrey S. Brown, The Food and Drug Administration's Early Access and Fast-Track Approval Initiatives: How Have They Worked?. 50 Food & Drug L. J. 503, 503 (1995).
279. See infra notes 179-187 and accompanying text.
280. See 21 C.F.R. § 312.34 (1996). The treatment IND program builds on several previous access programs that allowed patients suffering from life-threatening or serious illness to have "compassionate" access to new drugs that were not yet folly approved for marketing. See Frank E. Young et al., The FDA's New Procedures for the Use of Investigational Drugs for Treatment, 259 JAMA 2267 (1988).
281. The parallel track process, announced at 57 Fed. Reg. 13,250 (1992), provides an administrative process to expand availability of new drugs directed at HIV patients. Under the parallel track, patients who would otherwise be unable to participate in clinical trials of promising new drugs are allowed access to the drugs. However, the attending physicians are required to file reports and data with the FDA and there are several layers of oversight. See Shulman & Brown, supra note 237, at 509-10.
282. 57 Fed. Reg. 13 250 (1992) ("This parallel track policy describes processes specifically for AIDS and other HIV-related diseases.").
283. 21 C.F.R. § 312.80 (1996).
284. Subpart E states: The Food and Drug Administration (FDA) has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated. 21 C.F.R. § 312.80 (1996)
285. 21 C.F.R. § 312.84 (1996).
286. See text accompanying notes 185-186.
287. This "fast track" also allows clinical study of new drugs without requiring there to be a "placebo" control group. See Relihan, supra note 185, at 240.
288. See Shulman & Brown, supra note 237, at 511.
289. Id. at 517. For example, Flutamide, a drug used to treat prostate cancer completed FDA review in a record 3.7 months. Id. at 525.
290. Id. at 513.
291. See 21 C.F.R. §§ 314.500,601.40 (1996).
292. A surrogate endpoint is a desirable outcome demonstrated in the context of a similar, but not identical set of clinical circumstances or patient population. See 21 C.F.R. § 314.510 (1996).
293. See 21 C.F.R. §§ 314, 601 (1996).
294. See Shulman & Brown, supra note 237, at 515-16.
295. See id. at 516.
296. See H.R. Rep. No. 99-908, at 4 (1986), reprinted in 1986 U.S.C.C.A.N. 6344, 6347-48; supra notes 201-203 and accompanying text.
297. W. Page Keeton et al., Prosser and Keeton on the Law of Torts § 96, at 688 (5th ed. 1984).
298. Id. § 98, at 692-94.
299. Id. § 99, at 701-02.
300. See supra notes 201-203 and accompanying text; see also Subcomm. on Health & the Env't of the House Comm. on Energy & Commerce, 99th Cong. 2d Sess., Childhood Immunizations 21-33 (Comm. Print 1986).
301. See Vaccine Injury Compensation, 1984: Hearings on H.R. 556 before the Subcomm. on Health and the Environment of the House Comm. on Energy and Commerce, 98th Cong., 2d Sess. 295 (1984) (statement of Dr. Daniel Shaw, Jr. Vice President, Wyeth Laboratories).
302. See. e.g., Givens v. Lederle Lab., 556 F.2d 1341 (5th Cir. 1977); Reyes v. Wyeth Lab., 498 F.2d 1264 (5th Cir.), cert. denied, 419 U.S. 1096 (1974); Davis v. Wyeth Lab. Inc., 399 F.2d 121 (9th Cir. 1968).
303. See Thomas E. Baynes, Jr., Liability for Vaccine Related Injuries: Public Health Considerations and Some Reflections on the Swine Flu Experience, 21 St. Louis U. L.J. 44, 64-66 (1977). This congressional action was further spurred by the Legionnaire's Disease mini-epidemic in Philadelphia during that congressional session. Although swine flu is remembered as only a minor footnote today, in 1976 there was concern that it might rival a similar earlier flu that had taken 20 million lives worldwide. See
304. H. William Smith, III, Vaccinating AIDS Vaccine Manufacturers against Product Liability, 42 Case W. Res. L. Rev. 207, 219 (1992).
305. See generally Richard E. Neustadt & Harvey V. Fineberg, The Epidemic That Never Was: Policy Making and the Swine Flu Affair (1983).
306. 28 U.S.C. §§ 2671-2678 (1994).
307. Arnold W. Reitze, Jr., Federal Compensation for Vaccination Induced Injuries, 13 B.C. Envtl. Aff. L. Rev. 169, 178-79 (1986).
308. See Baynes, supra note 262, at 68.
309. Smith, supra note 262, at 221. The swine flu epidemic did not fully materialize.
310. See Reitze, supra note 264, at 181-82.
311. Smith, supra note 262, at 219. By the mid-1980s, the cost of claims was at $83 million and rising. Reitze, supra note 264, at 185.
312. See supra notes 260-263 and accompanying text.
313. See supra notes 259-260 and accompanying text.
314. Daniel A. Cantor, Striking a Balance between Product Availability and Product Safety: Lessons From the Vaccine Act, 44 Am. U. L. Rev. 1853, 1959 (1995); Keiser, supra note 201, at 16.
315. Pub. L. No. 99-660, 100 Stat. 3755 (codified at 42 U.S.C. §§3 00aa-2 to 6, 10 to 17, 19, 21, 23, 25 to 28, 31 to 33 (1994)).
316. 26 U.S.C. §§ 4131-4132 (1994).
317. See 42 U.S.C. §§ 300aa-11 to 16 (describing the filing process and requirements, vaccine injury tables, and compensation provisions and requirements).
318. 42 U.S.C. § 300aa-21.
319. Smith, supra note 262, at 227-28. California subsequently enacted a similar statute targeting development of AIDS vaccines. The California statute included no-fault provisions, but the patient was not foreclosed from seeking recovery from the manufacturer as well, although no "double dipping" was allowed. Id. at 229-30. This provision was short-lived and appears not to have been implemented in any substantive way prior to its repeal in 1995.
320. See generally Dillman, supra note 187.
321. See Charles Marwick, Congress Moving to Improve FDA Performance, 275 JAMA 670 (1996). There is, of course, no guarantee that FDA reform will improve upon the system; radical reform might so shake up the FDA regulatory bureaucracy that drug approval could be subject to even more delay and confusion.
322. See Rutherford, supra note 185, at 205-24.
323. See id. at 209-10.
324. See id. at 216. For an example of a recent bills proposing such measures, see Food and Drug Administration Performance and Accountability Act of 1995, S. 1477, 104th Cong., 1st Sess. (1995)
325. and the Drug and Biological Products Reform Act of 1996, H.R. 3199, 104th Cong., 2nd Sess. (1996).
326. For a detailed analysis of and proposal for such a reform, see Nina J. Crimm, A Tax Proposal to Promote Pharmacologic Research, to Encourage Conventional Prescription Drug Innovation and Improvement, and to Reduce Product Liability Claims 29 Wake Forest L. Rev. 1007 (1994).
327. See Medtronic, Inc. v. Lohr, 116 S. Ct. 2240 (1996) (holding that clause in Medical Devices Act preempting states from regulating safety and effectiveness of medical devices did not preempt all state law causes of action brought by injured patient against manufacturer of defective pacemaker).
328. See Kanusky, supra note 177, at 688-95; Eric M. Katz, Europe's Centralized New Drug Procedures: Is the United States Prepared to Keep Pace?, 48 Food & Drug L.J. 577 (1993).
329. There has already been some promising movement in this direction. For example, the recent extension of the patent term from 17 to 20 years was largely for the purpose of harmonizing the length of the term with that of other nations.
330. See Kanusky, supra note 177, at 703-06.
331. See, e.g., Daniel J. DeNoon, Mycobacterial Antigen 85: Key to Effective TB Vaccine?, Vaccine Wkly., Apr. 8, 1996, available in WESTLAW, 1996 WL 2001405;
332. Licensing/Collaboration Agreement on TB Vaccine Completed, Vaccine Wkly., Oct. 16, 1995, available in WESTLAW, 1995 WL 10121617;
333. Warren Wilson, PathoGenesis' New TB Fighter Shows Promise, Seattle Post-Intelligencer, Sept. 17, 1996, at B4.