First-in-Human Trial Participants: Not a Vulnerable Population,but Vulnerable Nonetheless

See, e.g., Westfall J. M. , “Practice-Based Research — ‘Blue Highways’ on the NIH Roadmap,” JAMA 297, no. 4 (2007): 403–406; Zerhouni E. A. , “Translational and Clinical Science — Time for a New Vision,” New England Journal of Medicine 353, no. 15 (2005): 1621–1623.

Gilbert S. , “Trials and Tribulations,” Hastings Center Report 38, no. 2 (2008): 14–18.

Steinbrook R. , “The Gelsinger Case,” in Emanuel E. , eds., The Oxford Textbook of Clinical Research Ethics (New York: Oxford University Press, 2008): At 110–120.

Suntharalingam G. , “Cytokine Storm in a Phase I Trial of the Anti-CD28 Monoclonal Antibody TGN1412,” New England Journal of Medicine 355, no. 10 (2006): 1018–1028.

Seidenfeld J. Horstmann E. Emanuel E. J. Grady C. , “Participants in Phase I Oncology Research Trials: Are They Vulnerable?” Archives of Internal Medicine 168, no. 1 (2008): 16–20.

O'Donnell D. O. , “First Time in Man Studies: A Contract Research Organization Perspective,” Journal of Clinical Pharmacology 30, no. 3 (1990): 217–18, at 217.

This article considers the ethics of FIH trials in adult subjects. For discussion of the special issues involved in pediatric FIH trials, see Kimmelman J. , “Staunch Protections: The Ethics of Haemophilia Gene Transfer Research,” Haemophilia 14, no. 1 (2008): 5–14. For a discussion of issues raised by FIH trials in pregnant women and fetuses, see Recombinant DNA Advisory Committee, Prenatal Gene Transfer: Scientific, Medical, and Ethical Issues , 2000, available at <http://www4.od.nih.gov/oba/rac/gtpcreport.pdf> (last visited November 20, 2008). For an analysis of issues raised by FIH trials in the developing world, see London A. J. Kimmelman J. , “Justice in Translation: From Bench to Bedside in the Developing World,” The Lancet 372, no. 9632 (2008): 82–85; Kimmelman J. , “Clinical Trials and SCID Row: The Ethics of Phase I Trials in Developing World,” Developing World Bioethics 7, no. 3 (2007): 128–135.

21 Code of Federal Regulations § 312.21. See also A. Nada Somberg J. , “First-in-Man (FIM) Clinical Trials Post-TeGenero: A Review of the Impact of the TeGenero Trial on the Design, Conduct, and Ethics of FIM Trials,” American Journal of Therapeutics 14, no. 6 (2007): 594–604, at 595–596 (first-in-human trials “aim to assess the safety and tolerability of new drug compounds by identifying their side effects, including their intensity, duration, and reversibility as a function of dose and corresponding dose/plasma concentration relationships after administration of initially single, then multiple, doses of a new drug compound without compromising participant safety”).

Bergstrom R. F. Lemberger L. , “First in Man Studies: An Industrial Perspective,” Journal of Clinical Pharmacology 30, no. 3 (1990): 212–217.

Wood A. J. Darbyshire J. , “Injury to Research Volunteers — The Clinical-Research Nightmare,” New England Journal of Medicine 354, no. 18 (2006): 1870–1871.

Horstmann E. , “Risks and Benefits of Phase I Oncology Trials, 1991 through 2002,” New England Journal of Medicine 352, no. 9 (2005): 895–904.

See Bergstrom Lemberger , supra note 9.

Aguilar L. K. Aguilar-Cordova E. , “Evolution of a Gene Therapy Trial,” Journal of Neuro-Oncology 65, no. 3 (2003): 307–315; Spink J. Geddes D. , “Gene Therapy Progress and Prospects: Bringing Gene Therapy into Medical Practice: The Evolution of International Ethics and the Regulatory Environment,” Gene Therapy 11, no. 22 (2004): 1611–1616.

Food and Drug Administration, Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies , January 2006, available at <www.fda.gov/cder/guidance/7086fnl.pdf> (last visited November 20, 2008).

European Medicines Agency, Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals , July 2008, available at <http://www.emea.europa.eu/pdfs/human/ich/028695en.pdf> (last visited November 20, 2008).

European Medicines Agency, Draft Guideline on Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products , March 2007, available at <www.emea.europa.eu/pdfs/human/swp/2836707en.pdf> (last visited November 20, 2008).

See Nada Somberg , supra note 8.

See, e.g., National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research , National Institutes of Health, Bethesda, Maryland, 1979, available at <http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm> (last visited November 20, 2008); World Medical Association, “Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects,” JAMA 284, no. 23 (2000): 3043–3045; “The Nuremberg Code,” New England Journal of Medicine 337, no. 20 (1997): 1436. See also Joffe S. Miller F. G. , “Bench to Bedside: Mapping the Moral Terrain of Clinical Research,” Hastings Center Report 38, no. 2 (2008): 30–42.

The Code recognizes a possible exception when the researcher acts as the experimental subject. See Id., (“Nuremberg Code”) at 1436. In the past, this practice was not unusual among researchers, and it reportedly persists in the modern era. See Altman L. K. , Who Goes First? The Story of Self-Experimentation in Medicine (Berkeley: University of California Press, 1998).

See “Nuremberg Code,” supra note 18, at 1436.

Joint ABPI/BIA Report, “Early Stage Clinical Trial Task Force,” in Department of Health, Expert Group on Phase I Clinical Trials, Final Report , Appendix D, at 18–19, December 2006, available at <www.dh.gov.uk> (last visited November 20, 2008).

See Nada Somberg , supra note 8.

Dowsing T. Kendall M. J. , “The Northwick Park Tragedy — Protecting Healthy Volunteers in Future First-in-Man Trials,” Journal of Clinical Pharmacy and Therapeutics 32, no. 3 (2007): 203–207.

See Nada Somberg , supra note 8.

Stroke Therapy Academic Industry Roundtable, “Recommendations for Standards Regarding Preclinical Neuroprotective and Restorative Drug Development,” Stroke 30, no. 12 (1999): 2752–2758, at 2752.

See Weihrauch M. R. Diehl V. , “Artificial Sweeteners — Do They Bear a Carcinogenic Risk?” Annals of Oncology 15, no. 10 (2004): 1460–1465.

Marincola F. M. , “Translational Medicine: A Two-Way Road,” Journal of Translational Medicine 1, no. 1 (2003): 1–2, available at <http://www.translational-medicine.com/content/1/1/1> (last visited November 20, 2008). In an effort to improve animal models in cancer research, investigators study companion animals with naturally occurring disease. The hope is that these animals are a closer model for human cancer patients than are laboratory animals whose disease was purposely induced. See Porrello A. Cardelli P. Spugnini E. P. , “Oncology of Companion Animals as a Model for Humans: An Overview of Tumor Histotypes,” Journal of Experimental and Clinical Cancer Research 25, no. 1 (2006): 97–105; Porrello A. Cardelli P. Spugnini E. P. , “Pet Models in Cancer Research: General Principles,” Journal of Experimental and Clinical Cancer Research 23, no. 2 (2004): 181–183.

See Aguilar and Aguilar-Cordova, supra note 13, at 311.

Davenport R. J. , “On Trial,” SAGE KE, June 16, 2004, available at <http://sageke.sciencemag.org> (last visited July 1, 2008).

Sabroe I. , “Identifying and Hurdling Obstacles to Translational Research,” Nature Reviews Immunology 7, no. 1 (2007): 77–82.

See Aguilar and Aguilar-Cordova, supra note 13.

See Marincola , supra note 28.

Hackam D. G. Redelmeier A. , “Translation of Research Evidence from Animals to Humans,” JAMA 296, no. 14 (2006): 1731–1732, at 1732.

Bebarta V. Luyten D. Heard K. , “Emergency Medicine Animal Research: Does Use of Randomization and Blinding Affect the Results?” Academic Emergency Medicine 10, no. 6 (2003): 684–687. The authors note that even though laboratory animal research typically involves less subject heterogeneity and opportunity for biased assessment than human research does, there are still variations among animals and observer biases that could affect animal study results.

Hampshire V. DeRenzo E. , “Moving Research from the Cage to the Bedside: The Need for IACUC/IRB Cooperation,” Lab Animal 31, no. 4 (2002): 27–31, at 30.

Hampshire and DeRenzo describe how additional animal studies could have produced better information on potential human risks of the gene transfer agent in the trial involving Jesse Gelsinger. See id., at 27. They also point out that negative findings from animal studies often remain unpublished, which can deprive investigators planning human studies of potentially important information. Id., at 29.

Kimmelman J. , Lost in Translation: Gene Transfer and the Ethics of First in Human Studies (Cambridge University Press, forthcoming). Kimmelman suggests that the preliminary work could include minimal risk “proof of principle” human studies to test physiological parameters or validate hypotheses related to the investigational intervention.

Kimmelman J. , “Ethics at Phase O: Clarifying the Issues,” Journal of Law, Medicine & Ethics 35, no. 4 (2007): 727–733. As Kimmelman observes, it remains to be seen whether exploratory INDs and other translational innovations will help sponsors engage in more efficient product development.

See Wood Darbyshire , supra note 10, at 1870.

See Nada Somberg , supra note 8, at 596.

This produces what is known as the “Minimal Anticipated Biological Effect Level.” See European Medicines Agency, supra note 16, at 7.

See Food and Drug Administration, supra note 14, at 9.

See Nada Somberg , supra note 8, at 597.

See European Medicines Agency, supra note 16, at 9.

See Nada Somberg , supra note 8, at 598.

See Bergstrom Lemberger , supra note 9.

See European Medicines Agency, supra note 16, at 9.

Shamoo A. E. Resnik D. B. , “Strategies to Minimize Risks and Exploitation in Phase I Trials on Healthy Subjects,” American Journal of Bioethics 6, no. 3 (2006): W1–W13, at W5.

Id., at W6.

See Nada Somberg , supra note 8, at 599–60.

See Wood Darbyshire , supra note 10.

See Department of Health, Expert Group on Phase I Clinical Trials, Final Report , December 2006, available at <www.dh.gov.uk> (last visited July 2, 2008); Nada Somberg , supra note 8; Levine C. Sugarman J. , “After the TGN1412 Tragedy: Addressing the Right Questions at the Right Time for Early-Phase Testing,” Hastings Center Bioethics Forum, April 17, 2006, available at <http://www.bioethicsforum.org/20060417clevinejsugarman.asp> (last visited November 20, 2008).

See Nada Somberg , supra note 8, at 599.

Dawson L. , “Safety Issues in Cell-Based Intervention Trials,” Fertility and Sterility 80, no. 5 (2003): 1077–1085; see European Medicines Agency, supra note 16, at 8.

Id., at 1083.

See Nada Somberg , supra note 8, at 599.

See Joint ABPI/BIA Report, supra note 21, at 23–24.

Steinbrook R. , “Protecting Research Subjects – The Crisis at Johns Hopkins,” New England Journal of Medicine 346, no. 9 (2002): 716–720.

Kimmelman J. , “Stable Ethics: Enrolling Non-Treatment-Refractory Volunteers in Novel Gene Transfer Trials,” Molecular Therapy 15, no. 11 (2007): 1904–1906.

Sugarman J. , “Ethical Considerations in Leaping from Bench to Bedside,” Science 285, no. 5436 (1999): 2071–2072.

Emanuel E. J. Miller F. G. , “Money and Distorted Judgments about Research: Ethical Assessment of the TeGenero TGN1412 Trial,” American Journal of Bioethics 7, no. 2 (2007): 76–81.

See Kimmelman , “Staunch Protections,” supra note 7.

See Kimmelman , supra note 38.

See Sugarman , supra note 65, at 2071.

See Steinbrook , supra note 3, at 113. Some commentators also criticized the choice of healthy volunteers for the TGN1412 trial. In that case, the test agent was being developed as a potential therapy for leukemia and autoimmune disease. Some said that it would have been better to recruit patients with the relevant diseases in whom approved therapies had failed. See Emanuel Miller , supra note 66, at 77.

See Committee on Ethical Considerations for Revisions to DHHS Regulations for Protection of Prisoners Involved in Research, Ethical Considerations for Research Involving Prisoners (Washington, D.C.: National Academies Press, 2006).

Elliott C. , “Guinea-Pigging,” New Yorker, January 7, 2008, at 36–41, at 36.

For examples of such deception, see McHugh J. , “Drug Test Cowboys: The Secret World of Pharmaceutical Trial Subjects,” Wired Magazine, April 24, 2007, available at <http://www.wired.com/wired/archive/15.05/feat_drugtest.html> (last visited November 20, 2008); Cohen L. , “Stuck for Money: To Screen New Drugs for Safety, Lilly Pays Homeless Alcoholics,” Wall Street Journal, November 14, 1996, at A1.

See Joint ABPI/BIA Report, supra note 21, at 24–25.

Tishler C. L. Bartholomae S. , “Repeat Participation among Normal Healthy Research Volunteers: Professional Guinea Pigs in Clinical Trials?” Perspectives in Biology and Medicine 46, no. 4 (2003): 508–520, at 512.

Elliott C. Abadie R. , “Exploiting a Research Underclass in Phase I Clinical Trials,” New England Journal of Medicine 358, no. 22 (2008): 2316–2317.

See Tishler Bartholomae , supra note 75.

See Shamoo Resnik , supra note 50, at W9.

Id., at W10; see Emanuel Miller , supra note 66.

See Elliott , supra note 72, at 37.

Id., at 40.

Nuffield Council on Bioethics Comment, in Department of Health, Expert Group on Phase I Clinical Trials, Final Report , Appendix D, at 61, December 2006, available at <www.dh.gov.uk> (last visited November 20, 2008). See also Grant R. W. Sugarman J. , “Ethics in Human Subject Research: Do Incentives Matter?” Journal of Philosophy and Medicine 29, no. 6 (2004): 717–738.

Dickert N. Grady C. , “What's the Price of a Research Subject? Approaches to Payment for Research Participation,” New England Journal of Medicine 341, no. 3 (1999): 198–203. The general view is that increased payment should not be offered for higher-risk studies. Nada and Somberg think that increased payment should be considered, but say that high payment could not legitimize unreasonably risky research. See Nada Somberg , supra note 8, at 601.

Id. (Nada and Somberg); Joffe Miller , supra note 18; Shamoo Resnik , supra note 50.

In an interview, one participant said, “I've worked as an electrician and seen guys get electrocuted. Being a lab rat is the only work situation where you've got round-the-clock medical attention. It's the safest job I've been in.” See McHugh , supra note 73, at 3.

See Nada Somberg , supra note 8, at 601.

See Tishler Bartholomae , supra note 75.

See Dickert Grady , supra note 84.

See Nada Somberg , supra note 8, at 601.

See Kimmelman , supra note 64; Morreim E. H. , “High-Profile Research and the Media: The Case of the AbioCor Artificial Heart,” Hastings Center Report 34, no. 1 (2004): 11–24; Albers G. W. Zivin J. A. Choi D. W. , “Ethical Standards in Phase I Trials of Neuroprotective Agents for Stroke,” Stroke 29, no. 8 (1998): 1493–1494.

See Dawson , supra note 56, at 1082.

Chen E. X. Tannock I. F. , “Risks and Benefits of Phase I Clinical Trials Evaluating New Anticancer Agents,” JAMA 292, no. 17 (2004): 2150–2151.

See Horstmann , supra note 11.

Id. For another evaluation of risks and benefits in phase I oncology trials, see Roberts T. G. , “Trends in the Risks and Benefits to Patients with Cancer Participating in Phase I Clinical Trials,” JAMA 292, no. 17 (2004): 2130–2140.

Agrawal M. Emanuel E. J. , “Ethics of Phase I Oncology Studies,” JAMA 290, no. 8 (2003): 1075–1082, at 1076.

See Horstmann , supra note 11.

Rothschild B. King N. , “Phase I Clinical Trials in Oncology,” New England Journal of Medicine 352, no. 23 (2005): 2451.

Kuehn B. M. , “Industry, FDA Warm to ‘Adaptive’ Trials,” JAMA 296, no. 16 (2006): 1955–1957; see Chen Tannock , supra note 94, at 2151. It is not clear that this approach will improve the risk-benefit ratio, however. A review of oncology trials published between 2002 and 2004 found that such design strategies were not associated with increased response rates and that subjects in such trials were at greater risk of experiencing severe or life-threatening toxicity. Koyfman S. A. , “Risks and Benefits Associated with Novel Phase I Oncology Trial Designs,” Cancer 110, no. 5 (2007): 1115–1124.

See Chen Tannock , supra note 94; Degos L. , “Phase I Trials in Cancer Treatment. The Maximum Tolerated Dose: A Barbarian Guideline,” Hematology Journal 1, no. 4 (2000): 219.

See Agrawal Emanuel , supra note 97, at 1077. For analysis questioning whether this kind of benefit should “count” in risk-benefit evaluations, see King N. Churchill L. , “Assessing and Comparing Potential Benefits and Risks or Harm,” in Emanuel E. , eds., The Oxford Textbook of Clinical Research Ethics (New York: Oxford University Press, 2008): 514–526.

See Chen Tannock , supra note 94, at 2150.

See Joffe Miller , supra note 18, at 37–39.

Horng S. , “Descriptions of Benefits and Risks in Consent Forms for Phase I Oncology Trials,” New England Journal of Medicine 347, no. 26 (2002): 2134–2140.

Grady C. Emanuel E. Horng S. , “Consent Forms for Oncology Trials,” New England Journal of Medicine 348, no. 15 (2003): 1496–1497, at 1497.

See Horng , supra note 105, at 2139.

King N. , “Consent Forms and the Therapeutic Misconception,” IRB: Ethics & Human Research 27, no. 1 (2005): 1–8, at 7.

Id., at 2. Studies indicate that many participants overestimate the chance of personal benefit in trials. For review and discussion, see Flory J. H. Wendler D. Emanuel E. J. , “Empirical Issues in Informed Consent for Research,” in Emanuel E. , eds., The Oxford Textbook of Clinical Research Ethics (New York: Oxford University Press, 2008): 645–660, at 651–52.

Henderson G. E. , “Uncertain Benefit: Investigators' Views and Communications in Early Phase Gene Transfer Trials,” Molecular Therapy 10, no. 2 (2004): 225–231.

Id., at 226–227.

Ryan D. P. , “Reality Testing in Cancer Treatment: The Phase I Trial of Endostatin,” The Oncologist 4 (1999): 501–508, at 505.

Annas G. J. , “The Changing Landscape of Human Experimentation: Nuremberg, Helsinki, and Beyond,” Health Matrix 2, no. 2 (1992): 119–140; Gordon J. , “when Consent to Serve as a Research Subject Is Not Informed,” Lahey Clinic Medical Ethics (Winter 2008): at 3.

Miller M. , “Phase I Cancer Trials: A Collusion of Misunderstanding,” Hastings Center Report 30, no. 4 (2000): 34–42.

Dresser R. , When Science Offers Salvation: Patient Advocacy and Research Ethics (New York: Oxford University Press, 2001): At 45–70, 129–50.

The therapeutic misconception arises when research participants confuse the objective of research, which is to generate knowledge, with the objective of therapy, which is to benefit the individual patient. In this situation, some may enroll in studies with the mistaken belief that each study component is aimed at patient care, rather than knowledge production. See Henderson G. E. , “Clinical Trials and Medical Care: Defining the Therapeutic Misconception,” PLoS Medicine 4, no. 11 (2007): e324, available at <http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040324&ct=1> (last visited November 20, 2008). In a discussion of translational science, one group advises scientists to “learn to articulate not only the promise of science, but also the difficulties that are associated with moving an idea along to the product stage, so that unrealistic expectations of perfect medicines for every disease in short time frames are not raised.” See Sabroe , supra note 31, at 79.

Kong W. M. , “Legitimate Requests and Indecent Proposals: Matters of Justice in the Ethical Assessment of Phase I Trials Involving Competent Patients,” Journal of Medical Ethics 31, no. 4 (2005): 205–208.

Id., at 207.

See Annas , supra note 113, at 138.

E.g., Seidenfeld , supra note 5; Agrawal Emanuel , supra note 97.

Id. (Agrawal and Emanuel), at 1077.

See King , supra note 108.

See Gordon , supra note 113.

See Kimmelman , “Staunch Protections,” supra note 7, at 2.

See Kimmelman , supra note 64, at 1904.

King N. , “The Healthy-Patient Paradox in Clinical Trials,” Atrium: The Report of the Northwestern Medical Humanities and Bioethics Program, no. 5 (2008): 9–11.

See Kimmelman , supra note 64, at 1905.

Id. See also Dresser supra note 115, at 21–43.

Id. (Kimmelman), at 1905.