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August 12, 2019

A Professional Standard for Informed Consent for Stem Cell Therapies

Author Affiliations
  • 1Berman Institute of Bioethics, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 3WT-MRC Cambridge Stem Cell Institute, Department of Clinical Neuroscience, University of Cambridge, Cambridge, England
  • 4University of Wisconsin Law School, Madison
  • 5Stanford Center for Advanced Studies in Behavioral Sciences, Stanford University, Palo Alto, California
JAMA. Published online August 12, 2019. doi:10.1001/jama.2019.11290

In November 2018, the US Food and Drug Administration (FDA) issued a press release that stated: “The potential health benefits of regenerative medicine have spurred major progress in stem-cell biology over the past several decades. But we continue to see bad actors exploit the scientific promise of this field to mislead vulnerable patients into believing they’re being given safe, effective treatments; when instead these stem cell producers are leveraging the field’s hype to push unapproved, unproven, illegal, and potentially unsafe products.”1

Over the last decade, there has been an increase in the number of “clinics” (570 in the United States alone according to a recent estimate) offering what is portrayed as “stem cell therapy” for conditions ranging from orthopedic injuries to Alzheimer disease.2 The unproven nature of these interventions suggests that patients who received them were, at a minimum, misled. At worst, they were severely injured, as in the case of at least 3 women who were left legally blind after intravitreal injections of platelet-rich plasma derived from tissue obtained through liposuction.3

The situation may soon improve given the FDA’s increased focus on enforcement of its human cellular and tissue product regulations (which has led to an injunction closing at least 1 of the companies running these clinics)4 and interest by plaintiff attorneys, which has resulted in the successful filing for class-action certification in California. This means that a “lawsuit alleging fraud in marketing … will proceed and may have 100s of patients involved.”5

Class-action certification may offer significant advantages to plaintiffs by reducing the need for duplication of efforts on behalf of each individual and consolidating the research necessary to pursue a case. If successful, patients who have received unproven stem cell–based interventions may be positioned to recover the cost of their procedures and (for some) compensation for their injuries. The effect is a deterrent that is designed to encourage a change in industry practices.

Despite these efforts, however, hundreds of clinics remain active and continue to advertise unproven products. Because stem cell–based interventions are being delivered to patients in both research and clinical settings, and some stem cell–based interventions have been shown to be safe and effective (eg, bone marrow transplantation for certain malignancies), it can be difficult for some patients to distinguish between receiving a stem cell–based intervention as standard of care vs in a proper clinical trial vs in clinical practice for unproven indications, which are potentially associated with harm.

Well-intended efforts to alert patients to the potential hazards of seeking unproven stem cell–based interventions, such as providing general information on reputable websites,6 have not proven effective in curtailing the use of unproven stem cell–based interventions. To supplement these approaches, the International Society for Stem Cell Research (ISSCR), a nonprofit professional organization, created a task force to develop a professional standard for consent for stem cell–based interventions offered outside a clinical trial. Such a standard could help ensure patients get the relevant information they need regarding a proposed intervention.

Expectations for Consent

Ethically, obtaining consent is a means of respecting patients’ autonomous wishes. Legally, informed consent protects patients’ liberty interests, specifically the right not to be touched or treated without their informed and voluntary permission. As a practical matter, informed consent provides an opportunity for patients to obtain the information they need about risks, benefits, and alternatives before they decide whether to proceed with an intervention.

In the research setting in the United States, regulations and institutional review boards provide guidance about the information that should be provided during the process of obtaining consent and how it should be communicated to patients. By contrast, outside the research setting, clinicians generally deliver the information they deem necessary on their own, ideally informed by an array of professional guidelines, but with little definitive guidance or oversight. Given this lack of specificity, there have been debates regarding the content of what must be disclosed during the informed consent process.

In some jurisdictions (eg, states within the United States), the standard rests on what a reasonable patient would want to know. In others, it rests on what other clinicians tend to offer. Ideally, these 2 standards would converge, but especially in a rapidly evolving field that includes marketing of interventions that have yet to be fully studied, there can be little credible guidance from other individual practitioners, nor can patients be expected to know the questions they need to ask. Developing a model for the content that should be conveyed to patients in this setting should benefit both patients and practitioners.

A Professional Standard for Stem Cell–Based Interventions

The ISSCR developed a professional standard for consent by assembling a task force of experts in stem cells, clinical practice, ethics, and the law. The task force created a draft standard, which was then reviewed by 30 individuals from 9 countries and revised based on their comments. The standard articulates the information that needs to be provided to patients (or their legally valid surrogates) to help them make an informed decision if offered a stem cell–based intervention outside a clinical trial.

Any clinic or practitioner offering such an intervention in this setting should include this information, along with anything else required by applicable laws, policies, practices, and regulations during the informed consent process. The full standard is available on the ISSCR website7 and the basic consent elements appear in the Box.

Box Section Ref ID
Box.

Consent Elements From the Standard for Stem Cell–Based Interventions

  • Rationale for treatment

  • Nature of the intervention

  • Oversight

  • Benefits

  • Risks

  • Immunosuppression

  • Adverse events

  • Manufacturing method and related risks

  • Costs

  • Rights

  • Organization

  • Alternatives

  • Data

Complete, unbiased information is particularly important in situations that present both serious risks and ambiguous evidence. Thus, having a professional standard for consent is important if patients are to be given a chance to make an informed and considered decision about receiving a stem cell–based intervention, many of which have not been proven to be either safe or effective. The primary reason for having a standard is to help ensure all patients considering a stem cell–based intervention receive this information.

The unproven nature of many stem cell–based interventions also makes it difficult for patients to complain of medical malpractice in the event of injury because there is no accepted standard of practice against which to judge clinics and their practitioners. However, a failure to meet an applicable standard for informed consent would provide an independent basis for liability. In other words, clinicians who do not meet the appropriate standard for disclosure can be sued for not obtaining proper consent.

Having a respected organization identify the essential elements of consent gives patients another avenue for complaint and provides the courts with a clear standard against which to judge the adequacy of consent. Although malpractice litigation is a problematic and time-consuming means of deterring substandard care, it may be an important adjunct to educational and regulatory efforts in this rapidly developing, rapidly commercializing field.

Conclusions

By developing a standard for consent, the ISSCR does not endorse the administration of unproven stem cell–based interventions, which should instead be subject to properly designed and conducted clinical trials. However, until such time as regulatory efforts catch up with this burgeoning field, unproven stem cell–based interventions will continue to be offered outside research trials. Patients deserve every means to be protected.

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Article Information

Corresponding Author: Jeremy Sugarman, MD, MPH, MA, Berman Institute of Bioethics, Johns Hopkins University, 1809 Ashland Ave, Baltimore, MD 21205 (jsugarman@jhu.edu).

Published Online: August 12, 2019. doi:10.1001/jama.2019.11290

Conflict of Interest Disclosures: Dr Sugarman reported being a member of the Merck KGaA bioethics advisory panel and stem cell research oversight committee; being a member of the IQVIA ethics advisory panel; and serving as a consultant to Portola Pharmaceuticals Inc. Dr Barker reported serving as a consultant to Living Cell Technologies, Novo Nordisk, Fujifilm Cellular Dynamics Inc, BlueRock Therapeutics, Sana Biotechnology, UCB, and Cellino. Ms Charo reported serving as a consultant to Johnson & Johnson.

Additional Contributions: We thank the members of the International Society for Stem Cell Research consent standard task force: Roger Barker, MRCP, PhD (chair; University of Cambridge, Cambridge, England), Alta Charo, JD (University of Wisconsin Law School, Madison), Inez de Beaufort, PhD (Erasmus University Medical Center, Rotterdam, the Netherlands), Rosario Isasi, JD (University of Miami, Miami, Florida), Richard Lee, MD (Harvard University, Cambridge, Massachusetts), Douglas Sipp, BA (RIKEN, Kobe, Japan), and Jeremy Sugarman, MD (co-chair; Johns Hopkins University, Baltimore, Maryland). The task force members were not compensated for their contributions. We also thank Eric Anthony (International Society for Stem Cell Research) for providing substantial logistical support in developing the consent standard. Mr Anthony received salary support for his contribution.

References
1.
US Food and Drug Administration. FDA warns StemGenex Biologic Laboratories LLC of illegally marketing an unapproved cellular product manufactured in a facility with significant manufacturing violations, putting patients at risk. https://www.fda.gov/news-events/press-announcements/fda-warns-stemgenex-biologic-laboratories-llc-illegally-marketing-unapproved-cellular-product. Accessed July 8, 2019.
2.
Turner  L, Knoepfler  P.  Selling stem cells in the USA: assessing the direct-to-consumer industry.  Cell Stem Cell. 2016;19(2):154-157. doi:10.1016/j.stem.2016.06.007PubMedGoogle ScholarCrossref
3.
Kuriyan  AE, Albini  TA, Townsend  JH,  et al.  Vision loss after intravitreal injection of autologous “stem cells” for AMD.  N Engl J Med. 2017;376(11):1047-1053. doi:10.1056/NEJMoa1609583PubMedGoogle ScholarCrossref
4.
US Food and Drug Administration. Statement on stem cell clinic permanent injunction and FDA’s ongoing efforts to protect patients from risks of unapproved products. https://www.fda.gov/news-events/press-announcements/statement-stem-cell-clinic-permanent-injunction-and-fdas-ongoing-efforts-protect-patients-risks. Accessed July 8, 2019.
5.
Knoepfler  P. In dark augur for clinic industry, court allows class action suit by 100s against Stemgenex. https://ipscell.com/2019/06/in-dark-augur-for-clinic-industry-court-allows-class-action-suit-by-100s-against-stemgenex/. Accessed July 8, 2019.
6.
International Society for Stem Cell Research. A closer look at stem cells. https://www.closerlookatstemcells.org/. Accessed July 8, 2019.
7.
International Society for Stem Cell Research. Informed consent standard for stem cell-based interventions offered outside of formal clinical trials. http://www.isscr.org/docs/default-source/policy-documents/isscr-informed-consent-standards-for-stem-cell-based-interventions.pdf. Accessed August 12, 2019.
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