Excerpts from Section 3.4 Guidelines for Stem Cell Research and Clinical Translation (2016), of the International Society for Stem Cell Research. The full version is available at http://www.isscr.org/docs/default-source/all-isscr-guidelines/guidelines-2016/isscr-guidelines-for-stem-cell-research-and-clinical-translation.pdf?sfvrsn=4
Section 3.4 Stem Cell-Based Medical Innovation
Historically, many medical innovations have been introduced into clinical practice without a formal clinical trials process. Some innovations have resulted in significant and long-lasting improvements in clinical care, while other s have been ineffective or harmful. Stem cell-based products typically entail complex manufacturing protocols and stem cell-based mechanisms of tissue repair and regeneration require considerable scientific expertise to exploit for clinical benefit. Consequently, clinical success with stem cell-based interventions is highly unlikely to follow from a merely empirical approach and thus, as a rule, stem cell-based products should rarely if ever be developed outside of a formal clinical trials process. Nonetheless, the ISSCR acknowledges that in some very limited cases, clinicians may be justified in attempting medically innovative stem cell-based interventions in a small number of seriously ill patients. Such limited attempts at medical innovation contrast with the marketing of unproven stem cell interventions noted in this section and Sidebar, Warning on the Marketing of Unproven Stem Cell-based Interventions.
WARNING ON THE MARKETING OF UNPROVEN STEM CELL-BASED INTERVENTIONS
The ISSCR condemns the administration of unproven stem cell-based interventions outside of the context of clinical research or medical innovation compliant with the guidelines in this document and relevant laws, particularly when it is performed as a business activity. Scientists and clinicians should not participate in such activities as a matter of professional ethics. For the vast majority of medical conditions for which putative “stem cell therapies” are currently being marketed, there is insufficient evidence of safety and efficacy to justify routine or commercial use. Serious adverse events subsequent to such procedures have been reported and the long-term safety of most stem cell-based interventions remains undetermined. The premature commercialization of unproven stem cell treatments, and other cell-based interventions inaccurately marketed as containing or acting on stem cells, not only puts patients at risk but also represents one of the most serious threats to the stem cell research community, as it may jeopardize the reputation of the field and cause confusion about the actual state of scientific and clinical development. Government authorities and professional organizations are strongly encouraged to establish and strictly enforce regulations governing the introduction of stem cell-based medical interventions into commercial use.
In the case of medical innovations using stem cells and their direct derivatives, unique considerations justify a heightened level of caution. The diseases that potentially could be targeted by stem cell-based interventions are some of the most intractable ones confronting clinicians, and interest in stem cell research has resulted in the organization of patient communities with high hopes for the prospect of future stem cell treatments (Lau et al., 2008; Hyun, 2013). Due to their relative novelty in science, stem cells and their direct derivatives may behave more unpredictably when delivered to patients than either drugs used off-label or modified surgical techniques. Attempts at medical innovation using stem cells and their direct derivatives may inadvertently violate physicians’ ethical obligation to “do no harm,” by producing more injury than benefit (Munsie & Hyun, 2014).
Innovative medical care and clinical research aim at different goals. The mere fact that a procedure is medically innovative does not qualify it as clinical research. Clinical research aims to produce generalizable knowledge about new cellular or drug treatments, or new approaches to surgery. Notably, the individual patient’s benefit is not the focus of clinical research, nor is the individual patient’s benefit the primar y focus of the human subjects review committees over seeing clinical research. In contrast, medical innovations do not aim to produce generalizable knowledge but are aimed primarily at providing new forms of clinical care that have a reasonable chance of success for individual patients with few or no acceptable medical alternatives. Unlike clinical research, then, the main goal of innovative care is to improve an individual patient’s condition.
Although attempting medically innovative care is not research per se, it should still be subject to scientific and ethical review and proper research subject protections. This is especially true when stem cell-based medical innovation provided to a small number of patients is considered promising enough to be applied to larger numbers of patients. At this critical stage of discover y and refinement of clinical practice, it is incumbent upon the practitioner to invite scrutiny by external experts in the form of peer review, institutional over sight, and presentation of observations and data in peer-reviewed medical publication so that the knowledge can benefit all.
Given the many uncertainties surrounding the infusion of cells in ectopic locations and the significant challenges to the processing and manufacture of cellular products, only in exceptional circumstances does the ISSCR believe it would be acceptable to attempt medical innovations involving stem cells and their direct derivatives. Given the experimental and highly uncertain nature of such interventions, providers should under no circumstances promote, advertise, attempt general recruitment of patients, or commercialize such interventions. If the goal is to develop generalizable knowledge, such interventions should be made the subject of a controlled, registered clinical trial. Approval for marketing and reimbursement should remain conditional upon the completion of clinical investigations that demonstrate safety and efficacy, as judged by rigorous independent expert regulatory review.
Provision of Innovative Care
Recommendation 3.4.1: Clinician-scientists may provide unproven stem cell-based interventions to at most a very small number of patients outside the context of a formal clinical trial and according to the highly restrictive provisions outlined in this section.
These provisions include, that:
a. There is a written plan for the procedure that includes:
i. Scientific rationale and justification explaining why the procedure has a reasonable chance of success, including any preclinical evidence of proof-of-principle for efficacy and safety.
ii. Explanation of why the proposed stem cell-based intervention should be attempted compared to existing treatments.
iii. Full characterization of the types of cells being transplanted and their characteristics as discussed in Section 3.1, Cell Processing and Manufacture.
iv. Description of how the cells will be administered, including adjuvant drugs, agents, and surgical procedures.
v. Plan for clinical follow-up and data collection to assess the effectiveness and adverse effects of the cell therapy.
b. The written plan is approved through a peer review process by appropriate experts who have no vested interest in the proposed procedure.
c. The patient is not eligible for an existing stem cell-based trial for this indication.
d. The clinical and administrative leadership of the healthcare institution supports the decision to attempt the medical innovation and the institution is held accountable for the innovative procedure.
e. All personnel have appropriate qualifications and the institution where the procedure will be carried out has appropriate facilities and processes of peer review and clinical quality control monitoring.
f. Voluntary informed consent is provided by patients who appreciate that the intervention is unproven and who demonstrate their understanding of the risks and possible benefits of the procedure.
g. There is an action plan for adverse events that includes timely and adequate medical care and if necessary psychological support services.
h. Insurance coverage or other appropriate financial or medical resources are provided to patients to cover any complications arising from the procedure.
i. There is a commitment by clinician-scientists to use their experience with individual patients to contribute to generalizable knowledge. This includes:
i. Ascertaining outcomes in a systematic and objective manner
ii. A plan for communicating outcomes, including negative outcomes and adverse events, to the scientific community to enable critical review (for example, as abstracts to professional meetings or publications in peer-reviewed journals).
iii. Moving to a formal clinical trial in a timely manner after experience with at most a few patients.
Not following such standards may exploit the hopes of patients, undermine public trust in stem cell research, and unnecessarily delay rigorous clinical trials. Strict application of the above criteria to many such clinical interventions offered outside of a formal clinical trial will identify significant shortcomings that should call into question the legitimacy of the purported attempts at medical innovation.
Munsie, M., & Hyun, I. (2014). A question of ethics: Selling autologous stem cell therapies flaunts professional standards. Stem Cell Research. doi:10.1016/j.scr.2014.04.014