Title: Setting Global Standards for Stem Cell Research and Clinical Translation: The 2016 ISSCR Guidelines
Abstract: •The ISSCR presents its new Guidelines for Stem Cell Research and Clinical Translation•The guidelines outline core principles and best practices for the field•Recommendations drive rigor and transparency in all aspects of stem cell research•The guidelines build widespread confidence in the integrity of the research enterprise The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016International Society for Stem Cell Research (ISSCR). (2016). Guidelines for stem cell research and clinical translation. http://www.isscr.org/guidelines2016.Google Scholar). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006International Society for Stem Cell Research (ISSCR). (2006). Guidelines for the conduct of human embryonic stem cell research. http://www.isscr.org/docs/default-source/hesc-guidelines/isscrhescguidelines2006.pdf.Google Scholar, ISSCR, 2008International Society for Stem Cell Research (ISSCR). (2008). Guidelines for the clinical translation of stem cells. http://www.isscr.docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf.Google Scholar) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them. The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016International Society for Stem Cell Research (ISSCR). (2016). Guidelines for stem cell research and clinical translation. http://www.isscr.org/guidelines2016.Google Scholar). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006International Society for Stem Cell Research (ISSCR). (2006). Guidelines for the conduct of human embryonic stem cell research. http://www.isscr.org/docs/default-source/hesc-guidelines/isscrhescguidelines2006.pdf.Google Scholar, ISSCR, 2008International Society for Stem Cell Research (ISSCR). (2008). Guidelines for the clinical translation of stem cells. http://www.isscr.docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf.Google Scholar) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them. As the largest international professional organization engaged with stem cell research, the International Society for Stem Cell Research (ISSCR) has promoted both rigorous scientific inquiry and careful ethical deliberations regarding stem cell science and regenerative medicine. Through its Guidelines for the Conduct of Human Embryonic Stem Cell Research (ISSCR, 2006International Society for Stem Cell Research (ISSCR). (2006). Guidelines for the conduct of human embryonic stem cell research. http://www.isscr.org/docs/default-source/hesc-guidelines/isscrhescguidelines2006.pdf.Google Scholar) and Guidelines for the Clinical Translation of Stem Cells (ISSCR, 2008International Society for Stem Cell Research (ISSCR). (2008). Guidelines for the clinical translation of stem cells. http://www.isscr.docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf.Google Scholar), the ISSCR has set high standards, offering concrete mechanisms for review and conduct of research and clinical development. These guidelines were designed to promote rapid yet responsible advances in fundamental knowledge and the clinical application of stem cell science. However, in the decade since the release of the first ISSCR guidelines, stem cell science has made remarkable advances but has also encountered numerous new ethical, social, and policy challenges. For example, new discoveries and techniques such as gene editing or mitochondrial replacement offer bold possibilities while also posing ethical conundrums. Moreover, stem cell science and clinical application are increasingly pursued across geographical and boundaries, necessitating the need for policies that can be applied internationally. In an effort to keep pace with these many new developments and future prospects, the ISSCR has undertaken a comprehensive revision of its guidelines to account for scientific progress, policy developments, globalization of stem cell activities, and evolving ethics scholarship. Below, we highlight what has been preserved and what is new in the 2016 ISSCR Guidelines for Stem Cell Research and Clinical Translation. We also provide a window into our deliberations and describe key elements of the process from which these revised guidelines emerged. Specific recommendations embodied in the document are presented in Table 1, giving the reader a synopsis of core principles.Table 1Summary of Recommendations from the ISSCR Guidelines for Stem Cell Research and Clinical TranslationSectionRecommendation2.1.1All 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.2.1.2The EMRO process should be conducted by qualified scientists, ethicists, and community members who are not directly engaged in the research under consideration.2.1.3To 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.2.1.4The 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.2.1.5Research 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.2.2.1Rigorous 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.2.2.2Explicit 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.2.2.3Review of procurement protocols must ensure that biomaterials donors are adequately informed about the specific aspects of their voluntary research participation.2.2.4Research oversight bodies must authorize all proposals to reimburse, compensate, or provide valuable considerations of any kind to providers of embryos, gametes, or somatic cells.2.2.5For 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.2.2.6Informed consent for research donation must be kept distinct from informed consent for clinical treatment.2.2.7The informed consent process and study design of human biomaterials procurement should be robust.2.3.1Proposals 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.2.3.2A 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.2.3.3Researchers 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.2.3.4The 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.2.3.5Documentation 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.2.3.6Institutions 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.2.4.1These ISSCR guidelines should be upheld and enforced through standards of academic, professional, and institutional self-regulation.3.1.1.1In 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.3.1.1.2Donors 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.3.1.2.1All 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.3.1.2.2The 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.3.1.2.3Components of animal origin used in the culture or preservation of cells should be replaced with human or chemically defined components whenever possible.3.1.2.4Criteria 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.3.1.2.5Funding 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.3.2.1.1Given 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.3.2.1.2Early 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.3.2.1.3All 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.3.2.2.1Cells 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.3.2.2.2Risks for tumorigenicity must be rigorously assessed for any stem cell-based product, especially if extensively manipulated in culture, genetically modified, or when pluripotent.3.2.2.3For all cell-based products, whether injected locally or systemically, researchers should perform detailed and sensitive biodistribution studies of cells.3.2.2.4Before 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.3.2.2.5Preclinical researchers should adopt practices to address long-term risks and to detect new and unforeseen safety issues.3.2.2.6Researchers, regulators, and reviewers should exploit the potential for using stem cell-based systems to enhance the predictive value of preclinical toxicology studies.3.2.3.1Trials 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.3.2.3.2Small 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.3.2.3.3Large 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.3.2.4.1Sponsors, 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.3.3.1.1All 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.3.3.1.2The 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.3.3.2.1Launch of clinical trials should be supported by a systematic appraisal of evidence supporting the intervention.3.3.2.2Risks 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.3.3.2.3When 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.3.3.2.4A 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.3.3.2.5Individuals 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.3.3.2.6Informed 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.3.3.2.7Prior 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.3.3.2.8Research teams must protect the privacy of human subjects.3.3.2.9Patient-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.3.3.3.1Consent 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.3.3.3.2In 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.3.3.3.3Researchers should take measures to maximize the scientific value of early phase trials.3.3.4.1Clinical 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.3.3.4.2Where 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.3.3.5.1An 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.3.3.5.2Given 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.3.3.5.3To 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.3.3.6.1All trials should be prospectively registered in public databases.3.3.6.2Investigators should report adverse events including their severity and their potential causal relationship with the experimental intervention.3.3.6.3Researchers 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.3.4.1Clinician-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.3.5.1.1The 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.3.5.1.2Developers, 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.3.5.1.3Registries 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.3.5.1.4Off-label uses of stem cell-based interventions should be employed with particular care, given uncertainties associated with stem cell-based interventions.3.5.2.1Stem cell-based interventions should be developed with an eye toward delivering economic value to patients, payers, and healthcare systems.3.5.2.2Developers, 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.4.1The stem cell research community should promote accurate, balanced, and responsive public representations of stem cell research.4.2When 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.4.3The provision of information to patients on stem cell-based interventions must be consistent with the primacy of patient welfare and scientific integrity.5.1Researchers, industry, and regulators should work toward developing and implementing standards on design, conduct, interpretation, and reporting of research in stem cell science and medicine.5.2These guidelines should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities. Open table in a new tab The revised guidelines reassert many of the bedrock tenets of the ISSCR’s 2006 and 2008 guidelines. At their core, the 2016 guidelines preserve the general imperative that ethically sensitive stem cell research projects should undergo a specialized oversight process. This oversight process, which earlier ISSCR guidelines labeled Stem Cell Research Oversight (SCRO), enlists stem cell-specific expertise and ethical review that acknowledge the uniquely sensitive aspects of research involving human embryos. The 2016 guidelines retain the original three categories of research that guide the oversight process. Category 1 allows routine aspects of research to be conducted under a streamlined process of administrative approval (for example, work with existing human embryonic stem cell or hESC lines). Category 2 defines research projects warranting special scrutiny (for example, derivation of new hESC lines). Category 3 describes impermissible research (for example, reproductive cloning and extended in vitro culture of human embryos beyond 14 days or formation of the primitive streak). Also retained is the requirement for review of certain human-animal chimera experiments, when high degrees of central nervous system or germ lineage chimerism are anticipated. The requirement for explicit consent from donors is emphasized for use of their biomaterials in sensitive aspects of stem cell research, such as the derivation of new hESC lines, generation of embryos via somatic cell nuclear transfer, or future use in commercial development. To facilitate widespread adoption of the informed consent principles embodied in these guidelines, the ISSCR is providing template informed consent documents that can be downloaded and customized to specific protocols (http://www.isscr.org). In the realm of clinical translation, the 2016 guidelines retain stringent standards of preclinical evidence and high aspirations for understanding the mechanism of action of stem cell-based interventions prior to clinical trials. The updated guidelines restate a strong condemnation of the now widespread marketing and delivery of unproven stem cell-based interventions, practices that free-ride on the excitement of stem cell science but have little scientific basis and exploit the hopes of patients and their families. The 2016 guidelines break new ground in several areas. They encompass a broader and more expansive scope of research and clinical endeavor and speak assertively to contentious issues of regulatory practice, the cost of regenerative medicine products, and public communication. The 2016 guidelines are now presented as a single document, with a preamble that articulates core ethical principles for guiding both basic and clinical stem cell research: the integrity of the research enterprise, the primacy of patient welfare, respect for research subjects, transparency, and social justice. These principles provide a foundation for the recommendations that follow in the guidelines and inform their interpretation. Among the most significant changes is the scope of research that warrants specialized review. Given that human induced pluripotent stem cells (iPSCs) do not engender the same sensitivities as derivation of new hESC lines, the new guidelines exclude the derivation of iPSCs from specialized review, instead calling upon committees that oversee human subjects to scrutinize donor cell procurement. Protocols that employ human iPSCs to achieve human-animal chimerism of the central nervous system or the admixture of human iPSCs with human embryos will, however, still trigger specialized review. Acknowledging that stem cell researchers engage in many forms of human embryo research that do not explicitly involve derivation or use of hESC lines, the guidelines broaden the scope of specialized review beyond the SCRO function to encompass all forms of human embryo research. The 2016 guidelines specify a process of embryo research oversight (EMRO), which encompasses both embryonic stem cell research and any human embryo research that may not explicitly pertain to stem cells or stem cell lines, such as single cell analyses, genome modification, and embryo chimerism. At present, the guidelines for EMRO review represent the most comprehensive set of principles to inform oversight of the emerging technologies being applied to human embryo research and are consistent with embryo research policy statements by the American College of Obstetricians and Gynecologists, 2006American College of Obstetricians and Gynecologists ACOG committee opinion no. 347, November 2006: using preimplantation embryos for research.Obstet. 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