1. Fundamental Ethical Principles
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The primary societal mission of basic biomedical research and its clinical translation is to alleviate and prevent human suffering caused by illness and injury. All such biomedical research is a collective effort. It depends on the public support and contributions of many individuals, including scientists, clinicians, patients and their advocates, research participants, members of industry, regulators and other governmental officials, legislators, and others. Such individuals often work across institutions, professions, and national boundaries and are governed by different social and cultural beliefs, regulatory systems, and expectations for moral conduct. Each may also be working toward different goals. When this collective effort works well, the social mission of responsible basic research and clinical translation is achieved efficiently alongside the private interests of its various contributors.
Ethical principles and guidelines help secure the basis for this collective effort together with an internationally coordinated framework to regulate research at all levels, including clinical trials and market access to proven interventions. This helps to give the public and research funding organizations confidence that generally accepted ethical boundaries will not be crossed in either basic or clinical research. Patients should be able to enroll in clinical research trusting that studies are well justified, appropriately designed and ethically sound, the risks and burdens are reasonable in relation to potential benefits, the quality and manufacturing of the experimental product fulfills the standards expected for safe human administration, and the study will collect meaningful information to support further development of the intervention. Physicians and payers need to be confident that the evidence they use to make important healthcare decisions is rigorous and unbiased. Organizations, including private firms, can invest in research and product development programs knowing that products will be promptly and fairly evaluated by regulators.
The International Society for Stem Cell Research (ISSCR) Guidelines pertain to human stem cell research, clinical translation, and related research activities. These guidelines promote an ethical, practical, appropriate, and sustainable enterprise for stem cell research and the development of cell therapies that will improve human health and should be available for patients in need. These guidelines do not supersede local laws and regulations. However, they complement existing legal frameworks and can inform the interpretation and development of laws applicable to stem cell research as well as provide guidance for research practices not covered by legislation. These guidelines build on a set of widely shared ethical principles in science, research with human subjects, and medicine (Nuremberg Code, 1949; Decleration of Helsinki of the WMA, 1964; Department of Health, and Education and Welfare, 1979; European Science Foundation, 2000; Medical Professionalism Project, 2002; Institute of Medicine, 2009; World Medical Association, 2018; Council for International Organizations of Medical Sciences, 2016). Some of the guidelines that follow are applicable to all basic research and clinical translation efforts. Others respond to challenges that are especially relevant to stem cell-based research and interventions. These include sensitivities surrounding research activities that involve the use of human embryos and gametes, irreversible risks associated with some cell-based interventions, including those that involve genome editing, the vulnerability and pressing medical needs of patients with serious illnesses and medical conditions that currently lack effective treatments, public expectations about medical advance and access, and competitiveness within this research context.
Integrity of the Research Enterprise
The primary goals of stem cell research are to advance scientific understanding, to generate evidence for addressing unmet medical and public health needs, and to develop safe and efficacious therapies for patients. This research should be overseen by qualified investigators and conducted in a manner that maintains public confidence. Research, whether basic, preclinical or clinical, must ensure that the information obtained will be trustworthy, reliable, accessible, and responsive to scientific uncertainties and priority health needs. Key processes for maintaining the integrity of the research enterprise include those for independent peer review and oversight, replication, institutional oversight, and accountability at each stage of research.
Primacy of Patient/Participant Welfare
Physicians and physician-researchers owe their primary duty of care to patients and/or research subjects. They must never excessively place vulnerable patients or research subjects at risk. Clinical testing should never allow promise for future patients to override the welfare of current research subjects. Further, human subjects should be stringently protected from procedures offering no prospect of benefit that involve greater than a minor increase over minimal risk. The application of stem cell-based interventions outside formal research settings should occur after products have been authorized by regulators and proven safe and efficacious, include long-term patient follow-up and adverse event reporting, and serve patients’ best interests. It should also ensure similar standards of product quality and safety expected for early clinical use and be conducted in authorized establishments operating under a formal regulatory framework. Promising innovative strategies should be systematically evaluated as early as possible and before application in large populations. It is a breach of professional medical ethics and responsible scientific practices to market or provide stem cell-based interventions prior to rigorous and independent expert review of safety and efficacy and appropriate regulatory approval.
Respect for Patients and Research Subjects
Researchers, clinical practitioners, and healthcare institutions should empower potential human research participants (human subjects) to exercise valid informed consent where they have adequate decision-making capacity. Patients, whether in research or care settings, must be offered accurate information about risks and the current state of evidence for novel stem cell-based interventions. Where individuals lack such capacity, surrogate consent should be obtained from lawfully authorized representatives.
Transparency
Researchers should promote the timely exchange of accurate scientific information to other interested parties. Researchers should communicate with various public groups, such as patient communities and individuals from the emerging do-it-yourself biology movement, to respond to their reasonable requests for relevant and needed information, and they should convey the scientific state of the art, including uncertainty about the safety, reliability, or efficacy of potential applications. Researchers and sponsors should promote open and prompt sharing of ideas, methods, data, and materials by publishing, in a timely manner, positive and negative results.
Social and Distributive Justice
Fairness demands that the benefits of clinical translation efforts should be distributed justly and globally, with particular emphasis on addressing unmet medical and public health needs. To that end, the scientific community is encouraged to work with private and public funders to emphasize addressing unmet needs by helping to identify promising areas of research, development, and application.
Social justice considerations include challenges due to structural injustices, such as socioeconomic inequalities, extant discriminatory practices, and histories of exclusion and marginalization. Advantaged populations should make efforts to share any benefits of research with disadvantaged populations. This would include ‘capacity building,’ both training and establishment of facilities, which gives benefit in the longer term. There should also be appropriate sharing of the burdens with disadvantaged populations. Trials should strive to enroll populations that reflect diversity such as age, sex, gender identity, and ethnicity. Risks and burdens associated with clinical translation should not be borne by populations that are unlikely to benefit from the knowledge produced in these efforts. The scientific community is encouraged to work with governments and industry to develop mechanisms to reduce the cost of clinical applications.
Generally, healthcare delivery systems, governments, insurance providers, and patients should not bear the financial costs of proving the safety and efficacy of experimental stem cell-based interventions. However, in some cases these parties may choose to fund clinical development, for example if there is an unmet medical need and insufficient investment from the commercial sector. Where there is a clear and substantial commercial potential for a product, the costs of testing safety and efficacy should be met by the investors. Developers should endeavor to reduce the cost of new products to make them accessible to as many patients as possible.
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