by Sonia Shah
39. Reshma Patil and Toufiq Rashid, “Strong Medicine,” Sunday Express, December 28, 2003, 11.
40. Gawande, “Dispatch from India.”
41. Jayaprakash Narayan, “Healthcare Is Sick,” Humanscape, September 2003, 17.
42. Interview with Yash Lokhandwala, November 28, 2003.
43. Madhumita Bose, “Doctor, Heal Thyself,” Business India, June 24–July 7, 2002, 107.
44. Soma Wadha, “Hypocratic Practice,” Outlook, February 3, 2003, 51.
45. Geoff Dyer, “Sepsis Treatment Makes Slow Start at Eli Lilly,” Financial Times, March 5, 2002, 20.
46. Eli Lilly press release, “Lilly Launches World’s Largest Severe Sepsis Clinical Trial: 11,000 Patients to Be Enrolled in Study of Xigris Use in Patients with Low Risk of Death,” September 17, 2002.
47. “Eli Lilly Launches Xigris to Combat ‘Blood Poisoning,’” Business Line, October 19, 2002.
48. Thomas M. Burton, “Left on the Shelf: Why Cheap Drugs That Appear to Halt Fatal Sepsis Go Unused—Steroids Need Big Human Trial, but Pharmaceutical Makers Lack Incentive to Fund One—Dr. Meduri’s 15-Year-Quest,” Wall Street Journal, May 17, 2002, A1.
49. Society of Critical Care Medicine, “ICU Issues and Answers: Sepsis: What You Should Know,” available at www.sccm.org/patient_family_resources/support_brochure.
50. When the reaction causes blood pressure to drop, depriving organs of oxygen, it’s called “septic shock.” When the infection is in the bloodstream itself, it’s called “septicemia.” Eli Lilly press release, “Lilly Launches World’s Largest Severe Sepsis Clinical Trial”; Society of Critical Care Medicine, “ICU Issues and Answers.”
51. Jane E. Brody, “New Hope for Taming Deadly Septic Shock,” New York Times, March 5, 2002, F1.
52. Gina Kolata, “Halted at the Market’s Door: How a $1 Billion Drug Failed,” New York Times, February 12, 1993, A1; Sandra Sugawara, “FDA Test Concerns Send Centocor’s Stock Plunging,” Washington Post, April 16, 1992, B11.
53. E.J. Ziegler et al., “Treatment of Gram-Negative Bacteremia and Septic Shock with HA-1A Human Monoclonal Antibody Against Endotoxin. A Randomized, Double-Blind, Placebo-Controlled Trial,” New England Journal of Medicine, February 14, 1991, 429–36.
54. Tim Friend, “Drug’s Value ‘Like Penicillin,’” USA Today, February 14, 1991, 1A.
55. Sandra Sugawara, “FDA Test Concerns Send Centocor’s Stock Plunging,” Washington Post, April 16, 1992, B11.
56. As Martin Tobin later pointed out, “If mortality is significantly decreased in one subgroup but overall mortality is not changed, logic dictates that some patients must have had an increased mortality.” Martin J. Tobin, “The Role of a Journal in a Scientific Controversy,” American Journal of Respiratory and Critical Care Medicine 168 (2003): 512.
57. Sally Squires, “Sepsis,” Washington Post, October 1, 1991, Z11.
58. “Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785).” If those on the drug had survived at the same rate as those on placebo, only 290 would have died rather than 318 (37 percent of 785). Richard V. McCloskey et al., “Treatment of Septic Shock with Human Monoclonal Antibody HA-1A,” Annals of Internal Medicine, July 1, 1994, 1–5.
59. “Murphy to Up Stake,” New Orleans Times-Picayune, January 19, 1993, C1.
60. “Drugmaker Takes a Nosedive,” Cleveland Plain Dealer, January 19, 1993, 1F.
61. Kolata, “Halted at the Market’s Door.”
62. FDA Center for Drug Evaluation and Research, Anti-infective Drugs Advisory Committee, transcript, October 16, 2001, 12.
63. See www.vericc.org/01_new/media_pbn_030908.htm.
64. Burton, “Left on the Shelf.”
65. Ibid.
66. Gordon R. Bernard et al., “Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis,” New England Journal of Medicine, March 8, 2001, 699–709.
67. Not to mention the fact that the steroid researchers had refused to let their placebo patients suffer for very long. After ten days, if patients hadn’t responded, they were switched to the treated group. The move, while compassionate, could have muddied the results. Burton, “Left on the Shelf.”
68. Bernard et al., “Efficacy and Safety of Recombinant Human Activated Protein C.”
69. Ibid.
70. See content.nejm.org/early_release/.
71. “‘Sepsis: The Peril of Infection’ a ‘Cutting Edge Medical Report’ iTV Special Premieres on the Health Network March 10,” PR Newswire, March 8, 2001.
72. “Bayer to Form International Sepsis Forum,” Pharmaceutical Business News, March 26, 1997.
73. According to the FDA analysis, there was but a one in twelve chance that this trend toward diminishing effectiveness and even harm had occurred simply by random chance. Bolstering the worrying trend was the fact that in unrelated studies sepsis researchers had similarly linked the severity of the disease with patients’ responses to treatment, i.e. P=.08. FDA Center for Drug Evaluation and Research, Anti-infective drugs advisory committee, transcript, October 16, 2001.
74. FDA Center for Drug Evaluation and Research, Anti-infective Drugs Advisory Committee, 247; H. Shaw Warren et al., “Risks and Benefits of Activated Protein C Treatment for Severe Sepsis,” New England Journal of Medicine, September 26, 2002, 1027–30.
75. Ibid.
76. Since the probability of the disturbing data on Xigris occurring by chance was higher than one out of twenty, neither the agency nor scientific convention required Lilly to mention it. The only hint emanating from the FDA was its statement that “not everyone will benefit” from Xigris. FDA Center for Drug Evaluation and Research, Anti-infective Drugs Advisory Committee, 323; U.S. Food and Drug Administration press release, “FDA Approves First Biologic Treatment for Sepsis,” November 21, 2001.
77. Jane E. Brody, “New Hope for Taming Deadly Septic Shock,” New York Times, March 5, 2002, F7.
78. Burton, “Left on the Shelf.”
79. Eli Lilly press release, “Lilly Launches World’s Largest Severe Sepsis Clinical Trial.”
80. Warren et al., “Risks and Benefits of Activated Protein C Treatment.”
81. FDA Center for Drug Evaluation and Research, Anti-infective Drugs Advisory Committee, 263.
82. “Eli Lilly to Make India Sourcing Hub,” India Business World, October 2002.
83. Eli Lilly press release, “Lilly Launches World’s Largest Severe Sepsis Clinical Trial.”
84. Interview with Farhad Kapadia, November 25, 2003.
85. Feroze Ahmed, “Parents Have the Heart to Let Them Die,” Hindu Online, August 18, 2003.
86. Eli Lilly clinical trials Web site, at www.lillytrials.com.
87. John Wurzelmann, “Presentation on Eastern Europe,” in Globalization of Clinical Trials panel, Maximizing Clinical Efficiency Phases conference (Washington, DC, October 9, 2003).
88. Edward Abraham, “Exploration of Drotrecogin Alfa (Activated) in Adult Patients with Severe Sepsis at Lower Risk of Death,” presentation, American College of Chest Physicians annual meeting (Seattle, WA, October 2004).
89. Dante Landucci, “The Surviving Sepsis Guidelines: ‘Lost in Translation,’” Critical Care Medicine 31, no. 7 (2004): 1598–99.
90. See www.esicm.org/PAGE_sursepsis/?1hmi.
91. Correspondence with D. Annane, February 2005.
92. P.C. Minneci et al., “Meta-Analysis: The Effect of Steroids on Survival and Shock During Sepsis Depends on the Dose,” Annals of Internal Medicine, July 2004, 47–56.
93. “Eli Lilly Slashes Therapy Cost for Sepsis by 40 Pc,” Global News Wire, July 31, 2004.
94. Greg S. Martin, “Ask the Experts about General Critical Care: Drotrecogin Alfa and Sepsis,” Medscape from WebMD, posted September 1, 2004, on www.medscape.com/viewarticle/487221.
95. Andrew Pollack, “Viagra Shows Promise as Lung Therapy,” New York Times, October 28, 2004, C8.
96. Abraham, “Exploration of Drotrecogin Alfa.”
97. FDA Web site, Medwatch, February 11, 2005. Also, Xigris, “Postmarking Study Commitments,” on www.accessdata.fda.gov.
98. See www.xigris.com.
99. Edward Abraham et al., “Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death,” New England Journal of Medicine, September 29, 2005.
100. Alex Berenson, “Blockbuster Drugs Are So Last Century,” New York Times, July 3, 2005.
101. “I don’t have the actual details of the trial,” he said. From correspondence with Dr. Farhad Kapadia, February 16, 2005.
8: Calibrating Ethical Codes
1. Interview with Ruth Faden, 2001.
2. David J. Rothman, “The Shame of Medical Research,” New York Review of Books, November 30, 2000; Public Citizen, “Letter to the World Medical Association Expressing Alarm at the Current Draft Revised Version of the Declaration of Helsinki,” HRG Publication #477, March 29, 1999.
3. Susan Okie, “Health Officials Debate Ethics of Placebo Use: Medical Researchers Say Guidelines Would Impair Some Studies,” Washington Post, November 24, 2000, A3.
4. David Brown, “Medical Research Group Revises Guidelines on Placebos,” Washington Post, October 8, 2000.
5. World Medical Association, “WMA History: Declaration of Helsinki,” available at www.wma.net/e/history/helsinki.htm; World Medical Association, “Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects,” available at www.wma.net; U.S. Food and Drug Administration, Guidance for Industry: Acceptance of Foreign Clinical Studies, March 2001, available at/www.fda.gov/cder/guidance/fstud.htm.
6. Brian Vastag, “Helsinki Discord? A Controversial Declaration,” JAMA, December 20, 2000, 2984; Okie, “Health Officials Debate Ethics of Placebo Use.”
7. FDA Division of Pulmonary and Allergy Drug Products, “Use of Placebo-Controls in Life Threatening Diseases: Is the Developing World the Answer?” Scientific Rounds, January 24, 2001.
8. Interview with Robert Temple, 2001.
9. U.S. Food and Drug Administration, Guidance for Industry.
10. E.M. Meslin, “Memorandum to the National Bioethics Advisory Commission. Materials Relating to Public Comments: International Report,” November 21, 2000, cited in Public Citizen, “Letter to the National Bioethics Advisory Commission Criticizing Their Draft Report on Ethics of Research in Developing Countries,” HRG Publication #1550, December 6, 2000, available at www.citizen.org/publications/release.cfm?ID=6751#N_2_.
11. Nancy Kass and Adnan A. Hyder, “Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulation,” commissioned paper, in National Bioethics Advisory Commission, Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries, Washington, DC, May 2001.
12. A.A. Hyder et al., “Ethical Review of Health Research: A Perspective from Developing Country Researchers,” Journal of Medical Ethics, February 2004, 68–72.
13. National Bioethics Advisory Commission, Recommendation 4.1 and 4.2, Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries, April 2001, cited in WMA Workgroup, September 2003.
14. Okie, “Health Officials Debate Ethics of Placebo Use.”
15. Bernhard Huitfeldt et al., “Choice of Control in Clinical Trials—Issues and Implications of ICH-E10,” Drug Information Journal, October/December 2001, 1147–56.
16. “Declaration of Helsinki Placebo Rule Being Reconsidered,” July 10, 2001, article provided by Dr. Ruth Macklin.
17. Interview with Delon Human, 2001.
18. See www.wma.net/e/policy/17-c_e.html.
19. Letter from Public Citizen to Delon Human, World Medical Association, August 28, 2003.
20. Laurence Hirsch and Harry Guess, “Some Clauses Will Hinder Development of New Drugs and Vaccines,” BMJ 323 (December 2001): 1417.
21. Pharmaceutical Research and Manufacturers Association discussion paper, June 2001, cited in World Medical Association, “Documentation for the Preparation of Note of Clarification on Paragraph 30 of the Revised Declaration of Helsinki,” September 2003.
22. Some have interpreted the clarification to Paragraph 30 as an affirmation of the requirement that study drugs be provided after trials end. The clarification reads, “The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic, and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Posttrial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.” The ambiguity as to whether study drugs must be provided or must simply be identified and described to ethics committees “depends on what ‘it’ means,” one bystander noted. See World Medical Association, “Workgroup Report on the Revision of Paragraph 30 of the Declaration of Helsinki,” September 2003; World Medical Association, “Declaration of Helsinki,” at www.wma.net; interview with Peter Lurie, March 22, 2005.
23. R.K. Lie et al., “The Standard of Care Debate: The Declaration of Helsinki Versus the International Consensus Opinion,” Journal of Medical Ethics 30 (2004): 190–99.
24. Karen Palmore Beckerman, “Long-Term Findings of HIVNET 012: The Next Steps,” The Lancet, September 13, 2003.
25. Interview with Jay Brooks Jackson, October 10, 2003.
26. S.H. Eshleman et al., “Selection and Fading of Resistance Mutations in Women and Infants Receiving Nevirapine to Prevent HIV-1 Vertical Transmission (HIVNET 012),” AIDS 15 (2001): 1951–57.
27. Beckerman, “Long-Term Findings of HIVNET 012.”
28. “South Africa Ends Nevirapine Monotherapy in HIV PMTCT, Due to Resistance Issues,” Pharma Marketletter, July 14, 2004.
29. “China Begins Legalizing Methadone as Part of Effort to Prevent HIV Transmission among Injection Drug Users,” Kaiser Daily HIV/AIDS Report, August 12, 2004.
30. Anne Bennett Swingle, “The Pathologist Who Struck Gold,” Hopkins Medical News, Spring/Summer 2001.
31. Interview with Jay Brooks Jackson, October 10, 2003.
32. Swingle, “The Pathologist Who Struck Gold.”
33. Nadeeja Koralage, “China to Offer Free HIV Testing and Treatment,” BMJ, April 24, 2004.
34. Letter from International AIDS Society to Secretary of the Expert Committee on the Selection and Use of Essential Medicines Policy, World Health Organization, January 14, 2005.
35. John G. McNeil et al., “HIV Vaccine Trial Justified,” Science, February 13, 2004, 961.
36. Jon Cohen, “Disappointing Data Scuttle Plans for Large-Scale AIDS Vaccine Trial,” Science, March 1, 2002, 1616.
37. “Thailand Going Through 3rd Phase of Developing AIDS Vaccine,” Global News Wire—Africa Asia Intelligence Wire, February 28, 2005.
38. Richard Horton, “AIDS: The Elusive Vaccine,” New York Review of Books, September 23, 2004.
39. Agence France Presse, “Experts Call for World’s Largest HIV Vaccine Trial to Be Scrapped,” Channel NewsAsia, July 15, 2004.
40. Interview with Robert Temple, September 2003.
9: The Emperor Has No Clothes:
The Vagaries of Informed Consent
1. Interview with Sten Vermund, 2001; World Health Organization, Control of Epidemic Menigococcal Disease: WHO Practical Guidelines, 2d ed., 6–12.
2. World Health Organization, “Disease Outbreaks Reported: Meningococcal Meningitis in Nigeria,” March 6, 1996.
3. Interview with Anne-Valerie Kaninda, 2001.
4. See FDA review, at www.fda.gov/cder/foi/nda/97/020760a.htm.
5. Interview with Anne-Valerie Kaninda, 2001; Roche Pharmaceuticals, “Rocephin (Ceftriaxone Sodium) for Injection” product information; Centers for Disease Control, “Meningococcal Disease Among College Students: ACIP Modifies Recommendations for Meningitis Vaccination,” October
20, 1999.
6. World Health Organization, Control of Epidemic Meningococcal Disease, 22–23; correspondence with Maria Santamaria, 2001.
7. Juan Walterspiel, MD v. Pfizer, Inc., Civil Action No. 3:98cv917, U.S. District Court, District of Connecticut, July 26, 1998, 3–4, 6, 9–10, 20; Abdullahi v. Pfizer, 51–52.
8. Walterspiel, MD v. Pfizer, Inc., 10.
9. Ibid., 14.
10. Joe Stephens, “Where Profits and Lives Hang in Balance: Finding an Abundance of Subjects and Lack of Oversight Abroad, Big Drug Companies Test Offshore to Speed Products to Market,” Washington Post, December 17, 2000, A1.
11. H. Veeken et al., “Priority During a Meningitis Epidemic: Vaccination or Treatment?” Bulletin of the World Health Organization, March 1998, 135.
12. Marie Doona and J. Bernard Walsh, “Use of Chloramphenicol as Topical Eye Medication: Time to Cry Halt? Bone Marrow Aplasia Also Occurs with Ocular Use,” BMJ, May 13, 1995, 1217.
13. Stephens, “Where Profits and Lives Hang in Balance”; “Roche Unit’s Drug Is Approved,” Wall Street Journal, August 31, 1993, A4.
14. Nancy Kass and Adnan A. Hyder, “Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regulations,” commissioned paper, National Bioethics Advisory Commission, Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries, vol. 2, May 2001, B-9.
15. Ibid., B-5
16. Sharon LaFraniere et al., “The Dilemma: Submit or Suffer,” Washington Post, December 19, 2000, A1.
17. P. Pitisuttithum et al., “Risk Behaviors and Comprehension among Intravenous Drug Users Volunteered for HIV Vaccine Trial,” Journal of the Medical Association of Thailand, January 1997, 80.
18. Daniel W. Fitzgerald et al., “Comprehension During Informed Consent in a Less-Developed Country,” The Lancet, October 26, 2002, 1301–2.
19. E. Hardy et al., Informed Consent and Fertility Regulation in Brazil, Final Report, 1998, unpublished, cited in Kass and Hyder, “Attitudes and Experiences,” 48.
20. Q.A. Karim et al., “Informed Consent for HIV Testing in a South African Hospital: Is It Truly Informed and Truly Voluntary?” American Journal of Public Health, April 1, 1998, 637–40.
