Dear Reader,

We invite you to consider and provide feedback on the following draft of the ISSCR’s “Guidelines for Stem Cell Research and Clinical Translation.” These guidelines represent an effort by a Guidelines Revision Task Force, working on behalf of the ISSCR Board of Directors and the ISSCR membership, to revise and update our existing guidance documents in response to the evolving scientific landscape and ethical considerations pertinent to the ISSCR’s mission of advancing stem cell science and its application to human disease.

Please email your feedback to info@isscr.org with the subject line “Comments on ISSCR Guidelines.” We encourage you to use the provided feedback form or similar format to submit your comments.

Comments are being accepted by email through 10 September, 2015.

Following this period of public comment, the Task Force will digest and discuss the feedback, and make suitable revisions in anticipation of a public release of a final document in January of 2016. While stem cell research offers great promise for the advancement of fundamental scientific knowledge and the relief of human suffering, it merits careful scientific as well as ethical deliberation, and compels constant vigilance so that scientific research and clinical practice is conducted with proper review and reflection.

The ISSCR greatly values your input as we work towards finalizing these Guidelines.

Jonathan Kimmelman, Task Force ChairGeorge Q. Daley, ISSCR Board of Directors

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Guidelines for Stem Cell Science 1

and Clinical Translation 2

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Draft June 26, 2015 5

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Table of Contents 1

1. Fundamental Ethical Principles ........................................................................................................... 3 2

2. Human Embryonic Stem Cell Research and Related Laboratory Research Activities ... 5 3

2.1 Review Processes ............................................................................................................................... 5 4

2.2 Procurement of Biomaterials ........................................................................................................ 9 5

2.3 Banking and Distribution of Human Pluripotent Stem Cell Lines ............................... 14 6

2.4 Mechanisms for Enforcement .................................................................................................... 17 7

3. Guidelines for Clinical Translation of Stem Cell-Based Research........................................ 18 8

3.1 Cell Processing and Manufacture ............................................................................................. 18 9

3.1.1 Sourcing Material ................................................................................................................... 18 10

3.1.2 Manufacture ............................................................................................................................. 20 11

3.2 Preclinical Studies .......................................................................................................................... 22 12

3.2.1 General Considerations ........................................................................................................ 22 13

3.2.2 Animal Safety Studies ........................................................................................................... 24 14

3.2.3 Animal Efficacy Studies ........................................................................................................ 26 15

3.2.4 Transparency and Publication .......................................................................................... 28 16

3.3 Clinical Research ............................................................................................................................. 28 17

3.3.1 Oversight .................................................................................................................................... 29 18

3.3.2 Standards for Ethical Conduct ........................................................................................... 29 19

3.3.3 Issues Particular to Early Phase Trials ........................................................................... 32 20

3.3.4 Issues Particular to Late Phase Trials ............................................................................ 33 21

3.3.5 Research Subject Follow-Up and Trial Monitoring ................................................... 34 22

3.3.6 Stem Cell-Based Medical Innovation .............................................................................. 35 23

3.3.7 Transparency and Reporting of Research Results .................................................... 38 24

3.4 Clinical application ......................................................................................................................... 39 25

3.4.1 Issues in clinical use .............................................................................................................. 39 26

3.4.2 Access and Economics .......................................................................................................... 41 27

4. Public Communications ....................................................................................................................... 42 28

5. Standards in Stem Cell Research ...................................................................................................... 44 29

ISSCR GUIDELINES UPDATES TASK FORCE ..................................................................................... 46 30

APPENDICES ................................................................................................................................................. 47 31

REFERENCES ................................................................................................................................................ 48 32

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1. Fundamental Ethical Principles 1 2 The primary social mission of basic biomedical research and its clinical translation is to 3 alleviate and prevent human suffering caused by illness and injury. All such biomedical 4 research is a collective endeavor. It depends on the contributions of many kinds of 5 individuals, including basic scientists, clinicians, patients, members of industry, advocates, 6 governmental officials, and others. Such individuals often work across institutions, 7 professions, and national boundaries, and are bound by different social and cultural beliefs, 8 regulatory regimes, and expectations for moral conduct. Each may also be working toward 9 different goals. When this collective effort works well, the social mission of clinical 10 translation is achieved efficiently, alongside the private interests of its various contributors. 11 12 Ethics principles and guidelines help secure the basis for this collective endeavor. Patients 13 can enroll in clinical research trusting that studies are well justified and the risks and burdens 14 reasonable in relation to potential benefits. Physicians and payers can be confident that the 15 evidence they use to make important health care decisions is rigorous and unbiased. Private 16 firms can invest in research programs knowing that public and institutional support will be 17 forthcoming for the foreseeable future. 18 19 The ISSCR guidelines pertain to human embryonic stem cell research and clinical 20 translation, and are meant to promote an efficient, appropriate and sustainable research 21 enterprise aimed at the development of stem cell-based interventions that will improve 22 human health. The guidelines that follow build on a set of widely shared ethical principles in 23 science(Banda, 2000; Institute of Medicine, 2009), research with human subjects, and 24 medicine.(1949; Department of Health and Education and Welfare, 1979; Medicine et al., 25 2002; World Medical Association, 1964) Some of these guidelines would apply for any 26 basic research and clinical translation efforts. Others respond to challenges that are 27 especially applicable to stem cell-based research. These include sensitivities surrounding 28 research that involves the use of human embryos and gametes; irreversible risks associated 29 with some cell-based interventions; the vulnerability and pressing medical needs of patients 30 with serious illnesses that currently lack effective treatments; public expectations about 31 medical advance and access; and the competitiveness within this research arena. 32 33 Integrity of the Research Enterprise 34 The primary goals of stem cell-based research are to advance scientific understanding and to 35 generate evidence for addressing unmet medical and public health needs. This research 36 should be overseen by qualified investigators and coordinated in a manner that ensures that 37 the information obtained will be trustworthy, reliable, accessible, and responsive to scientific 38 uncertainties and priority health needs. Doing so entails the need for independent peer 39 review, transparency, and continued monitoring at each stage of research. 40 41 42 Respect for Human Research Participants 43 Researchers, clinicians, and clinics should empower human subjects to exercise valid 44 informed consent where they have adequate decision-making capacity. This means that 45 patients—whether in research or care settings—should be offered accurate information about 46

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risks and the state of evidence for novel stem cell-based strategies. Where individuals lack 1 such capacity, surrogate consent should be obtained and subjects should be stringently 2 protected from nontherapeutic risks exceeding minor increase over minimal. In addition to 3 supporting the autonomy of human subjects, the principle of respect for research participants 4 should also be interpreted broadly to include accommodating the conscientious objections of 5 researchers or their support staff who may not ethically endorse every aspect of human stem 6 cell research. 7 8 Social Justice 9 The benefits of clinical translation efforts should be distributed justly and globally, with 10 particular emphasis on addressing the medical and public health needs for populations with 11 the greatest unmet health needs. Advantaged populations should make particular efforts to 12 share benefits with disadvantaged populations. Risks and burdens associated with clinical 13 translation should not be borne by populations that are unlikely to benefit from the 14 knowledge produced in these efforts. As much as possible, healthcare delivery systems, 15 already overburdened by the rising cost of health care, should not bear the additional costs of 16 proving the safety and efficacy of stem cell-based interventions. Instead, these should be 17 absorbed by research and commercial entities, which are expressly privileged to profit from 18 investing in new technology development. It is a matter of justice that the costs of uncertainty 19 about clinical utility be minimized and reduced to an acceptable level before novel treatments 20 are applied in healthcare systems. Where cell-based interventions are introduced into clinical 21 application amid uncertainties, their application should be coupled to evidence development. 22 23 Transparency 24 Parties to the testing and application of stem cell-based interventions should promote timely 25 exchange of accurate scientific information to other interested parties. Investigators should 26 communicate with various publics, such as patient communities, to respond to their 27 information needs, and should convey the scientific state of the art, including uncertainty 28 about the utility of clinical applications. Research teams should promote open and prompt 29 sharing of ideas, data and materials. 30 31 Primacy of Patient Welfare 32 Physicians and physician-researchers owe their primary duty to the patient and/or research 33 subject. Clinical testing should never allow promise for future patients to override the welfare 34 of current research subjects. Application of stem cell-based interventions outside of formal 35 research settings should be evidence based, subject to independent expert review, and seek to 36 serve the patients’ best interests. Promising innovative strategies should be systematically 37 evaluated as early as possible, and before application in large populations. The marketing and 38 provision of stem cell-based interventions to a large patient population prior to garnering 39 endorsement of safety and efficacy through a process of rigorous and independent review by 40 experts constitutes a breach of professional ethics, and unduly places vulnerable patients at 41 risk. 42

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2. Human Embryonic Stem Cell Research and Related Laboratory Research 1

Activities 2 3 The guidelines in this section pertain to the procurement, derivation, banking, distribution, 4 and preclinical use of pluripotent cells taken from the earliest stages of human development; 5 to the procurement of gametes and somatic cells for stem cell research; and to the in vitro and 6 animal modeling uses of human totipotent or pluripotent cells or human pluripotent stem cell 7 lines where the experiments raise particular concerns, as outlined in greater detail below. 8 9 The guidelines articulated in this chapter are compatible in their potential application to 10 various types of embryonic and fetal cells, embryonic germ cells derived from fetal tissue, 11 and in vitro research on human embryos and gametes. Institutions and investigators 12 conducting basic research with these human biomaterials should follow the guidelines insofar 13 as they pertain to the three categories of research discussed below. 14 15

2.1 Review Processes 16 17 Oversight 18 Recommendation 2.1.1: All human stem cell research that (1) involves pre-implantation 19 stages of human development, human embryos or embryo-derived cells, (2) entails 20 incorporating human totipotent or pluripotent cells into animal hosts to achieve a high 21 degree of chimerism of either the central nervous system or germ line, or (3) entail the 22 production of human gametes in vitro when such gametes are tested by fertilization or 23 for the creation of embryos, shall be subject to review, approval, and ongoing 24 monitoring by a stem cell research oversight (SCRO) process equipped to evaluate the 25 unique aspects of the science. The derivation of pluripotent stem cells from somatic cells 26 via genetic or chemical means of reprogramming does not require SCRO process 27 review as long as the research does not generate human embryos or entail sensitive 28 aspects of the research use of pluripotent stem cells as outlined herein. 29 30 The stem cell research oversight (SCRO) process can be performed at the institutional, local, 31 regional, national, or international level, or by some coordinated combination of those 32 elements provided that the review as a whole occurs effectively, impartially and rigorously. 33 Multi-institutional arrangements for coordinated review, which involve delegation of specific 34 parts of this review, shall be permitted as long as they meet that standard. A single review 35 rather than redundant review is preferable as long as the review is thorough and is capable of 36 addressing any uniquely sensitive elements of human stem cell research. Unless the review is 37 specifically designed to be comprehensive, the SCRO process shall not replace other 38 mandated institutional reviews that assess the participation of human subjects in research, or 39 the oversight for animal care, biosafety, or the like. Review should consider the protection of 40 sensitive medical data of human biomaterials donors. Such a review is typically done by a 41 local institutional review board or its equivalent, but could also be performed as part of the 42 SCRO process, which must exercise due regard for the authority of the institutional review 43 board and avoiding duplication of its functions. 44 45

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Composition of SCRO process review committees 1 Recommendation 2.1.2: SCRO Review committees executing the SCRO process should 2 be comprised of scientists, ethicists, and community members who are not directly 3 engaged in the research under consideration. 4 5 Potential participants in the SCRO process should be selected based on their highly relevant 6 area-specific scientific and/or clinical expertise, capacity for impartiality, and freedom from 7 political or financial conflict regarding the research to be evaluated. Those responsible for 8 formulating the mechanism or body to provide SCRO function must be cognizant of the 9 potential for conflicts of interest both financial and non-financial that might compromise the 10 integrity of the review process, and attempt to minimize or eliminate such conflicts. 11 12 Review Categories 13 Recommendation 2.1.3: To ensure that stem cell research is proceeding with due 14 consideration, to ensure consistency of research practices among scientists globally and 15 to specify the nature of scientific projects that should be subject to review, SCRO 16 process review committees or their equivalents should utilize the following three 17 categories of research. 18 19 2.1.3.1 Category 1 (Exempt From Full SCRO Process Review): Research that is permissible 20 after review under existing mandates and by existing committees, and is determined to be 21 exempt from full SCRO process review. Category 1 research includes the following 22 activities: 23 24

a) Research with pre-existing human embryo-derived stem cell lines that are confined 25 to cell culture or involve routine and standard research practice, such as assays of in 26 vitro differentiation or teratoma formation in immune-deficient mice; 27

28 b) Research that entails the reprogramming of somatic cells to pluripotency without 29 the creation of embryos or totipotent cells (e.g., generation of induced pluripotent 30 stem cells). 31

32 These guidelines recommend that all institutions pursuing Category 1 research establish an 33 administrative mechanism capable of determining that a) these projects can be adequately 34 reviewed by committees with jurisdiction over research on human tissues, animals, biosafety, 35 radiation, etc. and b) that full SCRO process review by a SCRO mechanism or body is not 36 required. This administrative mechanism should include a determination that the provenance 37 of the human embryo-derived stem cell lines to be used has been scrutinized and deemed 38 acceptable according to the principles outlined in this document, and that such research is in 39 compliance with scientific, legal and ethical norms. 40 41 2.1.3.2 Category 2 (Full SCRO Process Review): Forms of research that are permissible only 42 after full SCRO process review to address the issues pertinent to human pluripotent stem cell 43 research. Full review should be coordinated with other relevant oversight, such as that 44 provided by human subjects review boards or in vitro fertility clinical oversight bodies. 45 Forms of research requiring full review include the following activities: 46 47

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a) Research involving the derivation of new human pluripotent cell lines from human 1 embryos or discarded fetal tissues. This includes the creation of human embryos or 2 embryo-like structures expressly for stem cell research purposes (subject to applicable 3 local laws), regardless of how the embryos are created. SCRO process review should 4 consider the scientific justification for the creation and use of research embryos, 5 including, but not limited to, the importance of the research question at hand and the lack 6 of suitable alternative means to investigate this question. 7 8 b) Research in which human pluripotent stem cells derived by any means are used to 9 generate human totipotent cells that are defined as having the potential to sustain 10 embryonic or fetal development; 11 12 c) Research that generates human gametes and entails performing studies of fertilization 13 that produce human embryos; 14 15 d) Research in which human totipotent cells or pluripotent stem cells derived by any 16 means are mixed with pre-implantation human embryos. In no case shall such 17 experiments be sustained beyond initiation of primitive streak formation. 18 19 e) Forms of research that generate chimeric animals using human cells that have the 20 potential for high degrees of functional integration into the animals’ central nervous 21 systems or to generate human gametes. To assist SCRO process review of stem cell-22 based human-to-nonhuman chimera research, the ISSCR Ethics and Public Policy 23 Committee has provided an advisory report that guides reviewers through a series of 24 considerations not typically covered by institutional animal research committees but that 25 are relevant for SCRO review (Appendix 6). SCRO reviewers and investigators should 26 follow the proposed ethical standards presented in this report, while exercising 27 appropriate judgment in individual situations. 28

29 f) Institutions should determine whether chimera research involving human neural cells 30 that have the capacity to integrate into the nervous systems of laboratory animals should 31 be reviewed by either the SCRO or animal research review process. Such evaluations 32 should be triggered when the degree of functional integration is considerable enough to 33 raise concerns that the nature of the animal host may be substantially altered, and 34 especially when transplants occur in closely related primate species. Review by animal 35 care and use committees should be supplemented by scientists and ethicists with relevant 36 topic-specific expertise. 37

38 2.1.3.3 Category 3 (Prohibited Activities): Research that should not be pursued at this time 39 because of broad international consensus that such experiments lack a compelling scientific 40 rationale or raise substantial ethical concerns. Such forms of research include the following: 41 42

a) In vitro culture of any intact human embryo or organized cellular structures that might 43 manifest human organismal potential, regardless of derivation method, for longer than 14 44 days or until formation of the primitive streak begins, whichever occurs first. 45

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b) Research in which human embryos or any products of research involving human 1 totipotent or pluripotent cells are implanted into a human or non-human primate uterus. 2 3 c) Research in which gene-edited human embryos are implanted into a human or non-4 human primate uterus. Gene-edited human embryos are defined as human embryos with 5 in vitro modifications to their nuclear DNA and/or embryos generated from a human 6 gamete that has had its nuclear DNA modified in vitro. (For guidance on clinical 7 applications of human genome editing, see below.) 8

9 d) Research in which animal chimeras incorporating human cells with the potential to 10 form human gametes are bred to each other. 11

12 Related Laboratory Research Activities 13 Research involving the in vitro genetic manipulation of human embryos and gametes is 14 rapidly advancing internationally. Such experiments may inform mechanisms of early 15 human development, or lay the foundation for eradication of genetic disease. Two prominent 16 examples of this are (1) novel strategies to manipulate mitochondrial content of human 17 oocytes or embryos, and (2) human nuclear genome editing techniques, most notably the use 18 of the CRISPR/Cas9 system. Either of these examples might one day help prevent the 19 transmission of serious genetic diseases while allowing prospective parents to maintain a 20 genetic link to their offspring. 21 22 Preclinical research into the safety and efficacy of mitochondrial replacement strategies is 23 now underway and should continue under appropriate regulatory oversight. Mitochondrial 24 replacement therapy does not entail direct modification to the nuclear genome, depends upon 25 distinct technologies, and raises unique scientific and ethical concerns. Thoughtful scientific and 26 ethical discussions of this technology have recently occurred in the United Kingdom and are 27 underway in the United States and elsewhere in the world. The ISSCR applauds these current 28 efforts as a model for deliberations on germline nuclear genome editing technologies. Nuclear 29 genome editing techniques applied to the human germline are far less developed at this time, 30 and raise additional technological and societal challenges. Scientists currently lack an 31 adequate understanding of the fidelity and precision of CRISPR/Cas9 genome modification 32 of human embryos, as well as a full appreciation of the safety and potential long-term risks to 33 individuals born following such a process. As of the issuance of these guidelines, the ISSCR 34 supports only in vitro laboratory research on applications of nuclear genome editing 35 technologies to human embryos, performed under proper ethical oversight, to enhance basic 36 knowledge and to better understand the associated safety issues. ISSCR also calls for broad 37 public and international dialogue on the capabilities and limitations of these genome-editing 38 technologies and on the implications of their application to the human germ line. The ISSCR 39 asserts that a deeper and more rigorous deliberation on the ethical, legal and societal 40 implications of modifying the human germ line is essential if clinical application is ever to be 41 sanctioned. 42 43 Recommendation 2.1.4: Basic research on the safety and efficacy of modifying gametes 44 and/or pre-implantation human embryos is essential prior to their use in clinical 45 investigation of assisted reproductive strategies aimed at preventing the transmission of 46 genetic disorders. Until further clarity emerges on both scientific and ethical fronts, the 47

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ISSCR supports a moratorium on attempts to apply CRISPR/Cas9 and other nuclear 1 genome editing techniques to human embryos for the purpose of human reproduction. 2 3

2.2 Procurement of Biomaterials 4 5 The procurement of human gametes, embryos in vitro, fetal tissues, and somatic cells are 6 integral to the conduct of human stem cell research. The international community of 7 professional scientists conducting human stem cell research must ensure that human 8 biological materials are procured in a manner according to globally accepted principles of 9 research ethics and local laws and regulations. 10 11 Oversight of Procurement 12 Recommendation 2.2.1: Rigorous review must be performed prior to the procurement 13 of all gametes, embryos, or somatic cells that are destined for use in research. 14 Normally, human subjects review committees are responsible for conducting this 15 review, although SCRO process review may assist by providing stem cell-specific 16 expertise. 17 18 Review must ensure that vulnerable populations are not exploited due to their dependent 19 status or their compromised ability to offer voluntary consent, and that there are no undue 20 inducements or other undue influences for the provision of human biomaterials. 21 22 Consent for Biomaterials 23 Recommendation 2.2.2: Explicit and contemporaneous informed consent for the 24 provision of all biomaterials for stem cell research is ideal, including consent obtained 25 from all gamete donors for use of embryos in research. Informed consent should be 26 obtained at the time of proposed transfer of any biomaterials to the research team or 27 during the time that biomaterials are collected and stored for future research use. 28 29 Explicit consent must also be given for discarded tissues and cells collected during the course 30 of clinical practice if these biomaterials are used for stem cell research involving the creation 31 of human embryos (e.g., by somatic cell nuclear transfer or another method that reprograms 32 to totipotency). 33 34 Contemporaneous consent is not necessary if researchers procure somatic cells from a tissue 35 bank. However, somatic cells may be procured from a tissue bank only if the tissue bank’s 36 informed consent documents specifically designate embryo or gamete creation for stem cell 37 research as one of the possible uses of the donor’s tissues, and only if researchers use somatic 38 cells from tissue samples whose donors have clearly consented to this possible use. 39 40 In the case that human biomaterials are procured from a child or a decisionally incapacitated 41 adult, consent must be provided by a parent, legal guardian or other person authorized under 42 applicable law. Assent of the minor is also strongly encouraged. 43 44 Review for Biomaterials Collection for Research 45

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Recommendation 2.2.3: Reviews of procurement protocols must ensure that 1 biomaterials donors are adequately informed about the stem cell-specific aspects of 2 their voluntary research participation. 3 4 Researchers should exercise care in obtaining valid informed consent. The informed consent 5 process should take into account language barriers and the educational level of the 6 participants themselves. In order to facilitate the adoption of sound and uniform standards of 7 informed consent for the procurement of biomaterials for human stem cell research, the 8 ISSCR has made sample documents available to researchers by download from its 9 website.(Isscr.org, 2015) The samples will need to be customized for use in specific research 10 studies and to conform to local laws. 11 12 The informed consent document and process should cover the following statements (adapted 13 to the particular research project): 14 15

i. that the biomaterials will be used in the derivation of totipotent or pluripotent 16 cells for research; 17

ii. that the biomaterials will be destroyed during the process of deriving 18 totipotent or pluripotent cells for research; 19

iii. that derived cells and/or cell lines might be deposited and stored in a 20 repository many years and used internationally for future studies, many of 21 which may not be anticipated at this time; 22

iv. that cells and/or cell lines might be used in research involving genetic 23 manipulation of the cells, the generation of human-animal chimeras (resulting 24 from the mixing of human and non-human cells in animal models), or the 25 introduction of cells or their derivatives into human or animal embryos; 26

v. that the donation is made without any restriction or direction regarding who 27 may be the recipient of transplants of the cells derived, except in the case of 28 autologous transplantation; 29

vi. whether the donation is limited to specific research purposes and not others or 30 is for broadly stated purposes, including research not presently anticipated, in 31 which case the consent shall notify donors, if applicable under governing law, 32 of the possibility that permission for broader uses may later be granted and 33 consent waived under appropriate circumstances by an ethical or institutional 34 review board. The consent process should explore and document whether 35 donors have objections to the specific forms of research outlined in the 36 research protocol; 37

vii. disclosure of what donor medical or other information and what donor 38 identifiers will be retained; specific steps taken to protect donor privacy and 39 the confidentiality of retained information; and whether the identity of the 40 donor will be readily ascertainable to those who derive or work with the 41 resulting stem cell lines, or any other entity or person, including specifically 42 any oversight bodies and government agencies; 43

viii. disclosure of the possibility that any resulting cells or cell lines may have 44 commercial potential, and whether the donor will or will not receive financial 45 benefits from any future commercial development; 46

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ix. disclosure of any present or potential future financial benefits to the 1 investigator and the institution related to or arising from proposed research; 2

x. that the research is not intended to provide direct medical benefit to anyone 3 including the donor, except in the sense that research advances may benefit 4 the community; 5

xi. that neither consenting nor refusing to donate biomaterials for research will 6 affect the quality of care provided to potential donors; 7

xii. that there are alternatives to donating human biomaterials for research, and an 8 explanation of what these alternatives are; 9

xiii. (for donation of embryos) that the embryos will not be used to attempt to 10 produce a pregnancy, and will not be allowed to develop in culture in vitro for 11 longer than 14 days from conception; 12

xiv. (for experiments in embryonic stem cell derivation, somatic cell nuclear 13 transfer, somatic cell reprogramming, parthenogenesis, or androgenesis) that 14 the resulting cells or stem cell lines derived would carry some or all of the 15 DNA of the donor and therefore be partially or completely genetically 16 matched to the donor.; 17

xv. that nucleic acid sequencing of the resulting stem cell line is likely to be 18 performed, and data stored in databases available to the public or to qualified 19 researchers with confidentiality provisions; this may compromise the capacity 20 for donation to remain anonymous and/or de-identified; 21

xvi. whether there is a plan to share with the biomaterials donor any clinically 22 relevant health information discovered incidentally during the course of 23 research. 24

25 Payments to tissue providers for research 26 Recommendation 2.2.4: Research oversight committees must authorize all proposals to 27 reimburse, compensate, or provide valuable considerations of any kind for research 28 providers of embryos, gametes, or somatic cells. 29 30 Individuals who elect to provide stored embryos, gametes, or somatic cells for research 31 should not be reimbursed for the costs of storage prior to the decision to participate in 32 research. 33 34 For provision of somatic cells, sperm, or oocytes for research, reimbursement for direct 35 expenses incurred by donors as a consequence of research participation may be determined 36 during the review process. 37 38 For provision of fetal tissue after an elective abortion, no payment or valuable consideration 39 of any kind may be offered to donors for their procurement. 40 41 Payments to oocyte providers for research 42 Recommendation 2.2.5: For provision of oocytes for research, when oocytes are 43 collected outside the course of clinical treatment, at no time should compensation for 44 non-financial burdens ever constitute an undue inducement. 45 46

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In jurisdictions where oocyte provision for research is allowed, the human subjects 1 committee (IRB/ERB) and those responsible for conducting rigorous SCRO review must 2 assess the safety and the voluntary and informed choice of oocyte providers according to the 3 following standards: 4 5

i. There must be monitoring of recruitment practices to ensure that no vulnerable 6 individuals, for example, economically disadvantaged women, are 7 disproportionately encouraged to participate as oocyte providers for research. 8

ii. In jurisdictions where research participants are allowed compensation or 9 valuable consideration for incurred non-financial burdens, the amount of 10 financial recognition for the participant’s time, effort, and inconvenience must 11 be rigorously reviewed to ensure that such compensation does not constitute an 12 undue inducement. 13

iii. Compensation for oocyte providers’ time, effort, and inconvenience, if 14 permitted by local review committees, should be reasonably proportionate to 15 recompense levels for other types of research participation involving similarly 16 invasive and burdensome medical procedures. Compensation levels should aim 17 to acknowledge oocyte providers’ non-financial burdens incurred as a result of 18 their research participation, such as their physical discomfort and effort. 19

iv. At no time should payments or other rewards of any kind be given for the 20 number or quality of the oocytes that are to be provided for research. 21

v. To help guide review committees through the ethical considerations surrounding 22 oocyte collection and financial recognition of donors’ efforts, the ISSCR Ethics 23 and Public Policy Committee has produced a white paper explaining the 24 ISSCR’s position on these issues. Researchers and review committees should 25 consult Appendix 1 for further guidance. 26

vi. Oocyte procurement must be performed only by medically qualified and 27 experienced physicians, and non-aggressive hormone stimulation cycles and 28 frequent monitoring must be used to reduce the risk of ovarian hyperstimulation 29 syndrome (OHSS). 30

vii. Due to the unknown long-term effects of ovulation induction, women should 31 not undergo an excessive number of hormonally induced ovarian stimulation 32 cycles in a lifetime, regardless of whether they are induced for research or 33 assisted reproduction. The limits should be determined by thoughtful review 34 during the SCRO process, which should be informed by the latest available 35 scientific information about the health risks. 36

viii. There should be a provision for the research institution or funding source to pay 37 for the cost of any medical care required as a direct and proximate result of a 38 woman’s provision of oocytes for research. 39

ix. A fertility clinic or other third party responsible for obtaining consent or 40 collecting biomaterials should not be paid specifically for the material obtained, 41 but rather for specifically defined cost-based reimbursements and payments for 42 professional services. 43

44 Separating Research Donation Consent from Treatment 45

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Recommendation 2.2.6: Informed consent for research donation must be kept separate 1 from informed consent for clinical treatment. 2 3 To facilitate free and voluntary choice, decisions related to the donation of gametes or 4 creation of embryos for fertility treatment should be free of the influence of investigators 5 who propose to derive or use human pluripotent stem cells in research. During the course of 6 clinical treatment, researchers may not request that members of the fertility treatment team 7 generate more embryos or harvest more oocytes than necessary for the optimal fertility 8 treatment. Wherever possible, the treating physician or infertility clinician should not also be 9 the investigator who is proposing to perform research on the donated materials. 10 11 Consistent with fetal tissue research guidelines issued by the Network of European NCS 12 Transplantation and Restoration (NECTAR) and U.S. law, a woman’s decision to terminate a 13 pregnancy must not be influenced by the possible research use of her fetus’ tissues. Informed 14 consent for fetal tissue procurement and research should be obtained from the woman after 15 her clinical decision to terminate her pregnancy but before the abortive procedure. 16 17 Improving Informed Consent for Donation 18 Recommendation 2.2.7: Attempts should be made to improve the informed consent 19 process and study design of human biomaterials procurement. 20 21 The informed consent document is but one aspect of this process. The purpose of the 22 informed consent document is to record that all the ethically relevant information has been 23 discussed. The informed consent document alone can never take the place of a dialogue 24 between research staff and providers of human biomaterials. Researchers are thus encouraged 25 to focus on enriching the informed consent process itself, in addition to improving the design 26 of the protocol with respect to procurement. These processes can be enhanced in the 27 following ways: 28 29

i. Whenever possible, the person conducting the informed consent dialogue 30 should have no vested interest in the research protocol. If members of the 31 research team participate in the informed consent process, their role must be 32 disclosed and care must be taken to ensure that information is provided in a 33 transparent and accurate manner. 34

ii. Empirical research has shown that informed consent is most effective as a 35 dynamic, interactive, and evolving process as opposed to a static, one-time 36 disclosure event.(Flory and Emanuel, 2004) Thus, researchers should provide 37 ample opportunities for biomaterials donors to discuss their involvement in 38 the research protocol. 39

iii. Counseling services should be made available upon request to any providers 40 of human biomaterials prior to procurement. 41

iv. Procurement procedures should be revised in light of a) ongoing studies of the 42 long-term risks associated with oocyte retrieval; and b) research on informed 43 consent for all types of human biological materials procurement. 44

v. Researchers should consider on a regular basis, subject to annual review, the 45 possible use of alternatives to hormonally induced oocytes procured solely for 46

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stem cell research, such as oocytes derived from pluripotent stem cells, in 1 vitro maturation of oocytes from ovariectomy samples, and egg sharing 2 programs offered through infertility clinics. 3

2.3 Banking and Distribution of Human Pluripotent Stem Cell Lines 4 5 Proposals for derivations of new human pluripotent stem cell lines should be scientifically 6 justified and executed by scientists with appropriate expertise. Hand-in-hand with the 7 privilege to perform derivations is the obligation to distribute the cell lines to the research 8 community. 9 10 Banking in Derivation Protocols 11 Recommendation 2.3.1: A clear, detailed outline for banking and open access to the new 12 lines should be incorporated into derivation proposals. New pluripotent stem cell lines 13 should be made generally available as soon as possible following derivation and first 14 publication. 15 16 Consistent with the policies of many funders and scientific journals, the ISSCR encourages 17 researchers to deposit lines early into centralized repositories where the lines will be held for 18 release and distribution upon publication. Investigators performing derivations should have a 19 detailed, documented plan for characterization, storage, banking and distribution of new 20 lines. Investigators performing derivations should propose a plan to safeguard the privacy of 21 donors and for managing their health-related incidental findings. Investigators should also 22 inform donors that, in this era of data-intensive research, complete privacy protection might 23 be difficult to guarantee. 24

25 During the course of primary or secondary research with human stem cell lines, particularly 26 lines derived from somatic cells, investigators may discover information that may be of 27 importance to biomaterials donors. Therefore, investigators and stem cell repositories should 28 develop policies to address these possibilities. 29 30 Incidental Findings 31 Recommendation 2.3.2: Primary researchers and repositories should develop a policy 32 that states whether or not incidental findings will be returned to study participants. 33 This policy must be explained to potential participants during the informed consent 34 process, and participants should be able to choose which types of incidental findings 35 they wish to receive, if any. Reporting findings with relevance to public health may be 36 required by law in certain jurisdictions. 37 38 Because it is presently unclear what the net harms and benefits are of returning incidental 39 findings to biomaterials donors, a single approach to managing incidental findings may not 40 be appropriate across all studies and jurisdictions. 41 42 Nevertheless, in the case that there are plans to return incidental findings to research 43 participants, primary researchers must offer a practical and adequately resourced feedback 44 pathway to participants who desire such information that involves participants’ physicians 45 and the verification of any discovered incidental findings. 46

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1 Secondary researchers should be aware that they are typically prohibited from attempting to 2 contact or reidentify donors with incidental findings information. Recontact is a matter for 3 primary research sites or central repositories to manage. Secondary researchers however 4 should be aware of the incidental findings policies of either of these responsible parties. 5 6 Central repositories should adhere to the incidental findings policies of primary researchers 7 or others collecting biomaterials from donors that were disclosed during the informed 8 consent process and which produced the samples stored at the repository. 9 10 Repositories 11 Recommendation 2.3.3: The ISSCR encourages the establishment of national and 12 international repositories, which are expected to accept deposits of newly derived stem 13 cell lines and to distribute them on an international scale. 14 15 In order to facilitate easy exchange and dissemination of stem cell lines, repositories should 16 strive to form and adhere to common methods and standards (see also chapter 5). At a 17 minimum, each repository must establish its own guidelines and make those available to the 18 public. Repositories must have a clear, easily accessible material transfer agreement (MTA; a 19 sample MTA is available in Appendix 2). Each repository may have its own criteria for 20 distribution. The repository has right of refusal if a cell line does not meet its standards. 21 22 Repositories must also have clear, publicly available protocols for deposit, storage and 23 distribution of pluripotent stem cell lines and related materials. 24

25 For deposits, repositories must receive documentation pertinent to the depositor’s applicable 26 SCRO process. These documents should be kept on file at the repository. This will include, 27 but is not limited to, proof of institutional and/or SCRO approval of the process for 28 procurement of research materials according to ethical and legal principles of procurement as 29 outlined in these Guidelines, approval of protocols for derivation of new lines, copies of the 30 donor informed consent documents and what, if any, reimbursement of direct expenses or 31 financial considerations of any kind were provided to the donors. 32

33 Repositories should obtain all technical information from depositor. For example, methods 34 used in the derivation of lines, culture conditions, infectious disease testing, passage number 35 and characterization data. Repositories will make this information publicly available. If the 36 repository modifies depositor’s protocols or obtains additional data this will also be made 37 available. 38

39 Repositories should engage in, but are not limited to, the following: 40

i. Reviewing and accepting deposit applications; 41 ii. Assigning unique identifiers (catalogue number) to deposits; 42

iii. Characterizing cell lines; 43 iv. Human pathogen testing; 44 v. Expansion, maintenance and storage of cell lines; 45

vi. Quality assurance and quality control of all procedures; 46

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vii. Maintenance of website with pertinent characterization data, protocols and 1 availability of cell lines; 2

viii. Tracking distributed cell lines; 3 ix. Posting a clear and fair cost schedule for distribution of materials. 4

Repositories should distribute internationally and charge only the necessary 5 costs, which include shipping and handling; 6

x. Adhering to an action plan (as applicable) for the return of incidental health 7 related findings to donors. 8

9 Provenance of Stem Cell Lines 10 Recommendation 2.3.4: Documentation of the provenance of the stem cell lines is 11 critical if the cell lines are to be widely employed in the research community. 12 Provenance must be easily verifiable by access to relevant informed consent documents 13 and raw primary data regarding genomic and functional characterization. 14 15 Owing to the nature of the materials involved in the generation of human stem cell lines, 16 appropriate safeguards should be used to protect the privacy of donors and donor 17 information. In order for the stem cell lines to be as useful as possible and so as not to 18 preclude future potential therapeutic applications, as much donor information as possible 19 should be maintained along with the cell line, including, but not limited to: ethnic 20 background, medical history, and infectious disease screening. Subject to local laws, donor 21 samples and cell lines should be anonymized or de-identified using internationally accepted 22 standards for maintaining privacy. Informed consent and donor information will be gathered 23 and maintained by the repository, including whatever reimbursement of direct expenses or 24 financial or valuable considerations of any kind were provided in the course of the 25 procurement. 26 27 Access to Research Materials 28 Recommendation 2.3.5: Institutions engaged in human stem cell research, whether 29 public or private, academic or otherwise, should develop procedures whereby research 30 scientists are granted, without undue financial constraints or bureaucratic impediment, 31 unhindered access to these research materials for scientifically sound and ethical 32 purposes, as determined under these guidelines and applicable laws. 33 34 The ISSCR urges such institutions, when arranging for disposition of intellectual property to 35 commercial entities, to make best efforts to preserve nonexclusive access for the research 36 community, and to promote public benefit as their primary objective. The ISSCR endorses 37 the principle that as a prerequisite for being granted the privilege of engaging in human stem 38 cell research, researchers must agree to make the materials readily accessible to the 39 biomedical research community for non-commercial research. Administrative costs such as 40 shipping and handling should be borne by the receiving party so as not to pose an undue 41 financial burden on the entity or researcher providing the cells. 42 43 The ISSCR encourages scientists conducting human stem cell research to submit any human 44 stem cell lines they derive to national or international depositories that allow open 45 distribution in order to facilitate the wider dissemination of these valuable research tools 46

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across national boundaries. Scientists and stem cell bio-banks should work together to 1 harmonize standard operating procedures to facilitate international collaboration (see chapter 2 5). 3

2.4 Mechanisms for Enforcement 4 5 Recommendation 2.4.1: These ISSCR guidelines should be upheld and enforced 6 through standards of professional and institutional self-regulation. 7 8 The development of consensus in ethical standards and practices in human stem cell research 9 through thoughtful and transparent dialogue is a critical catalyst for international 10 collaboration to proceed with confidence, and for research from anywhere in the world to be 11 accepted as valid by the scientific community. These standards and practices should be 12 incorporated in a comprehensive code of conduct applicable to all researchers in the field. 13 Senior or corresponding authors of scientific publications should specifically be charged with 14 the responsibility of ensuring that the code of conduct is adhered to in the course of 15 conducting human stem cell research and of supervising junior investigators that work in 16 their respective organizations or projects. Institutions where such research is undertaken shall 17 strive to provide to researchers working on any such projects under their auspices, 18 particularly junior investigators, with up-to-date information on such standards and practices 19 on an ongoing basis. 20 21 Journal editors and manuscript reviewers should require an authors’ statement of adherence 22 to the ISSCR ‘Guidelines for Human Embryonic Stem Cell Research and Related Laboratory 23 Research Activities’ or adherence to an equivalent set of guidelines or applicable regulations, 24 and authors should include a statement that the research was performed after obtaining 25 approvals following a suitable SCRO review process. 26 27 Grant applicants, in particular the individual scientists undertaking the research, should 28 provide funding bodies with sufficient documentation to demonstrate that proposed research 29 is ethically and legally in accordance with relevant local and national regulations and also in 30 accordance with the ISSCR ‘Guidelines for the Human Embryonic Stem Cell Research and 31 Related Laboratory Research Activities’. Funding organizations should pledge to follow 32 these Guidelines or their equivalent and require entities whose research is funded by such 33 organizations to do the same. 34 35 In order to facilitate the adoption of globally-accepted standards and practice of human stem 36 cell research, the ISSCR has made available for download examples of informed consent 37 documents for obtaining human materials for stem cell research (gametes, embryos, somatic 38 tissues), and a Material Transfer Agreement for the sharing and distribution of materials (see 39 Appendices 2 and 3). These informed consent templates may be modified to comply with 40 local laws. See also chapter 5. 41 42 43 44 45 46

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3. Guidelines for Clinical Translation of Stem Cell-Based Research 1 2 The rapid advances in basic stem cell research and the many reports of successful cell-based 3 interventions in animal models of human disease have created high expectations for the 4 promise of regenerative medicine and cell therapies. Accompanying the enormous attention 5 paid by the media and the public to cellular therapies is the potentially problematic trend 6 towards premature initiation of clinical application and trials, far in advance of what is 7 warranted by sound, rigorous, and dispassionately assessed pre-clinical evidence. Clinical 8 experimentation is expensive and burdensome for research subjects. Investing in a novel 9 mode of medical intervention before there is a sound rationale, a plausible mechanism, and a 10 high probability of success squanders scant resources and needlessly exposes research 11 subjects to risk. This section advocates for a step-wise, prudent, and evidence-based advance 12 towards clinical translation. By adhering to a commonly accepted and robust set of practice 13 guidelines, stem cell science is best positioned to fulfill its potential. 14 15

3.1 Cell Processing and Manufacture 16 17 In most countries and jurisdictions, the use of cellular products for medical therapy is 18 regulated by governmental agencies to ensure the protection of patients and the prudent use 19 of resources so that novel therapies will be the most widely beneficial for the population. 20 Although some cell and stem cell based products have now been approved for use in humans, 21 a growing number of novel cellular products are being tested for myriad disease indications, 22 and present new challenges in their processing, manufacture, and pathways for regulatory 23 approval. Given the variety of potential cell products, these Guidelines emphasize that cell 24 processing and manufacture of any product be conducted with scrupulous, expert, and 25 independent review and oversight, to ensure as much as possible the integrity, function, and 26 safety of cells destined for use in patients. Even minimal manipulation of cells outside the 27 human body introduces risk of contamination with pathogens, and prolonged passage in cell 28 culture carries the potential for genomic and epigenetic instabilities that could lead to 29 deranged cell function or frank malignancy. While many countries have established 30 regulations that govern the transfer of cells into patients (Appendix 4), optimized standard 31 operating procedures for cell processing, protocols for characterization, and criteria for 32 release remain to be refined for novel derivatives of pluripotent cells and many attendant cell 33 therapies. 34 35 Given the unique proliferative and regenerative nature of stem cells and their progeny and the 36 uncertainties inherent in the use of this therapeutic modality, stem cell-based therapies 37 present regulatory authorities with unique challenges that may not have been anticipated 38 within existing regulations. The following recommendations involve general considerations 39 for cell processing and manufacture. Technical details pertaining to cell sourcing, 40 manufacture, standardization, storage, and tracking can be found in Appendix 5. 41

3.1.1 Sourcing Material 42 Donor Consent 43 Recommendation 3.1.1.1: In the case of donation for allogeneic use, the donor should 44 give written and legally valid informed consent that covers, where applicable, issues 45

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such as terms for potential research and therapeutic uses, incidental findings, potential 1 for commercial application, and other issues as described below. 2 3 Researchers should ensure that subjects (or their surrogate decision-makers) adequately 4 understand the following: 5

a) the tissue itself and the cell lines and/or differentiated progenitors may be subject to 6

storage. If possible, duration of storage should be specified; 7

b) that the donor may (or may not) be approached in the future to seek additional 8

consent for new uses, or to request additional material (blood or other clinical 9

samples) or information; 10

c) that the donor will be screened for infectious and possibly genetic diseases; 11

d) that the donated cells may be subject to genetic modification by the investigator; 12

e) that with the exception of directed donation, the donation is made without restrictions 13

regarding the choice of the recipient of the transplanted cells; 14

f) disclosure of medical and other relevant information that will be retained, and the 15

specific steps that will be taken to protect donor privacy and confidentiality of 16

retained information, including the date at which donor information will be 17

destroyed, if applicable; 18

g) the donor should be informed that in the case of pluripotent stem cells the ability to 19

destroy all samples may be limited and that with newer genetic techniques complete 20

anonymity may not be feasible 21

h) the intent of donor must be ascertained should medically relevant information of the 22

donor be discovered in the course of research (see sections 2.2.3 and 2.3.2 for a 23

discussion of incidental findings) 24

i) explanation of what types of genomic analyses (if any) will be performed and how 25

genomic information will be handled; and 26

j) disclosure that any resulting cells, lines or other stem cell-derived products may 27

have commercial potential, and whether any commercial and intellectual property 28

rights will reside with the institution conducting the research. 29

The initial procurement of tissue from a human donor may or may not require Good 30 Manufacturing Practice (GMP) certification, depending on the jurisdiction (Appendix 4), but 31 should always be conducted using GLP (good laboratory practices). It should also follow 32 regulatory guidelines related to human tissue procurement and maintain universal precautions 33 to minimize the risks of contamination, infection, and pathogen transmission. 34 35 36

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Donor Screening 1 Recommendation 3.1.1.2: Donors must be screened for infectious diseases and other 2 risk factors, as is done for blood and solid organ donation, and for genetic diseases as 3 appropriate. 4 5 Tissue procurement for generating pluripotent cells is similar to procurement of cells for 6 other purposes and should be governed by the same rules and regulations. However, an 7 important distinction between tissue donation and pluripotent stem cell generation that raises 8 the stakes of screening is that, whereas tissues are distributed to a limited number of 9 recipients, iPSC or other pluripotent-derived allogeneic tissues can potentially be implanted 10 in large populations. In addition, cells are likely to be expanded in culture and/or exposed to 11 xeno culture material prior to transplantation. As such the risks of transmission of 12 xenoviruses and other infectious agents such as prion particles is proportionately greater. 13 Scrupulous adherence to regulations and tracking of cells and the development of a risk 14 mitigation plan is crucial to translation and uptake of cell based therapies. Regulatory 15 agencies such as the US Food and Drug Administration and the European Medicines Agency 16 have issued guidance regarding donor testing.(Food and Drug Administration, 2007; The 17 Committee for Medicinal Products for Human Use (CHMP), 2007) 18

3.1.2 Manufacture 19 Quality Control in Manufacture 20 Recommendation 3.1.2.1: All reagents should be subject to quality control systems to 21 ensure the quality of the reagents prior to introduction into manufacturing. For 22 extensively manipulated stem cells intended for clinical application, GMP procedures 23 should be strictly followed. 24 25 The variety of distinct cell types, tissue sources, and modes of manufacture and use 26 necessitate individualized approaches to cell processing and manufacture. (For an expanded 27 discussion of the manufacturing process, see Appendix 5.) The maintenance of cells in 28 culture for any period of time places different selective pressures on the cells than when they 29 exist in vivo. Cells in culture age and may accumulate both genetic and epigenetic changes, 30 as well as changes in differentiation behavior and function. Scientific understanding of 31 genomic stability during cell culture is primitive at best and assays of genetic and epigenetic 32 status of cultured cells are still evolving. The guidance documents from the US FDA and 33 European Medicines Agency cited above provide a roadmap for manufacture and quality 34 control of cellular products, but given that many cellular products developed in the future 35 will represent entirely novel entities with difficult-to-predict behaviors, scientists must work 36 side-by-side with regulators to ensure that the latest information is available to inform the 37 regulatory process. An important goal is the development of universal standards to enable 38 comparisons of cellular identity and potency, which are critical for comparing studies and 39 ensuring reliability of dose-response relationships and assessments of mechanisms of 40 toxicity. 41 42 Processing and Manufacture Oversight 43 Recommendation 3.1.2.2: The degree of oversight and review of cell processing and 44 manufacture in protocols should be proportionate to the risk induced by manipulation 45

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of the cells, their source, the trial, and the number of research subjects who will be 1 exposed to them. 2 3 Pluripotent stem cells—regardless of particular cell type—carry additional risks due to their 4 pluripotency. These include the ability to acquire mutations when maintained for prolonged 5 periods in culture, to grow and differentiate into inappropriate cellular phenotypes, to form 6 benign teratomas or malignant outgrowths, and to fail to mature. These confer additional risk 7 to patients/subjects, and appropriate tests must be devised to ensure safety of stem cell 8 derived products. 9 10 Factors that confer greater risk to patient/subjects from cells include their differentiation 11 potential, source (autologous, allogeneic), type of genetic manipulation (if any), homologous 12 versus non-homologous or ectopic use, their persistence in the patient/subject, level of 13 species specificity for cell type, and the integration of cells into tissues or organs (versus, for 14 example, encapsulation). 15 16 When adequate cellular material is available, assays that should be applied include global and 17 comprehensive assessments of genetic, epigenetic, and functional assays, as judged by 18 rigorous review by a panel of independent experts. For cryopreserved or otherwise stored 19 products, any impact of short or long-term storage on product potency must be determined. 20 While some practitioners claim freedom to practice the use of cell therapies as long as the 21 cells are subject to only minimal manipulation, the onus rests on the practitioner to invite 22 scrutiny over their process of cell manipulation, such that independent, disinterested experts 23 can determine the proper level of regulatory oversight. Recent draft guidance provided by the 24 FDA for public comment represents a thoughtful and cogent set of principles to delineate 25 when manipulation of autologous cell-based products can no longer be considered minimal 26 and must therefore be subject to FDA oversight.(Food and Drug Administration, 2014) 27 28 In general, the stringency of review for cell processing and manufacture should increase as 29 cells are tested in later phase studies, used in practice settings, or administered to multiple 30 recipients. 31 32 Components of Animal Origin 33 Recommendation 3.1.2.3: Components of animal origin used in the culture or 34 preservation of cells should be replaced with human or chemically defined components 35 when possible. 36 37 Components of animal origin present risk of transferring pathogens or unwanted biological 38 material. In some circumstances, it may not be possible or optimal to follow this 39 recommendation. Researchers can rebut this presumption by demonstrating the infeasibility 40 of alternatives, and the favorability of risk/benefit in spite of using animal-based components. 41 42 Databases 43 Recommendation 3.1.2.4: Funding bodies, industry, and regulators should work 44 towards establishing a public database of clinically useful lines be developed that 45

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contains adequate information to determine the lines’ utility for a particular disease 1 therapy. 2 3 Some stem cell products entail minimal manipulation and immediate use, whereas other stem 4 cell products are intended for future use and thus necessitate storage. Precedents exist for 5 two types of stem cell banks: (a) private banks where cells are harvested from an individual 6 and stored for future use by that individual or designated family members; and (b) public 7 banks that procure, process, store, and deliver cells to matched recipients on a need-based 8 priority list, in a model akin to blood banking. The development of banks may be in the 9 public interest once stem cell-based treatments are proven effective and become the standard 10 of care. The composition of the bank must be constituted with adequate genetic diversity to 11 ensure wide access particularly if the government funds such a bank to ensure social justice 12 and widespread access. 13 14 Careful consideration in the design of the database must be made to promote access to 15 appropriate individuals while restricting the release of proprietary information. As it is 16 unlikely that any unified repository will be established, it is important to have a global 17 nonpartisan authority along the lines of the bone marrow registry or the Blood Bank 18 associations to promote harmonization of storage standards and the development of 19 consensus SOPs. 20

3.2 Preclinical Studies 21 22 The purpose of preclinical studies is to (a) provide evidence of product safety and (b) 23 establish proof-of-principle for therapeutic effects. International research ethics policies, such 24 as the Declaration of Helsinki and the Nuremberg Code, strongly encourage the performance 25 of animal studies prior to clinical trials. Before initiating clinical studies with stem cells in 26 humans, researchers should have persuasive evidence of clinical promise in appropriate in 27 vitro and/or animal models. A fundamental principle here is that preclinical studies must be 28 rigorously designed, reported, reviewed independently and subject to regulatory oversight 29 and reported, prior to initiation of clinical trials. This helps ensure that trials are scientifically 30 and medically warranted. 31 32 Cell-based therapy offers unique challenges for preclinical studies. In many cases 33 homologous cells in the same species are unavailable. Immune-suppressed animal models, 34 while useful, do not permit an understanding of the effect of the immune system on 35 transplanted cells. Since transplanted cells can change after transplantation in unpredictable 36 ways, extrapolating from an animal model to humans is even more challenging than for small 37 molecule products. 38

3.2.1 General Considerations 39 Animal Welfare 40 Recommendation 3.2.1.1: Given that research into stem-cell based therapeutic makes 41 heavy use of pre-clinical animal models, researchers should adhere to the principles of 42 the three Rs– Reduce numbers, Refine protocols, and Replace animals with in vitro or 43 non- animal experimental platforms whenever possible. 44 45

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This requirement is not incompatible with replication experiments or ensuring adequate 1 statistical power: indeed, these are key steps for ensuring animal experiments support robust 2 conclusions. It should also not be interpreted as suggesting that in vitro or non-animal 3 platforms are sufficient for supporting clinical investigations. For responsible animal 4 research, investigators planning to conduct animal studies using human stem cells and their 5 direct derivatives should refer to applicable ethical considerations described by the ISSCR 6 Ethics and Public Policy Committee (Appendix 6) and recommendations 2.1.1, 2.1.3.2, and 7 2.1.3.3. 8 9 Preclinical Study Objectives 10 Recommendation 3.2.1.2: Early phase studies should be preceded by rigorous 11 demonstration of safety and efficacy in preclinical studies. The strength of preclinical 12 evidence demanded for trial launch should be proportionate with the risks, burdens, 13 and ethical sensitivities of an anticipated trial. 14 15 Efficacy studies- sometimes also called “proof of principle”- provide the scientific rationale 16 for proceeding into human trials. More stringent design and reporting standards should be 17 demanded where planned trials involve research subjects with less advanced disease; when 18 invasive delivery approaches are anticipated; or where cells present greater risk and 19 uncertainty. However, prudent use of scientific resources means that even when research 20 subjects have advanced disease or risk is modest, studies should rest on sound scientific 21 evidence. 22 23 Study Validity 24 Recommendation 3.2.1.3: All preclinical studies testing safety and efficacy should be 25 designed in way that supports a precise, accurate and unbiased measure of clinical 26 promise. In particular, studies designed to inform trial initiation should be internally 27 valid; they should be representative of clinical scenarios they are intended to model, 28 and they should be replicated. 29 30 Like clinical trials, preclinical experiments confront many sources of bias and confounding, 31 including selection bias and publication bias. For decades, clinical researchers have sought to 32 minimize the effects of bias and confounding by using techniques like randomized allocation, 33 blinded outcome assessment, or power calculations. Such rigor should also apply in 34 preclinical studies intended to support trials. Numerous groups have articulated guidelines 35 for designing preclinical studies aimed at supporting trials.(Fisher et al., 2009; Henderson et 36 al., 2013; Landis SC et al., 2012) These guidelines recommend that: 37

1- researchers should reduce bias and random variation by ensuring their studies a) 38 have adequate statistical power; b) use appropriate controls; c) use randomization; 39 d) use blinding; e) establish- where appropriate- a dose-response relationship. 40

2- researchers and sponsors should ensure preclinical studies model clinical trial 41 settings, researchers should: a) characterize disease phenotype at baseline; b) select 42 animal models that best match human disease; c) use outcome measures that best 43 match clinical outcomes; and d) demonstrate a mechanism for treatment effect. 44

3- researchers and sponsors should ensure effects in animals are robust by replicating 45 findings- ideally in an independent laboratory and in a different animal system. 46

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4- researchers and sponsors should pre-specify and report whether a study is 1 exploratory (i.e. hypothesis generating or aimed at substantiating basic science 2 claims) or confirmatory (i.e. using pre-specified hypotheses and protocols and 3 powered to support robust claims). Preclinical researchers should only venture 4 claims of clinical utility after confirmatory studies. 5

3.2.2 Animal Safety Studies 6 Human cells will need to be produced under the conditions discussed in Chapter 4, Cell 7 Processing and Manufacture. Special attention should be paid to the characterization of the 8 cell population, including possible contamination by irrelevant cell types and when necessary 9 to the appropriate safeguards for controlling the unrestricted proliferation and/or aberrant 10 differentiation of the cellular product and its progeny. Cells grown in culture, particularly for 11 long periods or under stressful conditions, may become aneuploid or have DNA 12 rearrangements, deletions, and other genetic or epigenetic abnormalities that could 13 predispose them to cause serious pathologies such as tumor formation. 14 15 Cell characterization 16 Recommendation 3.2.2.1: Cells to be employed in clinical trials must first be rigorously 17 characterized to assess potential toxicities through in vitro studies and (where possible 18 for the clinical condition and tissue physiology to be examined) in animal studies. 19 20 Outside of the hematopoietic and stratified epithelia systems there is little clinical experience 21 with the toxicities associated with infusion or transplantation of stem cells or their 22 derivatives. In addition to known and anticipated risks (e.g. acute infusional toxicity, 23 deleterious immune responses, and tumorigenesis), cell-based interventions present risks that 24 can only be discovered with experience. Because animal models may not replicate the full 25 range of human toxicities associated with cell-based interventions, particular vigilance must 26 be applied in preclinical analysis. This section will define toxicities that are likely to be 27 unique to stem cells or their progeny. 28 29 Release criteria 30 Recommendation 3.2.2.2: Criteria for release of cells for transfer to research subjects in 31 trials must be designed to minimize risk from culture-acquired abnormalities. Final 32 product as well as in-process testing may be necessary for product release. 33 34 Given the nature of pluripotent cells and their innate capacity to form teratomas, there is a 35 particular concern for the potential tumorigenicity of hESCs and induced pluripotent stem 36 cells or their differentiated derivatives. In in-process testing, it will often be important to 37 assess karyotypic instabilities. 38 39 Tumorigenicity studies 40 Recommendation 3.2.2.3: Risks for tumorigenicity must be rigorously assessed for any 41 stem cell-based product, especially when extensively manipulated in culture, when 42 genetically modified, or when pluripotent. 43 44 The plan for assessing risks of tumorigenicity should be reviewed by an independent body 45 prior to initial trials. For pluripotent stem cell-derived products, a plan needs to be in place 46

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to minimize persistence of any remaining undifferentiated cells in the final product and to 1 demonstrate that level of purity in final product does not result in tumors in long-term animal 2 studies. 3 4 Biodistribution studies 5 Recommendation 3.2.2.4: For all cell-based products, whether injected locally or 6 systemically, researchers should perform detailed and sensitive biodistribution studies 7 of cells within the local organ as well as at distant sites. 8 9 Because of the potential for cells to persist or expand in the body, systemic delivery of cells 10 places extra burdens on investigators to understand the nature and extent by which cells 11 distribute throughout the body, lodge in tissues, expand and differentiate. Careful studies of 12 biodistribution, assisted by ever more sensitive techniques for imaging and monitoring of 13 homing, retention and subsequent migration of transplanted cell populations is imperative for 14 interpreting both efficacy and adverse events. While rodents or other small animal models are 15 typically a necessary step in the development of stem cell-based therapies, they are likely to 16 reveal only major toxic events. The similarity of many crucial physiological functions 17 between large mammals and humans may favor testing the biodistribution and toxicity of a 18 novel cell therapy in at least one large animal model. 19 20 Additional histological analyses or banking of organs for such analysis at late time points is 21 recommended. Depending on the laws and regulations of the specific country, biodistribution 22 and toxicity studies often need to be performed in a GLP (Good Laboratory Practice) 23 certified animal facility. 24 25 Route of cell administration, local or systemic, homologous or ectopic, can lead to different 26 adverse events, and consequently warrant different degrees of regulatory scrutiny. For 27 example, local transplantation into organs like the heart or the brain may lead to life-28 threatening adverse events related to the transplantation itself or to the damage that 29 transplanted cells may cause to vital structures. Especially in cases where cell preparations 30 are infused at anatomic sites distinct from the tissue of origin (for example, for non-31 homologous use), care must be exercised in assessing the possibility of local, anatomically 32 specific and systemic toxicities. 33 34 Ancillary Therapeutic Components 35 Recommendation 3.2.2.5: Before launching high-risk trials or studies with many 36 components, researchers should establish the safety and optimality of other 37 intervention components, like co-interventions, devices, or surgeries. 38 39 Cell-based interventions may involve other components besides cells, such as biomaterials, 40 engineered scaffolds, devices, as well as co-interventions like surgery, tissue procurement 41 procedures, and immunosuppression. These add additional layers of risk- and can interact 42 with each other. If fully implantable devices are used, separate toxicity studies need to be 43 carried out for the device and then separate studies will be warranted for the combo 44 cell/device product. Many subjects in cell-based intervention studies may be receiving 45 immunosuppressants or drugs for managing their disease. These can interact with cells. In 46

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cases where high standards of safety are demanded (e.g. studies involving high risk), 1 researchers should test their interaction. 2 3 Long-term safety studies 4 Recommendation 3.2.2.6: Preclinical researchers should adopt practices to address 5 long-term risks, and to detect new and unforeseen safety issues. 6 7 Given the probability for long term persistence of cells and the irreversibility of some cell-8 based interventions, testing of the long-term effect of cell transplants in animals is 9 encouraged and there should be stipulations in trials designed for long-term follow-up. 10 Length of follow up should vary with survival expectancy for patient populations projected 11 for study enrollment. 12 13 Potential of Stem Cells for Toxicology 14 Recommendation 3.2.2.7: Researchers, regulators, and reviewers should exploit the 15 potential for using stem cell science to enhance the predictive value of pre-clinical 16 toxicology studies. 17 18 Stem cell science holds out the prospect of testing toxicology in cell-based systems or 19 artificial organs that more faithfully mimic human physiology. Such approaches, though 20 unlikely to ever completely substitute for in vivo testing, hold substantial promise for 21 reducing burdens imposed on animals in safety testing and improving the predictive value of 22 preclinical safety studies. 23

3.2.3 Animal Efficacy Studies 24 Given the goals of stem cell-based therapy in tissue repair or disease eradication, preclinical 25 studies should ideally demonstrate evidence of a therapeutic effect (or proxy) in a relevant 26 animal model for the clinical condition and the tissue physiology to be studied. Mechanistic 27 studies utilizing cells isolated and/or cultured from animal models or diseased human tissues 28 are critical for defining the underlying biology of the cellular therapy. A complete 29 understanding of the biological mechanisms at work after stem cell transplantation in a 30 preclinical model is not a prerequisite to initiate human experimentation, especially in the 31 case of serious and untreatable diseases for which efficacy and safety have been 32 demonstrated in relevant animal models and/or in approved and conclusive human studies 33 with the same cell source. 34 35 Efficacy Evidence for Initiating Trials 36 Recommendation 3.2.3.1: Trials should generally be preceded by compelling preclinical 37 evidence of clinical promise in well-designed studies. Animal models suited to the 38 clinical condition and the tissue physiology should be used, unless there is conclusive 39 evidence of efficacy using similar products against similar human diseases. 40 41 Rigorous preclinical testing in animal models is especially important for stem cell-based 42 approaches, because cell therapies have distinctive pharmacological characteristics. Before 43 clinical testing, preclinical evidence should meet the following four conditions: 1) it should 44 establish a mechanism of action, 2) it should establish optimal conditions for applying the 45 cell-based intervention (e.g. dose, co-interventions); 3) it should demonstrate ability to 46

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modify disease or injury when applied in suitable animal systems, and 4) such disease 1 modification or injury control is of sufficient magnitude and durability to be clinically 2 meaningful. 3 4 The need for animal models is especially strong in the case of extensive ex vivo manipulation 5 of cells and/or when the cells have been derived from pluripotent stem cells. It should be 6 acknowledged, however, that preclinical assays including studies in animal models may 7 provide limited insight into how transplanted human cells will behave in human recipients 8 due to the context- dependent nature of cell behavior and the recipient’s immune response. 9 10 Small animal studies 11 Recommendation 3.2.3.2: Small animal models should be used to assess the 12 morphological and functional recovery caused by cell-based interventions, the 13 biological mechanisms of activity, and to optimize implementation of an intervention. 14 15 Immune-deficient rodents can be especially useful to assess human cell transplantation 16 outcomes, engraftment in vivo, stability of differentiated cells, and cancer risk. Many small 17 animal models of disease (for example rodents) can faithfully reproduce aspects of human 18 diseases, although there are considerable limitations. Small animal studies should also use 19 standard potency assays that quantify cell numbers required for large animal studies and 20 subsequent trials. 21 22 Large animal studies 23 Recommendation 3.2.3.3: Large animal models should be used for stem cell research 24 related to diseases that cannot be sufficiently addressed using small animal models 25 where anatomical factors are relevant for evaluation, where large animals are believed 26 to better emulate human pathology than small animal models, or where risks of 27 anticipated human clinical trials are high. 28 29 Large animals are often better representations of clinical systems insofar as they are often 30 genetically outbred, anatomically more similar, and generally immunocompetent. They 31 provide occasions to test co-interventions used in trials (e.g. adjunctive immunosuppressive 32 drug therapy) or the compatibility of surgical devices cell products. They also may be 33 essential to evaluate issues of scale up, or anatomical factors that are likely to mediate a 34 therapeutic effect (e.g. bone in a load-bearing model). 35 36 The need for invasive studies in non-human primates should be evaluated on a case-by-case 37 basis, and performed only if trials are expected to present high risk, and where nonhuman 38 primates are expected to provide information about cell-based interventions not unobtainable 39 with other models. 40 41 All studies involving the use of non-human primates must be conducted under the close 42 supervision of qualified veterinary personnel with expertise in their care and their unique 43 environmental needs. Particular care should be taken to minimize suffering and maximize 44 the value of studies by using rigorous designs and reporting results in full. 45

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3.2.4 Transparency and Publication 1 Recommendation 3.2.4.1: Sponsors, researchers, and clinical investigators should 2 publish preclinical studies in full, and in ways that enable an independent observer to 3 interpret the strength of the evidence supporting the conclusions. 4 5 Publication of preclinical studies serves many ends. It enables peer review of clinical 6 research programs, thus enhancing risk/benefit in trials. It redeems the sacrifice of animals 7 by disseminating findings from studies. It enables more sophisticated interpretation of 8 clinical trial results. It also makes possible the evaluation of preclinical models and assays, 9 thus promoting a more effective research enterprise. Many studies show biased patterns of 10 preclinical publication. Preclinical studies should be reported in full regardless of whether 11 they confirm, disconfirm, or are inconclusive with respect to the hypothesis they are testing. 12 The Guidelines recognize that publication may reveal commercially sensitive information 13 and therefore allow for a reasonable delay. Nevertheless, preclinical studies supporting a 14 trial should be published before the first report of trials. Animal studies should be published 15 according to well-recognized standards, such as ARRIVE criteria- (Animal Research: 16 Reporting In Vivo Experiments; these reporting guidelines have been endorsed by leading 17 biomedical journals).(Kilkenny C et al., 2010) 18

3.3 Clinical Research 19 20 Clinical research and trials of experimental interventions are an essential step in translating 21 cell-based treatments. However, they require participation of human subjects, whose rights 22 and welfare must be protected. They also generate information that will be used to guide 23 important decisions for patients, clinician scientists and policy makers. The integrity of this 24 information must be safeguarded. 25 26 Sponsors, investigators, host institutions, and regulators bear responsibility for ensuring the 27 ethical conduct of clinical trials. In addition, members of the broader research community 28 have responsibility for encouraging ethical research conduct. As with all clinical research, 29 clinical trials of stem cell-based interventions must follow internationally accepted principles 30 governing the ethical design and conduct of clinical research and the protection of human 31 subjects. (Department of Health and Education and Welfare, 1979; European Parliament and 32 Council of the European Union, 2001; World Medical Association, 1964) Key requirements 33 include adequate preclinical data, oversight, peer review by an expert panel independent of 34 the investigators and sponsors, fair subject selection, informed consent, research subject 35 monitoring, auditing of study conduct, trial registration and reporting. However, there are a 36 number of important stem cell-related issues that merit special attention. 37 38 Some interventions, like assisted reproduction technologies, present challenges for standard 39 trial designs and may be better evaluated using registries and innovative care pathways. 40 Such pathways should nevertheless involve a prespecified protocol, independent review for 41 scientific merit and ethics, and a plan for reporting. What follows in this section pertains to 42 trials as well as observational studies and innovative care pathways. 43

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3.3.1 Oversight 1 The overarching goals of research oversight is to ensure that a clinical trial is likely to be 2 safe, protect human subjects, have scientific merit, and that it is designed and carried out in a 3 manner that will yield credible data that will enhance scientific and medical understanding. 4 5 Prospective Review 6 Recommendation 3.3.1.1: All studies involving clinical applications of stem cell based 7 interventions must be subject to prospective review, approval, and ongoing monitoring 8 by independent human subjects committees.1 9 10 Independent prospective review is critical for establishing the ethical basis of systematic 11 human investigation, regardless of funding source. It minimizes conflicts of interest (both 12 financial and non-financial) that can prejudice research design; it maximizes the alignment of 13 the goals of the research with the subjects’ rights and welfare; and it promotes valid informed 14 consent. 15 16 Independent evaluation may also occur through other groups, including granting agencies, 17 local peer review, ethics committees, and data and safety monitoring boards. To initiate stem 18 cell-based clinical trials, investigators must follow and comply with local and national 19 regulatory approval processes. 20 21 Expert Review of Trials 22 Recommendation 3.3.1.2: The review process for stem cell-based clinical trials should 23 ensure that protocols are vetted by independent and disinterested experts who are 24 competent to evaluate (a) the in vitro and in vivo preclinical studies that form the basis 25 for proceeding to a trial and (b) the design of the trial, including the adequacy of the 26 planned end-points of analysis, statistical considerations, and disease-specific issues 27 related to human subjects protection. 28 29 Peer review should also judge whether the proposed stem cell-based clinical study is likely to 30 lead to important new knowledge or an improvement in health. Comparing the relative value 31 of a new stem cell intervention to established modes of therapy is integral to the review 32 process. Peer-review should be informed where feasible by a systematic review of existing 33 literature. If decisions must be made based solely on expert opinion because no relevant 34 literature is available, this should be described explicitly in the recommendations regarding a 35 particular study. 36

3.3.2 Standards for Ethical Conduct 37 Systematic Appraisal of Evidence 38 Recommendation 3.3.2.1: Launch of trials should be supported by a systematic 39 appraisal of evidence supporting the intervention. 40 Systematic review ensures that decision-making is supported by a transparent and complete 41 synthesis of evidence. It should consist, at a minimum, of a synthesis of unpublished studies 42 provided by the investigators, as well as a systematic search and synthesis of published 43

1 In some jurisdictions these are known as research ethics committees, institutional review boards, research ethics boards, and ethics committees.

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studies testing the intervention in animal systems. For early phase studies, such systematic 1 review will mostly involve synthesizing basic and preclinical investigations; for late stage 2 studies, systematic review is supplemented by clinical evidence. Systematic review should 3 also be informed by accessing and synthesizing findings involving the testing of similar 4 intervention strategies. Trial brochures should summarize the information gathered from 5 systematic review without any bias. 6 7 Risk-Benefit Analysis 8 Recommendation 3.3.2.2: Risks should be identified and minimized, unknown risks 9 acknowledged, and potential benefits to subjects and society estimated. Studies must 10 anticipate a favorable balance of risks and benefits. 11 12 Efficient designs that minimize risks and include the smallest number of subjects to properly 13 answer the scientific question(s) at hand should be employed. To minimize risks, eligibility 14 criteria in prelicensure stages should be designed with consideration of potential co-15 morbidities that may increase risk or modify the risk-benefit ratio. Studies should have 16 appropriate correlative studies to ensure that the maximum possible information on the safety 17 and activity of the approach being tested is obtained from each research subject. 18 19 Research Subjects Lacking Consent Capacity 20 Recommendation 3.3.2.3: When testing interventions in populations that lack capacity 21 to provide valid informed consent, risks from study procedures should be limited to no 22 greater than minor increase over minimal risk unless procedure risks are exceeded by 23 the prospect of therapeutic benefit. 24 25 Stem cell clinical trials frequently involve populations- like children or persons with 26 advanced central nervous system disorders- who lack capacity to provide valid informed 27 consent. Because such individuals cannot protect their own interests, they require extra 28 protections from research risk. This recommendation pertains to risks that lack a therapeutic 29 justification- for example, tissue biopsies to test biodistribution, sham procedures, or 30 withdraw of standard treatments to monitor response during unmedicated periods. Such 31 procedures should not exceed minor increase over minimal when trial populations lack 32 capacity to provide valid informed consent. Because definitions of minimal risk vary by 33 jurisdiction, researchers should adhere to policies defined by local institutional review 34 committees, or otherwise consider minimal risk as “risk that is no greater than that associated 35 with routine medical or psychological examination”. 36 37 Objectives of Trials 38 Recommendation 3.3.2.4: A stem cell-based intervention must aim at being clinically 39 competitive with or superior to existing therapies or occupy a unique therapeutic niche. 40 Being clinically competitive necessitates having reasonable evidence that the nature of 41 existing treatments pose some type of burden related to it that would likely be overcome 42 with the cell-based intervention should it prove to be safe and efficacious. 43 44 Genetic and acquired diseases differ widely in their degree of disability, morbidity, and their 45 available therapeutic options. These facts have a crucial impact on the decision to proceed to 46

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clinical application with a novel stem cell-based approach, which is itself experimental and 1 risky. 2 3 Subject Selection. 4 Recommendation 3.3.2.5: Individuals who participate in clinical stem cell research 5 should be recruited from populations that are in a position to benefit from the results of 6 this research. Groups or individuals must not be excluded from the opportunity to 7 participate in clinical stem cell research without rational justification. 8 9 Well-designed clinical trials and effective stem cell-based therapies should be accessible to 10 patients without regard to their financial status, insurance coverage, or ability to pay. In stem 11 cell-based clinical trials, the sponsor and principal investigator should make reasonable 12 efforts to secure sufficient funding so that no person who meets eligibility criteria is 13 prevented from enrollment because of his or her inability to cover the costs of the 14 experimental treatment. 15 16 Informed Consent. 17 Recommendation 3.3.2.6: Informed consent must be obtained from potential subjects or 18 their legally authorized representatives. Reconsent of subjects is warranted if 19 substantial changes in risks or benefits of a study intervention or alternative treatments 20 emerge over the course of investigation. 21 22 Culturally sensitive, voluntary informed consent is a necessary component in the ethical 23 conduct of clinical research and the protection of human subjects. Subjects should be made 24 aware that their participation is voluntary and not necessary for their continued clinical care, 25 and that participation or non-participation will not interfere with their ongoing clinical care. 26 In addition, consent discussions should emphasize that once the therapy is given it cannot be 27 retrieved or removed. Specific consent challenges in early phase trials are discussed below. 28 29 Assessment of Capacity 30 Recommendation 3.3.2.7: Prior to obtaining consent from potential subjects who have 31 diseases or conditions that are known to affect cognition, their capacity to consent 32 should be assessed formally. 33 34 Subjects and their conditions should not be excluded from biomedical advances involving 35 stem cells. At the same time, such subjects should be recognized as especially vulnerable, 36 and steps should be taken to involve guardians or surrogates who are qualified and informed 37 to make surrogate research judgments and to provide other protections. 38 39 Privacy 40 Recommendation 3.3.2.8: Research teams should make strong efforts to preserve the 41 privacy of study subjects. 42 43 Privacy is an important value in many settings. Moreover, there are longstanding professional 44 obligations to maintain confidentiality in medical care and research. Given the high profile of 45 many stem cell-based intervention trials, it is particularly important for research teams to take 46

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steps to protect the privacy of research subjects. For instance, research data should 1 maintained in secure charts or databases with access restricted to study staff and agencies 2 who have a regulatory right to review charts. 3 4 Patient Funded Trials 5 Recommendation 3.3.2.9: Patient sponsorship is an acceptable funding mechanism 6 provided studies are independently reviewed for scientific merit, integrity and priority. 7 8 Patient-funded trials present opportunities for patients to directly engage in the research 9 process and fund work that public and industry sponsors are unwilling to undertake. 10 Nevertheless, they present ethical and policy challenges. Patient funders may press for study 11 designs that eliminate design elements, like randomization to a comparator arm, eligibility or 12 exclusion criteria that are critical for promoting scientific validity and patient welfare. 13 Patient funders might also lack the skill to distinguish meritorious protocols from those that 14 are scientifically dubious. Finally, patient-funded trials may divert resources- such as study 15 personnel- from research activities that advance more promising research avenues, or that 16 serve less privileged populations. The above liabilities should be managed by requiring that 17 patient-funded trial protocols undergo independent review for scientific rationale, priority 18 and design. While input from patient communities can greatly enhance the research process, 19 decisions concerning the launch, design, conduct, analysis and reporting of studies should be 20 insulated from the influence of patient funders. 21

3.3.3 Issues Particular to Early Phase Trials 22 Initiation of clinical development is a pivotal step in translation. It provides the first 23 opportunity to evaluate methods and effects in human beings. It also represents the first 24 occasion where human beings are exposed to an unproven intervention. Because early phase 25 studies of cell-based interventions involve high levels of uncertainty, investigators, sponsors, 26 and reviewers may have very different views about the adequacy of preclinical support for 27 trial initiation. 28 29 Consent in Early Phase Trials 30 Recommendation 3.3.3.1: Consent procedures in any prelicensure phase- but especially 31 early phase trials of cell-based therapies should work to dispel research subject 32 overestimation of benefit and therapeutic misconception. 33 34 Early phase trials involving cell-based interventions generally enroll research subjects who 35 have exhausted standard treatment options. In many cases, as in the case of cardiac studies, 36 trials enroll individuals who have just experienced a life-altering medical event. Such 37 individuals may be prone to overestimating the therapeutic value of study participation, 38 overlooking the implications of study participation, or mistaking demarcated research 39 procedures for therapeutic ones (“therapeutic misconception”). Investigators should make 40 particular efforts to ensure that informed consent is valid. Among approaches that might be 41 considered are: conducting informed consent discussions that include an individual who is 42 independent of the research team; explaining to prospective subjects that major therapeutic 43 benefits in early phase studies are exceedingly rare; testing prospective subjects on 44 comprehension before accepting their consent; requiring a “cooling off” period between 45 provision of consent discussions and acceptance of consent; avoiding language that has 46

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therapeutic connotations (e.g. using words like “agent” or “cells,” rather than “therapy;” and 1 supplementing consent forms with additional educational materials. Resources for drafting 2 consent forms in early phase trials can be found at the National Institutes of Health Office of 3 Biotechnology Activities.(National Institutes of Health, 2014) 4 5 Pacing of Testing 6 Recommendation 3.3.3.2: In general, initial tests of a novel strategy should be tested 7 under lower risk conditions (e.g. low dose, less risky delivery procedure; less aggressive 8 co-interventions) before escalating to higher risk study conditions that are more likely 9 to confer therapeutic benefit. 10 11 The approach of risk escalation enables researchers to refine and test techniques before 12 advancing towards more aggressive strategies. It also helps to minimize the prospect of 13 catastrophic events that might undermine confidence in development in cell-based 14 interventions. Investigators should generally begin at lower doses and stagger testing. 15 Researchers should also generally validate safety and techniques in research subjects with 16 advanced disease before testing their products in research subjects with more recent disease 17 onset. There may nevertheless be situations where, because of delivery or disease target, a 18 cell product is not suitable for initial evaluation in individuals with advanced disease. 19 20 Maximizing Value 21 Recommendation 3.3.3.3: Researchers should take measures to maximize the scientific 22 value of early phase trials. 23 24 Most interventions tested in early phase trials do not eventually show safety and efficacy. 25 However, even unsuccessful translation efforts return a wealth of information for developing 26 cell-based interventions. Early phase researchers should take several steps to maximize what 27 is learned in early phase trials. First, where possible they should design studies that employ 28 pharmacodynamic components. These help researchers to determine whether cells have 29 reached or engaged their targets. Second, they should include standardized assays, 30 endpoints, or methods. This enables researchers to synthesize results from individual, 31 statistically underpowered trials (see chapter 5.1). Third, researchers should publish trials, 32 methods, and sub-analyses in full. Studies show that many aspects of early phase studies are 33 incompletely reported.(Camacho et al., 2005; Freeman and Kimmelman, 2012) Last, where 34 resources permit, researchers should bank tissues and/or approach research subjects or 35 families for permission to perform an autopsy in the event of death (see 3.3.5.3). 36

3.3.4 Issues Particular to Late Phase Trials 37 Late phase trials are aimed at providing decisive evidence of clinical utility. They do this by 38 using clinical measures of benefit, and by monitoring response over a longer, more clinically 39 relevant period. To protect the ability to draw valid conclusions about clinical benefit, late 40 phase trials generally use randomization and comparator arms. The choice of comparator 41 presents some distinctive ethical challenges in the context of stem cell-based interventions. 42 43 Choice of Comparators. 44

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Recommendation 3.3.4.1: Clinical research should compare new stem cell-based 1 interventions against the best therapeutic approaches that are currently or could be 2 made reasonably available to the local population. 3 4 The ISSCR recognizes that stem cell research is an international endeavor where local 5 standards of care differ dramatically. Due consideration should be given to achieve best 6 optimal care in a given locale, taking into consideration legitimate factors that impact on the 7 quality of care available locally. Trials should not be conducted in a foreign country solely to 8 benefit patients in the home country of the sponsoring agency. The test therapy, if approved, 9 should realistically be expected to become available to the population participating in the 10 clinical trial through existing health systems or those developed on a permanent basis in 11 connection with the trial. In addition, research should be responsive to the health needs of 12 the country in which it is conducted. For a trial with comparison arms, it may be justified to 13 perform a study comparing the stem cell-based approach with the best locally achievable 14 treatment and follow-up, if the local risk-benefit consideration allows. 15 16 Sham Comparators 17 Recommendation 3.3.4.2: Where there are no proven effective treatments for a medical 18 condition and stem cell-based interventions involve invasive delivery, it may be 19 appropriate to test them against placebo or sham comparators, assuming early 20 experience has demonstrated feasibility and safety of the particular intervention. 21 22 If early phase trials appear to demonstrate safety and efficacy, there may be compelling 23 scientific reasons to justify a placebo or sham arm. In all such cases, the choice of a control 24 arm should be explicitly justified. 25

Rigorous and internally valid evaluations of cell-based interventions may require randomized 26 trials in which “sham” procedures are employed as comparators. However, sham procedures 27 are burdensome and have no direct benefit for research subjects. Use of sham comparators is 28 only appropriate when they are crucial for a study’s internal validity, when studies are 29 adequately powered, and where researchers have minimized burdens by using the least 30 invasive sham option available. In addition, researchers should ensure that the validity 31 advantages of sham procedures are not undone by protocol flaws (e.g., factors that could 32 unblind research subjects or investigators). 33

Researchers should take particular care explaining the use of placebos or sham procedures 34 during the informed consent process. 35

3.3.5 Research Subject Follow-Up and Trial Monitoring 36 Data Monitoring 37 Recommendation 3.3.5.1: An independent data-monitoring plan is required for clinical 38 studies. When deemed appropriate, aggregate updates should be provided at 39 predetermined times or on demand. Such updates should include adverse event 40 reporting and ongoing statistical analyses if appropriate. Data monitoring personnel 41 and committees should be independent from the research team. 42

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Risk/benefit can change over the course of investigation, as safety and response is observed, 1 recruitment flags, or as new treatments become available. This is especially true for stem 2 cell based intervention trials, which are characterized by high uncertainty and rapidly 3 evolving science. The welfare of subjects must be carefully monitored throughout the 4 duration of stem cell-based clinical trials, study conduct interrupted if risk/benefit becomes 5 unfavorable, and subjects must be informed of new information about themselves, the trial, 6 or the intervention that might materially affect their continued participation in a study. 7 8 Long term follow-up 9 Recommendation 3.3.5.2: Subject withdrawal from the research should be done in an 10 orderly fashion to promote physical and psychological safety. Given the potential for 11 transplanted cellular products to persist, and depending on the nature of the 12 experimental stem cell-based intervention, subjects should be advised to undergo long-13 term health monitoring. Additional safeguards for ongoing research subject privacy 14 should be provided. 15 16 Long-term follow up provides an opportunity to monitor the emergence of late adverse 17 events, or the durability of benefit. Given the practical realities, conducting long-term 18 follow-up may be challenging. Investigators should develop and adopt measures to maintain 19 contact with research subjects. In addition, funding organizations should be encouraged to 20 develop mechanisms for supporting long-term follow-up. 21 22 Autopsy 23 Recommendation 3.3.5.3: To maximize the opportunities for scientific advance, 24 research subjects in cell-based intervention studies should be asked, in the event of 25 death, for consent to a partial or complete autopsy to obtain information about cellular 26 implantation and functional consequences. Requests for an autopsy must consider 27 cultural and familial sensitivities. Researchers should strive to incorporate a budget for 28 autopsies in their trials and develop a mechanism to ensure that these funds remain 29 available over long time horizons if necessary. 30 31 Though a delicate issue, access to post mortem material substantially augments the 32 information coming out of trials, enabling future product/delivery refinements in the treated 33 condition. Since consent for autopsy is typically obtained from the family members of 34 someone who has died, investigators should facilitate discussion of this issue among subjects 35 and appropriate family members well ahead of any predictable terminal event. 36

3.3.6 Stem Cell-Based Medical Innovation 37 Historically, many medical innovations have been introduced into clinical practice without a 38 formal clinical trials process. Some innovations have resulted in significant and long-lasting 39 improvements in clinical care, while others have been ineffective or harmful. In contrast to 40 the marketing of unproven stem cell interventions noted in Section 3.4, the ISSCR 41 acknowledges that in some very limited cases, clinicians may be justified in attempting 42 medically innovative stem-cell based interventions in a small number of their seriously ill 43 patients. 44 45

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In the case of medical innovations using stem cells and their direct derivatives, unique 1 considerations justify a heightened level of caution. The diseases which potentially could be 2 targeted by stem cell-based interventions are some of the most intractable ones confronting 3 clinicians – and interest in stem cell research has resulted in the organization of patient 4 communities with high hopes for the prospect of future stem cell treatments. Due to their 5 relative novelty in science, stem cells and their direct derivatives could behave more 6 unpredictably when delivered to patients than either drugs used off-label or modified surgical 7 techniques. Some attempts at medical innovation using stem cells and their direct derivatives 8 may inadvertently violate physicians’ ethical obligation to “do no harm,” by producing more 9 injury than benefit. 10 11 Innovative medical care and clinical research aim at different goals. The mere fact that a 12 procedure is medically innovative does not qualify it as clinical research. Clinical research 13 aims to produce generalizable knowledge about new cellular or drug treatments, or new 14 approaches to surgery. Notably, the individual patient’s benefit is not the focus of clinical 15 research, nor is the individual patient’s benefit the primary focus of the human subjects 16 research committees overseeing clinical research. In contrast, medical innovations do not 17 aim to produce generalizable knowledge but are aimed primarily at providing new forms of 18 clinical care that have a reasonable chance of success for individual patients with few or no 19 acceptable medical alternatives. Unlike clinical research, then, the main goal of innovative 20 care is to improve an individual patient’s condition. 21 22 Although attempting medically innovative care is not research per se, it should still be 23 subject to scientific and ethical review and proper research subject protections. This is 24 especially true when stem cell-based medical innovation provided to a small number of 25 patients is considered promising enough to be applied to larger numbers of patients. At this 26 critical stage of discovery and refinement of clinical practice, it is incumbent upon the 27 practitioner to invite scrutiny by external experts in the form of peer review, institutional 28 oversight, and presentation of observations and data in peer-reviewed medical publication so 29 that the knowledge can benefit all. 30 31 Given the many uncertainties surrounding the infusion of cells in ectopic locations and the 32 significant challenges to the processing and manufacture of cellular products, only in 33 exceptional circumstances does the ISSCR believe it would be acceptable to attempt medical 34 innovations involving stem cells and their direct derivatives. Given the experimental and 35 highly uncertain nature of such interventions, providers should under no circumstances 36 promote, advertise, attempt general recruitment of patients, or commercialize such 37 interventions — if the goal is to develop generalizable knowledge, such interventions should 38 be made the subject of a controlled, registered clinical trial. 39 40 Provision of innovative care 41 Recommendation 3.3.6.1: Clinician-scientists may provide unproven stem cell-based 42 interventions to at most a very small number of patients outside the context of a formal 43 clinical trial, provided that: 44

a) there is a written plan for the procedure that includes: 45

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i. scientific rationale and justification explaining why the procedure has a 1 reasonable chance of success, including any preclinical evidence of proof-2 of- principle for efficacy and safety; 3

ii. explanation of why the proposed stem cell-based intervention should be 4 attempted compared to existing treatments; 5

iii. full characterization of the types of cells being transplanted and their 6 characteristics as discussed in Section 3.1, Cell Processing and 7 Manufacture; 8

iv. description of how the cells will be administered, including adjuvant 9 drugs, agents, and surgical procedures; and 10

v. plan for clinical follow-up and data collection to assess the effectiveness 11 and adverse effects of the cell therapy; 12

b) the written plan is approved through a peer review process by appropriate 13 experts who have no vested interest in the proposed procedure; 14

c) the clinical and administrative leadership supports the decision to attempt the 15 medical innovation and the institution is held accountable for the innovative 16 procedure; 17

d) all personnel have appropriate qualifications and the institution where the 18 procedure will be carried out has appropriate facilities and processes of peer 19 review and clinical quality control monitoring; 20

e) voluntary informed consent is provided by patients who appreciate that the 21 intervention is unproven and who demonstrate their understanding of the risks 22 and possible benefits of the procedure; 23

f) there is an action plan for adverse events that includes timely and adequate 24 medical care and if necessary psychological support services; 25

g) insurance coverage or other appropriate financial or medical resources are 26 provided to patients to cover any complications arising from the procedure; and 27

h) there is a commitment by clinician- scientists to use their experience with 28 individual patients to contribute to generalizable knowledge. This includes: 29

i. ascertaining outcomes in a systematic and objective manner; 30 ii. a plan for communicating outcomes, including negative outcomes and 31

adverse events, to the scientific community to enable critical review (for 32 example, as abstracts to professional meetings or publications in peer-33 reviewed journals); and 34

iii. moving to a formal clinical trial in a timely manner after experience 35 with at most a few patients. 36 37

Not following such standards may exploit desperate patients, undermine public trust in stem 38 cell research, and unnecessarily delay better-designed clinical trials. Many who provide stem 39 cell-based therapies may claim that they offer innovative medical care not available in other 40 medical institutions because of the conservative nature of medical care. Strict application of 41 the above criteria to many clinical interventions offered outside of a formal clinical trial will 42 identify significant shortcomings that should call into question the legitimacy of the 43 purported attempts at medical innovation. 44 45

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3.3.7 Transparency and Reporting of Research Results 1 Registration 2 Recommendation 3.3.7.1: All trials should be prospectively registered in public 3 databases. 4 5 The registration of trials provides a key mechanism for promoting unbiased reporting of 6 trials. It offers transparency regarding promising stem cell based interventions, so that the 7 scientific community can monitor these efforts and incorporate them into future efforts, 8 thereby minimizing risk and maximizing benefits of clinical trials. In addition, registration 9 promotes access to clinical trials for patients who might not otherwise have a means of 10 knowing about them. 11 12 Reporting 13 Recommendation 3.3.7.2: Investigators should report adverse events, including their 14 severity and their potential causal relationship with the experimental intervention. 15 16 Knowing the safety profile of stem cell based interventions is critical for effective translation. 17 Timely analysis of safety information is also crucial for reducing the uncertainties 18 surrounding stem cell-based interventions. Unfortunately, many studies report deficiencies 19 in adverse event reporting for novel therapeutics.(Saini et al., 2014) Researchers should 20 report adverse events associated with cells, procedures, and all other aspects of the 21 intervention; when relevant, they should also actively report the absence of serious or fatal 22 adverse events. 23 24 Publication 25 Recommendation 3.3.7.3: Researchers should promptly publish aggregate results, 26 regardless of whether they are positive, negative or inconclusive. Studies should be 27 published in full and according to international reporting guidelines where applicable. 28 29 Publication of all results and analyses, regardless of whether an agent is advanced to further 30 translation or abandoned, is strongly encouraged to promote transparency in the clinical 31 translation of cell-based therapies, to ensure development of clinically effective and 32 competitive stem cell-based therapies, to prevent participants in future clinical trials from 33 being subjected to unnecessary risk, and to respect subject volunteers. As such, reporting 34 must be timely and accurate. Researchers should also consider ways to share individual 35 research subject data- provided adequate privacy protections for research subjects can be 36 assured. A recent U.S. Institute of Medicine Report(Institute of Medicine, 2015) offers 37 principles on data sharing- researchers, sponsors and others should adhere to these principles. 38 39 If the particular project can be described according to internationally recognized reporting 40 guidelines, this format should be used. For example, researchers should report all 41 randomized trials according to CONSORT; see also chapter 5.(Begg et al., 1996) Journal 42 editors have a role to play in facilitating publication of inconclusive and disconfirmatory 43 findings. 44 45

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3.4 Clinical application 1 2 As is the case with other forms of medicine, stem cell-based interventions may be introduced 3 into clinical use upon the completion of clinical studies that establish a risk–benefit balance 4 appropriate to the medical condition and patient population for which they are intended. 5 Processes for determining the safety and efficacy of any stem cell-based intervention set 6 forth in the preceding sections should be followed as a consensus standard by the research 7 and medical communities. 8 9 However, even after clinical studies of the highest standard have been completed and 10 regulatory approval pathways cleared, close attention must be paid to ensuring the safety and 11 effectiveness of interventions that have entered routine or commercial clinical use, and the 12 fairness of access in a manner consistent with local legal requirements and standards and the 13 standards of ethical, evidence-based medicine. These standards include ongoing monitoring 14 of safety and outcomes, and ensuring accessibility to those who have the most pressing 15 clinical need. 16 17 Warning on the marketing of unproven stem cell interventions 18 The ISSCR condemns the administration of unproven stem cell-based interventions outside 19 of the context of clinical research or medical innovation compliant with the guidelines in this 20 document, particularly when it is performed as a business activity. Scientists and clinicians 21 should not participate in such activities as a matter of professional ethics. For the vast 22 majority of medical conditions for which putative 'stem cell therapies' are now being 23 marketed, there is insufficient evidence of safety and efficacy to justify routine or 24 commercial use. Numerous cases of serious adverse events subsequent to such procedures 25 have been reported, and the long-term safety of most cell-based interventions remains 26 undetermined. The premature commercialization of unproven stem cell treatments, and other 27 cell-based interventions inaccurately marketed as containing or acting on “stem cells,” not 28 only puts patients at risk, it also represents one of the most serious threats to the stem cell 29 research community, as it may jeopardize the reputation of the field and cause confusion 30 about the actual state of scientific and clinical development. Government authorities and 31 professional organizations are strongly encouraged to establish and strictly enforce 32 regulations governing the introduction of stem cell-based medical interventions into 33 commercial use. 34

3.4.1 Issues in clinical use 35 Bio- and Pharmacovigilance 36 Recommendation 3.4.1: Developers, manufacturers, providers and regulators of stem 37 cell-based interventions should continue to systematically collect and report data on 38 safety, efficacy, and utility after they enter clinical use. 39 40 Stem cell based interventions can remain biologically active for long periods, and thus may 41 present risks with long latencies. Additionally, stem cells and their derivatives can exhibit a 42 range of dynamic biological activities and therefore be potentially difficult to predict and 43 control. These may lead to pathologies including tumorigenesis, hyperplasia, and the 44 secretion of bioactive factors that may exert secondary effects on physiological processes 45 such as inflammation or immune response. Some types of stem cells are capable of migration 46

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after transplantation, meaning there is a risk of off-target effects and inappropriate 1 integration. Further, tracking the locations of transplanted cells may be impossible using 2 current technologies. 3 4 For these reasons, monitoring patients’ overall health status over the long term is critical, and 5 plans for the funding and conduct of long-term monitoring should be incorporated into study 6 protocols early in the development of new interventions. These monitoring activities may 7 include systematic post-market studies, event and outcome reporting by providers and/or 8 patients, patient registries, and/or economic analyses of comparative effectiveness. Results of 9 such monitoring activities should be promptly reported to regulatory authorities and the 10 medical community. 11 12 Patient Registries 13 Recommendation 3.4.2: Registries of specific patient populations can provide valuable 14 data on safety and outcomes within defined populations. However, they should not be 15 used as a substitute for stringent evaluation through clinical trials prior to introduction 16 into standard care. 17 18 Patient registries designed to collect secondary safety and outcome data within a population 19 of patients can complement clinical trials. However, registries should not substitute for 20 rigorous scientific testing, as the introduction of untested interventions involves unacceptable 21 risk to patients and threatens the integrity of science-based medicine. Stakeholders in stem 22 cell-based therapeutics, including researchers, physicians, regulatory bodies, industry, and 23 patient and disease advocacy groups, should cooperate to develop safety and outcome 24 registries to collect additional data on stem cell-based interventions that have been validated 25 for clinical use. 26 27 Off-label use 28 Recommendation 3.4.3: Off-label uses of stem cell-based interventions should be 29 employed with particular care, given uncertainties associated with stem cell-based 30 interventions. 31 32 Physicians often use interventions for indications or patient populations other than those for 33 which they have been shown to be safe and efficacious. Such “off-label” applications 34 constitute a common aspect of medical practice. Nevertheless, they present distinctive 35 challenges for stem cell-based interventions. 36 37 First, depending on the jurisdiction, many stem cell based interventions are not covered by a 38 label due to exemption from regulation. This can limit physicians' access to reliable 39 information on validated uses. Second, the complex and novel biological properties of living 40 cells present uncertainties about long-term safety and effectiveness. Physicians should 41 therefore exercise particular care when applying stem cell-based interventions off-label. As a 42 rule, off-label use should be offered only when supported by high quality evidence, or in 43 situations consistent with current scientific knowledge, local legal and institutional 44 regulations, and the standards of the international medical community. 45 46

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As a general principle, physicians should conduct controlled, supervised studies of approved 1 interventions for unapproved uses. Patients must be informed in advance if a proposed off-2 label use has not been evaluated for safety and/or efficacy with respect to their specific 3 medical condition. 4

3.4.2 Access and Economics 5 Support for stem cell research depends in part on its potential for advancing scientific 6 knowledge, which may result in the development of clinical applications. As such, 7 institutions, researchers, and providers in both the public and private sectors have a 8 responsibility to attend to issues of public benefit, and specifically to ensure that research 9 findings and benefits thereof are accessible to the international scientific community and, 10 importantly, to those in need. The stem cell research community benefits from providing 11 patients and the general public access to scientific information, opportunities to participate in 12 clinical research, and treatment. For these reasons, research, clinical, and commercial 13 activities should seek to maximize affordability and accessibility. 14 15 Comparative Value for Healthcare Systems and Access Issues 16 Recommendation 3.4.2.1: Stem cell-based interventions should be developed with an 17 eye towards delivering economic value to patients, payers, and health care systems. 18 The selection and delivery of clinical interventions is based on decisions made by patients, 19 health care professionals and payers. Key factors that influence such decisions include the 20 known risks and benefits of available treatment options, individual preferences on the part of 21 patients and treatment providers, and comparative availability and cost. Developers, 22 manufacturers and providers of stem cell-based interventions should recognize that, along 23 with safety, efficacy and accessibility, economic value is an important measure of the overall 24 utility of any therapeutic. They should also participate in studies intended to assess 25 comparative effectiveness, particularly in countries in which such studies are legally 26 mandated. Such studies involve the systematic comparison of currently available therapies 27 for their full range of benefits, and provide important information for medical decision-28 making. 29 30 Pricing 31 Recommendation 3.4.2.2: Developers, funders, providers, and payers should work to 32 ensure that cost of treatment does not prevent patients from accessing stem cell 33 interventions for life-threatening or seriously debilitating medical conditions. 34 35 Sponsors of research aimed at the development of stem cell-based interventions targeting 36 seriously debilitating or life-threatening medical conditions should seek to support access to 37 safe and efficacious therapeutics to any patient in need, irrespective of financial status. 38 Access for participants in clinical research leading to the development of a licensed stem cell 39 therapy is a particular priority. 40 41 Private firms seeking to develop and market stem cell-based interventions should work with 42 public and philanthropic organizations to make safe and effective products available on an 43 affordable basis to disadvantaged patient populations. Government regulators and funders 44 should provide accelerated review, designated funding, or other incentives to support broad 45

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access to products, particularly in cases in which an intervention is developed in whole or in 1 part through public investment. 2 3

4. Public Communications 4 5 Stem cell research has received a great deal of attention from policy makers, the popular 6 press, and popular culture more broadly, including social media. Given its scientific and 7 clinical potential and the controversies that have surrounded the field, this high public profile 8 is understandable. However popular representations are frequently far from ideal. Potential 9 benefits are sometimes exaggerated, and the challenges to clinical application and risks are 10 often understated. Inaccurate or incomplete representations of this sort can have tangible 11 impacts on the expectations of the general public and patient communities, and on the setting 12 of health and science policies. Inaccurate or incomplete representations can also be exploited 13 by companies and individuals advertising stem cells for unproven clinical uses. 14 15 Public Representation of Science 16 Recommendation 4.1: The stem cell research community should ensure that public 17 representations of stem cell research are accurate and balanced. 18 The high level of public and media interest in the field provides stem cell scientists with 19 ample opportunities to communicate their findings through a variety of popular and social 20 media. The research community is encouraged to engage with the public in this way. 21 22 While such opportunities may allow scientists to gain recognition and understanding for their 23 work among non-specialists, they also have the potential to fuel inaccurate public perceptions 24 about the current state of scientific progress, potential for application, and associated risks 25 and uncertainties.(Kamenova and Caulfield, 2015) Scientists, clinicians, science 26 communications professionals at academic and research institutions, and industry 27 spokespersons should strive to ensure that benefits, risks and uncertainties of stem cell 28 science are not misrepresented. 29 30 Care should be taken throughout the science communication process, including in the 31 presentation of results, the promotion of research and translation activities, the use of social 32 media, and any communication with print and broadcast media. Efforts should be made to 33 seek timely corrections of inaccurate or misleading public representations of research 34 projects, achievements, or goals. Scientists should also be particularly careful about 35 disclosing research findings that have not been published in a scientific journal or passed 36 peer review, as premature reporting can undermine public confidence if findings are 37 subsequently disproven. 38 39 Scientists should work closely with communications professionals at their institution to 40 create information resources that are easy to understand without oversimplifying, and that do 41 not underplay risks and uncertainties. Similarly, communications specialists, including 42 journalists, have a responsibility to ensure that any informational materials referring to 43 research achievements adhere to these principles, and that the scientists in charge of 44 correspondence relating to the findings have reviewed and agreed to the content prior to 45

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release; for potentially sensitive or high-profile cases, it is advisable to seek additional 1 comments from independent experts to ensure objectivity and balance. 2 3 Communications about Clinical Trials 4 Recommendation 4.2: When describing clinical trials, investigators, sponsors, and 5 institutions should emphasize that research is primarily aimed at generating systematic 6 knowledge on safety and efficacy, not therapeutic care. 7 8 Human investigations designed to evaluate safety and/or efficacy should not be described 9 using language that might suggest the primary intent as the delivery of care, as this 10 encourages confusion about the risk–benefit profile of study participation (see 3.3.3.1). 11 Communications about ongoing studies should explain that clinical efficacy is not 12 established, and that the results may reveal the intervention to be ineffective or, in some 13 cases, harmful. It is advisable for scientists engaged in clinical research to establish 14 communications with relevant patient and advocacy groups, to promote clear understanding 15 of the clinical research process and the current state of progress in developing stem cell-16 based treatments for specific medical conditions. Additionally, researchers should exercise 17 great care when making forward-looking statements regarding the potential outcome of any 18 study. 19 20 Communications about Clinical Care 21 Recommendation 4.3: The provision of information to patients on stem cell-based 22 interventions must be consistent with the primacy of patient welfare and scientific 23 integrity. 24 25 The provision of accurate information on risks, limitations, possible benefit, and available 26 alternatives to patients is essential in the delivery of healthcare. Provision of clinical 27 information, including recommendations on use, should center on the importance of 28 consultation with medical professionals directly familiar with the individual patient’s case, 29 and the seeking of independent expert opinion. The goal of clinical communications is to 30 enable autonomous, well-informed decision-making by patients. 31 32 Given the novelty of stem cell-based interventions and the fact that many countries do not 33 have well-established regulatory pathways governing introduction into clinical use in, 34 providers should exercise restraint in their communications regarding the clinical utility of 35 such treatments. The use of language that could be construed as promotional, promissory, or 36 suggestive of clinical effectiveness in reference to stem cell-based interventions for which 37 efficacy has not been established is to be avoided. In the event that new stem cell-based 38 interventions are authorized for use for a specified indication, care must be taken to avoid 39 communications that might indicate or suggest to patients that such intervention is 40 efficacious for other indications. 41 42 Regulatory and law enforcement authorities are encouraged to investigate and, when 43 appropriate, restrict unsupported marketing claims made by commercial actors, to the extent 44 that these violate relevant consumer protection, truth in advertising, securities, and commerce 45 laws within a given jurisdiction. 46

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5. Standards in Stem Cell Research 1 2 Translation of cell-based interventions is a collaborative endeavor among scientists, clinics, 3 industry, regulators, and patients. Standards help enable such collaborations, and support 4 efficient clinical translation in many ways. For instance, they allow scientists to compare 5 outcomes of trials and enable clinics to reproduce treatments reported in published studies. 6 Regulatory standards also reduce the costs of uncertainty for private actors, facilitate 7 independent review, and engender trust among patients. 8 9 Standards Development 10 Recommendation 5.1: Researchers, industry and regulators should work towards 11 developing and taking up standards on design, conduct, interpretation, and reporting of 12 research in stem cell science and medicine. 13 14 There are numerous areas where standards development would greatly advance the science of 15 stem cells and its clinical application. Particular opportunities include standards for: a) 16 consent and procurement, b) manufacturing regulations, c) cell potency assays, d) reference 17 materials for calibrating instruments; e) minimally acceptable changes during cell culture, f) 18 method of delivery, and selection of recipients for novel stem cell-based therapies; g) 19 reporting of animal experiments; h) design of trials; i) reporting of trials; j) principles for 20 defining information in datasets as “sensitive” such that there is a justified withholding or 21 delay of study reporting. 22 23 ISSCR encourages scientists, regulators, and other stakeholders to collaborate on timely 24 development of standards for stem cell research and translation. To promote common and 25 universal standards for consent and procurement of biomaterials, the ISSCR has provided 26 template donor consent forms (Appendix 3). 27 28 Revisiting Ethical Guidelines 29 Recommendation 5.2: These guidelines should be periodically revised to accommodate 30 scientific advances, new challenges, and evolving social priorities. 31 32 New ethical challenges in the conduct of stem cell research that are on the horizon must be 33 addressed in a timely manner to ensure that science proceeds in a socially responsible and 34 ethically acceptable fashion. To enhance the likelihood that the international scientific 35 research community will be bound together by a common set of principles governing the 36 performance of stem cell research, these guidelines for basic human pluripotent stem cell 37 research and clinical translation should be updated to reflect emerging evidence, challenges, 38 and values. Given that new forms of biomedical research are rapidly proceeding that either 39 directly or indirectly engage stem cell science and entail production or manipulation of 40 human embryos, institutions must periodically review the categories and jurisdiction of the 41 SCRO mechanism, and other institutional review mechanisms, to ensure that sensitive 42 research is properly covered. Such research includes novel techniques to manipulate the 43 mitochondrial content of human oocytes and embryos, the germline modification of human 44 beings, and the in vitro creation and culture of human embryo-like structures. These areas of 45 research merit careful scientific as well as ethical deliberation, and compel constant vigilance 46

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so that scientific research and clinical practice is conducted with proper independent expert 1 review and reflection. 2 3 4 5 6

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ISSCR GUIDELINES UPDATES TASK FORCE 1 2 Steering Committee 3

Jonathan Kimmelman, PhD, Chair, McGill University, Canada 4

Nissim Benvenisty, MD, PhD, Hebrew University, Israel 5

Timothy Caulfield, LLM, FRSC, University of Alberta, Canada 6

George Daley, MD, PhD, Boston Children's Hospital, USA 7

Helen Heslop, MD, Baylor College of Medicine, USA 8

Insoo Hyun, PhD, Case Western Reserve University School of Medicine, USA 9

Charles Murry, MD, PhD, University of Washington, USA 10

Douglas A. Sipp, Riken Center for Developmental Biology, Japan 11

Lorenz Studer, MD, Sloan-Kettering Institute for Cancer Research, USA 12

Jeremy Sugarman, MD, MPH, MA, Johns Hopkins University, USA 13

14 Members 15

Jane Apperley, MBChB, Imperial College School of Medicine, UK 16

Roger Barker, PhD, MRCP, Cambridge Center for Brain Repair, UK 17

Paolo Bianco, MD, Sapienza University of Rome, Italy 18

Annelien Bredenoord, PhD, University Medical Center Utrecht, Netherlands 19

Christopher Breuer, MD, Nationwide Children's Hospital, USA 20

Marcelle Cedars, MD, University of California San Francisco, School of Medicine, USA 21

Joyce Frey-Vasconcells, PhD, Frey-Vasconcells Consulting, USA 22

Jin, Ying Jin, MD, PhD, Institute of Health Sciences, China 23

Richard T. Lee, MD, Partners Research Facility, USA 24

Chris McCabe, M.Sc., PhD, University of Edmonton, Canada 25

Megan Munsie, PhD, Stem Cells Australia / University of Melbourne, Australia 26

Steven Piantadosi, MD, PhD, Cedars-Sinai, USA 27

Mahendra Rao, MD, PhD, New York Stem Cell Foundation, USA 28

Masayo Takahashi, MD, PhD, RIKEN Center for Developmental Biology, Japan 29

Mark Zimmerman, PhD, Janssen Research and Development LLC, USA 30

31 32

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APPENDICES 1 2 Appendix 1: Position Statement on the Provision and Procurement of Human Eggs for Stem 3

Cell Research 4 5 Appendix 2: Sample Material Transfer Agreement 6 7 Appendix 3: Informed Consent Documents for Obtaining Human Materials for Stem Cell 8

Research 9 10 Appendix 4: Regulations That Govern the Transfer of Cells into Patients 11 12 Appendix 5: Technical Details Pertaining to Cell Sourcing, Manufacture, 13

Standardization, Storage and Tracking 14 15 Appendix 6: Conduct of Animal Studies Using Human Stem Cells 16 17 18 19

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REFERENCES 1

2 (1949). Nuremberg Code. In Trials of War Criminals before the Nuremberg Military 3 Tribunals under Control Council Law No 10, Vol 2 (Washington, DC: U.S. Government 4 Printing Office), pp. 181-182. 5 Banda, E. (2000). Good scientific practice in research 6 and scholarship (European Science Foundation). 7 Begg, C., Cho, M., Eastwood, S., Horton, R., Moher, D., Olkin, I., Pitkin, R., Rennie, D., 8 Schulz, K.F., Simel, D., et al. (1996). Improving the quality of reporting of randomized 9 controlled trials. The CONSORT statement. JAMA : the journal of the American Medical 10 Association 276, 637-639. 11 Camacho, L.H., Bacik, J., Cheung, A., and Spriggs, D.R. (2005). Presentation and 12 subsequent publication rates of phase I oncology clinical trials. Cancer 104, 1497-1504. 13 Department of Health, and Education and Welfare (1979). Report of the National 14 Commission for the Protection of Human Subjects of Biomedical and Behavioral 15 Research (The Belmont Report). 44 Fed. Reg. 23, 192. 16 European Parliament and Council of the European Union (2001). Directive 2001/20/EC 17 of the European Parliament and of the Council of 4 April 2001 on the approximation of 18 the laws, regulations and administrative provisions of the Member States relating to the 19 implementation of good clinical practice in the conduct of clinical trials on medicinal 20 products for human use. (Official Journal of the European Union). 21 Fisher, M., Feuerstein, G., Howells, D.W., Hurn, P.D., Kent, T.A., Savitz, S.I., and Lo, E.H. 22 (2009). Update of the stroke therapy academic industry roundtable preclinical 23 recommendations. Stroke 40, 2244-2250. 24 Flory, J., and Emanuel, E. (2004). Interventions to improve research participants' 25 understanding in informed consent for research: a systematic review. JAMA : the 26 journal of the American Medical Association 292, 1593-1601. 27 Food and Drug Administration (2007). Guidance for Industry: Eligibility Determination 28 for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (U.S. 29 Department of Health and Human Services). 30 Food and Drug Administration (2014). Minimal Manipulation of Human Cells, Tissues, 31 and Cellular and Tissue-Based Products: Draft Guidance (U.S. Department of Health and 32 Human Services). 33 Freeman, G.A., and Kimmelman, J. (2012). Publication and reporting conduct for 34 pharmacodynamic analyses of tumor tissue in early-phase oncology trials. Clinical 35 cancer research : an official journal of the American Association for Cancer Research 18, 36 6478-6484. 37 Henderson, V.C., Kimmelman, J., Fergusson, D., Grimshaw, J.M., and Hackam, D.G. (2013). 38 Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A 39 Systematic Review of Guidelines for In Vivo Animal Experiments. PLoS medicine 10, 40 e1001489. 41 Institute of Medicine (2009). On Being a Scientist: A Guide to Responsible Conduct in 42 Research: Third Edition (Washington, DC: The National Academies Press). 43 Institute of Medicine (2015). Sharing Clinical Trial Data: Maximizing Benefits, 44 Minimizing Risks (Washington, DC: National Academies Press). 45

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Isscr.org (2015). International Society for Stem Cell Research. 1 Kamenova, K., and Caulfield, T. (2015). Stem cell hype: media portrayal of therapy 2 translation. Science translational medicine 7, 278ps274. 3 Kilkenny C, Browne WJ, Cuthill IC, Emerson M, and Altman DG (2010). Improving 4 bioscience research reporting: the ARRIVE guidelines for reporting animal research. 5 Plos Biol 8, e1000412. 6 Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, 7 Darnell RB, Ferrante RJ, Fillit H, et al. (2012). A call for transparent reporting to 8 optimize the predictive value of preclinical research. Nature 490, 187-191. 9 Medicine, A.F.A.B.o.I., Medicine, A.-A.F.A.C.o.P.-A.S.o.I., and European Federation of 10 Internal, M. (2002). Medical professionalism in the new millennium: a physician 11 charter. Annals of internal medicine 136, 243-246. 12 National Institutes of Health (2014). Informed Consent Guidance for Human Gene Trials 13 subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 14 Acid Molecules (Office of Science Policy: Office of Biotechnology Activities). 15 Saini, P., Loke, Y.K., Gamble, C., Altman, D.G., Williamson, P.R., and Kirkham, J.J. (2014). 16 Selective reporting bias of harm outcomes within studies: findings from a cohort of 17 systematic reviews. Bmj 349, g6501. 18 The Committee for Medicinal Products for Human Use (CHMP) (2007). Guideline on 19 Human Cell-Based Medicinal Products (European Medicines Agency ). 20 World Medical Association (1964). Declaration of Helsinki. 21

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