Research ethics

Informed consent and therapeutic misconception

The conventional wisdom about research participants is that 'true informed consent is impossible' and that 'research participants misunderstand the purpose and the risks and benefits of research because they are so desperate.' But do we really need to be that pessimistic? Perhaps these beliefs also reflect our failure to accurately understand the participants' perspective. For example, in a series of studies, we have shown that when a participant seems to not understand the purpose of research, it is most likely due to their not interpreting (in the way we intend them) the questions we are using to measure their understanding. Kevin Weinfurt has reminded us of this common fallacy among researchers in a recent article. This research draws on considerations of pragmatics.

Part of this confusion is also likely due to the widespread belief that, since the primary purpose of research is societal or scientific, there is something wrong with participants in clinical trials being motivated by a desire for therapeutic benefit. But this confuses motivation with understanding. (People are motivated by money in buying a lottery ticket but they aren't confused about what it is--a gamble). In fact, this confusion keeps us from providing the kind of information that would be useful to people who are in fact motivated by desire for benefit. Several of my studies are designed to probe this issue. For example, many early phase research informed consent forms use the phrase "it is not guaranteed that you will benefit" as though benefit is so likely that the question really is about whether it is certain or not. Or when available effective treatments are withheld in order to test a new drug, we seldom tell the subjects all that we should about what they are giving up.

Cho, H.L., Kim, S.Y.H., Fitzhugh, C., Hsieh, M., Tisdale, J., Grady, C. Motivations and Decision-Making of Adult Sickle Cell Patients in High-Risk Clinical Research. Biology of Blood and Marrow Transplantation. 2020;26(6):1225-1232

Cho HL, Miller DG, Kim SYH. Understanding people's 'unrealistic optimism' about clinical research participation. J Med Ethics. 2020;46(3):172-177.

Dickert NW, Eyal N, Goldkind S, Grady C, Joffe S, Lo B, Miller FG, Silbergleit R, Weinfurt KP, Wendler D, Kim SYH. Re-Framing Consent for Clinical Research: A Function-Based Approach. American Journal of Bioethics. 2017;17(12):3-11.

Kim SYH, De Vries R, Holloway RG, Wilson RM, Parnami S, Kim HM, Frank S, Kieburtz K. Sham Surgery Controls in Parkinson Disease Clinical Trials: Views of Participants. Movement Disorders 2012; 27(11): 1461-1465.

Kim SYH, De Vries R, Wilson RM, Parnami S, Frank S, Kieburtz K, Holloway RG. Research Participants’ ‘Irrational’ Expectations: Common or Commonly Mismeasured? IRB: Ethics & Human Research 2013; 35(1): 1-9.

Kim SYH, Wilson R, DeVries R, Kim HM, Holloway RG, Kieburtz K. Could the High Prevalence of Therapeutic Misconception Partly Be a Measurement Problem? IRB: Ethics & Human Research 2015;37(4):11-18.

Kim SYH, DeVries R, Parnami S, Wilson R, Kim HM, Frank S, Holloway RG, Kieburtz K. AreTherapeutic Motivation and Having One’s Own Doctor as Researcher Sources of Therapeutic Misconception? Journal of Medical Ethics. 2015; 41: 391-397. DOI: 10.1136/medethics-2013-101987.

Kim SYH, Wilson R, De Vries R, Kim HM, Holloway RG, Kieburtz K. “It is not guaranteed that you will benefit”: True but misleading? Clinical Trials. doi: 10.1177/1740774515585120.

Chen S, McCullumsmith C, Kim SYH. Disclosing the Potential Impact of Placebo Controls in Antidepressant Trials. British Journal of Psychiatry Open. Jun 2015, 1 (1) 1-5; DOI: 10.1192/bjpo.bp.115.000109

Kim SYH, Wilson R, De Vries R, Ryan KA, Holloway RG, Kieburtz K. Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception? Journal of Medical Ethics. March 10, 2016.

Kim SYH, Holloway RG, Frank S, Wilson R, Kieburtz K. Trust in Early Phase Research: Therapeutic Optimism and Protective Pessimism. Medicine, Health Care and Philosophy 2008; 11(4): 393-401.

Kim SYH, Schrock L, Wilson RM, Frank SA, Holloway RG, Kieburtz K, De Vries RG. An Approach to Evaluating Therapeutic Misconception: A Pilot Study in Gene Transfer for Parkinson’s Disease. IRB: Ethics & Human Research 2009; 31(5): 7-14.

Kimmelman J, Lemmens T, Kim SYH. Analysis of Consent Validity for Invasive, Nondiagnostic Research Procedures. IRB: Ethics & Human Research. 2012; 34(5): 1-7.

Kim SYH, De Vries R, Holloway RG, & Kieburtz K. (2016). Understanding the ‘therapeutic misconception’ from the research participant’s perspective. Journal of Medical Ethics. doi: 10.1136/medethics-2016-103597

Kim SYH. Clinical Trials Without Consent?Perspectives in Biology and Medicine. 2016; 59 (1), 132-146. DOI: 10.1353/pbm.2016.0023

Pragmatic RCTs and Comparative Effectiveness Trials

Comparative effectiveness research (CER) compares two or more already-in-use treatments (often FDA approved) to determine which is the most effective. Although most of this research is observational ('big data' research of medical records), CER can also involve head-to-head randomized clinical trials (RCTs). Drug companies have little incentive to conduct head-to-head trials. But such studies could be invaluable in keeping down overall health care costs.

Since such studies involve treatments that are already used in clinical practice (i.e., they do not involve novel or experimental treatments with a lot of unknowns), some have argued that perhaps such studies add no additional risk beyond the risks of usual treatment. Some have argued, based on this line of reasoning, that some CER studies do not even need informed consent. I have doubts about this line of reasoning.

My work focuses on how to analyze research risks in CER RCTs, whether informed consent can be ethically waived in some CER RCTs, and when traditional written informed consent may be not only unnecessary but less than ideal.

Kim SYH. Comparative Effectiveness Research, Learning Health Systems, and Pragmatic Randomized Controlled Trials. In: Iltis AS, MacKay D, eds. The Oxford Handbook of Research Ethics. Oxford University Press; 2020.

Dickert NW, Wendler D, Devireddy CM, Goldkind S, Ko Yi-An, Speight CD, Kim SYH. Understanding Preferences Regarding Consent for Pragmatic Trials in Acute Care. Clinical Trials. 2019; 15:567-578

Miller, D. G., Kim, S. Y. H., Li, X., Dickert, N. W., Flory, J., Runge, C. P., & Relton, C. (2018). Ethical Acceptability of Postrandomization Consent in Pragmatic Clinical Trials.JAMA Network Open, 1(8), e186149. doi:10.1001/jamanetworkopen.2018.6149

Kim SYH. Ethical Issues in Pragmatic Trials of ‘Standard-of-Care’ Interventions in Learning Healthcare Systems. Learning Health Systems. 2018: 1-5.

Dickert NW, Wendler D, Devireddy CM, Goldkind S, Ko Yi-An, Speight CD, Kim SYH. Consent Preferences for Pragmatic Trials in Acute Illness. J Am College Cardiology. 2018: 71(9); 1051-1053.

Miller DG, Kim SYH, Li X, Dickert NW, Flory J, Runge CP, Relton C. Ethical Acceptability of Post-Randomization Consent in Pragmatic Clinical Trials: A National Survey of the US General Public. JAMA Network Open. 2018;1(8):e186149. Doi:10.1001/jamanetworkopen.2018.6149.

Vickers AJ, Young-Afat DA, Ehdaie B, Kim SYH. Just-in-time consent: the ethical case for an alternative to traditional informed consent in randomized trials comparing an experimental intervention with usual care. Clinical Trials. 2017:1740774517746610.

Kim SYH, Flory J, Relton C. Ethics and Practice of Trials within Cohorts (TwiCs): An Emerging Pragmatic Trial Design. Clinical Trials. 2017:1740774517746620.

The previous two publications were accompanied by two invited commentaries.

Wendler, D. Commentary: innovative approaches to informed consent for randomized clinical trials: identifying the ethical challenges. Clinical Trials.

Weijer, C, Goldstein, C, Taljaard, M. Commentary: TwiC or Treat? Are trials within cohorts ethically defensible? Clinical Trials IN PRESS.

Our responses:

Vickers A, Young-Afat D, Ehdaie B, Kim SYH. Rejoinder. Clinical Trials. 2017:1740774517746638.

Kim SYH, Flory J, Relton C. Rejoinder. Clinical Trials. 2018; 15(1): 27-28.

Kalkman S, Kim SYH, van Thiel GJMW, Diederick E, Grobbee DE, van Delden JJM. Ethics of informed consent for pragmatic trials with new interventions. Value in Health. 2017.

Kim SYH, Miller FG. Informed Consent for Pragmatic Trials: The Integrated Consent Model. New Eng J Medicine 2014; 370:769-72.

Kim SYH, Miller FG. Varieties of standard-of-care treatment randomized trials: Ethical implications. JAMA. 2015;313(9):895-896.

Nayak RK, Wendler D, Miller FG, Kim SYH. Pragmatic Randomized Trials Without Standard Informed Consent?: A National Survey. Annals of Internal Medicine. 2015;163(5):356.

Kim SYH, Miller FG. Ethical Complexities in Standard of Care Randomized Trials: A Case Study of MorningVersus Nighttime Dosing of Blood Pressure Drugs. Clinical Trials. 2015 doi: 10.1177/1740774515607213

Kim SYH, Miller FG. Waivers and Alterations to Consent in Pragmatic Clinical Trials: Respecting the Principle of Respect for Persons. IRB: Ethics & Human Research.

Miller FG, Kim SYH. Personal Care in Learning Health Care Systems. Kennedy Institute of Ethics Journal. Volume 25, Number 4, December 2015, pp. 419-435

Chen S, Kim SYH. A Framework for Analysis of Research Risksand Benefits to Participants in Standard of Care Pragmatic Clinical Trials. Clinical Trials. doi: 10.1177/1740774516656945.

Kalkman S, Kim SYH, van Thiel GJMW, Diederick E, Grobbee DE, van Delden JJM. Ethics of informed consent for pragmatic trials with new interventions. Value in Health. 2017.

IRB Reform

The IRB system wastes money and resources on oversight of extremely low risk, non-controversial research that do not need it. Those resources could better be used to improve oversight of more risky and controversial studies.

Kim SYH, Ubel PA, De Vries RD. Pruning the Regulatory Tree. Nature 2009; 457: 534-535.

Wilson RM, Kieburtz K, Holloway RG, Kim SYH. Evidence-Based Research Ethics and Determinations of ‘Engagement’ in Research. IRB: Ethics & Human Research 2014; 36(2): 10-13.

Kim SYH. ‘Human Subjects Research’ as Stigmatized Activity: Implications for Oversight Reform. Cortex. 2015. doi:10.1016/j.cortex.2015.04.020.

"Of making ELSI research there is no end, and much of it wearies the soul."

--with apologies to the writer of Ecclesiastes, my (meager) contributions to an overworked field

Gornick MC, Ryan KA, Kim SYH. Impact of Non-Welfare Interests on Willingness to Donate to Biobanks: An Experimental Survey. Journal of Empirical Research in Human Research Ethics. 2014;9(4):22-33.

Tomlinson T, De Vries R, Ryan K, Kim H, Lehpamer N, Kim SYH. Moral concerns and the willingness to donate to a research biobank. JAMA. 2015;313(4):417-419. PMC4443895.

Kim SYH, Karlawish J, Berkman BE. Ethics of Genetic and Biomarker Test Disclosures in Neurodegenerative Disease Prevention Trials. Neurology. 2015; 84(14): 1488-1494.

Grady C, Eckstein L, Berkman B, Brock D, Cook-Deegan R, Fullerton S, Hansson N, Hull S, Kim SY, Lo B, Pentz R, Rodriguez, Weil C, Wilfond B, Wendler D. Broad Consent for Research with Biological Samples: Workshop Conclusions. Am J Bioethics, in press.

De Vries, R. G., Tomlinson, T., Kim, H. M., Krenz, C. D., Ryan, K. A., Lehpamer, N., & Kim, S. Y. H. (2016). The moral concerns of biobank donors: the effect of non-welfare interests on willingness to donate. Life Sciences, Society and Policy, 12(1), 1-15. doi: 10.1186/s40504-016-0036-4

De Vries, R. G., Tomlinson, T., Kim, H. M., Krenz, C., Haggerty, D., Ryan, K. A., & Kim, S. Y. (2016). Understanding the Public's Reservations about Broad Consent and Study-By-Study Consent for Donations to a Biobank: Results of a National Survey. PLoS ONE, 11(7), e0159113. doi: 10.1371/journal.pone.0159113