2. Laboratory-based Human Embryonic Stem Cell Research, Embryo Research, and Related Research Activities
Return to TOC | 2021 Guidelines for Stem Cell Research and Clinical Translation
Stem cell and embryo research show great promise for advancing our understanding of human development and disease, including research to address issues pertinent to the earliest stages of human development, such as: the causes of miscarriage; epigenetic, genetic and chromosomal disorders; and human reproduction. Furthermore, the derivation of some types of stem cell lines necessitates the use of human embryos.
Scientific research on and with human embryos and embryonic stem cell lines in culture is viewed as ethically permissible in many countries when performed under rigorous scientific and ethical oversight. This is consistent with policy statements of other organizations, most notably, the American Society for Reproductive Medicine (Ethics in Embryo Research Task Force and Ethics Committee of the American Society for Reproductive Medicine, 2020), the European Society of Human Reproduction and Embryology (ESHRE Taskforce on Ethics and Law, 2001), the American College of Obstetricians and Gynecologists (2006) and the United Kingdom (UK) Human Fertilisation and Embryology Authority (2019). Creating embryos for research, which is permitted in relatively few jurisdictions, is required to develop and ensure both standard and novel methods involving IVF (including the use of mitochondrial replacement techniques, in vitro derived gametes, etc.) are safe, efficient, and effective as well as to give information about the first steps of human development.
This section of the Guidelines pertains to:
The banking, derivation, distribution, and preclinical use of human pluripotent stem cells, including human embryonic stem cells (hESCs).
The procurement of human embryos, gametes, and somatic cells for stem cell research and in vitro embryo studies not explicitly entailing stem cell derivation.
The transfer of human pluripotent stem cells into animal host embryos in vitro.
Generation of stem cell-based models of human development.
Animal research that involves the transfer of human stem cells or their direct derivatives into animal hosts.
Institutions and researchers conducting basic research with these human cells and tissues should follow the guidelines insofar as they pertain to the categories of review discussed below.
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Oversight
Recommendation 2.1.1: All research that (a) involves preimplantation stages of human development, in vitro human embryo culture, derivation of new embryo-derived cells or lines, integrated stem cell-based embryo models, 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, as appropriate, through a specialized oversight process capable of evaluating the unique aspects of the science and the associated ethical issues (see below).
The specialized scientific and ethics oversight process encompasses the review of human embryo and related stem cell research. The process can be performed at the institutional, local, regional, national, or international level or by some coordinated combination of those elements and need not be served by a single, specific committee, so long as the oversight process as a whole occurs effectively, impartially, and rigorously. Provided appropriate expertise is available to ensure that the scientific, ethical, and legal aspects of the research can be rigorously evaluated, the specialized oversight can occur through preexisting institutional review processes that assess the participation of human subjects in research, the procurement of human tissues in and for research, or biosafety and ethical issues associated with research. For example, existing review bodies such as the Embryonic Stem Cell Research Oversight (ESCRO; Institute of Medicine and National Research Council, 2005), Stem Cell Research Oversight (SCRO; ISSCR Guidelines, 2006), or Embryo Research Oversight (EMRO; ISSCR Guidelines 2016) committees in the U.S., or the UK HFEA and regional ethics committees (RECs), are well positioned to perform review and oversight of embryo and related research. A single rather than redundant review is preferable as long as this is thorough and capable of addressing any uniquely sensitive elements of human embryo research and hESC research.
Recommendation 2.1.2: The specialized scientific and ethics oversight process must include an assessment of the scientific rationale and merit of research proposals, the relevant expertise of the researchers, and the ethical permissibility and justification for the research as discussed below.
Scientific rationale and merit of the proposal: Research involving human embryonic cells or human embryos and gametes requires that scientific goals and methods be scrutinized to ensure scientific rigor. Adequate and appropriate scientific justification for performing the research using the specified materials is required.
Relevant expertise of researchers: Appropriate expertise and training of the researchers to perform the stated experiments must be ascertained in order to ensure the appropriate use of research materials. For the derivation of new human embryo-derived cell lines, the formation of human embryo models from stem cells, or experiments that involve the use of human embryos, relevant expertise would include prior experience with embryo culture and stem cell derivation in animal systems and competence in the culture and maintenance of human embryonic stem cells. Researchers performing derivations of embryo-derived cell lines should have a detailed, documented plan for characterization, storage, banking, and distribution of new lines.
Ethical permissibility and justification: Research goals must be assessed within an ethical framework to ensure that research proceeds in a transparent and responsible manner. The project proposal should include a discussion of alternative methods and provide a rationale for performing the experiments in a human rather than animal model system, for the proposed methodology, and if the studies involve preimplantation human embryos, a justification for the anticipated numbers to be used.
Recommendation 2.1.3: The committee or body conducting the specialized scientific and ethics oversight process is responsible for (a) advising researchers on the categorization of research (see Recommendation 2.2), (b) determining whether a research proposal constitutes permissible or non-permissible research, (c) monitoring and periodically reviewing ongoing research, and (d) overseeing the provenance of the human pluripotent stem cell lines used in Category 2 Research (see section 2.2.2).
The responsible committee or entity should interpret these guidelines, define research practices, and monitor compliance. Researchers are encouraged to consult the committee or entity for advice on how to determine whether research is exempt as Category 1A (see 2.2.1)
Composition of Research Review and Oversight Bodies
Recommendation 2.1.4: The specialized scientific and ethics oversight process should be conducted by qualified scientists, ethicists, legal and regulatory experts, and community members who are not directly engaged in the research under consideration. The oversight process must include participants with the following perspectives:
Scientists and/or physicians with relevant expertise, including representation from scientists that are not directly engaged in the research under consideration. Relevant expertise includes areas of stem cell biology, assisted reproduction, developmental biology, and clinical medicine.
Ethicists with the ability to interpret the ethical justifications for, and implications of, the research under consideration.
Those familiar with relevant local policies and statutes governing the research.
Community members, unaffiliated with the institution where the research is conducted through employment, who are impartial and reasonably familiar with the views and needs of patients and patient communities who could be benefited by stem cell research, and community standards.
Additional members with relevant expertise not already represented on the oversight body should be included as required, for example to cover research involving human genetics, physiology, molecular biology, etc.
The policies and regulations of each country or jurisdiction will determine whether the specialized scientific and ethics oversight process will be performed by internal or external bodies at the institutional or national level. Participants in the specialized scientific and ethics oversight process should be selected based on their relevant area-specific expertise (e.g., scientific, clinical, ethics, research policy). Those engaged in the oversight process must be cognizant of potential financial and non-financial conflicts of interest that might compromise the integrity of the review. Such conflicts must be disclosed, evaluated, and minimized, or eliminated as much as possible.
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Recommendation 2.2: To ensure that human embryo and related stem cell research is proceeding with due consideration, to ensure consistency of research practices among scientists globally, and to specify the types of scientific projects that should be subject to review, the research review and oversight process should use the three categories described in this section.
2.2.1 Category 1
2.2.1A: Category 1A. Research determined to be exempt from a specialized scientific and ethics oversight process after being assessed by the appropriate existing mandates and committees for laboratory research. Category 1A research includes the following activities:
Research with human pluripotent stem cell lines that is confined to cell culture and involves routine research practices, such as differentiation into tissue-specific cell types.
Research that entails the reprogramming of human somatic cells to pluripotency (for example, the generation of induced pluripotent stem cells).
Research that entails the use of human fetal tissue and cells, only if these cells and tissues have been procured according to the recommendations under section 2.3 below.
Research on stem cell culture systems that model specific stages of development or specific anatomic structures rather than the continuous development of an intact embryo or fetus. These would include but are not restricted to models of amnion formation, neural tube development, development of primordial germ cells, placental structures, 2D or 3D models of gastrulation or post-gastrulation events, and in vitro stem cell-derived organoids in culture that recapitulate most aspects of organ function, but not those that fall under subsequent categories.
The transplantation of human stem cells, their derivatives, or other human cells into postnatal animal hosts (see Recommendation 2.2.1.1).
Organoid Research
At this time, there is no biological evidence to suggest any issues of concern, such as consciousness or pain perception with organoids corresponding to CNS tissues, that would warrant review through the specialized oversight process. However, researchers should be aware of any ethical issues that may arise in the future as organoid models become more complex through long-term maturation or through the assembly of multiple organoids (Hyun et al. 2020).
2.2.1B: Category 1B. Research that is reportable to the entity or body responsible for the specialized scientific and ethics oversight process, but not normally subject to further or ongoing review, at the discretion of the entity responsible for the oversight process and subject to regulations and policies in the jurisdiction. Category 1B research includes the following activities:
Research that entails the in vitro formation of human stem cell-based embryo models that are not intended to represent the integrated development of the entire embryo including its extraembryonic membranes.
Chimeric embryo research in which human pluripotent stem cells are transferred into non-human, mammalian embryos and cultured in vitro for the minimum time necessary to achieve the scientific objective without gestation.
Research on in vitro gametogenesis from human cells including genetically modified pluripotent stem cells, which does not involve attempts at fertilization and the generation of embryos.
Scientists pursuing Category 1A and B research are recommended to consult with appropriate institutional review committees or the committee or body responsible for the specialized scientific and ethics review process (see Recommendation 2.1.3) to determine the categorization of new research proposals. Committees with the jurisdiction over the relevant research should oversee the provenance of cells, tissues and derived human pluripotent stem cell lines to ensure that procurement and derivation is deemed acceptable according to the principles outlined in this document (see Section 2.3 and Section 2.4) and is in compliance with rigorous scientific, legal, and ethical standards.
Category 1B covers in vitro chimeric embryo research and in vitro gametogenesis for which there is no intent to generate a human embryo or fetus. Researchers are encouraged when possible to report on existing or planned in vitro experiments to the committee responsible for the specialized scientific and ethics oversight process to help identify cases that may warrant full review in the future.
Studies Transplanting Human Stem Cells or Their Direct Derivatives into the Central Nervous Systems of Animals
Recommendation 2.2.1.1: Research involving the transfer of human stem cells or their direct neural and/or glial derivatives into the central nervous systems of postnatal animal hosts requires review by institutional animal research oversight committees supplemented by reviewer expertise in stem cell or developmental biology. (ISSCR Guidelines, 2006; Academy of Medical Sciences, 2011). Such oversight should weigh the potential benefits of the research and should utilize available baseline non-human animal data grounded in rigorous scientific knowledge or reasonable inferences and involve a diligent application of animal welfare principles.
Institutions should determine whether research involving human cells that have the capacity to integrate into the nervous systems of laboratory animals requires supplementation of the pre-existing animal research review process with scientists and ethicists that have relevant topic-specific expertise.
To assist review and oversight of stem cell-based human-to-non-human animal research, the ISSCR has provided an advisory report that guides reviewers through a series of considerations not typically covered by institutional animal research committees, but that are relevant for review (Hyun et al., 2021). Past experiences with genetically altered laboratory animals have shown that reasonable caution might be warranted if changes carry the potential to produce new defects and deficits. Current best practices dictate that research involving modified animals must involve the following:
the establishment of baseline animal data;
ongoing data collection during research concerning any deviation from the norms of species-typical animals;
the use of small pilot studies to ascertain any changes in the welfare of modified animals; and
ongoing monitoring and reporting to animal research oversight committees authorized to decide the need for real-time changes in protocols and, if necessary, the withdrawal of animal subjects.
Research that may result in the presence of human gametes and their precursors in the gonads of laboratory animals is of not of significant ethical concern per se, as long as the animals are not allowed to breed (see Category 3 below).
Reviewers and investigators should follow the proposed ethical standards presented in the 2020 white paper and Appendix 1, while exercising appropriate judgment in individual situations. Research involving animals should also generally comply with the principles of the 3Rs (see: www.nc3rs.org.uk) and follow the ‘ARRIVE guidelines’ (Percie du Sert et. al 2020).
2.2.2 Category 2
2.2.2 Category 2. Forms of research with embryos, certain chimeras, and stem cell-based embryo models that are permissible only after review and approval through a specialized scientific and ethics review process. A comprehensive review should be coordinated with other relevant oversight, such as that provided by human subjects review committees, in vitro fertilization (IVF) clinic oversight bodies, and animal research review processes and the research should comply with local law and policy. All such research should have a compelling scientific rationale and necessitate the use of these materials rather than employ alternative models. The research should use the minimum number of embryos necessary to achieve the scientific objective. Forms of research requiring comprehensive review by a specialized review process encompass the following activities:
Procurement and use of IVF human embryos for research in vitro.
Procurement of human gametes to create research embryos in vitro.
Research that generates human gametes from any progenitor cell type in vitro, when this entails performing studies of fertilization that produce human zygotes and embryos. The gametes may be derived from human pluripotent stem cells, oogonia, or spermatogonial stem cells that have been maintained in vitro, and they may be genetically modified or not. Any human embryos obtained from such gametes must only be studied in vitro, or be used to derive stem cell lines, such as embryonic stem cells.
Research involving the genetic alteration of human embryos or gametes used to make embryos in vitro.
Derivation of new cell lines from human embryos (not confined to pluripotent cell lines).
Research involving the in vitro culture of human embryos where embryos are maintained in culture until the formation of the primitive streak or 14 days from fertilization, whichever occurs first.
Generation of stem cell-based embryo models that represent the integrated development of the entire embryo including its extraembryonic membranes. These integrated stem cell-based embryo models should be maintained in culture for the minimum time necessary to achieve the scientific objective.
Research aimed at generating human totipotent cells that have the potential to sustain embryonic development in vitro.
Chimera research in which human pluripotent stem cells or their derivatives with broad potential are introduced into a) a non-human embryo or fetus in utero or b) a non-human embryo in vitro followed by transfer into a non-human uterus. Such experiments – if they are scientifically justified for the use of non-human primates above all other laboratory species – must exclude great and lesser ape species hosts (i.e., chimpanzees, gorillas, orangutans, bonobos, gibbons, and siamangs), as apes are prohibited from being used for invasive research in most parts of the world.
Transferring human embryos to a human uterus following mitochondrial replacement.
Culture of Human Embryos Beyond formation of the primitive streak or 14 Days
It is currently not technically feasible to culture human embryos beyond formation of a primitive streak or 14 days post-fertilization. However, culture systems are evolving, making this a possibility in the near future. Understanding the primitive streak, early germ layer development and primordial germ cell formation in humans is crucial to improve our understanding of and interventions for infertility, in vitro fertilization, pregnancy loss, and developmental disorders that occur or originate soon after implantation. Research using embryos is also crucial to validate integrated stem cell-based embryo models, which in the future may provide a more practical alternative to understanding some aspects of early human development.
Recommendation 2.2.2.1: Given advancements in human embryo culture, and the potential for such research to yield beneficial knowledge that promotes human health and well-being, the ISSCR calls for national academies of science, academic societies, funders, and regulators to lead public conversations touching on the scientific significance as well as the societal and ethical issues raised by allowing such research. Should broad public support be achieved within a jurisdiction, and if local policies and regulations permit, a specialized scientific and ethical oversight process could weigh whether the scientific objectives necessitate and justify the time in culture beyond 14 days, ensuring that only a minimal number of embryos are used to achieve the research objectives.
Human-Animal Chimeric Embryo Research
Recommendation 2.2.2.2: Chimeric embryo and in utero research described in ‘Category 2, i’ (see above) should proceed for the minimum time necessary to achieve the scientific aim. This research must proceed incrementally, stopping at well-defined timepoints to assess the degree and scope of chimerism during development before proceeding to full gestation, if full gestation is among the well-justified goals of the research. To avoid unpredictable and widespread chimerism, researchers should endeavor to use targeted chimerism strategies to limit chimerism to a particular organ system or region of the gestating chimeric animal.
Techniques such as blastocyst complementation, whereby a specific cell type or organ is effectively deleted as the host embryo develops, can lead to a specific cell type or organ being replaced entirely by derivatives from the donor-derived pluripotent stem cells. By itself this targeted chimerism may not prevent contributions elsewhere in the chimera, thus the need for an incremental approach. Nonetheless, if the host cells have an advantage over the donor cells, such as even a slightly faster rate of cell replication, then the donor cells will be disadvantaged and effectively selected against, leading to a little or no contribution outside the organ of choice.
As a general principle, non-human primate species should only be used when all other species, more distant in evolution from humans, are inadequate for the scientifically well justified research question being pursued. Appropriate research aims include understanding human development, understanding species barriers to chimerism, and treating disease. Any research involving non-human primates must utilize common laboratory species that are widely used in biomedical research (which excludes apes). Trained veterinary staff specializing in the care of non-human primates must be closely involved in the review and oversight of studies involving the transfer of human stem cells and their derivatives into nonhuman primate hosts.
Mitochondrial Replacement Techniques
Recommendation 2.2.2.3: Further research should be undertaken to refine and assess the safety and efficacy of Mitochondrial Replacement Techniques (MRT), including minimizing a) the risk of mitochondrial carryover and b) disruptions to the interaction between mitochondrial and nuclear genomes. In addition, further research on polar body transfer techniques and the use of mitophagy or genome editing is needed to reduce or eliminate pathogenic mitochondrial DNA. Such research should be subject to review by a specialized oversight process as Category 2 Research (Section 2.1.5.2).
MRT is being explored to prevent the transmission of serious mitochondrial DNA-based diseases in at-risk pregnancies (see Section 3.4.8). MRT most commonly involves transferring the nuclear DNA from the prospective mother’s oocyte or fertilized oocyte (pronuclear stage) to that of a mitochondrial donor from which the nuclear DNA has been removed [maternal spindle transfer (MST) or pronuclear transfer (PNT), respectively]. The mitochondrial donor is selected to be free of known pathogenic mutations. Input from clinicians and scientists with relevant expertise in mitochondrial and embryo biology should augment the review process for evaluating clinical protocols that entail uterine transfer of human embryos for the purpose of human reproduction.
2.2.3 Category 3
2.2.3A Category 3A. Research activities currently not permitted. Research under this category should not be pursued at this time because the approaches are currently unsafe or raise unresolved ethical issues. There may be valid reasons for undertaking the research in the future, but this should not proceed until the safety and ethical issues are resolved. Such research includes:
Research in which human embryos that have undergone modification to their nuclear genome are transferred into or gestated in a human uterus. Genome-modified human embryos include human embryos with engineered alterations to their nuclear DNA and embryos generated from a human gamete that has had its nuclear DNA modified, when such modifications could be inherited through the germline. While there are valid reasons for pursuing this line of research, which may include situations where correcting a deleterious gene variant is the only way that prospective parents may have a genetically-related child (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020), conduct of such research will be dependent on appropriate policies, regulations, and oversight.
Research in which human embryos that have undergone editing to their mitochondrial genome are transferred into or gestated in a human uterus, as current knowledge of such interventions is inadequate to ensure safety.
The use of human gametes differentiated from human stem cells for the purposes of fertilization and human reproduction. If the safety, policy, and regulatory issues are resolved, this approach may be desirable, for example in cases where treatment of childhood cancer has led to infertility, or as a route to heritable genome editing as indicated in (a) above.
2.2.3B Category 3B: Prohibited research activities. Research under this category should not be pursued because of broad international consensus that such experiments lack a compelling scientific rationale or are widely considered to be unethical. Such research includes:
Transfer of human stem cell-based embryo models to the uterus of either a human or animal host.
Research in which human embryos produced by reprogramming of nuclei are implanted into a human or animal uterus (often referred to as human reproductive cloning).
Research in which animal chimeras incorporating human cells with the potential to form human gametes are bred to each other.
Transfer of chimeric embryos mixing animal and human cells (whether predominantly animal or human) to the uterus of a human or great or lesser ape (i.e., chimpanzees, gorillas, orangutans, bonobos, gibbons, and siamangs).
Transfer of a human embryo(s), irrespective of its origins, to an animal uterus.
Emerging Categories of Embryo Research That Merit Close Review: Heritable Genome Editing
Recommendation 2.2.3.1: Until there is further scientific clarity regarding how to achieve desired genetic alterations, additional evidence for safety, and wider discussion and consensus on ethics (i.e., whether it should be done and, if so, under which circumstances), any attempt to edit the mitochondrial genome or modify the nuclear genome of human embryos for the purpose of human reproduction is premature and should not be permitted at this time (see Section 2.2.3A, Category 3A, a).
Preclinical research that entails modifying the nuclear genomes of gametes, zygotes, and human embryos may be permissible under a rigorous specialized oversight process (Category 2). Such research promises to enhance fundamental knowledge and is essential to inform deliberations about the potential safety and use of nuclear or mitochondrial DNA genome editing in strategies aimed at preventing the transmission of serious genetic disorders.
Scientists currently lack an adequate understanding of the fidelity and precision of techniques for genome editing of human embryos, as well as a full appreciation of the safety, ethics, and potential long-term risks and benefits to individuals born following such a process. This is described in more detail in the recent report, Heritable Human Genome Editing, from the International Commission on the Clinical Use of Human Genome Editing (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020), which suggests a responsible translational pathway in certain circumstances, albeit one that cannot currently be met. Of note, the focus of this report was on developing a responsible translational pathway; it did not include a broad look at the societal and ethical issues, as these were outside its task. Such issues have been considered elsewhere (e.g. by the Nuffield Council on Bioethics). The forthcoming report from the WHO Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing will bear in mind societal views and ethical principles, but this will focus on mechanisms of governance.
Basic and preclinical research is needed to minimize the potential harms resulting from intended and unintended edits, which could be passed to future generations, as well as direct or indirect effects of the editing process that could affect embryo viability or developmental potential.
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The procurement of human gametes, embryos, fetal tissues, and somatic cells is integral to the conduct of human embryo and stem cell research. Human biological materials must be procured in accordance with generally accepted principles of research ethics and laws and policies in their respective jurisdictions.
2.3.1 Review Process for the Procurement of Human Cells and Tissues
Recommendation 2.3.1. The review process for the procurement of human cells and tissues should be predicated on the source of the material and its intended use as described in the three tiers below.
Tier 1. Banked and historical cell lines. The procurement of cell lines from repositories or banks is permissible if the materials have been deposited and distributed consistent with the original consent for use of the donated human cells and tissues and these guidelines (see Section 2.4, Derivation, Banking and Distribution of Human Stem Cell Lines) and the standards at the time (Sugarman et al. 2008). Toward this end, the repositories or banks should require certification from depositors confirming the ethical provenance of such cells, including consent and ethics approvals. The use of historical cell lines from pathological specimens, such as HeLa, are permissible for use in stem cell research that is otherwise compliant with these guidelines. Likewise, stem cell lines procured from vendors are permissible for stem cell research, provided the vendor generated and distributed the stem cell lines in a manner consistent with the original donor consent and contemporaneous ethical and regulatory standards. The procurement of Tier 1 cell lines should not be used for reproductive purposes.
Tier 2. Fresh human somatic cells and tissues. The procurement of fresh human somatic cells and tissues for stem cell research purposes should be reviewed by existing research review committees bolstered by stem cell specific expertise in accordance with generally accepted principles of research ethics and laws and regulations in the respective jurisdiction and these guidelines (see Sections 2.3.2 and 2.3.3).
Tier 3. Gametes and embryos. The procurement of human gametes and embryos that are destined for use in human embryo research and stem cell research must be reviewed through the specialized oversight process and existing research review committees in accordance with generally accepted principles of research ethics and laws and regulations in the respective jurisdiction and these guidelines (see Sections 2.3.2 and 2.3.3).
Review by a specialized oversight process (Tier 3) or existing research review committee bolstered by stem cell-specific expertise must ensure that vulnerable populations are not exploited due to their dependent status or any compromised ability to offer voluntary consent and that there are no undue inducements or other undue influences for the provision of human cells and tissues.
2.3.2 Informed Consent for the Donation of Human Cells and Tissues
Recommendation 2.3.2.1: Embryos, fetal tissue, and other cells and tissues should be used in research only if voluntary informed consent was obtained from the donors before the research commences. The informed consent process should be robust and document the prospect of therapeutic and commercial applications as well as the potential research uses, such as the creation of hESCs, iPSCs, other immortalized cell lines, embryos, and gametes. In the case of fetal tissue, consent from the woman donating the tissue is sufficient. In the case of embryos made with donor gametes, this consent should be obtained from the gamete donors and the party(ies) with authorization to donate the embryo.
Most patients and research subjects may donate cells or tissues with broad consent to a range of future uses; however, the broad consent does not apply to use of donated cells and tissues for reproductive purposes. The consent may be obtained at the time of tissue collection or with a re-contact for additional consent to use donated cells and tissues for reproductive purposes.
In the case that human cells and tissues are procured from a minor or adult that lacks the decision-making capacity to provide informed consent, consent must be provided by a parent, legal guardian, or other legally authorized person. Whenever feasible, the assent of the minor or decisionally incapacitated adult is also strongly encouraged.
Empirical research has shown that informed consent is most effective as a dynamic, interactive, and evolving process as opposed to a static, one-time disclosure event (Flory and Emanuel, 2004). The informed consent document alone can never take the place of a meaningful dialogue between the person obtaining consent and the donors of human cells and tissues. The informed consent process can be enhanced in the following ways:
Whenever possible, the person conducting the informed consent dialogue should have no vested interest in the research protocol. If members of the research team participate in the informed consent process, their role and any other potential conflicts of interest must be disclosed, and care taken to ensure that information is provided in a transparent, accurate, unbiased manner.
The person conducting the informed consent process should provide ample opportunities for cell and tissue donors to ask questions and discuss their involvement in the research protocol.
Counseling services should be made available upon request to any potential providers of human cells and tissues prior to procurement.
Consent processes and documents should be revised in light of new research on informed consent for all types of human biological materials procurement and where relevant, ongoing studies of the long-term risks associated with oocyte retrieval.
Separating Research Consent from Treatment
Recommendation 2.3.2.2: Informed consent for research use must be distinct from informed consent for clinical treatment.
Decisions related to the provision of gametes or the creation of embryos for fertility treatment should be a voluntary choice that is free from undue influence by researchers who propose to use these cells in research. During the course of clinical treatment, researchers may not request that members of the fertility treatment team generate more embryos or harvest more oocytes than necessary for the patient’s optimal fertility treatment. Wherever possible, the treating infertility clinician should not be the investigator who is proposing to perform research on the procured materials.
Consistent with fetal tissue research guidelines issued by the Network of European CNS Transplantation and Restoration (NECTAR) and U.S. regulations, a woman’s decision to terminate a pregnancy must not be influenced by the possible research use of her fetus’ tissues (Boer, 1994; OHRP, 1993). Informed consent for fetal tissue procurement and research should be obtained from the woman only after her decision to legally terminate her pregnancy but before the abortion procedure, or after a spontaneous abortion. Medical procedures must not put the woman at any increased risk solely to facilitate the research use of donated fetal tissues. Clinicians obtaining informed consent and clinics at which informed consent is sought may not profit from the procurement of fetal tissues for research.
Review of Cell and Tissue Collection for Embryo and Stem Cell Research
Recommendation 2.3.2.3: Review of procurement protocols must ensure that cell and tissue donors are adequately informed about the specific aspects of their voluntary research participation.
Researchers should exercise care in seeking and obtaining informed consent from prospective donors. The informed consent process should take into account language barriers, the educational level and reading comprehension level of the research subjects, and any other impediments to good communication. Empirical research has shown that comprehension during the informed consent process improves with the use of interactive methods interaction (Flory and Emanuel, 2004). To facilitate the adoption of adequate and uniform standards of informed consent for the procurement of cells and tissues for research, the ISSCR provides template documents that can be downloaded and customized to specific protocols (Appendix 2). These sample documents will need to be customized for use in specific research studies and conform to local laws and policies.
If pluripotent stem cells are to be derived from procured cells or tissues, the informed consent document and discussion should cover information that addresses key aspects of human stem cell research, including but not limited to the fact that an immortal stem cell line could be established that is a partial or full genetic match to the cell or tissue donor and that the stem cell line could be shared with other researchers outside the institution and jurisdiction for other research purposes that may not be fully anticipated at this time. For a list of informed consent discussion points, see Appendix 3.
Incidental Findings
Recommendation 2.3.2.4: Researchers should develop a policy that states whether and how incidental findings will be provided to cell and tissue donors. This policy must be explained during the informed consent process. Cell and tissue donors should be able to choose whether they wish to receive incidental findings, if any. Reporting findings with relevance to public health may be required by law in certain jurisdictions.
During the course of research with human stem cell lines, particularly lines derived from somatic cells, investigators may discover information that may be of importance to cell and tissue donors, such as BRCA1/2 mutations. Because the net harms and benefits of disclosing incidental findings to cell and tissue donors are presently unclear, a single approach to managing incidental findings may not be appropriate across all studies and jurisdictions. When studies include a plan to disclose incidental findings to research subjects, researchers must offer a practical and adequately resourced feedback mechanism that involves donors’ physicians and, where possible, the verification of any discovered incidental findings.
For a given sample, secondary researchers should adhere to the incidental findings policies that were developed by the primary researchers (or others collecting cells and tissues) and disclosed to donors during the informed consent process.
If re-contact is required, instructions on how to report incidental findings (report to provider, researcher, institution, physician, etc.) should be specified in the material transfer agreement. Re-contact is a matter for primary research sites to manage. However, secondary researchers should be aware of the incidental findings policies of either of these responsible parties.
Successful implementation of a policy on incidental findings depends crucially on the traceability of cell line distribution. Therefore, all providers and recipients should ensure that cell lines are used under strict compliance with material transfer agreements and the regulations in the informed consent process.
Consent for De-identified Cells and Tissues
Recommendation 2.3.2.5: Researchers are encouraged to discuss the potential for genomic sequencing to connect de-identified cells and tissues to donors and their relatives during the informed consent process for the donation.
Cells and tissues donated for research are often de-identified to protect the privacy of donors. Due to advances in genomic sequencing, it may be possible for researchers to connect de-identified cell and tissue samples with donors or their relatives. Researchers are encouraged to require confidentiality when sharing genomic data that has the potential to connect donors and family members with de-identified cells and tissues.
2.3.3 Payments to Individuals Donating Cells and Tissue for Research
Recommendation 2.3.3.1: Research oversight committees must authorize all proposals to reimburse for out-of-pocket expenses to donors of embryos, sperm, or somatic cells.
Individuals who choose to provide previously stored cells and tissues for research should not be reimbursed for the costs of storage prior to the decision to participate in research. For the provision of fresh somatic cells or sperm for research, reimbursement for out-of-pocket expenses incurred by donors may be determined during the review process. For the provision of embryos or fetal tissue for research, no payment or valuable consideration of any kind beyond reimbursement of out-of-pocket expenses may be offered to donors for their procurement.
Recommendation 2.3.3.2: For the provision of oocytes for research, when oocytes are collected outside the course of clinical treatment, compensation for non-financial burdens should not constitute an undue inducement.
Because women carry particular burdens during the procurement of their gametes, their efforts should be acknowledged fairly and appropriately. At the same time, precaution is needed to avoid the potential for exploitation.
In jurisdictions where the provision of oocytes for research is legally permissible, the human subjects review committee and those responsible for conducting specialized research oversight must assess the safety and the voluntary and informed choice of women to provide oocytes for research according to the following standards:
There should be monitoring of recruitment practices of oocyte donors to ensure that the decision of women to donate their oocytes is free of undue inducement and exploitation.
In jurisdictions where research subjects are allowed compensation or valuable consideration for incurred non-financial burdens, the amount of financial recognition for the subject’s time, effort, and inconvenience must be reviewed to ensure that such compensation does not constitute an undue inducement.
Compensation for oocyte providers’ time, effort, and inconvenience, if permitted by local laws and human subjects review committees, should be reasonably consistent with compensation levels for other types of research participation involving similarly invasive and burdensome medical procedures. Compensation levels should aim to acknowledge oocyte providers’ non-financial burdens incurred as a result of their research participation, such as their physical discomfort and effort.
At no time should payments or other rewards of any kind be given for the number or quality of the oocytes that are to be provided for research.
Oocyte procurement must be performed only by medically qualified and experienced clinicians, and frequent monitoring and dose adjustment must be used to reduce the risk of ovarian hyperstimulation syndrome.
Due to the potential long-term effects of ovulation induction, women should undergo a limited number of hormonally induced ovarian stimulation cycles in a lifetime, regardless of whether they are induced for research or assisted reproduction. The limits should be determined by a thoughtful research review and oversight process, which should be informed by the latest available scientific information about the health risks.
A fertility clinic or other third party responsible for obtaining consent or collecting cells or tissues should not be paid for the material obtained. It should be eligible for specifically defined cost-based reimbursements and payments for professional services. Fertility clinics should not profit from providing tissues for research.
To help guide review committees through the ethical considerations surrounding oocyte collection and financial recognition of providers’ efforts, the ISSCR Ethics and Public Policy Committee developed an advisory report outlining their deliberations on these issues (Haimes et al., 2013).
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Recommendation 2.4.1: Proposals for derivations of new hESC lines should be scientifically justified and executed by scientists with appropriate expertise. A clear, detailed outline for banking new lines should be incorporated into derivation proposals. Whenever feasible, the distribution of new hESC lines to the research community is strongly encouraged following derivation and first publication.
Consistent with the policies of many funders and scientific journals, researchers should deposit lines into centralized repositories where the lines will be held for release and distribution upon publication. Researchers performing derivations should have a detailed, documented plan for characterization, storage, banking, and distribution of new lines. Researchers performing derivations should propose a plan to safeguard the privacy of donors and inform donors that, in this era of data-intensive research, complete privacy protection might be difficult or impossible to guarantee.
Although a specialized oversight process is not required for derivation of non-embryonic stem cell lines, the general principles and aspirational goals for banking and distribution apply widely to all classes of scientifically valuable stem cell lines. It is understood that cell lines (e.g. pluripotent stem cells, neural stem cells, hematopoietic stem cells) made for commercial purposes may not be available for general distribution. In addition, cell lines made for autologous applications may not be suitable or available for general distribution.
Repositories & Registries for Stem Cell Lines
Recommendation 2.4.2: National and international repositories should accept deposits of newly derived stem cell lines to preserve them, maintain them to a high standard, and ensure their authenticity. Repositories are encouraged to distribute them internationally to enable their dissemination. Researchers are encouraged to deposit data on stem cell lines into registries.
Repositories should strive to adhere to common methods and standards to facilitate the easy exchange and dissemination of stem cell lines (see also Section 5, Standards in Stem Cell Research). At a minimum, each repository must establish its own guidelines and must have a clear, easily accessible material transfer agreement. A sample material transfer agreement is available in Appendix 4. Each repository may have its own criteria for distribution. Repositories should also have clear, publicly available protocols for the deposit, storage, and distribution of pluripotent stem cell lines and related materials. The repository has the right of refusal if a cell line does not meet its standards.
Repositories must require written assurances from depositors that research materials were procured according to the ethical principles and compliant with the regulations and policies of the respective jurisdiction. Depositors should attest that they were subject to appropriate oversight (IRB or equivalent) for all human subjects work, obtained informed consent from research material donors, and maintain consent documentation for the distribution and use of the research material. Provider/depositors must also provide written assurances that the MTA provided for the transfer of materials contains all restrictions, regulations, and obligations consistent with the informed donor consent for the use of the materials. Repositories must receive and preserve the material transfer agreements for any material deposit and ensure its full execution prior to the transfer of materials to the requesting investigators.
Repositories should obtain all available technical information from the depositor, for example, methods used in the derivation of lines, culture conditions, infectious disease testing, passage number and characterization data. Repositories should make this information available to researchers. If the repository modifies the depositor’s protocols or obtains additional data, this information should also be made available.
Repositories should engage in, but are not limited to, the following:
Reviewing and accepting deposit applications.
Assigning unique identifiers (catalogue number) to deposits.
Expansion, maintenance and storage of cell lines.
Quality assurance and quality control of all procedures.
Maintenance of website with pertinent characterization data, protocols and availability of cell lines.
Maintaining databases to allow tracking and distribution of the cell lines to primary researchers.
Posting a clear and fair cost schedule for distribution of materials. Repositories should endeavor to distribute internationally and charge only the necessary costs, which include shipping and handling.
Preserve cell lines for future use.
Provenance of Stem Cell Lines
Recommendation 2.4.3: 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 material transfer agreements and data demonstrating the identity of the cell line and uses allowed under the original informed consent. If a cell line has the potential to be used clinically, researchers are encouraged to provide information on the materials used for derivation and expansion.
Appropriate safeguards should be used to protect the privacy of donors and donor information due to the nature of the materials involved in the generation of human stem cell lines. For stem cell lines to be as useful as possible and so as not to preclude future potential therapeutic applications, as much donor information as possible should be maintained along with the cell line (see Recommendation 3.2.1.2). Subject to local laws, donor samples and cell lines should be anonymized or de-identified as stipulated in the informed consent forms.
Material transfer agreements or their equivalents must be consistent with the informed consent, and include all limitations, restrictions and obligations set forth by the material provider. These MTAs must be presented to the repository previous to or at the time of the material deposit and must be maintained by the repository while it holds the materials. Material providers must maintain documentation regarding consent and inform the receiving parties about relevant regulations thereof, including whatever reimbursement of direct expenses or financial or valuable considerations of any kind were provided in the course of the procurement.
Access to Research Materials
Recommendation 2.4.4: Institutions engaged in human stem cell research performed with public funding are encouraged to develop procedures whereby researchers are granted access to research materials for scientifically and ethically appropriate purposes, as determined under these guidelines and applicable laws.
Researchers are encouraged to make the materials readily accessible to the biomedical research community for non-commercial research. When arranging for the disposition of material rights generated with public funding to commercial entities, institutions are encouraged to preserve non-exclusive access for the research community. If materials are made available as a researcher-to-researcher transfer from a repository or bank, the costs of cell line expansion, handling, and shipping should be borne by the receiving party so as not to pose an undue financial burden on the entity or researcher providing the cells.
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Recommendation 2.5.1: These guidelines should be upheld and enforced through standards of academic, professional, and institutional self-regulation.
These guidelines were developed collaboratively to form an international consensus for the ethical standards and practices in human embryo and stem cell research. These standards and practices represent a comprehensive code of conduct applicable to all researchers in the field. They are a critical catalyst that ensures international collaboration and research can proceed with confidence from anywhere in the world in a manner accepted as valid by the scientific and ethics communities.
Grant applicants, in particular the individual scientists undertaking the research, should provide funding bodies with sufficient documentation to demonstrate that the proposed research complies with relevant local and national regulations and these guidelines or their equivalent. Funding organizations should pledge to follow these guidelines or their equivalent and require entities whose research is funded by such organizations to do the same.
Senior or corresponding authors of scientific publications should specifically be charged with the responsibility of ensuring that the code of conduct embodied in these guidelines is adhered to in the course of conducting human embryo and stem cell research; this includes the supervision of junior investigators that work for their respective organizations or on their research projects. Institutions where human embryo and stem cell research is undertaken should strive to provide researchers working on any such projects under their auspices, particularly junior investigators, with current information on such standards and practices.
Ensuring that research is performed according to scrupulous ethical standards is a legitimate concern for the peer review and editorial process of scientific publication. Journal editors and manuscript reviewers may request access to research protocols and provenance documents to enable adequate review of the ethical framework and oversight of the research process and may request an authors’ statement of adherence to these or an equivalent set of guidelines or applicable regulations. Authors should include a statement that the research was performed after obtaining approvals following a suitable research oversight process.
Finally, as stated previously, the ISSCR has made available for download examples of informed consent documents for obtaining human materials for research (gametes, embryos, and somatic cells) and a material transfer agreement for the sharing and distribution of materials in order to facilitate the adoption of globally accepted standards and practice of human embryo and stem cell research (Appendices 2 and 3). These templates may be modified to comply with the policies and regulations in their respective jurisdiction.
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