Table 1.

Summary of Recommendations from the ISSCR Guidelines for Stem Cell Research and Clinical Translation

Section	Recommendation
2.1.1	All research that (a) involves preimplantation stages of human development, human embryos, or embryo-derived cells or (b) entails the production of human gametes in vitro when such gametes are tested by fertilization or used for the creation of embryos shall be subject to review, approval, and ongoing monitoring by a specialized human embryo research oversight (EMRO) process capable of evaluating the unique aspects of the science. The derivation of human pluripotent stem cells from somatic cells via genetic or chemical means of reprogramming (for example, induced pluripotent stem cells or iPSCs) requires human subjects review but does not require specialized EMRO as long as the research does not generate human embryos or entail sensitive aspects of the research use of human totipotent or pluripotent stem cells as outlined in this section.
2.1.2	The EMRO process should be conducted by qualified scientists, ethicists, and community members who are not directly engaged in the research under consideration.
2.1.3	To ensure that human embryo and embryonic stem cell research is proceeding with due consideration, to ensure consistency of research practices among scientists globally, and to specify the nature of scientific projects that should be subject to review, research review and oversight should use the three categories of review described in this section.
2.1.4	The ISSCR supports laboratory-based research that entails modifying the nuclear genomes of gametes, zygotes and/or preimplantation human embryos, performed under a rigorous EMRO process. Such research will enhance fundamental knowledge and is essential to inform any thoughtful deliberations about the potential safety and use of nuclear genome modification in strategies aimed at preventing the transmission of genetic disorders. Until further clarity emerges on both scientific and ethical fronts, the ISSCR holds that any attempt to modify the nuclear genome of human embryos for the purpose of human reproduction is premature and should be prohibited at this time.
2.1.5	Research that entails incorporating human totipotent or pluripotent cells into animal hosts to achieve chimerism of either the central nervous system or germline requires specialized research oversight. Such oversight should utilize available baseline animal data grounded in rigorous scientific knowledge or reasonable inferences and involve a diligent application of animal welfare principles.
2.2.1	Rigorous review must be performed prior to the procurement of all gametes, embryos, or somatic cells that are destined for use in human embryo and stem cell research.
2.2.2	Explicit and contemporaneous informed consent for the provision of all biomaterials for embryo and embryonic stem cell research is necessary, including from all gamete donors. Informed consent should be obtained at the time of proposed transfer of any biomaterials to the research team or during the time that biomaterials are collected and stored for future research use.
2.2.3	Review of procurement protocols must ensure that biomaterials donors are adequately informed about the specific aspects of their voluntary research participation.
2.2.4	Research oversight bodies must authorize all proposals to reimburse, compensate, or provide valuable considerations of any kind to providers of embryos, gametes, or somatic cells.
2.2.5	For provision of oocytes for research, when oocytes are collected outside the course of clinical treatment, compensation for nonfinancial burdens should not constitute an undue inducement.
2.2.6	Informed consent for research donation must be kept distinct from informed consent for clinical treatment.
2.2.7	The informed consent process and study design of human biomaterials procurement should be robust.
2.3.1	Proposals for derivations of new human embryonic stem cell lines should be scientifically justified and executed by scientists with appropriate expertise. Hand-in-hand with the privilege to perform these derivations is the obligation to distribute the cell lines to the research community.
2.3.2	A clear, detailed outline for banking and open access to the new lines should be incorporated into derivation proposals. New pluripotent stem cell lines should be made generally available as soon as possible following derivation and first publication.
2.3.3	Researchers and repositories should develop a policy that states whether and how incidental findings will be returned to research subjects. This policy must be explained during the informed consent process and potential subjects should be able to choose which types of incidental findings they wish to receive, if any. Reporting findings with relevance to public health may be required by law in certain jurisdictions.
2.3.4	The ISSCR encourages the establishment of national and international repositories that are expected to accept deposits of newly derived stem cell lines and to distribute them on an international scale.
2.3.5	Documentation of the provenance of stem cell lines is critical if the cell lines are to be widely employed in the research community. Provenance must be easily verifiable by access to relevant informed consent documents and raw primary data regarding genomic and functional characterization.
2.3.6	Institutions engaged in human stem cell research, whether public or private, academic or nonacademic, should develop procedures whereby research scientists are granted, without undue financial constraints or bureaucratic impediment, unhindered access to research materials for scientifically sound and ethical purposes, as determined under these guidelines and applicable laws.
2.4.1	These ISSCR guidelines should be upheld and enforced through standards of academic, professional, and institutional self-regulation.
3.1.1.1	In the case of donation of cells for allogeneic use, the donor should give written and legally valid informed consent that covers, where applicable, terms for potential research and therapeutic uses, return of incidental findings, potential for commercial application, and other issues.
3.1.1.2	Donors should be screened for infectious diseases and other risk factors, as is done for blood and solid organ donation, and for genetic diseases as appropriate.
3.1.2.1	All reagents and processes should be subject to quality control systems and standard operating procedures to ensure the quality of the reagents and consistency of protocols used in manufacturing. For extensively manipulated stem cells intended for clinical application, good manufacturing practice (GMP) should be followed.
3.1.2.2	The degree of oversight and review of cell processing and manufacturing protocols should be proportionate to the risk induced by manipulation of the cells, their source and intended use, the nature of the clinical trial, and the number of research subjects who will be exposed to them.
3.1.2.3	Components of animal origin used in the culture or preservation of cells should be replaced with human or chemically defined components whenever possible.
3.1.2.4	Criteria for release of cells for use in humans must be designed to minimize risk from culture-acquired abnormalities. Final product as well as in-process testing may be necessary for product release and should be specified during the review process.
3.1.2.5	Funding bodies, industry, and regulators should work to establish a public database of clinically useful lines that contains adequate information to determine the lines’ utility for a particular disease therapy.
3.2.1.1	Given that preclinical research into stem cell-based therapeutics makes heavy use of animal models, researchers should adhere to the principles of the three Rs: reduce numbers, refine protocols, and replace animals with in vitro or nonanimal experimental platforms whenever possible.
3.2.1.2	Early phase human studies should be preceded by rigorous demonstration of safety and efficacy in preclinical studies. The strength of preclinical evidence demanded for trial launch should be proportionate with the risks, burdens, and ethical sensitivities of the anticipated trial.
3.2.1.3	All preclinical studies testing safety and efficacy should be designed in ways that support precise, accurate, and unbiased measures of clinical promise. In particular, studies designed to inform trial initiation should have high internal validity; they should be representative of clinical scenarios they are intended to model and they should be replicated.
3.2.2.1	Cells to be employed in clinical trials must first be rigorously characterized to assess potential toxicities through studies in vitro and, where possible for the clinical condition and tissue physiology to be examined, in animals.
3.2.2.2	Risks for tumorigenicity must be rigorously assessed for any stem cell-based product, especially if extensively manipulated in culture, genetically modified, or when pluripotent.
3.2.2.3	For all cell-based products, whether injected locally or systemically, researchers should perform detailed and sensitive biodistribution studies of cells.
3.2.2.4	Before launching high-risk trials or studies with many components, researchers should establish the safety and optimality of other intervention components, like devices or co-interventions such as surgeries.
3.2.2.5	Preclinical researchers should adopt practices to address long-term risks and to detect new and unforeseen safety issues.
3.2.2.6	Researchers, regulators, and reviewers should exploit the potential for using stem cell-based systems to enhance the predictive value of preclinical toxicology studies.
3.2.3.1	Trials should generally be preceded by compelling preclinical evidence of clinical promise in well-designed studies. Animal models suited to the clinical condition and the tissue physiology should be used unless there is very strong evidence of efficacy using similar products against similar human diseases.
3.2.3.2	Small animal models should be used to assess the morphological and functional recovery caused by cell-based interventions, the biological mechanisms of activity, and to optimize implementation of an intervention.
3.2.3.3	Large animal models should be used for stem cell research when they are believed to better emulate human anatomy or pathology than small animal models and where risks to human subjects in anticipated clinical trials are high.
3.2.4.1	Sponsors, researchers, and clinical investigators should publish preclinical studies in full and in ways that enable an independent observer to interpret the strength of the evidence supporting the conclusions.
3.3.1.1	All research involving clinical applications of stem cell-based interventions must be subject to prospective review, approval, and ongoing monitoring by independent human subjects review committees.
3.3.1.2	The review process for stem cell-based clinical research should ensure that protocols are vetted by independent experts who are competent to evaluate (a) the in vitro and in vivo preclinical studies that form the basis for proceeding to a trial and (b) the design of the trial, including the adequacy of the planned endpoints of analysis, statistical considerations, and disease-specific issues related to human subjects protection.
3.3.2.1	Launch of clinical trials should be supported by a systematic appraisal of evidence supporting the intervention.
3.3.2.2	Risks should be identified and minimized, unknown risks acknowledged, and potential benefits to subjects and society estimated. Studies must anticipate a favorable balance of risks and benefits.
3.3.2.3	When testing interventions in human subjects that lack capacity to provide valid informed consent, risks from study procedures should be limited to no greater than minor increase over minimal risk unless the risks associated with the intervention are exceeded by the prospect of therapeutic benefit.
3.3.2.4	A stem cell-based intervention must aim at ultimately being clinically competitive with or superior to existing therapies or meet a unique therapeutic demand. Being clinically competitive necessitates having reasonable evidence that the nature of existing treatments poses some type of burden related to it that would likely be overcome should the stem cell-based intervention prove to be safe and effective.
3.3.2.5	Individuals who participate in clinical stem cell research should be recruited from populations that are in a position to benefit from the results of this research. Groups or individuals must not be excluded from the opportunity to participate in clinical stem cell research without rational justification. Unless scientifically inappropriate, trials should strive to include women as well as men and members of racial and/or ethnic minorities.
3.3.2.6	Informed consent must be obtained from potential human subjects or their legally authorized representatives. Reconsent of subjects must be obtained if substantial changes in risks or benefits of a study intervention or alternative treatments emerge over the course of the research.
3.3.2.7	Prior to obtaining consent from potential adult subjects who have diseases or conditions that are known to affect cognition, their capacity to consent should be assessed formally.
3.3.2.8	Research teams must protect the privacy of human subjects.
3.3.2.9	Patient-sponsored and pay-to-participate trials pose challenges for ensuring scientific merit, integrity, and priority as well as fairness. Accordingly, these financial mechanisms should be used only if they are approved and supervised by a rigorous independent review body that espouses the principles outlined in these guidelines regarding integrity of the research enterprise, transparency, and patient welfare.
3.3.3.1	Consent procedures in any prelicensure phase, but especially early phase trials of stem cell-based interventions, should work to dispel potential research subjects’ overestimation of benefit and therapeutic misconception.
3.3.3.2	In general, initial tests of a novel strategy should be tested under lower risk conditions before escalating to higher risk study conditions even if they are more likely to confer therapeutic benefit.
3.3.3.3	Researchers should take measures to maximize the scientific value of early phase trials.
3.3.4.1	Clinical research should compare new stem cell-based interventions against the best therapeutic approaches that are currently or could be made reasonably available to the local population.
3.3.4.2	Where there are no proven effective treatments for a medical condition and stem cell-based interventions involve invasive delivery, it may be appropriate to test them against placebo or sham comparators, assuming early experience has demonstrated feasibility and safety of the particular intervention.
3.3.5.1	An independent data-monitoring plan is required for clinical studies. When deemed appropriate, aggregate updates should be provided at predetermined times or on demand. Such updates should include adverse event reporting and ongoing statistical analyses if appropriate. Data monitoring personnel and committees should be independent from the research team.
3.3.5.2	Given the potential for transplanted cellular products to persist, and depending on the nature of the experimental stem cell-based intervention, subjects should be advised to undergo long-term health monitoring. Additional safeguards for ongoing research subject privacy should be provided. Subject withdrawal from the research should be done in an orderly fashion to promote physical and psychological welfare.
3.3.5.3	To maximize the opportunities for scientific advance, research subjects in stem cell-based intervention studies should be asked for consent to a partial or complete autopsy in the event of death to obtain information about cellular implantation and functional consequences. Requests for an autopsy must consider cultural and familial sensitivities. Researchers should strive to incorporate a budget for autopsies in their trials and develop a mechanism to ensure that these funds remain available over long time horizons if necessary.
3.3.6.1	All trials should be prospectively registered in public databases.
3.3.6.2	Investigators should report adverse events including their severity and their potential causal relationship with the experimental intervention.
3.3.6.3	Researchers should promptly publish aggregate results regardless of whether they are positive, negative or inconclusive. Studies should be published in full and according to international reporting guidelines.
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.
3.5.1.1	The introduction of novel products into routine clinical use should be dependent on the demonstration of an acceptable balance of risk and clinical benefit appropriate to the medical condition and patient population for which new treatments are designed.
3.5.1.2	Developers, manufacturers, providers, and regulators of stem cell-based interventions should continue to systematically collect and report data on safety, efficacy, and utility after they enter clinical use.
3.5.1.3	Registries of specific patient populations can provide valuable data on safety and outcomes of stem cell-based interventions within defined populations but should not substitute for stringent evaluation through clinical trials prior to introduction into standard care.
3.5.1.4	Off-label uses of stem cell-based interventions should be employed with particular care, given uncertainties associated with stem cell-based interventions.
3.5.2.1	Stem cell-based interventions should be developed with an eye toward delivering economic value to patients, payers, and healthcare systems.
3.5.2.2	Developers, funders, providers, and payers should work to ensure that cost of treatment does not prevent patients from accessing stem cell-based interventions for life-threatening or seriously debilitating medical conditions.
4.1	The stem cell research community should promote accurate, balanced, and responsive public representations of stem cell research.
4.2	When describing clinical trials in the media or in medical communications, investigators, sponsors, and institutions should provide balance and not emphasize statistically significant secondary results when pre-specified primary efficacy results are not statistically significant. They should also emphasize that research is primarily aimed at generating systematic knowledge on safety and efficacy, not therapeutic care.
4.3	The provision of information to patients on stem cell-based interventions must be consistent with the primacy of patient welfare and scientific integrity.
5.1	Researchers, industry, and regulators should work toward developing and implementing standards on design, conduct, interpretation, and reporting of research in stem cell science and medicine.
5.2	These guidelines should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.