MRM Insights: Ethical conduct of pay-to-participate trials
Me. Erika Kleiderman
Ms. Amanda MacPherson
Every month, in MRM Insights, a member of the MRM Network is writing about stem cells and regenerative medicine from a different perspective. This month, Amanda MacPherson (Research Assistant in the STREAM Research Group, member of the MRM Ethics Committee) and Me. Erika Kleiderman (Research Associate at the Centre of Genomics and Policy, member of the MRM Executive Committee, Chair of the MRM Ethics Committee) are discussing the ethical conduct of pay-to-participate clinical trials.
Ethical conduct of pay-to-participate trials
On May 14, 2020, a case study was published in the New England Journal of Medicine describing the implantation of dopaminergic cells derived from induced pluripotent stem cells (iPSCs) into a patient with Parkinson’s disease.1,2 A notable detail was nestled in the fine print of the funding section: the trial was partly funded by the patient himself.
Clinical trials that are funded by participants are referred to as “pay-to-participate” or “pay-to-play” (PTP) trials.3,4 Although not legally prohibited, organizations such as the International Society for Stem Cell Research (ISSCR) have urged caution in the conduct of PTP trials,5 while others have issued recommendations discouraging or condemning their conduct.6 Nevertheless, PTP trials are becoming increasingly common, especially within the context of cell and gene therapies, and regenerative medicine more broadly. Recent examples include trials involving the injection of blood plasma from young donors to slow aging and the use of stem cells to treat autism,7,8 neither of which was backed by strong evidence of efficacy in humans.
PTP trials raise a number of ethical issues, as pointed out by numerous ethicists with respect to the Parkinson’s trial.9 The ethical concerns associated with such clinical trials relate to study design and scientific validity, the evaluation of risks and benefits, the validity of informed consent, and issues of justice.3 In the context of the Parkinson’s trial, the patient himself was a former physician and therefore, likely capable of understanding the potential risks and benefits of undergoing an experimental procedure, as well as providing valid, informed consent. For the purpose of this commentary, we will focus on the issues of scientific validity and justice related to PTP trials.
Scientific validity
Scientific validity is a requirement of ethical clinical research.10 Research that is not properly designed to produce scientifically valid results is considered unethical, as it exposes participants to risks and uses limited research resources without the potential to generate clinically actionable information. Results of clinical research can be compromised by bias, and PTP trials are particularly susceptible to certain biases. For instance, investigators may be inclined to enrol participants not based on eligibility criteria that have been determined by the best available science, but by who is able to pay.11 The Parkinson’s trial, for example, enrolled a single participant who was a wealthy former physician and businessman, and did not explicitly report any eligibility criteria. Therefore, it seems likely that he was recruited on the basis of his prior involvement in and funding of the associated preclinical research, rather than any particular inclusion criteria.
In addition, when participants effectively become paying clients, it may discourage the use of rigorous methods such as randomization and placebo controls. Concerns about randomization are a commonly cited reason for declining to participate in a trial,12 so investigators seeking to maximize recruitment in PTP trials may be more likely to forgo these methods that patients may otherwise find unappealing. This is compounded by the fact that patients have a higher stake in the outcomes given that they are both personally and financially invested, so they may be more likely to demonstrate the placebo effect (i.e. an improvement that is not attributable to the treatment but to the participant’s belief in the effectiveness of the treatment).13 In turn, unblinded investigators may further encourage this self-fulfilling belief. The investigators of the Parkinson’s trial clearly acknowledged this as a limitation.
Justice
Justice is one of three guiding principles of ethical human subject research and refers to the proportionate distribution of risks and benefits among research subjects, so as not to overburden or underprivilege any individuals or groups (i.e. fair and equitable distribution).14,15 While the aim of clinical research is to produce generalizable knowledge rather than to provide therapeutic treatment,15 participants may experience incidental benefits in addition to psychological benefits from their participation, such as a sense of purpose and contribution to society. Enrolling only participants who are able to afford participation withholds any of these potential benefits from those who cannot afford to pay. It demonstrates a shift in focus towards financial eligibility rather than clinical eligibility during the recruitment process.4,11 Therefore, even if the recruitment process may, in theory, be based on justified inclusion criteria, the reality leads to an inequity due to the significant price tag associated with participation.
In addition to justice concerns at the level of individual trials, PTP trials also constitute a use of limited clinical research resources, such as experienced personnel and research sites, that may be better allocated towards developing more socially valuable or accessible treatments that could benefit the collective good. Although a treatment for Parkinson’s would be of high social value given the lack of disease-modifying interventions,16 other interventions, such as injecting “young blood” to slow aging, could be considered frivolous and vanity-driven when so many patients with chronic and/or life-threatening illnesses still lack effective and accessible treatment options.
Finally, cell and gene therapies, such as iPSC transplants, are unlikely to be affordable or accessible to most patients even if they are shown to be safe and effective. Patients are already facing challenges accessing approved gene therapies due to limited manufacturing capacity and difficulty covering the costs of treatment, as the North American healthcare system is not structured to handle large, one-time payments.17 Ultimately, the purpose of developing and testing novel cell and gene therapies is to improve the lives and decrease the pain and suffering of patients down the line, but high costs may work against this purpose. Accessibility of new treatments is an important issue that does not receive much attention early in development, and only becomes apparent once a treatment has received regulatory approval.
Science is a collective good, and should not be subject to the whims of the wealthy. Contrary to publicly or privately funded clinical trials, PTP trials are often profit-driven and focus on the short-term goal of providing access to unproven, potentially risky interventions, while making compromises to study design that may result in substandard clinical evidence. Therefore, safeguards and improved oversight are needed to ensure that PTP trials are aligned with the principles of ethical research.
References
1. Schweitzer JS, Song B, Herrington TM, et al. Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease. N Engl J Med. 2020;382(20):1926-1932. doi:10.1056/NEJMoa1915872
2. Begley S. A secret experiment revealed: In a medical first, doctors treat Parkinson’s with a novel brain cell transplant. STAT News. https://www.statnews.com/2020/05/12/medical-first-parkinsons-brain-cell-transplant-stem-cells/. Published May 12, 2020. Accessed May 13, 2020.
3. Emanuel EJ, Joffe S, Grady C, Wendler D, Persad G. Clinical research: Should patients pay to play? Sci Transl Med. 2015;7(298):298ps16. doi:10.1126/scitranslmed.aac5204
4. Lynch HF, Joffe S. Pay-to-Participate Trials and Vulnerabilities in Research Ethics Oversight. JAMA. 2019;322(16):1553-1554. doi:10.1001/jama.2019.14703
5. International Society for Stem Cell Research (ISSCR). Guidelines for Stem Cell Research and Clinical Translation.; 2016. https://www.isscr.org/policy/guidelines-for-stem-cell-research-and-clinical-translation
6. European Academies’ Science Advisory Council (EASAC), Federation of European Academies of Medicine (FEAM). Challenges and Potential in Regenerative Medicine.; :40. Accessed June 21, 2020. https://www.feam.eu/wp-content/uploads/EASAC-FEAM-Report-on-Regenerative-Medicine-June-2020.pdf
7. Kaiser J. Young blood antiaging trial raises questions. Science. Published online August 1, 2016. Accessed June 18, 2020. https://www.sciencemag.org/news/2016/08/young-blood-antiaging-trial-raises-questions
8. Furfaro H. Experts Question Rationale for Stem Cell Trial for Autism. The Scientist. Published online August 2, 2019. Accessed June 18, 2020. https://www.the-scientist.com/news-opinion/experts-question-rationale-for-stem-cell-trial-for-autism-66226
9. Begley S. Ethics questions swirl around historic Parkinson’s experiment. STAT News. https://www.statnews.com/2020/05/14/ethics-questions-swirl-around-historic-parkinsons-experiment/. Published May 14, 2020. Accessed May 14, 2020.
10. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283(20):2701-2711.
11. Wenner DM, Kimmelman J, London AJ. Patient-Funded Trials: Opportunity or Liability? Cell Stem Cell. 2015;17(2):135-137. doi:10.1016/j.stem.2015.07.016
12. Jenkins V, Fallowfield L. Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy. Br J Cancer. 2000;82(11):1783-1788. doi:10.1054/bjoc.2000.1142
13. Sipp D. Pay-to-participate funding schemes in human cell and tissue clinical studies. Regen Med. 2012;7(6 Suppl):105-111. doi:10.2217/rme.12.75
14. 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.; 1979.
15. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, 2nd edition (TCPS2). Published online December 2018. https://ethics.gc.ca/eng/policy-politique_tcps2-eptc2_2018.html
16. Feustel AC, MacPherson A, Fergusson DA, Kieburtz K, Kimmelman J. Risks and benefits of unapproved disease-modifying treatments for neurodegenerative disease. Neurology. 2020;94(1):e1-e14. doi:10.1212/WNL.0000000000008699
17. Capra E, Smith J, Yang G. Gene therapy research comes of age: Opportunities and challenges to getting ahead. McKinsey & Company. Published October 2, 2019. Accessed June 24, 2020. https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/gene-therapy-coming-of-age-opportunities-and-challenges-to-getting-ahead
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