Dear Reader, Comments are being accepted by through 10 September, 2015.

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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 Chair

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Guidelines for Stem Cell Science

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and Clinical Translation

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Draft June 26, 2015

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1. Fundamental Ethical Principles

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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 invitro 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

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stages of human development, human embryos or embryo-derived cells, (2) entails

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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

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production of human gametes in vitro when such gametes are tested by fertilization or

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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

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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

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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

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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 invitro fertility clinical oversight bodies. 45

Forms of research requiring full review include the following activities: 46

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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) Invitro 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

invitro modifications to their nuclear DNA and/or embryos generated from a human 6

gamete that has had its nuclear DNA modified invitro. (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 invitro 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 clarityemerges on both scientific and ethical fronts, the

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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

(16)

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

(17)

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

(18)

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 and3). These informed consent templates may be modified to comply with 40

local laws. See also chapter 5. 41

42 43 44 45

(19)

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

(20)

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

(21)

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

(22)

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

(23)

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, researchersshould 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