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Ethics and Bias in Clinical Trial Enrollment in Stroke

  • Stroke (J Meschia, Section Editor)
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Abstract

Purpose of Review

To familiarize the reader with ethical concerns and potential scientific bias in management and conduction of clinical stroke trials.

Recent Findings

The goal of clinical trials in stroke is to find effective interventions for stroke prevention, acute treatment, and rehabilitation and recovery. Acute trials must be designed in the context of the time-sensitivity of revascularization therapies. Standard ethical constraints apply. However, informed consent is hindered by tight time windows for reperfusion therapy and frequent cognitive impairment in patients. These might be mitigated by using visual decision aids. Non-traditional methods of consent such as utilization of surrogates, telemedicine, and exception from informed consent are critical for successful and unbiased conduction of stroke trials. Stroke centers must have an a priori plan for deciding which trial to offer multiple-trial eligible patients. Historic non-generalizability of stroke trials due to under-enrollment of women, racial minorities, and age extremes is improving, but adequate representative recruitment and retention require up-front planning and training.

Summary

Stroke trials have become less biased and more representative in the last decades, but there is still research to be done to improve ethical and unbiased recruitment and retention.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. Circulation. 2011;123:2111–9.

    Article  Google Scholar 

  2. Ahn C, Ahn D. Randomized clinical trials in stroke research. J Investig Med. 2010;58:277–81.

    Article  Google Scholar 

  3. Lyden PD, Meyer BC, Hemmen TM, Rapp KS. An ethical hierarchy for decision making during medical emergencies. Ann Neurol. 2010;67:434–40.

    Article  Google Scholar 

  4. Hallstrom A, Friedman L, Denes P, Rizo-Patron C, Morris M, CAST Investigators, et al. Do arrhythmia patients improve survival by participating in randomized clinical trials? Observations from the Cardiac Arrhythmia Suppression Trial (CAST)and the Antiarrhythmics Versus Implantable Defibrillators Trial (AVID). Control Clin Trials. 2003;24:341–52.

    Article  Google Scholar 

  5. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001;54:217–24.

    Article  CAS  Google Scholar 

  6. West J, Wright J, Tuffnell D, Jankowicz D, West R. Do clinical trials improve quality of care? A comparison of clinical processes and outcomes in patients in a clinical trial and similar patients outside a trial where both groups are managed according to a strict protocol. Qual Saf Health Care. 2005;14:175–8.

    Article  CAS  Google Scholar 

  7. Khoja L, Horsley L, Heesters A, Machin JD, Mitchell C, Clamp AR, et al. Does clinical trial participation improve outcomes in patients with ovarian cancer? ESMO Open. 2016;1:e000057.

    Article  CAS  Google Scholar 

  8. Sarkar RR, Matsuno R, Murphy JD. Pancreatic cancer: survival in clinical trials versus the real world. J Clin Oncol. 2016;34:216–6.

    Article  Google Scholar 

  9. •• The Belmont Report : Ethical Principles and Guidelines for the Protection of Human Subjects of Research https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html: Department of Health, Education, and Welfare; The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979. The Belmont Report is the original U.S. guideline outlining ethical principles in clinical research. Though written in 1979, it is still the landmark publication that sets the standards to which all clinical human research must adhere to today.

  10. Sun JH, Tan L, Yu JT. Post-stroke cognitive impairment: epidemiology, mechanisms and management. Ann Transl Med. 2014;2:80.

    PubMed  PubMed Central  Google Scholar 

  11. Kasner SE, Baren JM, Le Roux PD, et al. Community views on neurologic emergency treatment trials. Ann Emerg Med. 2011;57:346–354 e346.

    Article  Google Scholar 

  12. Decker C, Chhatriwalla E, Gialde E, Garavalia B, Summers D, Quinlan ME, et al. Patient-centered decision support in acute ischemic stroke: qualitative study of patients’ and providers’ perspectives. Circ Cardiovasc Qual Outcomes. 2015;8:S109–16.

    Google Scholar 

  13. Gillies K, Cotton SC, Brehaut JC, Politi MC, Skea Z. Decision aids for people considering taking part in clinical trials. Cochrane Database Syst Rev. 2015:CD009736.

  14. Sundaresan P, Ager B, Turner S, Costa D, Kneebone A, Pearse M, et al. A randomised controlled trial evaluating the utility of a patient decision aid to improve clinical trial (RAVES 08.03) related decision-making. Radiother Oncol. 2017;125:124–9.

    Article  Google Scholar 

  15. Flaherty ML, Karlawish J, Khoury JC, Kleindorfer D, Woo D, Broderick JP. How important is surrogate consent for stroke research? Neurology. 2008;71:1566–71.

    Article  CAS  Google Scholar 

  16. Rose DZ, Kasner SE. Informed consent: the rate-limiting step in acute stroke trials. Front Neurol. 2011;2:65.

    Article  Google Scholar 

  17. • Hotter B, Ulm L, Hoffmann S, Katan M, Montaner J, Bustamante A, et al. Selection bias in clinical stroke trials depending on ability to consent. BMC Neurol. 2017;17:206. This study examined clinical characteristics of stroke patients able to consent versus those who had lost autonomy. It supports the concept that to exclude patients unable to consent from trials is unethical.

  18. Protection of Human Subjects; Informed Consent Part II 61 FR 51498. https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm118960.htm US Food and Drug Administration, 1996.

  19. Leira EC, Kaldjian LC, Ludwig BR, Torner JC, Olalde HM, Hacke W, et al. Lack of international consensus on ethical aspects of acute stroke trials. J Stroke Cerebrovasc Dis. 2012;21:200–4.

    Article  Google Scholar 

  20. Cramer S. The STRONG STUDY: the stroke, sTress, RehabilitatiON, and genetics study [online]. Available at: https://thestrongstudy.com/index.php. Accessed 02/03/2019.

  21. George BP, Doyle SJ, Albert GP, Busza A, Holloway RG, Sheth KN, et al. Interfacility transfers for US ischemic stroke and TIA, 2006-2014. Neurology. 2018;90:e1561–9.

    Article  Google Scholar 

  22. Saver JL, Kidwell C, Eckstein M, Ovbiagele B, Starkman S, Investigators F-MPT. Physician-investigator phone elicitation of consent in the field: a novel method to obtain explicit informed consent for prehospital clinical research. Prehosp Emerg Care. 2006;10:182–5.

    Article  Google Scholar 

  23. Ranta A, Whitehead M, Gunawardana C, Cariga P, Iniesta I, Watson I, et al. International Telestroke: the first five cases. J Stroke Cerebrovasc Dis. 2016;25:e44–5.

    Article  Google Scholar 

  24. Alfredo Caceres J, Greer DM, Goldstein JN, Viswanathan A, Suarez JI, Brau L, et al. Enrollment of research subjects through telemedicine networks in a multicenter acute intracerebral hemorrhage clinical trial: design and methods. J Vasc Interv Neurol. 2014;7:34–40.

  25. Xing C, Arai K, Lo EH, Hommel M. Pathophysiologic cascades in ischemic stroke. Int J Stroke. 2012;7:378–85.

    Article  Google Scholar 

  26. Armstrong S, Langlois A, Laparidou D, Dixon M, Appleton JP, Bath PM, et al. Assessment of consent models as an ethical consideration in the conduct of prehospital ambulance randomised controlled clinical trials: a systematic review. BMC Med Res Methodol. 2017;17:142.

  27. •• Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research. Title 21, Code of Federal Regulations, Section 50.24 (21 CFR 50.24). Available at https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM249673.pdf Accessed June 20, 2018: U.S. Department of Health and Human Services Food and Drug Administration; Office of Good Clinical Practice, 2013. This is the FDA guidance on everything investigators need to know regarding ethics and policy of exception from informed consent, including which studies are eligible for the method, the principles guiding its use, and how to use the method.

  28. NIH StrokeNet. Funded by a Grant from the National Institutes of Health [online]. Available at: https://www.nihstrokenet.org/. Accessed 07/28/2018.

  29. Mott M, Janis S, Koroshetz WJ. StrokeNet takes off: National Institute of Neurological Disorders and Stroke organizational update. Stroke. 2016;47:e51–2.

    Article  Google Scholar 

  30. Majersik J. Ethics and Bias of enrolling in competing trials: a StrokeNet survey and status update. NIH StrokeNet National Meeting; 2/9/2015; Nashville, TN, USA.

  31. Informed Consent Information Sheet. Guidance for IRBs, Clinical Investigators, and Sponsors. DRAFT GUIDANCE. http://www.fda.gov/RegulatoryInformation/Guidances/ucm404975.htm Accessed July 31, 2018: Federal Drug Administration, 2014.

  32. •• Saver JL. Coping with an embarrassment of riches. How stroke centers may participate in multiple, concurrent clinical stroke trials. Stroke. 1995;26:1289–92. Though over two decades old, this paper remains the only publication to thoroughly examine the many scientific biases present among various methods of allocating trials to patients.

    Article  CAS  Google Scholar 

  33. Bandyopadhyay S, Bayer AJ, O'Mahony MS. Age and gender bias in statin trials. QJM. 2001;94:127–32.

    Article  CAS  Google Scholar 

  34. Burke JF, Brown DL, Lisabeth LD, Sanchez BN, Morgenstern LB. Enrollment of women and minorities in NINDS trials. Neurology. 2011;76:354–60.

    Article  CAS  Google Scholar 

  35. Morgenstern LB, Smith MA, Lisabeth LD, Risser JM, Uchino K, Garcia N, et al. Excess stroke in Mexican Americans compared with non-Hispanic whites: the brain attack surveillance in Corpus Christi project. Am J Epidemiol. 2004;160:376–83.

    Article  Google Scholar 

  36. Howard G, Kissela BM, Kleindorfer DO, McClure LA, Soliman EZ, Judd SE, et al. Differences in the role of black race and stroke risk factors for first vs. recurrent stroke. Neurology. 2016;86:637–42.

    Article  CAS  Google Scholar 

  37. Limdi NA, Howard VJ, Higginbotham J, Parton J, Safford MM, Howard G. US mortality: influence of race, geography and cardiovascular risk among participants in the population-based REGARDS cohort. J Racial Ethn Health Disparities. 2016;3:599–607.

    Article  Google Scholar 

  38. Uchino K, Risser JM, Smith MA, Moye LA, Morgenstern LB. Ischemic stroke subtypes among Mexican Americans and non-Hispanic whites: the BASIC project. Neurology. 2004;63:574–6.

    Article  CAS  Google Scholar 

  39. Trivedi MM, Ryan KA, Cole JW. Ethnic differences in ischemic stroke subtypes in young-onset stroke: the stroke prevention in young adults study. BMC Neurol. 2015;15:221.

    Article  Google Scholar 

  40. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research: amended, November 28, 2017. Public Health Service Act sec. 492B, 42 U.S.C. sec. 289a-2. http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. Accessed July 31, 2018.

  41. Revision: NIH Policy and Guidelines on the Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects. Notice Number: NOT-OD-18-116. Available at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html. Accessed August 21, 2018: National Institutes of Health, 2017.

  42. Boden-Albala B, Carman H, Southwick L, Parikh NS, Roberts E, Waddy S, et al. Examining barriers and practices to recruitment and retention in stroke clinical trials. Stroke. 2015;46:2232–7.

    Article  Google Scholar 

  43. • Haley SJ, Southwick LE, Parikh NS, Rivera J, Farrar-Edwards D, Boden-Albala B. Barriers and strategies for recruitment of racial and ethnic minorities: perspectives from neurological clinical research coordinators. J Racial Ethn Health Disparities. 2017;4:1225–36. This paper provides a ground-level view by research coordinators of both barriers and strategies to overcome those barriers in recruiting representative racial minorities. It is excellent as a training tool for coordinators and investigators.

    Article  Google Scholar 

  44. Gorelick PB, Harris Y, Burnett B, Bonecutter FJ. The recruitment triangle: reasons why African Americans enroll, refuse to enroll, or voluntarily withdraw from a clinical trial. An interim report from the African-American antiplatelet stroke prevention study (AAASPS). J Natl Med Assoc. 1998;90:141–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. • Occa A, Morgan SE, Potter JE. Underrepresentation of Hispanics and other minorities in clinical trials: Recruiters’ perspectives. J Racial Ethn Health Disparities. 2018;5:322–32. This paper provides excellent ground-level perspective of barriers to recruiting minorities into clinical trials.

    Article  Google Scholar 

  46. Roberts J, Waddy S, Kaufmann P. Recruitment and retention monitoring: facilitating the mission of the National Institute of Neurological Disorders and Stroke (NINDS). J Vasc Interv Neurol. 2012;5:14–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sheffet AJ, Howard G, Sam A, Jamil Z, Weaver F, Chiu D, et al. Challenge and yield of enrolling racially and ethnically diverse patient populations in low event rate clinical trials. Stroke. 2018;49:84–9.

    Article  Google Scholar 

  48. Gencheva E, Sloan M, Leurgans S, Raman R, Harris Y, Gorelick P, et al. Attrition and non-compliance in secondary stroke prevention trials. Neuroepidemiology. 2004;23:61–6.

    Article  CAS  Google Scholar 

  49. Berge E, Stapf C, Al-Shahi Salman R, et al. Methods to improve patient recruitment and retention in stroke trials. Int J Stroke. 2016;11:663–76.

    Article  Google Scholar 

  50. Sanossian N, Rosenberg L, Liebeskind DS, Starkman S, Eckstein M, Stratton S, et al. A dedicated Spanish language line increases enrollment of Hispanics into prehospital clinical research. Stroke. 2017;48:1389–91.

    Article  Google Scholar 

  51. Thayabaranathan T, Cadilhac DA, Srikanth VK, Fitzgerald SM, Evans RG, Kim J, et al. Maximizing patient recruitment and retention in a secondary stroke prevention clinical trial: lessons learned from the STAND FIRM study. J Stroke Cerebrovasc Dis. 2016;25:1371–80.

    Article  Google Scholar 

  52. Leira EC, Viscoli CM, Polgreen LA, Gorman M, Kernan WN, on behalf of the ITI. Distance from home to research center: a barrier to in-person visits but not treatment adherence in a stroke trial. Neuroepidemiology. 2018;50:137–43.

    Article  Google Scholar 

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Funding

Jennifer Juhl Majersik declares significant research funding from NIH/NINDS (1U24NS107228).

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  1. Stroke Center, University of Utah, 175 N Medical Center Drive, Third Floor, Salt Lake City, UT, 84132, USA

    Jennifer Juhl Majersik

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Correspondence to Jennifer Juhl Majersik.

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Jennifer Juhl Majersik declares that she has no conflict of interest.

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Majersik, J.J. Ethics and Bias in Clinical Trial Enrollment in Stroke. Curr Cardiol Rep 21, 49 (2019). https://doi.org/10.1007/s11886-019-1139-3

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