by Sonia Shah
46. See www.ed.gov/rschstat/research/pubs/rigorousevid/guide_pg5.html.
47. Randomized controlled trials can be conducted with either placebo or “active” controls, and either way they correct for many difficulties in determining the effects of a medical intervention, not least the fact that ordinarily most minor sicknesses and conditions are “self-limiting”; that is, they go away on their own. In addition, chronic problems generally cycle up and down, becoming intense for a while, then lightening up, then becoming intense again. If an experimental drug or new medical intervention is judged solely by how it appears to affect patients, there is no way to account for this. If the patients rally, maybe the drug worked, or perhaps the condition simply improved on its own. Moerman, Meaning, Medicine, and the “Placebo Effect,” 12.
48. Mannfred A. Hollinger, Introduction to Pharmacology (Philadelphia: Taylor & Francis, 1997), 205.
49. Roy Porter, The Greatest Benefit to Mankind: A Medical History of Humanity (New York: W.W. Norton, 1997), 270.
50. Jerry Avorn, Powerful Medicines: The Benefits, Risks and Costs of Prescription Drugs (New York: Alfred A. Knopf, 2004), 53.
51. Paul Starr, The Social Transformation of American Medicine: The Rise of a Sovereign Profession and the Making of a Vast Industry (New York: Basic Books, 1982), 346; and Sarah Marie Lambert and Howard Markel, “Making History: Thomas Francis, Jr., MD, and the 1954 Salk Poliomyelitis Vaccine Field Trial,” Archives of Pediatrics and Adolescent Medicine, May 2000, 512.
52. Marcia Meldrum, “‘A Calculated Risk’: The Salk Polio Vaccine Field Trials of 1954,” BMJ, October 31, 1998, 1233–36.
53. Lambert and Markel, “Making History,” 512.
54. Anita Guerrini, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: Johns Hopkins University Press, 2003), 125; Meldrum, “‘A Calculated Risk.’”
55. While politically palatable, the historical comparison would certainly dilute the trial’s rigor. However the comparison bore out, the results would be open to a range of fair criticism. If fewer vaccinated subjects contracted polio than unvaccinated ones, it could be because they had been less exposed to poliovirus because the weather was different, or perhaps were generally older and could fight off the virus more effectively, or maybe polio in the unvaccinated subjects had been diagnosed differently, and on and on. Since the two groups hadn’t been tracked under precisely similar conditions, at the same time, or in the same place, results based on contrasting the groups would be like the proverbial comparison of apples to oranges: no one thing could explain why the two tasted so different. Meldrum, “‘A Calculated Risk.’”
56. Louis Lasagna, “Placebos and Controlled Trials under Attack,” European Journal of Clinical Pharmacology 15 (1979): 373–74; Pearce Wright, “Louis Lasagna,” The Lancet, October 25, 2003, 1423; Voice of America, “Science in the News: The Lives of Peter Safar and Louis Lasagna,” transcript, August 18, 2003.
57. Robert Temple and Susan S. Ellenberg, “Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments,” Annals of Internal Medicine, September 19, 2000, 456–57.
58. E-mail interview with Paul S. Kelly, January 26, 2005.
59. Interview with Rosemary Soave, January 27, 2005.
60. Robert I. Misbin, “Placebo-Controlled Trials in Type 2 Diabetes,” Diabetes Care 24, no. 4 (2001): 768–74.
61. E-mail correspondence from Joanna Hasegawa, January 25, 2003.
62. E-mail correspondence from Robert Black, January 22, 2005.
63. Most of the infectious diarrhea there stems from viruses, not parasites, with a small percentage caused by bacteria. Rehydration and antibiotics are “the only sensible therapy.” E-mail correspondence from Chandra Gulhati, January 25, 2005.
64. R. Rodriguez-Garcia et al., “Effectiveness and Safety of Mebendazole Compared to Nitazoxanide in the Treatment of Giardia Lamblia in Children,” Review Gastroenterology Mexico, July/September 1999, 122–26; Cesar E. Davila-Gutierrez et al., “Nitazoxanide Compared with Quinfamide and Mebendazole in the Treatment of Helminthic Infections and Intestinal Protozoa in Children,” American Journal of Tropical Medicine and Hygiene 66, no. 3 (2002): 251–54; Uri Belkind-Valdovinos, “Evalucion de la nitazoxanida en dosis unica y por tres dias en parasitosis intestinal,” Salud Publica de Mexico, May/June 2004, 333–40.
65. By February 2005 Kelly was in the process of asking the manufacturers for a quote in order to ascertain whether the University Teaching Hospital might be able to afford a supply of the drug. Interview with Paul S. Kelly, February 16, 2005.
3: Growing the Pharma Monolith
1. Press release, “Salix Pharmaceuticals Announces Positive Results of Rifaximin Study,” November 11, 2004.
2. Globalization of Clinical Trials panel, Maximizing Clinical Efficiency Phases conference (Washington, DC, October 9, 2003).
3. Philip J. Hilts, Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation (New York: Alfred A. Knopf, 2003), 23–25.
4. Roy Porter, The Greatest Benefit to Mankind: A Medical History of Humanity (New York: W.W. Norton, 1997), 368, 663–64.
5. Hilts, Protecting America’s Health, 46, 53.
6. Paul Ehrlich developed the concept of chemotherapy, synthesizing sulphanilamide in 1907. The drug didn’t go into production until after Gerhard Domagk of I.G. Farbenindustrie refined the drug in 1932. Mannfred A. Hollinger, Introduction to Pharmacology (Philadelphia: Taylor & Francis, 1997), 207; Porter, The Greatest Benefit to Mankind, 452–54.
7. Anita Guerrini, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: Johns Hopkins University Press, 2003), 111.
8. Hilts, Protecting America’s Health, 90; Hollinger, Introduction to Pharmacology, 300–301.
9. Back in 1928 a compound produced by a soil mold—penicillin—had been found to have profound bacteria-killing properties. Penicillin didn’t just slow bacterial cell growth, as sulfanilamide did—it killed the cells outright. Not only that, the compound attacked bacterial cells selectively, leaving mammalian cells untouched and making even large doses of the drug theoretically safe for humans. The trouble was that the mold produced vanishingly small amounts of the compound, and even these quantities deteriorated fast. Producing enough stable penicillin to treat a single patient had proven so difficult for researchers at Oxford that they had resorted to recycling the chemical from the patient’s urine; in the end, the team ran out of penicillin and the infected patient had perished. Hollinger, Introduction to Pharmacology, 134–35; Porter, The Greatest Benefit to Mankind, 456–57; Hilts, Protecting America’s Health, 101–4.
10. Laurie Garrett, Betrayal of Trust: The Collapse of Global Public Health (New York: Hyperion, 2000), 323.
11. Ironically, at the time leading drug companies all refused to develop this promising drug into a more practical one, despite the entreaties of government officials. They considered the investment too risky, worrying that the life-saving drug might suddenly stop working, as had happened with sulfa drugs. Only after a government-sponsored project figured out how to increase the mold’s yield of the drug by 120-fold did drug companies reluctantly agree to start producing penicillin. Hilts, Protecting America’s Health, 102–3.
12. Paul Starr, The Social Transformation of American Medicine: The Rise of a Sovereign Profession and the Making of a Vast Industry (New York: Basic Books, 1982), 342.
13. “Funding for Health Research and Development, According to Source of Funds: United States, Selected Fiscal Years 1970–99,” in Health, United States, 2001 (Hyattsville, MD: National Center for Health Statistics, 2001), 346.
14. Fran Hawthorne, The Merck Druggernaut: The Inside Story of a Pharmaceutical Giant (Hoboken, NJ: John Wiley & Sons, 2003), 26.
15. Daniel Callahan, What Price Better Health? Hazards of the Research Imperative (Los Angeles: University of California Press, 2003), 237.
16. Hilts, Protecting America’s Health, 121–22, 130.
>
17. Ibid., 146–47.
18. Jordan Goodman, Anthony McElligot, and Lara Marks, eds., Useful Bodies: Humans in the Service of Medical Science in the Twentieth Century (Baltimore: Johns Hopkins University, 2003), 14.
19. Hollinger, Introduction to Pharmacology, 92, 109; Hilts, Protecting America’s Health, 150.
20. Hilts, Protecting America’s Health, 149.
21. Ibid., 144–54.
22. The condition had previously been so rare that few physicians had ever seen it before. Medical editors rushed to find photographs to illustrate the condition in their new textbooks but came up empty-handed. They resorted to Francisco de Goya’s nineteenth-century painting of a phocomelic infant instead. Hollinger, Introduction to Pharmacology, 108.
23. Hilts, Protecting America’s Health, 155.
24. Ibid., 131–43, 157–58.
25. Ibid., 164.
26. Hollinger, Introduction to Pharmacology, 310.
27. Allen A. Mitchell, “Systematic Identification of Drugs That Cause Birth Defects—a New Opportunity,” New England Journal of Medicine, December 25, 2003, 2556–59.
28. Instead, the new rules required proof of efficacy, even though whether thalidomide worked was never really the issue. Just a few years after its fall from grace, thalidomide was resurrected as a treatment for leprosy. The drug continued to be used by pregnant women, who predictably bore phocomelic babies, particularly in Portuguese-speaking Brazil, where thalidomide was sold with English-language warnings on the side of the box. A drug with complex clinical effects, thalidomide is currently being investigated as a treatment for a range of diseases, from cancers to AIDS. Now sedation is considered the “side” effect. Vittal Katikireddi, “Thalidomide: A Second Chance?” BMJ, February 14, 2004, 412; “Thalidomide: A Second Chance?” BBC program transcript, February 12, 2004, available at www.bbc.co.uk/science/horizon/2004/thalidomidetrans.shtml.
29. Hilts, Protecting America’s Health, 161, 164–65, 172.
30. Sandra Panem, The Interferon Crusade (Washington, DC: Brookings Institution, 1984), 2.
31. See, for example, web.mit.edu/invent/a-winners/a-boyercohen.html.
32. See, for example, www.amgen.com/rnd/history.html.
33. Hawthorne, The Merck Druggernaut, 24.
34. Panem, The Interferon Crusade, 86.
35. Hilts, Protecting America’s Health, 255.
36. “Percentage of New Products and Processes That Were Dependent on Academic Research, for Selected Industries in the United States: 1975–85,” Science and Engineering Indicators, 2000 (Arlington, VA: National Science Foundation, 2000), 7–18.
37. U.S. Bureau of Census, “National Health Expenditures—Summary, 1960 to 1999, and projections, 2000 to 2010,” Statistical Abstract of the U.S.: 2001, Washington, DC, January 2002, 91. The economy as a whole, in contrast, just bettered doubling in size. The GDP in 1974 was $1,635.2 billion; the GDP in 1984 was $3,932.7 billion. “Population and U.S. Gross Domestic Product, 1949–2000,” Annual Energy Review, 2000 (Washington, DC: Energy Information Administration, August 2001), 351.
38. Martha M. Hamilton, “Drug Companies Lobby to Revise Compromise Bill,” Washington Post, July 29, 1984, G1.
39. Katherine Greider, The Big Fix: How the Pharmaceutical Industry Rips Off American Consumers (New York: PublicAffairs, 2003), 30–31.
40. See “Drop in Death Rates for Diseases Treated with Pharmaceuticals, 1965–1996,” available at www.quintiles.com, citing U.S. National Center for Health Statistics 1998.
41. Porter, The Greatest Benefit to Mankind, 718.
42. Hawthorne, The Merck Druggernaut, 85.
43. Garrett, Betrayal of Trust, 374.
44. Joe Graedon and Teresa Greadon, “On the Horizon: New Drugs Show Promise,” St. Louis Dispatch, January 2, 1990, 8D.
45. Sally Squires, “Even Young Adults Can Increase Life Expectancy by Cutting Cholesterol,” Washington Post, December 11, 1985, 5.
46. Morton Mintz, “Critics Sound Alarm as Firms Pin Hopes on Cholesterol Drug,” Washington Post, March 8, 1987, H5.
47. Hilts, Protecting America’s Health, 144–45.
48. Maryann Napoli, “Cholesterol Skeptics and the Bad News about Statin Drugs,” Center for Medical Consumers, June 2003, available at www.medicalconsumers.org/pages/cholesterol_skeptics.html.
49. Mevacor was followed by the release of Prozac in 1987. The market for drugs to treat depression wasn’t a very big one at the time. Before 1980, depression was considered a relatively rare condition, treated primarily with psychotherapy or tranquilizers. Psychiatrists also prescribed the so-called tricyclic drugs, cheap meds that had been developed in the 1950s. In the early 1980s, Astra and Duphar Laboratories had tried and failed to cut into the depression market with “selective serotonin reuptake inhibitors” (SSRI) drugs like Prozac, which tinkered with serotonin levels in the brain. But SSRI drugs Zelmid and Luvox didn’t work any better than the tricyclic antidepressants, had unexpected and unacceptable side effects, and were more expensive to boot. The drugs bombed.
Eli Lilly didn’t bother proving that Prozac was more effective than the other SSRIs or the older tricyclic antidepressants. The drug barely worked better than placebo. In four of the eight centers that conducted placebo-controlled trials of Prozac for the drug’s FDA application, patients improved more on placebos than Prozac. But the FDA approved the drug regardless. After all, Prozac didn’t need to be more effective than already available antidepressants. According to drugmaker Eli Lilly, Prozac was safer. To their physicians’ chagrin, some depressed patients on tri-cyclic drugs crossed the thin line dividing medicine from poison, using their antidepressants as toxins with which to kill themselves. Such patients would remain just as depressed and suicidal on Prozac, but they wouldn’t be able to use the drug for this purpose, as it is nearly impossible to die from an overdose of Prozac. The drug also appeared to be more acceptable to patients—fewer dropped out of trials because of irritating side effects such as constipation and dry mouth.
The lack of pesky side effects and its one-size-fits-all dosing made Prozac “an easy drug for doctors to prescribe,” London’s Independent noted. It was just in the nick of time. Employers were “wary of paying the bill for a lifetime of 45-minute sessions for long-winded Woody Allens,” as Forbes put it. If eons of expensive talk therapy could be eliminated with ten-second scribbles on a prescription pad, so be it.
Within a year of its release, Prozac was the bestselling antidepressant drug of all time. In 1989, about six million Americans took home prescriptions for the new drug, more than double the number who had popped the just as effective but much cheaper tricyclic drugs less than a decade before. Sufferers banded together with Lilly to “raise awareness” about the scourge of depression. Some patient groups conveniently shared offices with the PR offices of drug companies selling the spanking new antidepressants.
Whereas depression had once been considered rare, now it was considered all too common, afflicting no fewer than one in ten Americans, more of whom now sought help, which more often came in the form of Prozac or another of the SSRI drugs that followed hot on Prozac’s trail. Magazines splashed Prozac on their covers, dubbing it a “wonder drug” and a “breakthrough.” Even pet dogs were put on Prozac. David Healy, Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression (New York: New York University Press, 2004), 35, 111; M.S. Lima and J. Moncrieff, “Drugs Versus Placebo for Dysthymia (Cochrane Review),” in The Cochrane Library, issue 3 (Chichester, UK: John Wiley & Sons, 2004); Richard Grant, “The Prozac Generation,” The Independent, January 30, 1994, 12; Robert Langreth, “Just Say No,” Forbes.com, November 29, 2004; Natalie Angier, “New Antidepressant Is Acclaimed but Not Perfect,” New York Times, March 29, 1990, 9; Paul E. Greenberg et al., “The Economic Burden of Depression in the United States: How Did It Change Between 1990 and 2000?” Journal of Clinical Psychiatry, December 2003, 1465–73.
50. Hawthorne, The Merck Druggernaut,
37.
51. Ranjit B. Mani, “The Evaluation of Disease Modifying Therapies in Alzheimer’s Disease: A Regulatory Viewpoint,” Statistics in Medicine 23 (2004): 305–14.
52. J.A. O’Shaughnessy et al., “Commentary Concerning Demonstration of Safety and Efficacy of Investigational Anti-cancer Agents in Clinical Trials,” Journal of Clinical Oncology, December 1991, 2225–32.
53. Thomas R. Fleming and David L. DeMets, “Surrogate End Points in Clinical Trials: Are We Being Misled?” Annals of Internal Medicine, October 1, 1996, 605; see also Bruce M. Psaty et al., “Surrogate End Points, Health Outcomes, and the Drug-Approval Process for the Treatment of Risk Factors for Cardiovascular Disease,” JAMA, August 25, 1999, 786–90.
54. Cardiologists had been so certain of the drugs’ lifesaving abilities—touted by magazines such as U.S. News & World Report—that when the placebo-controlled trial was first proposed at a meeting, some were moved to cry “You are immoral! You are immoral!” from the audience. Hilts, Protecting America’s Health, 231; Associated Press, “Researcher Links Heart Drugs to 2,250 Deaths,” New York Times, July 26, 1989, 13.
55. Fleming and DeMets, “Surrogate End Points in Clinical Trials.”
56. Food and Drug Administration, “Establishment of Prescription Drug User Fee Rates for Fiscal Year 2005,” Federal Register, August 2, 2004; Greider, The Big Fix, 105.
57. Hilts, Protecting America’s Health, 336.
58. Greider, The Big Fix, 105.
59. Washington Business Information/FDAnews, “Senate Bill to Give FDA Authority over Tobacco Products Finds Unlikely Support,” June 4, 2004.
60. Editorial, “The Hazards of Seldane,” New York Times, January 17, 1997, 30.
61. John Schwartz, “FDA Relaxes Rules for On-Air Drug Ads; Changes Allow Product’s Purpose to Be Stated,” Washington Post, August 9, 1997, 1.
62. Ibid.
63. Milt Freudenheim, “Influencing Doctor’s Orders,” New York Times, November 17, 1998, 2.
