Subversive Subjects: Rule-Breaking and Deception in Clinical Trials

Epstein S. , Impure Science: AIDS, Activism, and the Politics of Knowledge (Berkeley: University of California Press, 1996): At 204.

Researcher Kenneth Shulz observed that because requirements like randomization “annoy human nature,” people involved in research may be tempted to evade those requirements. See Schulz K. F. , “Subverting Randomization in Controlled Trials,” Journal of the American Medical Association 274, no. 18 (1995): 1456–1458.

Smith D. L. , “Patient Nonadherence in Clinical Trials: Could There Be a Link to Postmarketing Patient Safety?” Drug Information Journal 46, no. 1 (2012): 27–34, at 28.

Shumaker S. A. Dugan E. Bowen D. J. , “Enhancing Adherence in Randomized Controlled Clinical Trials,” Controlled Clinical Trials 21, no. 5 (2000): 226S–232S, at 226S.

Some rule violations have a more serious impact on research findings than do other violations. But any violation of a rule designed to strengthen the validity of data presents a threat to study quality.

See Wendler D. Miller F. G. , “Deception in Clinical Research,” in Emanuel E. J. , eds., Oxford Textbook of Clinical Research Ethics (Oxford: Oxford University Press, 2008): At 315–324.

Articles from the publication are collected in Helms R. , ed., Guinea Pig Zero: An Anthology of the Journal for Human Research Subjects (New Orleans: Garrett County Press, 2002). The publication is available at <http://www.guineapigzero.com> (last accessed November 4, 2013).

Abadie R. , The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects (Durham, North Carolina: Duke University Press, 2010).

Resnik D. B. Koski G. , “A National Registry for Healthy Volunteers in Phase 1 Clinical Trials,” Journal of the American Medical Association 305, no. 12 (2011): 1236–1237.

See Abadie , supra note 8, at 81–82.

See also Solow B. , “The Secret Lives of Guinea Pigs,” Independent Weekly, February 9, 2000.

See Tishler C. L. Bartholomae S. , “Repeat Participation Among Normal Healthy Research Volunteers,” Perspectives in Biology and Medicine 46, no. 4 (2003): 508–520;.

Apseloff G. Swayne J. K. Gerber N. , “Medical Histories May Be Unreliable in Screening Volunteers for Clinical Trials,” Clinical Pharmacology & Therapeutics 60, no. 3 (1996): 353–356.

Hermann R. Heger-Mahn D. Mahler M. Seibert-Grafe M. Klipping C. Breithaupt-Grogler K. de Mey C. , “Adverse Events and Discomfort in Studies on Healthy Subjects: The Volunteer's Perspective,” European Journal of Clinical Pharmacology 53, no. 3–4 (1997): 207–214;.

McHugh J. , “Drug Test Cowboys: The Secret World of Pharmaceutical Trial Subjects,” Wired, April 24, 2007, available at <http://www.wired.com/wired/archive/15.05/feat_drugtest.html> (last accessed November 4, 2013);

Patriquin M. , “Inside the Human Guinea Pig Capital of North America,” MacLeans 122, no. 33 (2009); Solow, supra note 10. A University of Pennsylvania School of Medicine official observed, “We ask subjects to disclose if they're participating in other trials–but if someone wants to lie, I won't necessarily know if they're simultaneously doing a trial across town.”

Glenn D. , “Inside the Risky World of Drug-Trial ‘Guinea Pigs,’” Chronicle of Higher Education, July 11, 2010.

See Solow, supra note 10.

See Abadie , supra note 8, at 60–61;.

Dulce T. , “Spanish Fly Guinea Pig: PPD Pharmaco, Where Slackers Refuel,” in Helms, supra note 7, at 34;.

Elliott C. , “Guinea-Pigging,” The New Yorker, January 7, 2008;.

Solow, supra note 10.

See Patriquin, supra note 11;.

Solow, supra note 10.

See Patriquin, supra note 11;.

Apseloff Swayne Gerber , supra note 11.

See Abadie , supra note 8, at 60–61;.

Dulce , supra note 13, at 37.

See Hermann , supra note 11;.

Cohen L. P. , “Stuck for Money: To Screen New Drugs for Safety, Lilly Pays Homeless Alcoholics,” Wall Street Journal, November 14, 1996.

See Abadie , supra note 8, at 24.

These terms are used interchangeably. Both terms are criticized on grounds that they “subtly exaggerate the importance of the clinician,” suggesting a hierarchical rather than egalitarian relation between the medical professional and layperson. Steiner J. F. Earnest M. A. , “The Language of Medication-Taking,” Annals of Internal Medicine 132, no. 11 (2000): 926–30.

Holm S. , “What Is Wrong With Compliance?” Journal of Medical Ethics 19, no. 2 (1993): 108–110.

Fisher J. A. , Medical Research for Hire: The Political Economy of Pharmaceutical Clinical Trials (New Brunswick, NJ: Rutgers University Press, 2009): At 187;.

Abadie R. , “Tracking Professional Guinea Pigs,” October 15, 2010, available at <http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=4933&blogid=140> (last visited November 4, 2013).

For a description of payment practices in studies offering payment to both healthy volunteers and patient-subjects, see Grady C. Dickert N. Jawetz T. Gensler G. Emanuel E. , “An Analysis of U.S. Practices of Paying Research Participants,” Contemporary Clinical Trials 26, no. 3 (2005): 365–375.

See Smith , supra note 3, at 30.

Simmons M. S. Nides M. A. Rand C. S. Wise R. A. Tashkin D. P. , “Unpredictability of Deception in Compliance with Physician-Prescribed Bronchodilator Use in a Clinical Trial,” Chest 118, no. 2 (2000): 290–295.

Cohen J. , “Human Nature Sinks HIV Prevention Trial,” available at <http://news.sciencemag.org/sciencenow/2013/03/human-nature-sinks-hiv-preventio.html> (last visited November 4, 2013).

See Fisher , supra note 20, at 189.

Bradley C. , “Designing Medical and Educational Intervention Studies,” Diabetes Care 16, no. 2 (1993): 509–18, at 511.

See also C. Brewin and C. Bradley, “Patient Preferences and Randomised Clinical Trials,” BMJ 299, no. 6694 (1989): 313–315 (“despite having full information and giving consent, patients may still find themselves allocated to non-preferred treatments, which lowers their motivation to make the treatment work”).

Moyer A. , “Psychomethodology: The Psychology of Human Participation in Science,” Journal of Psychology of Science and Technology 2, no. 2 (2009): 59–72, at 64.

Finn R. , Cancer Clinical Trials: Experimental Treatments & How They Can Help You (Sebastopol, CA: O'Reilly, 1999): At 18, 31.

Subjects have a protected right to withdraw from research despite their earlier consent to participate. See C.F.R. § 46.116(a) (8) (2011). At the same time, individuals ought to enter trials with a good faith intention to remain unless participation becomes too burdensome.

See Epstein , supra note 1, at 228.

See also Arras J. D. , “Noncompliance in AIDS Research,” Hastings Center Report 20, no. 5 (1990): 24–32.

See Moyer , supra note 26, at 64.

Id.

See Smith , supra note 3, at 29.

See Fisher , supra note 20, at 192.

See McHugh , supra note 11.

See Mann H. , “Deception in the Single-Blind Run-In Phase of Clinical Trials,” IRB: Ethics & Human Research 29, no. 2 (2007): 14–17;.

Miller F. Wendler D. Swartzman L. , “Deception Research on the Placebo Effect,” PLoS Medicine 2, no. 9 (2005): 853–859.

Blackhart G. C. Brown K. E. Clark T. Pierce D. L. Shell K. , “Assessing the Adequacy of Postexperimental Inquiries in Deception Research and the Factors that Promote Participant Honesty,” Behavior Research Methods 44, no. 1 (2012): 24–40.

Resnik D. B. Ness E. , “Participants' Responsibilities in Clinical Research,” Journal of Medical Ethics 38, no. 12 (2012): 746–750.

See Smith , supra note 3.

A study of normal volunteers showed that only about two-thirds of them promptly informed investigators about adverse events; the remainder withheld information temporarily or permanently. See Hermann , supra note 11.

See Epstein , supra note 1, at 204. Subjects in the first placebo-controlled trial of AZT for HIV/AIDS admitted to sharing pills, but the trial still found that the drug was beneficial. Epstein reports that the subjects' noncompliance did not have a major impact on the study's outcome: “Noncompliance effectively blurred the differences between the treatment arm and the placebo arm, so the demonstration of a statistically significant difference became all the more impressive.” Id., at 238.

Mitka M. , “FDA and Pharma Seek Better Ways to Assess Drug Safety, Efficacy in Clinical Trials,” JAMA 307, no. 24 (2012): 2576–2577, at 2576.

For specific cases in which initially approved dosages were later lowered due to safety concerns, see Smith , supra note 3.

See Abseloff , supra note 11, at 356.

See Fisher , supra note 20, at 182–183;.

Mitka , supra note 40, at 2576.

See Rice S. Trafimow D. , “Known versus Unknown Threats to Internal Validity,” American Journal of Bioethics 11, no. 4 (2011): 20–21.

See Tishler Bartholomae , supra note 11;.

Apseloff , supra note 11.

See Apseloff , supra note 11.

Id.

See Abadie , supra note 8, at 74, 158;.

Shamoo A. Resnik D. B. , “Strategies to Minimize Risks and Exploitation in Phase One Trials on Healthy Subjects,” American Journal of Bioethics 6, no. 3 (2006): W1–W13.

See Hermann , supra note 11.

Miller F. G. Wertheimer A. , “Facing Up to Paternalism in Research Ethics,” Hastings Center Report 37, no. 3 (2007): 24–34.

De Ville K. , “The Case Against Contract: Participant and Investigator Duty in Clinical Trials,” American Journal of Bioethics 11, no. 4 (2011): 16–18, 17.

See Arras , supra note 28.

Id., at 25.

See also Resnik and Ness, supra note 36.

“Just Another Lab Rat! Mission Statement,” 2013, available at <jalr.org/mission.html> (last visited November 15, 2013). The website is a project of Paul Clough, a man who earns his living through clinical trial participation.

See O'Meara A. , Chasing Medical Miracles: The Promise and Perils of Clinical Trials (New York: Walker & Company, 2009): At 111–112.

Schaefer G. O. Emanuel E. J. Wertheimer A. , “The Obligation to Participate in Research,” Journal of the American Medical Association 302, no. 1 (2009): 67–72, at 68.

Helms R. , “The What, Why, and How of the GPZ Grading System,” in Helms, supra note 7, at 3–4. See also “22 Nights and 23 Days: Diary of #1J, Drug Study Subject,” 2006, available at <http://www.guineapigzero.com/23days.html> (last accessed April 26, 2013);

Hellard M. E. Sinclair M. I. Forbes A. B. Fairley C. K. , “Methods Used to Maintain a High Level of Participant Involvement in a Clinical Trial,” Journal of Epidemiological and Community Health 55, no. (2001) 348–351. In a telling incident, after Harper's Magazine published some of Helms's report cards, a facility receiving a bad grade sued Helms for libel.

See Abadie , supra note 6, at 52–53;.

Elliott , “Research Volunteers Wanted. Earn Up to $7000,” Tin House, Spring 2008, at 103–06, 104.

See Abadie , supra note 8, at 57, 139;.

Finn , supra note 27, at 119;.

McHugh , supra note 11;.

Public Responsibility in Medicine and Research, “In Their Own Voices: A Discussion with Research Subjects Who Also Work in The Field of Subject Protection,” December 7, 2010, available at <http://www.meetingproceedings.com/2010/aerc/contents/index.asp> (last accessed April 26, 2013; restricted access).

Guinea Pigs Get Paid, “Tips for Clinical Trials and Clinical Study Volunteers,” 2009, available at <http://www.gpgp.net/tips.html> (last accessed November 4, 2013).

See Fisher , supra note 20, at 196–97.

Public Responsibility in Medicine and Research, “What Do Research Subjects Have to Say about Informed Consent?” December 3, 2011, available at <http://www.eventscribe.com/2011/PRIMR/SearchByDay.asp?day=12/3/2011> (last visited April 26, 2013; restricted access).

See Abadie , supra note 8, at 10–11.

See Elliott , supra note 55, at 104.

See “21 Nights and 23 Days,” supra note 55. In another sign of depersonalization, a volunteer reported that test site staff called him by his trial number instead of his name.

See Abadie , supra note 8, at 29.

See Abadie , supra note 8, at 157.

See Fisher , supra note 20, at 184–85.

Public Responsibility in Medicine and Research, “A Discussion with Research Subjects and Their Advocates,” November 15, 2009, available at <http://www.meetingproceedings.com/2009/aerc/contents/index.asp> (last visited November 4, 2013).

See Fisher , supra note 20, at 190.

Elliot E. , “Panic at Penn,” in Helms, supra note 7, at 29–33, 29.

Shelton D. L. , “Patients in Clinical Trials Don't Always Follow the Program,” American Medical News, September 11, 2000.

See Blackhart , supra note 35, at 36.

Rand C. S. Sevick M. A. , “Ethics in Adherence Promotion and Monitoring,” Controlled Clinical Trials 21, no. 5 (2000): 241S–247S, 245S.

Redfearn S. , “Smart-Pill Technology Could Monitor Patient Compliance While Improving Clinical Trial Data Quality,” April 4, 2011, available at <http://www.centerwatch.com/news-online/article/1338/> (last visited November 4, 2013).

See Rand Sevick , supra note 70, at 245S.

Other nations have such registries, and some U.S. research institutions do, as well. To be effective in our mobile society, registries need to cover a wide geographic area. See Resnik and Koski, supra note 9. For this reason, a private U.S. venture called Verified Clinical Trials is attempting to establish a worldwide registry. “Verified Clinical Trials,” available at <http://www.verifiedclinicaltrials.com (last visited November 4, 2013).

See Shumaker , supra note 4, at 228S.

Id.

See Simmons , supra note 22, at 294.

See also Shumaker , supra note 4.

Edwards S. , “Assessing the Remedy: The Case for Contracts in Clinical Trials,” American Journal of Bioethics 11, no. 4 (2011): 3–12, at 3.

Robertson J. , “Contractual Duties in Research, Surrogacy, and Stem Cell Donation,” American Journal of Bioethics 11, no. 4 (2011): 13–14.

See Resnik Ness , supra note 36.

See Smith , supra note 3, at 32.

See Fisher , supra note 20, at 193–198.

See Shumaker , supra note 4, at 229S.

See Smith , supra note 3, at 30.

Education will not always do the trick, however. Research coordinators told Jill Fisher that subjects who understand the scientific justification for placebo-controlled trials are not necessarily more accepting of assignment to a placebo group. See Fisher , supra note 20, at 189–190.

Reame N. K. , “Treating Research Subjects as Unskilled Wage Earners: A Risky Business,” American Journal of Bioethics 1, no. 2 (2001): 53–54.

Id., at 54.

Elliott C. , “Justice for Injured Research Subjects,” New England Journal of Medicine 367, no. 1 (2012): 6–8;.

Dresser R. , “Aligning Regulations and Ethics in Human Research,” Science 337, no. 6094 (2012): 527–528.

See, for example, Helms R. , “La Crème de la Crème: Thomas Jefferson University,” in Helms, supra note 7, at 8–9;.

Donno , “Awake with a Vengeance,” in id., at 22–27. Abadie reports that in recent years, competition among research organizations has produced improved conditions in some locales but not others. He also learned that some guinea pigs do not like the “fancy sites” because they are too large and impersonal.

See Abadie , supra note 8, at 22–23. The comments on staff behavior bring to mind Michael Kahn's plea for more emphasis on basic etiquette in medical training: “The very notion of good manners may seem quaint or anachronistic, but it is at the heart of the mission of other service-related professions.

The goals of a doctor differ in obviously important ways from those of a Nordstrom's employee, but why shouldn't the clinical encounter similarly emphasize the provision of customer satisfaction through explicit actions?” Kahn M. , “Etiquette-Based Medicine,” New England Journal of Medicine 358, no. 19 (2008): 1988–89, at 1988.

McDonald D. Lamberti M. J. , “The Psychology of Clinical Trials: Understanding Physician Motivation and Patient Perception,” Centerwatch Research Brief, October 4, 2006, available at <http://www.centerwatch.com/news-online/article/566/the-psychology-of-clinical-trials-understanding-physician-motivation-and-patient-perception> (last visited November 4, 2013).

See Hellard , supra note 55.

See Epstein , supra note 1, at 208–264;.

Dresser R. , When Science Offers Salvation: Patient Advocacy and Research Ethics (New York: Oxford University Press, 2001): At 21–43.

Weisfeld N. English R. A. Claiborne A. B. , Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020 (Washington, DC: National Academies Press, 2012).

Meurer W. Lewis R. Berry D. , “Adaptive Clinical Trials: A Partial Remedy for the Therapeutic Misconception?” Journal of the American Medical Association 307, no. 22 (2012): 2377–78.

See Floyd A. Moyer A. , “Effects of Participant Preferences in Unblinded Randomized Controlled Trials,” Journal of Empirical Research on Human Research Ethics 5, no. 2 (2010): 81–93;.

Janevic M. Janz N. K. Dodge J. A. Lin X. Pan W. Sinco B. R. Clark N. M. , “The Role of Choice in Health Education Intervention Trials: A Review and Case Study,” Social Science and Medicine 56, no. 7 (2003): 1581–1594.

See Arras , supra note 28, at 31.

See also Finn , supra note 27, at 117, describing subject's success in convincing researchers to require a lower number of biopsies in a trial.

Researchers addressing subversive subjects in deception research note that there are “several ethical and methodological reasons why researchers should use deception sparingly.” The inability to accurately detect subjects' awareness of deception is “yet another reason” for reducing their use of this technique. See Blackhart , supra note 35, at 36.

Lynch J. A. , “‘Through a Glass Darkly’: Researcher Ethnocentrism and the Demonization of Research Participants,” American Journal of Bioethics 11, no. 4 (2011): 22–23;.

Marsh V. Kamuya D. Rowa Y. Gikonyo C. Molyneux S. , “Beginning Community Engagement at a Busy Biomedical Research Programme: Experiences from the KEMRI CGMRC-Wellcome Trust Research Programme,” Social Science & Medicine 67, no. 5 (2008): 721–733.

See Moyer , supra note 26, at 68.

Jonas H. , “Philosophical Reflections on Experimenting with Human Subjects,” Daedalus, 98, no. 2 (1969): 219–247, at 236.

Empirical evidence should be collected on the effectiveness of different strategies to reduce rule-breaking.

See Abadie , supra note 8, at 51.

In a panel presentation to researchers and Institutional Review Board staff and committee members, Helms called on the audience to value what healthy guinea pigs do for modern medicine. “Don't think about us as couch potatoes who just take money,” he asked. See Public Responsibility in Medicine and Research, supra note 65.

See Abadie , supra note 8, at 41;.

Stunkel L. Grady C. , “More Than the Money: A Review of the Literature Examining Healthy Volunteer Motivations,” Contemporary Clinical Trials 32, no. 3 (2011): 342–352.

Hermann , supra note 11.