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The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006, ISSCR, 2008) 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, 2006) and Guidelines for the Clinical Translation of Stem Cells (ISSCR, 2008), 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.
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 (2006), the American Society for Reproductive Medicine (Ethics Committee of American Society for Reproductive Medicine, 2013), the European Society for Human Reproduction and Reproductive Endocrinology (ESHRE Taskforce on Ethics and Law, 2001), and the Human Fertilisation and Embryology Authority (HFEA) of the United Kingdom.
In concordance with recent deliberations in the United Kingdom, the United States, and elsewhere, the 2016 guidelines articulate principles for evaluating both basic and clinically applied research on mitochondrial replacement in embryos aimed at preventing transmission of diseases that are caused by mutations in the mitochondrial genome. In addition, the 2016 guidelines consider basic research on editing of the nuclear genomes of embryos in the permissible category, subject to a rigorous EMRO process. However, given current uncertainties about the safety of nuclear genome editing and a lack of societal consensus on whether any form of heritable nuclear genome editing should be allowed, the guidelines consider uterine transfer of human embryos that have undergone modification of their nuclear genome impermissible at this time. Nonetheless, we recognize that the potential benefits and harms of such technologies remain poorly understood and that more scientific research and ethical inquiry are needed to inform future policy.
Another aspect of the guidelines that has evolved over time is the permissibility of compensating women who provide oocytes for research. Based on a white paper from the ISSCR Ethics and Public Policy Committee (Haimes et al., 2013), the new recommendations reflect an evolving consensus that compensating women who provide oocytes can be ethically permissible. The 2016 guidelines specify a review to determine appropriate compensation for oocyte providers’ nonfinancial burdens, so long as such payments do not constitute an undue financial inducement to participate.
Researchers are developing novel methods to probe human development, including the formation of complex organoids and embryo-like structures that manifest potential for self-organization. Experiments wherein tissue aggregates manifest markers of the human primitive streak (for example, Warmflash et al., 2014) or in which human embryos are cultured to reveal post-implantation stages of development (for example, Deglincerti et al., 2016 and Shahbazi et al., 2016) challenge the time-honored limitations of human embryo culture, widely known as the “14 day rule.” Embodied in the 1984 Warnock commission report issued in the wake of the first practice of in vitro fertilization (Warnock, 1985), the 14 day rule precludes culture of intact preimplantation human embryos beyond the point of streak formation or 14 days. Applying the standard of primitive streak formation requires judgment and in light of advances in organoid biology, synthetic biology, chimera research, tissue engineering, and recent experiments that have extended embryo culture, there have been recent calls for its reassessment (Hyun et al., 2016). Still more challenging, the task force has provided principles of review for experiments in which human cells might self-organize into embryo-like structures with the realistic potential to become a living organism. The task force concluded that human embryo-like structures at any stage of development should not be maintained in culture for more than the minimal period of time necessary for the study, with the scientific merit of the experiments evaluated in a rigorous EMRO process. Here again, the ISSCR guidelines articulate a core principle to be interpreted by local review, subject to local customs, mores, and legal restrictions. For this emerging area of research on human development, specific elements of review and the distinctions between permissible and impermissible experiments must be re-evaluated over time in light of scientific advances and continued deliberations.
Despite the relatively immature state of our scientific understanding of mechanisms of stem cell differentiation, transplantation, and tissue integration, clinical testing of stem cell applications has proceeded rapidly, and as judged by the task force, prematurely in many cases. Against calls for relaxed standards for autologous use of cell products, the guidelines retain an emphasis on high standards of cell processing and manufacture. Recent revelations that fungal contamination of drugs prepared by a United States pharmacy caused infections and dozens of deaths (Smith et al., 2013) serve as a reminder that injection into patients of any material, whether chemical or cellular, irrespective of the degree of ex vivo processing, carries the risk of devastating complications. The 2016 guidelines retain the high standard of good manufacturing practice (GMP) in the preparation of cell-based therapeutics.
The guidelines recognize the many opportunities for improving the conduct and reporting of preclinical studies in stem cell research. They recommend that human studies proceed only after rigorous demonstration of safety and efficacy in adequately powered preclinical studies and that clinical trial protocols be subject to rigorous peer review that scrutinizes the weight of preclinical evidence, and balances risk with opportunity, as appropriate to the stage of the trial. The guidelines have sought further to address the problem of irreproducibility of research, articulating high standards for preclinical design, study reporting, and an imperative to publish negative as well as positive results.
Guidance is provided regarding clinical trials involving subjects with diminished capacity. The guidelines also address the use of placebo and sham surgical controls, which have been criticized in the past in the context of studies of surgically implanted cell transplants for Parkinson’s disease (Macklin, 1999). Patient funding of clinical trials and direct payments by patients to participate in clinical trials is a trend that, while making some research possible, also raises concerns for the integrity of the research enterprise, objectivity, and patient welfare. The 2016 guidelines articulate a highly limited set of circumstances under which patients may provide funding for trials in which they enroll. New recommendations stipulate that protocols that involve patient funding undergo independent review for scientific rationale, priority, and design and be conducted with independent oversight.
New sections in the 2016 guidelines articulate high standards for transparency in the conduct and reporting of clinical trials, prospective registration in public databases (for example, https://clinicaltrials.gov), reporting of adverse events, and an imperative to publish both negative and equivocal results. Guidelines for the provision of innovative care outside of formal clinical trials have been strengthened and extended, as have admonitions against off-label use of approved cell-based therapies, given the uncertainties associated with heterologous applications of stem cells. A commentary devoted to aspects of clinical translation in the new guidelines appears elsewhere (Kimmelman et al., 2016a).
The 2016 guidelines encourage developers of stem cell-based medicines to aspire to social justice and fairness in their pricing of new products, stipulating that new therapies should provide economic value to patients, payers, and health care systems and that costs should not prevent patients from accessing stem cell interventions for life-threatening or seriously debilitating medical conditions. Developers are encouraged to engage in studies intended to assess comparative effectiveness, as legally mandated in some countries.
With rising commercial interest in stem cell-based medicines, some countries have adopted or are considering streamlined regulatory pathways that grant conditional marketing approval for regenerative medicine products after early stage trials that establish only a baseline of safety and some promise of efficacy. The task force vigorously debated the advantages and potential risks of regulatory changes in the standards of safety and efficacy required for marketed products. The deliberations of the task force and the recommendations embodied in the guidelines emphasize considerations of patient welfare and concerns for patient safety, equity, and the financial sustainability of health care systems. Fewer than one in ten drugs that enter early phase clinical testing gain regulatory approval, while roughly two-thirds of drugs that progress from phase I to more advanced stages ultimately fail for reasons of either safety or ineffectiveness (Waring et al., 2015). Striking the right balance between facilitating patient access to new therapies and rigorous evaluation of new therapies continues to present a challenge for drug regulation. Unless thoughtful choices are made regarding which products are afforded expedited review and conditional marketing approval, regenerative medicine products approved based on early stage trial results could prove either unsafe or ineffective when tested more widely and rigorously. Noting examples where interventions entered clinical practice based on promising pilot clinical data that were ultimately not substantiated in randomized clinical trials (for example, high-dose chemotherapy and autologous bone marrow transplantation for advanced breast cancer; Rettig, 2007), the task force was wary that premature market authorization and clinical practice of unproven intervention strategies can slow their rigorous evaluation in formal trials and erode confidence in the scientific standards of the field. Moreover, there is concern that asking patients, insurance providers, and health care systems to bear the cost of therapies that might not be safe or effective would further stress health care systems and patients already burdened by rising costs.
The guidelines task force took special note of the rising visibility of stem cell research and the exuberance for clinical translation over the past decade. The new guidelines strengthen calls for responsible communication by scientists, clinicians, science communications professionals, industry spokespersons, and members of the media. Exaggeration of potential benefits or understatement of challenges and risks can have tangible impacts on the expectations of the general public, patient communities, and physicians and on the setting of health and science policies (Caulfield et al., 2016).
The process of revising and updating the ISSCR guidelines began at the 2014 annual ISSCR meeting in Vancouver, Canada, when the ISSCR board of directors empaneled a special task force. The task force of 25 scientists, ethicists, and experts in health care policy, with representatives from nine countries, was chaired by bioethicist Jonathan Kimmelman (McGill University). George Daley (Boston Children’s Hospital) and Insoo Hyun (Case Western Reserve University), chairs of the guidelines task forces of 2006 and 2008, respectively, provided continuity and thematic consistency across the three ISSCR guidelines efforts.
The work of revisions fell most heavily upon a core steering committee comprised of Nissim Benvenisty, Timothy Caulfield, Helen Heslop, Charles Murry, Douglas Sipp, Lorenz Studer, and Jeremy Sugarman, who alongside Hyun, Daley, and Kimmelman served as co-chairs of working subgroups of the larger task force. Deliberations began in August 2014 with biweekly conference calls and face-to-face meetings in Boston and at the ISSCR Annual Meeting in June 2015 in Stockholm, when a draft version of the revised guidelines was released. A three-month period of public comment followed, and targeted inquiries were made to a large number of individuals and organizations for feedback. The task force made particular efforts to solicit perspectives from diverse and underrepresented stakeholders. The taskforce also sought perspectives from individuals within regulatory authorities, funding agencies, industry, patient advocacy organizations, and professional societies. Ultimately, comments and critiques were received from 85 individuals and organizations, reflecting the seriousness with which the global community responded to the issuance of the draft guidelines (Table 2). All responses, including many in exhaustive detail, were cataloged, reviewed, and considered by multiple members of the steering committee, with consultation from working group members on select issues. For the critical last phase of revision, the steering committee was supported by Sally Temple, ISSCR president-elect, who fostered additional communication with the society’s executive committee and board of directors. In this final phase, issues flagged in review as contentious were weighed, debated, and reassessed by the working sub-groups and steering committee. After revising the draft released in Stockholm, a penultimate version of the guidelines document was then presented to the ISSCR board of directors at its meeting in December 2015. Following discussion and debate, the ISSCR board of directors voted unanimously to approve the revised guidelines, which were then subject to extensive reformatting, referencing, and assembly of appendices into a final document, which we now release (ISSCR, 2016).
While we believe the 2016 ISSCR guidelines represent a considerably broader as well as more integrated set of principles and best practices to direct the review of both basic and clinical research protocols, we acknowledge that no guidelines can represent the final word. We appreciate that just as stem cell science and medicine have evolved over the last decade, new challenges will surface that necessitate an ongoing process of reflection, review, reinterpretation, and future revision. Such a contemplative and iterative process is healthy and essential to maintain a culture of adherence to sound ethical principles of research conduct. The 2016 ISSCR guidelines give confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests (Kimmelman et al., 2016b).
Finally, Paolo Bianco, a member of our task force who passed away suddenly and unexpectedly in November 2015, was a stalwart advocate for rigor in science and evidence-based clinical application. He was also a passionate and vocal critic of practitioners who violated the standards embodied in our guidelines. In recognition of Paolo’s legacy, the task force has dedicated the 2016 ISSCR guidelines to his memory.
The authors thank the many individuals and organizations who reviewed the draft guidelines and provided comments or otherwise contributed to our deliberations. Despite earnest efforts to digest and consider all feedback, we apologize for the errors that persist in the document, and invite ongoing comment. As a scientific advisor to the following companies, G.Q.D. receives consulting fees or holds equity in MPM Capital, Epizyme, True North, Solasia, Verastem, Raze, and 28/7. J.F.A. acknowledges the support of the Imperial NIHR-BRC. R.A.B. is an advisor to Living Cell Technologies for a New Zealand-based clinical trial. C.K.B. is the founder of LYST Therapeutics, received grant support from Gunze Limited, and is on the scientific advisory board for Cook Biomedical. H.E.H. is founder of Viracyte and holds a licensing agreement with Cell Medica and a collaborative research agreement with Celgene and Bluebird Bio. M.R. works as a consultant in the field of regenerative medicine and serves on the board and SAB of several companies. The opinions expressed by the author are solely his own and do not reflect the policy or work of the companies he is affiliated with. L.S. is a member of the Scientific Advisory Board of Neurona Therapeutics. J.S. is a member of the Bioethics Advisory Committee and Stem Cell Research Oversight Committee for Merck KGaA, for which he receives consulting income and reimbursement for travel expenses. M.T. has research funds from Healios and Sumitomo Dainippon Pharma. M.Z is an employee of Viacyte, Inc.