Defining and Describing Benefit Appropriately in Clinical Trials

This is the outdated but persistent distinction between “nontherapeutic” and “therapeutic” research. See, for example, World Medical Association Declaration of Helsinki, “Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects,” revised 1996, reprinted in JAMA, 277 (1997): 925–26; see also Capron A.M. , “Ethical and Human-Rights Issues in Research on Mental Disorders That May Affect Decision-Making Capacity,” N. Engl. J. Med., 340 (1999): 1430–34; Rolleston F. Miller J.R. , “Therapy or Research: A Need for Precision,” IRB, 3, no. 7 (1981): 1–3; Levine R. , “The Need to Revise the Declaration of Helsinki,” N. Engl. J. Med., 341 (1999): 531–34.

Appelbaum P.S. Roth L.R. Lidz C. , “The Therapeutic Misconception: Informed Consent in Psychiatric Research,” International Journal of Law & Psychiatry, 5 (1982): 319–329; Appelbaum P.S. , “False Hopes and Best Data: Consent to Research and the Therapeutic Misconception,” Hastings Center Report, 17, no. 2 (1987): 20–24; Appelbaum P.S. , “Commentary: Examining the Ethics of Human Subjects Research,” Kennedy Institute of Ethics Journal, 6 (1996): 283–287. It has also been called the “therapeutic illusion.” Katz J. , “Statement by Individual Committee Member,” in Advisory Committee on Human Radiation Experiments, Final Report (Oxford University Press, 1996): 545.

Churchill L.R. , “Genetic Research as Therapy: Implications of ‘Gene Therapy’ for Informed Consent,” Journal of Law, Medicine & Ethics, 26 (1998): 38–47. See also Kolata G. , “Separating Research From News,” New York Times, July 18, 2000.

Grady D. , “Patient or Guinea Pig? Dilemma of Clinical Trials,” New York Times, Jan. 5, 1999.

Kolata G. , “When the Dying Enroll in Studies: A Debate Over False Hopes,” New York Times, Jan. 29, 1994.

The Common Rule is the shorthand name for the set of federal regulations that govern federally funded research with human subjects. The regulations, which implement Pub. L. 93–348 (the National Research Act of 1974), were harmonized into the Common Rule in 1991 for 17 federal departments and agencies, and are codified separately for each. The Common Rule itself was published in the Federal Register, 56 Fed. Reg. 28,012 (June 18, 1991). The codifications most familiar to those involved in research oversight are the U.S. Department of Health and Human Services regulations, 45 C.F.R. pt. 46, and the Food and Drug Administration regulations, 21 C.F.R. pts. 50 and 56. The FDA has not adopted the Common Rule; its regulations are somewhat modified, though overall quite similar.

§___.111(a)(2).

§___. 116(a)(3).

I am indebted to Alex Capron for the “reasonable chance/reasonable choice” formulation.

45 C.F.R. pt. 46, subpt. D, “an intervention or procedure that holds out the prospect of direct benefit for the individual subject.”

45 C.F.R. pt. 46, subpt. B, “the purpose of the activity is to meet the health needs of the mother” or “the particular fetus”; a revised subpart B, which has for some time been awaiting final signoff, would change this.

National Bioethics Advisory Commission, Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity, Report and Recommendations of the National Bioethics Advisory Commission (December 1998) [hereinafter cited as NBAC Report] (“protocol that … offers the prospect of direct medical benefit to the subject”).

45 C.F.R. pt. 46, subpt. C, research on innovative practices “which have the intent and reasonable probability of improving the health and well-being of the subject.”

FDA, 21 C.F.R. § 50.24; DHHS, 61 Fed. Reg. 51,531 (preclinical studies and other evidence “support the potential for the intervention to provide a direct benefit to the individual subjects”).

FDA, 21 C.F.R. § 56.102(d) (“life-threatening situation in which no standard acceptable treatment is available” — potential benefit implicit); 21 C.F.R. § 50.23(b) (informed consent also waived if “immediate use of the test article is, in the investigator's opinion, required to preserve the life of the subject”).

FDA, 21 C.F.R. § 312.34–35 (data show that drug “may be effective”). A “treatment IND” is the use of an investigational new drug (IND) for treatment. The FDA issues “IND numbers” to unapproved drugs to authorize their testing for eventual approval.

See, for example, Pear R. , “Managed-Care Plans Agree to Help Pay the Costs of Their Members in Clinical Trials,” New York Times, Feb. 9, 1999; “NIH, HMO Group Pact Will Enable Increased Member Access To Clinical Trials,” The Blue Sheet, Feb. 17, 1999; Kolata G. Eichenwald K. , “Group of Insurers Will Pay for Experimental Cancer Therapy,” New York Times, Dec. 16, 1999; Pear R. , “Clinton to Order Medicare to Pay New Costs,” New York Times, June 7, 2000. Both individual states and the federal government are moving toward mandating insurer coverage of late-phase clinical trials on a case-by-case basis according to their potential for direct benefit as well as coverage of routine medical expenditures in research if they would be covered outside the research setting.

NBAC Report, supra note 12, at 45, citing National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Research Involving Those Institutionalized as Mentally Infirm (1978): At 31, and Keyserlingk E.W. , “Proposed Guidelines for the Participation of Persons with Dementia as Research Subjects,” Perspectives in Biology and Medicine, 38 (1995): 319–62, at 327–28.

Churchill L.R. , “Toward a More Robust Autonomy: Revising the Belmont Report,” paper prepared for NBAC (presented April 17, 1999).

Dickert N. Grady C. , “What's the Price of a Research Subject? Approaches to Payment for Research Participation,” N. Engl. J. Med., 341 (1999): At 198.

For example, a purpose statement that declares, “The purpose of this research is to develop a new kind of cancer treatment, which works by helping the body's immune system to attack cancer cells,” could be misleading in a consent form for a Phase I study when the intervention has not yet been tried in humans. Potential subjects could easily take this to mean that in this Phase I study they will receive a “new treatment” that “works.”

See NBAC Report, supra note 12; Keyserlingk , supra note 18.

Final Report (June 15, 1998): At 21 (visited Dec. 11, 2000) <http://ohrp.osophs.dhhs.gov/hsp_report/hsp_final_rpt.pdf>.

Boucher R.C. Knowles M.R. , “Clinical Protocol: Gene Therapy for Cystic Fibrosis Using E1-Deleted Adenovirus: A Phase I Trial in the Nasal Cavity, The University of North Carolina at Chapel Hill,” Human Gene Therapy, 5 (1994): 615–639. In the Purpose section, the consent form states: “I understand that this study is not designed for treatment, and that I will not get any medical benefit from this nose study of adenoviral gene transfer” (at 636). In the Benefits section, the form states: “I will not benefit directly from the nose study of adenoviral gene transfer” (at 638).

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 , DHEW Pub. No. (OS) 78–0012, (Washington, D.C.: U.S. Gov't Printing Office, 1978). The Belmont Report was reprinted in the Federal Register in 1979 and is now available online at <http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm>.

The IRB Guidebook was published in hard copy in 1993, and is currently available at <http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm>.

The FDA Information Sheets were last updated in 1998. They are available at <http://www.fda.gov/oc/oha/irb/toc.html> as well as in hard copy.

NBAC Report, supra note 12, at 44, citing National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Research Involving Those Institutionalized as Mentally Infirm (1978): At 31. See also Berg J.W. , “Legal and Ethical Complexities of Consent with Cognitively Impaired Research Subjects: Proposed Guidelines,” Journal of Law, Medicine & Ethics, 24 (1996): 18–35, at 24–25.

For example, the guidance document provided for investigators preparing gene transfer research protocols (Appendix M of the NIH Guidelines, “Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Human Subjects”) requires “clear itemization” in the consent form of “types of adverse experiences, their relative severity, and their expected frequencies.” It suggests that risks of harm be categorized as mild, moderate, and severe, and that any verbal descriptions of frequency, such as rare, uncommon, or frequent, be explained. It also mandates mention of the possibility of unforeseen harms (Appendix M-III-B-1-e). See King N.M.P. , “Rewriting the ‘Points to Consider’: The Ethical Impact of Guidance Document Language,” Human Gene Therapy, 10 (1999): 133–39.

I am indebted to Dr. Jon Gordon for first calling my attention to this concern.

Crewsdon J. , “Human Trials of Cancer Treatment Set to Begin,” Chicago Tribune, reprinted in Herald-Sun, Durham, N.C., Oct. 18, 1999; see also Russo F. , “The Clinical-Trials Bottleneck,” Atlantic Monthly, May 1999, at 30–36 (“no more than 20 percent” of experimental interventions succeed in Phase III trials, where success is defined as extending median survival by 25 percent); Kolata , supra note 3.

Moreno J. , “Updating Protections for Human Subjects Involved in Research,” JAMA, 280 (1998):1954.

“Human Guinea Pigs,” U.S. News Online, May 24, 1999 (visited Dec. 12, 2000) <http://www.usnews.com/usnews/issue/990524/nycu/trials.b.htm>.

See King N.M.P. , “Experimental Treatment: Oxymoron or Aspiration?” Hastings Center Report, 25, no. 4 (1995): 6–15; Churchill L.R. , supra note 3; Goldner J. , “An Overview of Legal Controls on Human Experimentation and the Regulatory Implications of Taking Professor Katz Seriously,” Saint Louis University Law Journal, 38 (1993): 63–134, at 125.

The essential goal of clinical research is to “develop or contribute to generalizable knowledge.” Common Rule, §__.102(d). In order to achieve this goal, proposed research must demonstrate both value and validity — that is, the research must ask a question that is of scientific and societal importance (value) and the research design must have the capacity to answer that question, in either the affirmative or the negative (validity). Emanuel E. , “What Makes Clinical Research Ethical?” JAMA, 283 (2000): 2701–2711.

Of course, a continuing failure to produce data supporting direct benefit in later phases of research will affect the promise of the line of research and its aspirational benefit.

Katz J. , personal communication (November 1997).

Freedman B. , “Equipoise and the Ethics of Clinical Research,” N. Engl. J. Med., 317 (1987): 141–45.

The extensive debate about the ethics of randomization in Phase III clinical trials is largely about when enough evidence exists to assert that one treatment is superior. This complex literature is beyond the scope of the present discussion of early-phase trials.

See the NCI booklet “Taking Part in Clinical Trials: What Cancer Patients Need to Know,” available online at <http://cancertrials.nci.nih.gov/understanding/bookshelf/treatment/index.html>. This change is based not only on the reasons stated but also on the growing use of diagnostic technologies to give information on tumor cell types and their probable responses to conventional treatments, as well as on the development of new classes of investigational interventions that may have effects on treatment-refractory disease.

See, for example, Groopman J. , “Dr. Fair's Tumor,” The New Yorker, Oct. 26/Nov. 2, 1998, at 78–102.

See, for example, Daugherty C. , “Impact of Therapeutic Research on Informed Consent and the Ethics of Clinical Trials: A Medical Oncology Perspective,” Journal of Clinical Oncology, 17 (1999): 1601–17.

Daugherty C. , “Perceptions of Cancer Patients and Their Physicians Involved in Phase I Trials,” Journal of Clinical Oncology, 13 (1995): 1062–72.

Some have argued for redesigning Phase I trials, especially in oncology and other serious diseases, to cluster intervention dosing around the probable maximum tolerated dose (MTD) as predicted by lab and animal studies. See, for example, B. Brody, Chapter 8, in The Ethics of Biomedical Research: An International Perspective (Oxford: Oxford University Press, 1998); Kipnis K. , “Vulnerability in Research Subjects: An Ethical Taxonomy,” paper prepared for NBAC (July 2000). However, it is not clear that this would substantially increase the likelihood of direct benefit in Phase I trials. That would be true only if the drug is actually effective, if the duration of the trial is sufficient to produce meaningful clinical effects, and if the projections about the MTD turn out to be reasonably accurate. With no previous human experience and probably rather sketchy preclinical data, that is a lot of ifs. See also Miller M. , “Phase I Cancer Trials: A Collusion of Misunderstanding,” Hastings Center Report, 30, no. 4 (2000): 34–43, at 39–40.

See, for example, “The Biotech Death of Jesse Gelsinger,” New York Times Magazine, Nov. 28, 1999. Gelsinger, who had just turned eighteen, was enrolled in a Phase I safety and toxicity study in which corrected genetic material, combined with a modified adenovirus vector, was injected into subjects with a genetic deficiency of an essential enzyme called ornithine transcarbamylase, which affects liver function. The injection apparently caused an overwhelming inflammatory response. At the time, safety concerns in the field of gene transfer research were directed primarily toward the risk of inadvertently altering subjects' germlines (a safety issue for the subjects' future offspring) and long-term risks of causing mutations in subjects (an issue similar to the possibility that successful cancer treatment could cause new malignancies decades from now). Little attention was directed toward risks of immediate and direct harm since the worst that had been publicly discussed was “flu-like symptoms” after an injection of genetic material in a modified viral carrier “vector,” like adenovirus. The consent form for the study in which Gelsinger died promised no direct benefit to subjects, but Gelsinger's father testified before the U.S. Congress last February that he and his son were given somewhat different and misleading information during the consent process. Jesse Gelsinger's death has spurred significant new oversight activity in all human subjects research. See, for example, Shalala D. , “Protecting Research Subjects—What Must Be Done,” N. Engl. J. Med., 343 (2000): At 800.

See, for example, Stephenson J. , “Gene Therapy Trials Show Clinical Efficacy,” JAMA, 283 (2000): 589–90.

All claims of benefit, including collateral benefit, should address all three dimensions of benefit. In some respects, collateral benefit claims may be questioned, but that discussion is beyond the scope of this paper.

See Daugherty , supra note 43.

See, for example, Carpenter W.T. Conley R.R. , “Sense and Nonsense: An Essay on Schizophrenia Research Ethics,” Schizophrenia Research, 35 (1999): 219–225, at 223. See also supra note 44.

Levine R. , “Uncertainty in Clinical Research,” Law, Medicine & Health Care, 16 (1988): 174–82.

See The Belmont Report, supra note 25. The Belmont Report defines treatment (or “practice”) as “interventions that are designed solely to enhance the well being of an individual patient … and that have a reasonable expectation of success.”

Katz J. , “Human Experimentation and Human Rights,” Saint Louis University Law Journal, 38 (1993): 7–54, at 25–26. But see Norquist G. , “Expanding the Frontier of Treatment Research,” Prevention & Treatment, 2 (1999):1–5.

Kolata G. Eichenwald K. , “In Pediatrics, A Lesson in Making Use of Experimental Procedures,” New York Times, Oct. 3, 1999.

Patients who are uninsured, underinsured, or otherwise economically vulnerable are, in general, at some risk of exploitation when researchers, even with the best of intentions, offer them research participation as a treatment substitute. Levine R. , Ethics and Regulation of Clinical Research, 2d ed., (New Haven: Yale University Press, 1988): 82–84; Kolata G. Eichenwald K. , “For the Uninsured, Experiments May Provide the Only Treatment,” New York Times, June 22, 1999.

See, for example, Light D. , “Life, Death, and the Insurance Companies,” N. Engl. J. Med., 330 (1994): 498–500; Boren S. , “I Had a Tough Day Today, Hillary,” N. Engl. J. Med., 330 (1994): 500–502.

Rowlings P.A. , “Factors Correlated With Progression-Free Survival After High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation for Metastatic Breast Cancer,” JAMA, 282 (1999): 1335–43; Gradishar W.J. , “High-Dose Chemotherapy and Breast Cancer,” JAMA, 282 (1999): 1378–80.

Kolata G. Eichenwald K. , “Health Business Thrives on Unproven Treatment, Leaving Science Behind,” New York Times, Oct. 2, 1999.

Unfortunately, the ability to disseminate and apply the best current knowledge gleaned from clinical trials is compromised by publication bias in the reporting of study data. See, for example, Rennie D. , “Fair Conduct and Fair Reporting of Clinical Trials,” JAMA, 282 (1999): 1766–68. This raises the problem of how the results of clinical research can and should influence practicing physicians.