Informed Consent for the Human Research Subject with a Neurologic Disorder

Abstract

The doctrine of informed consent sits at the intersection of law, ethics, and neuroscience, posing unique challenges for human subject research involving neurological patients. These challenges are compounded by the variegated nature of both neurological injury and the law governing research consent. This article provides a framework for investigators likely to encounter subjects with some degree of neurological impairment, whose capacity to consent requires scrupulous assessment prior to enrollment in research trials. We consider several researches and disease contexts—from emergency epilepsy research to long-term dementia research—and clarify the ethical and legal principles governing consent for participation in each. We additionally explore empirical research on consent capacity and survey several areas of emerging ethical import that will require the attention of investigators in decades to come.

Keywords

consent - capacity - law - ethics - neurologic

• References

• 1 Berg JW, Appelbaum PS, Grisso T. Constructing competence: formulating standards of legal competence to make medical decisions. Rutgers Law Rev 1996; 48 (02) 345-371
• 2 Faden RR, Beauchamp TL. A History and Theory of Informed Consent. Oxford: Oxford University Press; 1986
• 3 Hooper SM, Chiong W. Decision-making capacity and frontal lobe dysfunction. In: The Human Frontal Lobes: Functions and Disorders. 3rd ed. New York: Guilford Press; 2017: 184-199
• 4 Sabatino CP, Basinger SL. Competency: reforming our legal fictions. J Ment Health Aging 2000; 6 (02) 119-144
• 5 Uniform Law Commission. Uniform Health Care Decisions Act 1994. Available at: http://www.uniformlaws.org/shared/docs/health%20care%20decisions/uhcda_final_93.pdf . Accessed June 27, 2018
• 6 Appelbaum PS. Clinical practice. Assessment of patients' competence to consent to treatment. N Engl J Med 2007; 357 (18) 1834-1840
• 7 American Bar Association (ABA), Commission on Law and Aging, and American Psychological Association. Assessment of Older Adults with Diminished Capacity: A Handbook for Lawyers. Washington, DC: ABA; 2005
• 8 In re Milton, 29 Ohio St. 3d 20 (1987)
• 9 45 C.F.R. § 46.116 (2017)
• 10 45 C.F.R. § 46.102(i) (2017)
• 11 National Bioethics Advisory Committee. An Overview of the Issues. In: Research Involving Persons with Mental Disorders That May Affect Decision Making Capacity. Available at: https://bioethicsarchive.georgetown.edu/nbac/capacity/Overview.htm . Published December 1998. Accessed February 27, 2018
• 12 Marson DC, McInturff B, Hawkins L, Bartolucci A, Harrell LE. Consistency of physician judgments of capacity to consent in mild Alzheimer's disease. J Am Geriatr Soc 1997; 45 (04) 453-457
• 13 Markson LJ, Kern DC, Annas GJ, Glantz LH. Physician assessment of patient competence. J Am Geriatr Soc 1994; 42 (10) 1074-1080
• 14 Karlawish J. Measuring decision-making capacity in cognitively impaired individuals. Neurosignals 2008; 16 (01) 91-98
• 15 Pachet A, Astner K, Brown L. Clinical utility of the mini-mental status examination when assessing decision-making capacity. J Geriatr Psychiatry Neurol 2010; 23 (01) 3-8
• 16 Kim SYH, Caine ED. Utility and limits of the mini mental state examination in evaluating consent capacity in Alzheimer's disease. Psychiatr Serv 2002; 53 (10) 1322-1324
• 17 Raymont V, Buchanan A, David AS, Hayward P, Wessely S, Hotopf M. The inter-rater reliability of mental capacity assessments. Int J Law Psychiatry 2007; 30 (02) 112-117
• 18 Grisso T, Appelbaum PS, Hill-Fotouhi C. The MacCAT-T: a clinical tool to assess patients' capacities to make treatment decisions. Psychiatr Serv 1997; 48 (11) 1415-1419
• 19 Appelbaum PS, Grisso T. MacCAT-CR: MacArthur Competence Assessment Tool for Clinical Research. Sarasota, FL: Professional Resource Press; 2001
• 20 Marson DC, Cody HA, Ingram KK, Harrell LE. Neuropsychologic predictors of competency in Alzheimer's disease using a rational reasons legal standard. Arch Neurol 1995; 52 (10) 955-959
• 21 Beauchamp TL. The idea of a “standard view” of informed consent. Am J Bioeth 2017; 17 (12) 1-2
• 22 Chiong W. Ethical issues in inpatient neurology. In: Josephson SA, Freeman WD, Likosky DJ. , eds. Neurohospitalist Medicine. Cambridge: Cambridge University Press; 2011
• 23 Jongsma KR, van de Vathorst S. Beyond competence: advance directives in dementia research. Monash Bioeth Rev 2015; 33 (2-3): 167-180
• 24 Shalowitz DI, Garrett-Mayer E, Wendler D. The accuracy of surrogate decision makers: a systematic review. Arch Intern Med 2006; 166 (05) 493-497
• 25 Kim SYH. The ethics of informed consent in Alzheimer disease research. Nat Rev Neurol 2011; 7 (07) 410-414
• 26 82 F.R. § 7149(III)(E)(4) (2017)
• 27 Cal. Health & Safety Code § 24178 (2000)
• 28 K.S.A. § 65–4974 (2017)
• 29 NJ St. § 26:14–1–5 (2013)
• 30 Okla. Stat. Ann. tit. 63 §3101–3102 (2014)
• 31 American Bar Association (ABA), Commission on Law and Aging. Default Surrogate Consent Statutes. Available at: https://www.americanbar.org/content/dam/aba/administrative/law_aging/2014_default_surrogate_consent_statutes.authcheckdam.pdf . Updated January 2018. Accessed February 27, 2018
• 32 Silbergleit R, Lowenstein D, Durkalski V, Conwit R. ; Neurological Emergency Treatment Trials (NETT) Investigators. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics. Epilepsia 2011; 52 (Suppl. 08) 45-47
• 33 21 C.F.R. § 50.24 (1996)
• 34 United States Department of Health and Human Services, Food and Drug Administration. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent for Emergency Research 2011. Available at: https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm249673.pdf . Accessed June 27, 2018
• 35 Silbergleit R, Biros MH, Harney D, Dickert N, Baren J. ; NETT Investigators. Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience. Acad Emerg Med 2012; 19 (04) 448-454
• 36 Dickert NW, Mah VA, Baren JM. , et al. Enrollment in research under exception from informed consent: the Patients' Experiences in Emergency Research (PEER) study. Resuscitation 2013; 84 (10) 1416-1421
• 37 Fehr AE, Scicluna VM, Pentz RD, Haggins AN, Dickert NW. Patient and surrogate views of community consultation for emergency research. Acad Emerg Med 2017; 24 (11) 1410-1414
• 38 Rose DZ, Kasner SE. Informed consent: the rate-limiting step in acute stroke trials. Front Neurol 2011; 2: 65
• 39 45 C.F.R. § 46.116(d) (2009)
• 40 Feldman WB, Kim AS, Josephson SA, Lowenstein DH, Chiong W. Effect of waivers of consent on recruitment in acute stroke trials: a systematic review. Neurology 2016; 86 (16) 1543-1551
• 41 Thomalla G, Boutitie F, Fiebach JB. , et al. Effect of informed consent on patient characteristics in a stroke thrombolysis trial. Neurology 2017; 89 (13) 1400-1407
• 42 Weintraub S, Wicklund AH, Salmon DP. The neuropsychological profile of Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2 (04) a006171
• 43 Jefferson AL, Lambe S, Moser DJ, Byerly LK, Ozonoff A, Karlawish JH. Decisional capacity for research participation in individuals with mild cognitive impairment. J Am Geriatr Soc 2008; 56 (07) 1236-1243
• 44 Kim SYH, Karlawish JH, Kim HM, Wall IF, Bozoki AC, Appelbaum PS. Preservation of the capacity to appoint a proxy decision maker: implications for dementia research. Arch Gen Psychiatry 2011; 68 (02) 214-220
• 45 Jaworska A. Respecting the margins of agency: Alzheimer's patients and the capacity to value. Philos Public Aff 1999; 28 (02) 105-138
• 46 Karlawish J, Kim SYH, Knopman D, van Dyck CH, James BD, Marson D. The views of Alzheimer disease patients and their study partners on proxy consent for clinical trial enrollment. Am J Geriatr Psychiatry 2008; 16 (03) 240-247
• 47 Stocking CB, Hougham GW, Danner DD, Patterson MB, Whitehouse PJ, Sachs GA. Speaking of research advance directives: planning for future research participation. Neurology 2006; 66 (09) 1361-1366
• 48 Davis DS. Ethical issues in Alzheimer's disease research involving human subjects. J Med Ethics 2017; 43 (12) 852-856
• 49 National Institutes of Health. Office of Extramural Research. Research Involving Individuals with Questionable Capacity to Consent: Points to Consider 2009. Available at: https://grants.nih.gov/grants/policy/questionablecapacity.htm . Accessed July 27, 2018
• 50 Saxman SB. Ethical considerations for outcome-adaptive trial designs: a clinical researcher's perspective. Bioethics 2015; 29 (02) 59-65
• 51 Kodish E, Eder M, Noll RB. , et al. Communication of randomization in childhood leukemia trials. JAMA 2004; 291 (04) 470-475
• 52 Weijer C, Grimshaw JM, Taljaard M. , et al. Ethical issues posed by cluster randomized trials in health research. Trials 2011; 12: 100
• 53 Ranta A, Dovey S, Weatherall M, O'Dea D, Gommans J, Tilyard M. Cluster randomized controlled trial of TIA electronic decision support in primary care. Neurology 2015; 84 (15) 1545-1551
• 54 Miller FG, Emanuel EJ. Quality-improvement research and informed consent. N Engl J Med 2008; 358 (08) 765-767
• 55 Feldman B. , et al. Correspondence. Head positioning in acute stroke. N Engl J Med 2017; 377 (11) 1101-1103
• 56 McRae AD, Weijer C, Binik A. , et al. When is informed consent required in cluster randomized trials in health research?. Trials 2011; 12: 202
• 57 Weijer C, Grimshaw JM, Eccles MP. , et al; Ottawa Ethics of Cluster Randomized Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomized trials. PLoS Med 2012; 9 (11) e1001346
• 58 Taljaard M, Weijer C, Grimshaw JM, Eccles MP. ; Ottawa Ethics of Cluster Randomised Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomised trials: precis for researchers and research ethics committees. BMJ 2013; 346: f2838
• 59 Arias JJ, Karlawish J. Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet. Neurology 2014; 82 (08) 725-729