Larry R. Churchill, PhDAnn Geddes Stahlman Professor of Medical EthicsCenter for Biomedical Ethics and SocietyVanderbilt University Medical Center

“The belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge.”

“It is not a misconception to believe that participants probably will receive good clinical care during research, but it is a misconception to believe that the primary purpose of clinical trials is treatment…”

---National Bioethics Advisory Committee (NBAC), 2001

---

“When a research subject fails to appreciate the distinction between the imperatives of clinical research and of ordinary treatment, and therefore inaccurately attributes therapeutic intent to research procedures.” (italics added)

---Lidz and Appelbaum, 2002

Research subjects with “entirely therapeutic orientations,” believe that procedures of clinical trials are all designed solely to help them, do not recognize research aims as present and primary.

-- Appelbaum, Roth and Litz,

1982

TM invalidates consent

The first principle of The Belmont Report (1979), which is the ethical basis for the U.S. federal regulations, is “respect for persons”—persons have the right to decide for themselves whether to participate in research on the basis of information about the nature of the trial, potential benefits and harms, the alternatives, etc.

“Subject Interview study” – 1,900 subjects interviewed at 19 academic medical centers; 67% responded that they had joined the trial “to get better treatment” and “did not readily make distinctions between research and medical treatment”

---done in conjunction with the Human

Radiation Experiments National Commission Report, 1996.

Empirical studies of clinical trials, predominantly early stage Ca trials, indicate that subjects are often motivated to participate in research by expectation of direct medical benefit, and when asked, blur the distinction between research and treatment.

Rodenhuis, S., W. J. van den Heuvel, et al. (1984). "Patient motivation and informed consent in a phase I study of an anticancer agent." Eur J Cancer Clin Oncol 20(4): 457-62.

Kodish, E., C. Stocking, et al. (1992). "Ethical issues in phase I oncology research: a comparison of investigators and institutional review board chairpersons." J Clin Oncol 10(11): 1810-6.

Tomamichel, M., C. Sessa, et al. (1995). "Informed consent for phase I studies: evaluation of quantity and quality of information provided to patients." Ann Oncol 6(4): 363-9.

Daugherty, C., M. J. Ratain, et al. (1995). "Perceptions of cancer patients and their physicians involved in phase I trials." J Clin Oncol 13(5): 1062-72.

Daugherty, C. K., D. M. Banik, et al. (2000). "Quantitative analysis of ethical issues in phase I trials: a survey interview of 144 advanced cancer patients." Irb 22(3): 6-14.

Schaeffer, M. H., D. S. Krantz, et al. (1996). "The impact of disease severity on the informed consent process in clinical research." Am J Med 100(3): 261-8.

Yoder, L. H., T. J. O'Rourke, et al. (1997). "Expectations and experiences of patients with cancer participating in phase I clinical trials." Oncol Nurs Forum 24(5):891-6.

Itoh, K., Y. Sasaki, et al. (1997). "Patients in phase I trials of anti-cancer agents in Japan: motivation, comprehension and expectations." Br J Cancer 76(1): 107-13.

Joffe, S., E. F. Cook, et al. (2001). "Quality of informed consent: A new measure of understanding among research subjects." Journal of the National Cancer Institute 93(2): 139-147.

Churchill, L.R., Nelson, D.K., Henderson, G.E., King, N.M.P., Davis, A.M., Leahey, E., and Wilfond, B.S., “Assessing Benefit in Clinical Research: Why Diversity in Benefit Assessment Can Be Risky,” IRB: Ethics and Human Research 25 No. 3 (May-June, 2003), pp. 1-7.

Joffe, S., E. F. Cook, et al. (2001). "Quality of informed consent in cancer clinical trials: a cross- sectional survey." Lancet 358(9295): 1772-7.

Kass, N. E., M. R. Natowicz, et al. (2003). "The use of medical records in research: what do patients want?" J Law Med Ethics 31(3): 429-33.

Meropol, N. J., K. P. Weinfurt, et al. (2003). "Perceptions of patients and physicians regarding phase I cancer clinical trials: implications for physician-patient communication." J Clin Oncol 21(13): 2589-96.

Weinfurt, K. P., L. D. Castel, et al. (2003). "The correlation between patient characteristics and expectations of benefit from Phase I clinical trials." Cancer 98(1): 166-75.

King, N.M.P., Henderson, G., Churchill, L., Davis, A., Hull, S., Nelson, D., Parham-Vetter, P., Rothschild, B., Easter, M., Wilfond, B., “Consent Forms and the Therapeutic Misconception,” IRB: Ethics and Human Research, Vol. 27, No. 1, 2005, pp. 1-8.

Why participate in a clinical trial?Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.

----from the NIH website, http://www.clinicaltrials.gov/

( pre-2011)

From the NIH website: October 26, 2011

People participate in clinical trials for a variety of reasons. Healthy volunteers say they participate to help others and to contribute to moving science forward. Participants with an illness or disease also participate to help others, but also to possibly receive the newest treatment and to have the additional care and attention from the clinical trial staff. Clinical trials offer hope for many people and an opportunity to help researchers find better treatments for others in the future.

Participants with an illness or disease also participate to help others, but also to possibly receive the newest treatment and to have the additional care and attention from the clinical trial staff. NIH website

People participating in clinical research have access to experimental medications or devices before they become available to the general public. Univ. of Iowa website

Contextual features: research done in same setting as medical care, by many of the same personnel, researchers wear IDs that indicate they are doctors, wear white coats, etc.—environment looks and feels therapeutic.

Dual role issues: researchers are often also physicians, tend to think of and describe their research as “care,” sometimes as “the best care,” or as “new, or cutting edge treatments,” or present the long-range aims for a line of research in therapeutic terms, which are interpreted by subjects as benefits they may receive through participating…

Misleading, or ambiguous consent forms

Rebecca Dresser, “The Ubiquity and Utility of the Therapeutic Misconception,” Social Philosophy & Policy 19:271-294, 2002.

_______________, When Science Offers Salvation, Oxford University Press, 2001

Before 1990, 80% of clinical research occurred in academic medical centers

Currently 75% of clinical research is conducted in the clinics of community practitioners.

Between 35-50% of all U.S. physicians have conducted clinical trials

Analysis of 321 consent forms for gene transfer research, 1990-2000; all early phase:

>’research’ and ‘treatment’ used as interchangeable terms

>surrogate endpoints (e.g., tumor shrinkage, immune response) discussed but not distinguished from clinical endpoints (e.g., survival time, improved quality of life)

>benefits to society and inclusion benefits not distinguished from possible medical benefits for participants

---N. King, G. Henderson, L. Churchill, et al., “Consent Forms

and the Therapeutic Misconception: The Example of Gene Transfer Research,” IRB (2005); 27,1:1-8.

“You may or may not benefit.” “Personal benefit cannot be

guaranteed.” “This trial is not intended to benefit

you, although we will monitor results for any improvements in your condition.”

“You are unlikely to receive any lasting benefit from joining this study.”

“Participating in this trial will not improve your health.”

65 of 95 participants in Phase 1 oncology trials did not know they were enrolled in research.

89 of 95 participants in Phase 1 trials estimated their chances of benefit as >20%, or risk as 0.

--Pentz, White, Harvey et al., Cancer 118

(18):4571-78, 2012

The subject knows it is research, but has an unrealistic expectation of being helped by the trial. For example: the investigator thinks the chances of a participant benefiting from a Phase 1 Trial are remote (<2%)

but the subject thinks it is 50%.

When System 1 intuitions overwhelm System 2 logical thinking

Daniel Kahneman, Thinking: Fast and Slow, 2011.

Does this jeopardize consent?

Is the difference between ‘expectations’ and ‘hopes’ helpful here?

Example: participant who is confident, after an explanation of risks, that he/she is immune to harms, or tends to minimize them.

--from the MOMS trial:

1. “No harm will come to me. My grandfather (or God) is watching over me”

2. “I’m sure Vanderbilt wouldn’t be offering this trial if it weren’t safe.”

3. “I don’t want to hear about the possible problems. It will only upset me.”

Do these jeopardize consent?

Again, ‘expectations’ vs. ‘hopes’?

1. How confident are you that the experimental therapy will control your Ca?2. If 100 people were to participate in this study, how many could expect to have their Ca controlled as a result?

Estimates were higher for 1 than 2, but both still showed therapeutic overestimation. --Weinfurt et al., J. Clin Oncol. 2012

Nancy, M. P. King, Wake Forest Gail Henderson, UNC-Chapel HillBen Wilfond, Children’s Hospital,

SeattleDan Nelson, UNC-Chapel Hill

larry.churchill@vanderbilt.edu