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Guidelines for the Clinical Translation of Stem Cells December 3, 2008 www.isscr.org © 2008, International Society for Stem Cell Research
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Preface
The Guidelines for the Clinical Translation of Stem Cells (hereafter Guidelines)
highlight the scientific, clinical, regulatory, ethical, and social issues that should be
addressed so that basic stem cell research is responsibly translated into appropriate
clinical applications for treating patients. The Guidelines offer recommendations
founded on general principles for scientific, clinical, and ethical conduct that
should be followed by all translational stem cell researchers, clinician-scientists, and
regulators in the international community.
The Guidelines pertain to clinical translational research involving products from
human embryonic or other pluripotent stem cells, novel applications of fetal
or somatic (adult) stem cells, and hematopoietic or other stem cells used for
applications outside established standards of care. The Guidelines address three
major areas of translational stem cell research: (a) cell processing and manufacture;
(b) preclinical studies; and (c) clinical research. The Guidelines also address issues
of social justice as they relate to translational stem cell research and access to such
research and clinically established stem cell-based therapies. Detailed technical
information and links to resources are available for scientists, regulators, policy
makers, and patients in the Appendices.
The Guidelines were developed by the Task Force for the Clinical Translation of Stem
Cells, a multidisciplinary group of stem cell researchers, clinicians, ethicists, and
regulatory officials from 13 countries.
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells3
Contents Page
1) Introduction 4
2) Position on Unproven Commercial
Stem Cell Interventions 4
3) Responsibility for Conduct 5
4) Cell Processing and Manufacture 6
5) Preclinical Studies 8
6) Clinical Research 11
7) Stem Cell-Based Medical Innovation 15
8) Considerations of Social Justice 16
9) Ongoing Review of Guidelines 17
10) Acknowledgements 17
11) Appendices 18
Guidelines for the Clinical Translation of Stem Cells www.isscr.org4
1. Introduction • Stem cells and their derivatives may act on several
targets and exert both beneficial and detrimental
Stem cell research holds tremendous promise for the effects, most notably, the risk of ectopic tissue
development of novel therapies for many serious diseases and tumor formation. Thus, preclinical evidence of
and injuries. While stem cell-based treatments have safety is of utmost importance.
been established as a clinical standard of care for some
conditions, such as hematopoietic stem cell transplants • Cellular transplants may persist for many years
for leukemia and epithelial stem cell-based treatments for in patients, or their actions may be irreversible,
burns and corneal disorders, the scope of potential stem thus necessitating careful patient monitoring and
cell-based therapies has expanded in recent years due to extended follow-up.
advances in stem cell research.
• Stem cells may be harvested from donors of
At the same time, the scale of media coverage for early- different ages, sexes, and ethnicities, bearing
stage stem cell research has raised the hopes of many different molecular signatures. The standardization
patients afflicted with currently incurable diseases and of donation procedures and the establishment
disabling conditions. Those involved with testing novel of rigorous quality control for harvested somatic
stem cell-based interventions should be keenly aware that (adult) stem cells have only just commenced.
patients may bring unrealistic expectations to clinical trials
of experimental therapies. Such considerations underscore the need for
independent expert peer review prior to clinical
The public, too, should recognize that in all areas of investigation to ensure the integrity of the research and
medicine, the maturation of an early-phase, experimental informed consent processes.
intervention into an accepted standard of medical practice
is a long and complex process usually involving many 2. Position on Unproven Commercial
years of rigorous preclinical and clinical testing and many Stem Cell Interventions
setbacks and failures. Only with time and experience do
most new clinical treatments come to be accepted by The ISSCR recognizes an urgent need to address the
medical professionals. problem of unproven stem cell interventions being
marketed directly to patients. Numerous clinics around
Attempts to develop a stem cell-based intervention into the world are exploiting patients’ hopes by purporting
an accepted standard of medical practice are particularly to offer new and effective stem cell therapies for
difficult processes for the following reasons. seriously ill patients, typically for large sums of money
and without credible scientific rationale, transparency,
• Stem cells and their direct derivatives represent, oversight, or patient protections. The ISSCR is deeply
in most cases, an entirely novel product, requiring concerned about the potential physical, psychological,
that investigators assist in the design and and financial harm to patients who pursue unproven
development of both the manufacturing process stem cell-based “therapies” and the general lack of
and the assays that assure the safety, purity, scientific transparency and professional accountability
stability, and potency of the final product. of those engaged in these activities.
• Stem cell self-renewal and differentiation are The marketing of unproven stem cell interventions
difficult to control, leading to long experiments is especially worrisome in cases where patients with
with unavoidable heterogeneity in results. severe diseases or injuries travel across borders to
seek treatments purported to be stem cell-based
• Animal models of many diseases do not accurately “therapies” or “cures” that fall outside the realm of
reflect the human disease and toxicological studies standard medical practice. Patients seeking medical
in animals are sometimes poor at predicting toxicity services abroad may be especially vulnerable because
in humans. of insufficient local regulation and oversight of host
clinics. Some locales may further lack a system for
• Transplantation studies where human cells are medical negligence claims, and there may be less
implanted in animals cannot provide full prediction accountability for the continued care of foreign
of immune or other biologic responses to human patients. To help address some of these concerns, the
cells in patients.
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells5
ISSCR offers a patient guide in Appendix 1 to help Recommendation 1: Institutions where preclinical
individuals and their doctors make informed choices or clinical research involving stem cells or their
when contemplating a stem cell-based intervention direct derivatives is performed should take
either locally or abroad. efforts to ensure that investigators are aware of
these Guidelines and other relevant policies and
The ISSCR recognizes a distinction between the regulations and put them into practice.
commercial purveyance of unproven stem cell
interventions and legitimate attempts at medical While there is a need for meticulous oversight of all
innovation outside the context of a formal clinical trial. varieties of clinical research, clinical investigations
Responsible clinician-scientists may have an interest in using stem cell-based products raise unique issues that
providing medically innovative care to a few patients require specialized scientific expertise and a rigorous
using stem cells or their derivatives prior to proceeding scientific and ethical review. Supplementary expertise
to a formal clinical trial. In these circumstances, the in the scientific or ethical issues pertinent to stem cells
ISSCR strongly recommends that clinician-scientists might, for example, be accessed through consultation
follow the policy outlined below in Section 7, Stem with stem cell research oversight (SCRO) committees.
Cell-Based Medical Innovation.
Recommendation 2: Human subjects review
In all other circumstances, the ISSCR condemns the committees must review clinical research involving
administration of unproven uses of stem cells or their (a) products from human embryonic or other
direct derivatives to a large series of patients outside of pluripotent stem cells; (b) novel applications
a clinical trial, particularly when patients are charged of fetal or somatic (adult) stem cells; and (c)
for such services. Scientists and clinicians should not hematopoietic or other stem cells used for
participate in such activities as a matter of professional applications outside established standards of care.
ethics. Health care institutions and research institutions The human subjects review of stem cell-based
should not participate in such activities. Regulators in clinical protocols must enlist stem cell-specific
countries where such illegitimate therapies are offered scientific and ethical expertise. The ISSCR does
have a responsibility to prevent exploitation of patients not anticipate that stem cell research oversight
and, if necessary, to close fraudulent clinics and to take committees will be required to conduct a separate
disciplinary action against the clinicians involved. review, although some members of stem cell
research oversight committees may be used as
The ISSCR recognizes the value of having separate consultants to the human subjects review process.
jurisdictions provide their own regulations covering
medical innovations using stem cells or their direct Given the novelty and unpredictability of early stem
derivatives and strongly recommends the creation of cell-based clinical research, it is of utmost importance
such regulations through consultation with expert that the peer review process be conducted with
scientists, clinicians, and ethicists. Clinician-scientists the highest possible rigor and integrity. Institutional
and their institutions have a duty to follow local human subjects review committees are ultimately
regulations or laws, whenever they exist. responsible for review of clinical trials with stem
cell-based products, and thus to ensure the highest
3. Responsibility for Conduct degree of scientific rigor in the review, should enlist
experts in the review process, and where applicable,
Given the wide variety of stem cell-based interventions work in conjunction with stem cell research oversight
that may be developed, the Guidelines cannot committees (or their independent equivalents),
address in detail each conceivable research proposal. animal care and use committees, biosafety boards,
Researchers, regulators, and members of institutional and any other relevant regulatory bodies to conduct
bodies reviewing stem cell-based translational research a coordinated review of all aspects of the proposed
proposals must therefore use their best professional research. In locales without stem cell expertise, the
judgment about how to apply the Guidelines to specific ISSCR will help identify appropriate domain experts to
protocols. What follows are core principles identified by assist in the human subjects review process.
the ISSCR Task Force for the Clinical Translation of Stem
Cells and offered in the form of recommendations. Regardless of the recommendations encompassed in
this document, scientists and clinicians should comply
with local policies and adhere to local, national, and
Guidelines for the Clinical Translation of Stem Cells www.isscr.org6
international guidelines relevant to research. Scientists accepted principles of research ethics. Cells for therapy
and clinicians must also be guided by principles should be procured under guidelines regulating the
articulated in documents that have become part of the procurement of human blood, tissues, and organs with
international heritage of research ethics (Appendix 2.1). additional considerations specific to the derivation of
human embryonic stem cells (hESCs) (Appendix 2.3).
4. Cell Processing and Manufacture Especially pertinent are the considerations outlined in
the following recommendation.
The majority of stem cells and their derivatives
represent novel products with which scientists and Recommendation 3: In the case of donation for
clinicians have little experience in human patients. Cell- allogeneic use, the donor should give written
based products present new and potentially unknown informed consent that covers, where applicable,
challenges in their processing and manufacture. the following issues:
Given the variety of different potential cell products,
these Guidelines emphasize that cell processing and (a) that cells and/or cell lines may be subject to
manufacture of any product be conducted under storage. If possible, duration of storage should
scrupulous, expert, and independent review and be specified;
oversight, to ensure as much as possible the quality
and safety of the cells. All of the possible standard (b) that the donor may (or may not) be
operating procedures for cell processing are not yet approached in the future to seek additional
delineated. In addition, distinct principles pertain consent for new uses, or to request additional
depending upon the extent of manipulation of the cells material (blood or other clinical samples) or
prior to use in patients. Typically, minimally manipulated information;
products (commonly defined as cells maintained in
culture under non-proliferating conditions for short (c) that the donor will be screened for
periods of time, normally less than 48 hours) require infectious and possibly genetic diseases;
less burdensome characterization and control than
cell products subjected to extensive manipulations ex (d) that the donated cells may be subject to
vivo. Also, distinct principles pertain depending upon genetic modification by the investigator;
the source of cells (autologous versus allogeneic), their
differentiation potential (unipotent versus multipotent), (e) that with the exception of directed
their intended use (for homologous versus non- altruistic donation, the donation is made
homologous functions), their persistence in the patient, without restrictions regarding the choice of
and the integration of cells into tissues or organs the recipient of the transplanted cells;
(versus, for example, encapsulation).
(f) disclosure of medical and other relevant
Many countries have established regulations that govern information that will be retained, and the
the transfer of cells into patients (Appendix 2.2). Given specific steps that will be taken to protect
the unique proliferative and regenerative nature of stem donor privacy and confidentiality of retained
cells and their progeny and the uncertainties inherent information, including the date at which
in the use of this therapeutic modality, stem cell-based donor information will be destroyed, if
therapies present regulatory authorities with unique applicable;
challenges that may not have been anticipated within
the existing framework or regulations. The following (g) explanation of what types of genomic
recommendations involve general considerations for cell analyses (if any) will be performed and how
processing and manufacture. Technical details pertaining genomic information will be handled; and
to cell sourcing, manufacture, standardization, storage,
and tracking can be found in Appendix 3. (h) disclosure that any resulting cells, lines
or other stem cell-derived products may
4.1 Sourcing Material have commercial potential, and whether any
commercial and intellectual property rights
Scientists and clinicians conducting human stem cell will reside with the institution conducting the
research must ensure that human biological materials research.
are procured in a manner according to globally
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells7
The initial procurement of tissue from a human 4.2 Manufacture
donor may not require Good Manufacturing Practice
(GMP) certification, depending on the jurisdiction The variety of distinct cell types, tissue sources,
(Appendix 2.4), but should always be conducted and modes of manufacture and use necessitate
using sterile techniques and universal precautions to individualized approaches to cell processing and
minimize the risks of contamination, infection, and manufacture. (For an expanded discussion of the
pathogen transmission. manufacturing process, see Appendix 3.) The
maintenance of cells in culture for any period of time
Recommendation 4: Donors must be screened places different selective pressures on the cells than
for infectious diseases, as is done for blood and when they exist in vivo. Cells in culture age and may
solid organ donation, and for genetic diseases as accumulate both genetic and epigenetic changes, as
appropriate. well as changes in behavior. Unfortunately, scientific
understanding of genomic stability during cell culture is
4.1.1 Variability in Source. Unlike chemicals primitive at best and assays of genetic and epigenetic
or recombinant protein products that can be status of cultured cells are still evolving.
manufactured to high degrees of homogeneity,
manufactured cells or those harvested and processed Recommendation 7: Acknowledging the
from different anatomic sites or unrelated individuals limitations in current assays, scientists and
present significant challenges of biological variability. regulators must work together to develop
In the case of allogeneic therapies, the establishment common reference standards for minimally
of a single master cell source may mitigate variability. acceptable changes during cell culture, to ensure
In autologous therapies, cell supply may be limited, quality and safety of cell therapy, and to facilitate
thereby precluding extensive tests of product quality. comparisons across studies.
Given the general lack of experience of investigators
with the manufacture, culture, or use of stem cells and Recommendation 8: The level of regulation and
their derivatives, definitions of identity and potency oversight should be proportional to the degree
remain to be determined during the course of future of risk raised by the particular cell product and
research. These unique aspects of cell manufacture intended use (autologous versus allogeneic use,
motivate the next recommendation. minimally versus highly manipulated cell products,
use for homologous versus non-homologous
Recommendation 5: In the course of development functions).
of stem cell-based products, it is imperative to
validate surrogate markers of the identity and When adequate cellular material is available, assays
potency of cell products. that might be required include mRNA, microRNA, and
protein expression and activity, rates of proliferation,
4.1.2 Production. Inclusion of animal materials in the global patterns of methylation and chromatin
cell manufacturing process does not preclude human modification, and in the logical extreme, complete
use, as stipulated in existing guidelines for medicinal sequencing of the genome, as determined after
products (Appendix 2.2), but raises unique concerns rigorous review by a panel of independent experts.
that must be addressed by additional testing to Defining optimal quality control for cultured cell
minimize the risk of transmission of animal pathogens products remains a key goal of current stem cell
and reaction to the animal proteins. Thus it is essential research.
to maintain detailed documentation to track all
materials used in cell production. Recommendation 9: To facilitate international
collaboration and universal access to stem
Recommendation 6: Where possible, components cell-based treatments (both during clinical trials
of animal origin used in the culture or and when established as standards of clinical
preservation of cells should be replaced with care), there is a need to develop appropriate
human components or with chemically defined quality management systems for donation,
components to reduce the risk of accidental procurement, testing, coding, processing,
transfer to patients of unwanted chemical or preservation of stem cell potency, storage,
biological material or pathogens. and distribution of the cells. For extensively
manipulated stem cells (either autologous or
Guidelines for the Clinical Translation of Stem Cells www.isscr.org8
allogeneic) destined to clinical application, the include the International Stem Cell Forum’s initiatives to
ISSCR recommends adherence to GMP procedures, develop recommendations for the storage, deposit, and
which includes minimizing risks to patients from analysis of hESCs. Further initiatives include proposals for
unwanted cell products. the collection of a minimal amount of information on
the human embryos used to derive hESC lines. Models
Recommendation 10: Cellular therapeutics that for obtaining appropriate information on the different
incorporate gene repair or genetic modification available hESC and other pluripotent cell lines and
must adhere to regulatory guidelines set forth for Web-based registries should be put in place. The ISSCR
both gene therapy and cell therapy. is committed to playing a role in helping to organize the
stem cell therapy sector to ensure as much uniformity in
These recommendations are not meant to supervene the preclinical and clinical practice as possible.
current established practice standards for the therapeutic
use of cells (for example, for bone marrow stem 5. Preclinical Studies
cells). However, consistent with evolving standards of
regulation, future cell therapy products may be regulated The purpose of preclinical studies is to (a) provide
under more stringent guidelines than currently applied. evidence of product safety and (b) establish proof-
of-principle for the desired therapeutic effect. Before
4.2.1 Cell Banking. Some stem cell products entail initiation of clinical studies with stem cells in humans,
minimal manipulation and immediate use, whereas other persuasive evidence in an appropriate in vitro and/or
stem cell products are intended for future use and thus animal model must support the likelihood of a relevant
necessitate storage, sometimes long-term. Precedents positive clinical outcome. A fundamental operative
exist for two types of stem cell banks: (a) private banks principle here is that preclinical studies must be
where cells are harvested from an individual and stored subject to rigorous and independent peer review and
for future use by that individual or designated family regulatory oversight prior to initiation of clinical trials, in
members; and (b) public banks that procure, process, order to ensure that the performance of clinical studies
store, and deliver cells to matched recipients on a need- is scientifically and medically warranted.
based priority list, in a model akin to blood banking.
The development of banks may be in the public interest Recommendation 11: Sufficient preclinical studies
once stem cell-based treatments are proven effective in relevant animal models – whenever possible for
and become the standard of care. The composition of the clinical condition and the tissue physiology
the bank must be constituted with adequate genetic to be studied – are necessary to make proposed
diversity to ensure wide access. stem cell-based clinical research ethical, unless
approved, controlled, and conclusive humans
4.2.2 Developing Uniformity in Standards. Given that studies are already available with the same cell
universal standards have emerged governing blood source. Investigators should develop preclinical
transfusion and hematopoietic transplantation therapies, cell therapy protocols in small animal models,
uniform standards should likewise emerge relating to as well as in large animal models when deemed
identification of donors, consent and procurement, necessary by independent peer review or
manufacturing regulations, method of delivery, and regulatory review.
selection of recipients for novel stem cell-based
therapies. Several non-profit organizations have taken Preclinical testing in animal models, whenever
the lead in providing accreditation services for cellular feasible, is especially important for stem cell-based
therapies. For example, the Alliance for Harmonisation approaches because stem cells can act through
of Cellular Therapy Accreditation (AHCTA), a collective multiple mechanisms, and because it is difficult to
of professional organizations (see Appendix 4), is predict behavior in an animal from cell culture studies
developing a minimum set of standards for the collection alone. Physiological integration and long-lived tissue
and use of hematopoietic stem and progenitor cells, reconstitution are hallmarks of stem cell-based
including cord blood, that include minimal required therapeutics for many disease applications. Animal
testing of the donor, a donor identification number, models will be relevant to assessing possible adverse
and an identification of the process of obtaining tissue, effects of implanted cellular products. The need for
along with tracking and tracing requirements and animal models is especially strong in the case of
product labeling nomenclature including information extensive ex vivo manipulation of cells and/or when the
on split number and clinical expiry date. Other efforts cells have been derived from pluripotent stem cells.
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells9
It should be acknowledged, however, that preclinical engraftment in vivo, stability of differentiated cells,
assays including studies in animal models may provide and cancer risk. Many small animal models of disease
limited insight into how transplanted human cells (for example rodents) can faithfully reproduce aspects
will behave in human recipients due to the context- of human diseases, although there are considerable
dependent nature of cell behavior and the recipient’s limitations. Large animal models may be more
immune response. These uncertainties must be borne in informative than small animal models with respect to
mind during the independent peer review of preclinical several factors, such as disease complexity, effective cell
data. Only when compelling preclinical data are dosage, response, cell survival after transplantation, and
available is careful and incremental testing in patients tissue-related inflammatory and immunologic barriers to
justified, and then always subject to rigorous and long-term cellular engraftment. Furthermore, for many
independent scientific and ethical oversight. therapeutic applications, large animal models may be
essential to evaluate issues of scale-up, physiology (such
Recommendation 12: Because new and as cardiac physiology), migration, and feasibility.
unforeseen safety concerns may arise with
clinical translation, frequent interaction between Recommendation 14: Large animal models should
preclinical and clinical investigators is strongly be used for stem cell research related to diseases
encouraged. that cannot be sufficiently addressed using small
animal models or where structural tissue such as
5.1 Efficacy bone, cartilage, or tendon need to be tested in
a load-bearing model. The selected large animal
Given the goals of stem cell-based therapy in tissue model must offer an appropriate context for
repair or disease eradication, preclinical studies should studying the human disease and conditions of
demonstrate proof-of-principle for a desired therapeutic specific interest.
effect in a relevant animal model whenever possible
for the clinical condition and the tissue physiology to However, it should be recognized that while genetically
be studied. Mechanistic studies utilizing cells isolated immunocompromised small animal models are
and/or cultured from animal models or diseased human available for testing, large animals need adjunctive
tissues are desirable for defining the underlying biology immunosuppressive drug therapy to accept human cell
of the cellular therapy. The Guidelines recognize that a transplants. The side effects of the drugs may interfere
complete understanding of the biological mechanisms with any long-term evaluation of experimental success.
at work after stem cell transplantation in a preclinical
model is not a mandatory prerequisite to initiate human Recommendation 15: The need for studies in
clinical experimentation, especially in the case of serious non-human primates should be evaluated
and untreatable diseases for which efficacy and safety on a case-by-case basis, and performed only
have been demonstrated in relevant animal models if the studies promise to provide necessary
and/or in approved and conclusive human studies with and otherwise unobtainable information for
the same cell source. experimental therapeutic application of stem
cells or their progeny in patients. All studies
Recommendation 13: Small animal models should involving the use of non-human primates must be
be used to test the transplantation of wild-type conducted under the close supervision of qualified
and/or diseased and genetically-corrected stem veterinary personnel with expertise in their care
cells, to assess the morphological and functional and their unique environmental needs.
recovery caused by cell therapy, and to investigate
the biological mechanisms of tissue restoration or International codes of research ethics, such as the
repair. Small animal studies should also assess the Declaration of Helsinki and the Nuremberg Code,
dosage and route of administration of potential strongly encourage the performance of preclinical
cell therapies, the optimal age and disease animal studies prior to clinical trials in humans. Efforts
stage for therapeutic efficacy, and the cellular should be made to point out that diseased animals
distribution, survival, and tissue integration. are not provided ad hoc but selected to try a new
experimental therapy using stem cells that may, in the
Immune-deficient rodents can be especially useful long term, benefit many patients with similar conditions
to assess human cell transplantation outcomes, and injuries. Responsible animal research adheres to
the principles of the three Rs– Reduce numbers, Refine
Guidelines for the Clinical Translation of Stem Cells www.isscr.org10
protocols, and Replace animals with in vitro or non- Recommendation 17: Criteria for release of cells
animal experimental platforms whenever possible. for transfer to patients must be designed to
Investigators planning to conduct animal studies using minimize risk from culture-acquired abnormalities.
human stem cells and their direct derivatives should
refer to applicable ethical considerations described by Given the nature of pluripotent cells and their innate
the ISSCR Ethics and Public Policy Committee (Appendix capacity to form teratomas, there is a particular concern
3) and the ISSCR Guidelines for the Conduct of Human for the potential tumorigenicity of hESCs and induced
Embryonic Stem Cell Research. pluripotent stem cells or their differentiated derivatives.
5.2 Toxicity Recommendation 18: Risks for tumorigenicity
must be assessed for any stem cell-based product,
Human cells will need to be produced under the especially when extensively manipulated in
conditions discussed in Section 4, Cell Processing and culture or when genetically modified. A clear plan
Manufacture. Special attention should be paid to to assess the risks of tumorigenicity for any cell
the characterization of the cell population, including product must be implemented under the direction
possible contamination by irrelevant cell types and of an independent review body prior to approval
when necessary to the appropriate safeguards for for human clinical use.
controlling the unrestricted proliferation and/or aberrant
differentiation of the cellular product and its progeny. Cell preparations that show a high risk or incidence
of abnormal tissue formation or tumorigenesis might
Recommendation 16: Cells to be employed in entail design of a “suicide strategy” involving genetic
clinical trials must first be rigorously characterized modification of the cells to render them susceptible
to assess potential toxicities through in vitro to cell killing with an exogenous drug (for example,
studies and (where possible for the clinical incorporation of the thymidine kinase gene into cells,
condition and tissue physiology to be examined) thereby rendering them sensitive to gancyclovir). It
in animal studies. should be noted, however, that once a cellular therapy
has undergone genetic modification, the use of the
Outside of the hematopoietic and stratified epithelia genetically modified cells will be considered a gene
systems there is little clinical experience with the transfer intervention that may involve an additional
toxicities associated with infusion or transplantation layer of regulatory oversight pertinent to gene transfer
of stem cells or their derivatives. In addition to the research. The relative risks and benefits of such
known and anticipated potential risks, including acute mechanisms should be addressed by an independent
infusional toxicity, deleterious immune responses, review body during the regulatory oversight process.
unexpected behavior of the cellular product, and
tumorigenesis, there are likely to be unanticipated Route of cell administration – local or systemic – may
toxicities that will only be learned with experience. lead to different adverse events. Local, intramuscular
Animal models may not replicate the full range of or subcutaneous injection of cells is unlikely to
human toxicities; therefore, particular vigilance must produce acute systemic adverse events (unless antigen-
be applied in preclinical analysis of the toxicities presenting cells are transplanted) but may eventually
of cell-based interventions. This section will define result in local destruction of donor cells. Similarly,
toxicities that are likely to be unique to stem cells local application of engineered skin grafts may result
or their progeny. in destruction of the graft and consequent tissue
damage and inflammation, but are unlikely to elicit
Cells grown in culture, particularly for long periods or systemic adverse events. On the other hand, even
under stressful conditions, may become aneuploid or local transplantation into organs like the heart or
have DNA rearrangements, deletions, and other genetic the brain may lead to life-threatening adverse events
or epigenetic abnormalities that could predispose them related to the transplantation itself or to the damage
to cause serious pathologies such as cancer. that transplanted cells may cause to vital structures.
Especially in cases where cell preparations are infused
at anatomic sites distinct from the tissue of origin (for
example, for non-homologous use), great care must
be exercised in assessing the possibility of local and
systemic toxicities.
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells11
Because of the potential for cells to persist or expand ii. whether these cells have been
in the body, systemic delivery of cells raises additional developed with appropriate
toxicity questions. The long-term consequences of manufacturing standards;
fusion of delivered cells to host cells are not known.
Given the dissimilarities of animal and human iii. preclinical data on their use in animal
physiology, preclinical models may not faithfully and/or other models for evaluating
anticipate all potential deleterious events. In particular, their safety and efficacy; and
animal models are inadequate for assessing pain and
its exacerbation by cell therapies, and many anticipated iv. any early clinical data, if available,
disease targets are associated with pain. which address safety issues in the
short and medium term and continued
While rodents or other small animal models are a observation for long term effects;
necessary step in the development of stem cell-based
therapies, they are likely to reveal only major toxic (b) address the risks of stem cell-based
events. The similarity of many crucial physiological interventions including, for example, cell
functions between large mammals and humans may proliferation and/or tumor development,
favor testing the toxicity of a novel cell therapy in at least exposure to animal source materials, risks
one large animal model. Moreover, consideration should associated with viral vectors, and risks as
be given to long-term monitoring of animals as a source yet unknown;
of information on the late effects of cell therapies.
(c) provide the utmost clarity regarding the
Recommendation 19: Cell cultures and animal potential benefits of participating in the
models should be used to test the interaction trial with stem cells, since patients may have
of cells with drugs to which recipients will be recourse to reasonable therapeutic alternatives;
exposed. These include the immunosuppressants the informed consent process must emphasize
planned for recipients, as well as other drugs the novel and experimental aspects of cell
that might be used to treat their underlying based interventions. It is important to minimize
disease process. misconceptions patients may have about the
potential for therapeutic efficacy;
6. Clinical Research
(d) disclose any financial and non-financial
As with all clinical research, clinical trials of stem cell- conflicts of interest among the investigators,
based interventions must follow internationally accepted sponsors, and institutions in which the stem
principles governing ethical conduct of clinical research cell research is being conducted;
and the protection of human subjects. Key requirements
include regulatory oversight, peer review by an expert (e) monitor research subjects for long-
panel independent of the investigators and sponsors, term health effects and protection of the
fair subject selection, informed consent, and patient confidentiality of their health data;
monitoring. However, there are a number of important
stem cell-related issues that merit special attention. (f) provide a clear, timely, and effective plan
for adverse event reporting;
Recommendation 20: Stem cell-based clinical
researchers should: (g) offer a clinical plan to provide treatment
for toxicity, including treatment of tumors
(a) cooperate with and share scientific that might arise. This plan might include
expertise to assist other investigators and compensation for research-related injuries;
human subjects research review committees and
in assessing:
(h) ensure that insurance coverage or
i. the biological characteristics of the other appropriate financial or medical
cells to be used in clinical trials; resources are available to patients to cover
potential complications arising from their
research participation.
Guidelines for the Clinical Translation of Stem Cells www.isscr.org12
6.1 Regulatory Oversight 6.2 Standards for Peer Review
The goal of regulatory review and oversight is to ensure 6.2.1 Elements of the Peer Review Process. Assessment
that the stem cell-based clinical trial is likely to be safe, of clinical protocols for stem cell-based interventions,
has scientific merit, and that it is designed and carried especially those using novel preparations of stem cells,
out in a manner that will yield credible data that will be requires unique expertise.
of value to the biomedical research community.
Recommendation 23: The peer review process
Recommendation 21: All studies involving for stem cell-based clinical trials should have
clinical applications of stem cells, whether appropriate expertise to evaluate (a) the in vitro
publicly or privately sponsored, must be subject and in vivo preclinical studies that form the
to independent review, approval, and ongoing basis for proceeding to a clinical trial and (b) the
monitoring by human subjects research oversight scientific underpinnings of the trial protocol,
bodies with supplemental appropriate expertise the adequacy of planned end-points of analysis,
to evaluate the unique aspects of stem cell statistical considerations, and disease-specific
research and its application in a variety of clinical issues related to human subject protection.
disciplines. This review and oversight process
must be independent of the investigators Peer review should also judge whether the proposed
regardless of whether it occurs at the institutional, stem cell-based clinical study is likely to lead to
regional, or national level, and regardless of improvement in health or may generate important new
whether investigators employ the services of a knowledge. Comparing the relative value of a new
contract research organization. stem cell intervention to established modes of therapy
is integral to the review process.
Independent review and informed consent are required
in stem cell-based clinical trials to minimize the 6.2.2 Risk-Benefit Analysis. As discussed in Section
possibility of conflict of interest which may prejudice 5, Preclinical Studies, there should be persuasive
the research design by investigators, to maximize preclinical evidence of safety and benefit for the stem
the coincidence of the goals of the research with the cell-based intervention to justify proceeding to clinical
subjects’ interests, and to maximize respect for the trials in humans.
voluntary nature of the subjects’ participation.
Recommendation 24: Risks should be identified
Independent evaluation of stem cell research projects and reduced, and potential benefits to subjects
occurs through multiple groups, including granting must be realistically delineated but not
agencies, local peer review, and data and safety overemphasized. Subject selection can affect the
monitoring boards. To initiate stem cell-based clinical risks and benefits of the study and subjects should
trials, it is critical that investigators follow and comply be selected to minimize risks, maximize the ability
with a local and national regulatory approvals process. to analyze results, and enhance the benefits to
individual subjects and society.
Recommendation 22: In countries where there
is no official national regulatory body, the ISSCR 6.2.3 Comparison with Existing Therapy. Genetic
strongly encourages governments to develop a and acquired diseases differ widely in their degree of
regulatory competence at the national, regional, disability, morbidity, and their available therapeutic
or local level to monitor clinical interventions with options. These facts have a crucial impact on the
stem cell-based products. The ISSCR will strive to decision to proceed to clinical application with a novel
provide professional advice to those governing stem cell-based approach, which is itself experimental
bodies interested in building their own capacities and potentially risky.
for regulatory oversight.
Recommendation 25: As a general principle, a
In many countries, the regulatory approval process stem cell-based approach must aim at being
requires a statement from the investigator outlining clinically competitive or superior to existing
well-defined goals of the clinical trial, detailed therapies. If an efficacious therapy already
research protocols, manufacturing guidelines, and exists, the risks associated with a stem cell-based
toxicology information.
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells13
approach must be low and the stem cell-based Recommendation 27: As far as possible, groups
approach must offer a potential advantage or individuals who participate in clinical stem cell
(for example, better functional outcome; single research should be in a position to benefit from
procedure (cell administration) versus life- the results of this research. Groups or individuals
long drug therapy with associated side effects; must not be excluded from the opportunity to
reduction in long-term cost). If an efficacious participate in clinical stem cell research without
therapy is not available, then the severity of the rational justification.
disease, especially if the disease to be treated
is severely disabling and life-threatening, might 6.2.6 Standards for Voluntary Informed Consent.
justify the risks of a stem cell-based experimental Culturally-sensitive voluntary informed consent is
intervention in patients. Maximum effort should a necessary component in the ethical conduct of
be made to minimize the risks for all possible clinical research and protection of human subjects.
adverse events associated with stem cell-based With respect to stem cell-based interventions, for
approaches. Care must also be taken to not take which desperate patients might unrealistically expect
advantage of the hopes of patients with poor therapeutic benefit, the informed consent process
short-term prognoses. must clearly state the experimental and preliminary
nature of the clinical intervention. Investigators involved
6.2.4 Standard of Care. The ISSCR recognizes that stem in clinical research must carefully assess whether
cell research is an international endeavor where local participants understand the essential aspects of the
standards of care differ dramatically. Due consideration study – specifically, that this may be the first time the
should be given to achieve best optimal care in a given experimentally-derived cells have been administered to
locale, taking into consideration legitimate factors that humans, that animal studies may not predict effects of
impact the quality of care available locally. The ISSCR cell therapies in humans, that the aim of the study may
strongly discourages conduct of trials in a foreign simply be to assess safety, that the risks are unknown,
country solely to benefit patients in the home country and that, historically, some human participants in early
of the sponsoring agency. The test therapy, if approved, drug trials have experienced serious adverse effects,
should realistically be expected to become available to including death. Subjects should be made aware
the population participating in the clinical trial through that their participation is entirely voluntary and not
existing health systems or those developed on a necessary for their continued clinical care, and that
permanent basis in connection with the trial. For a trial participation or non-participation will not interfere with
with comparison arms, it may be justified to perform a their ongoing clinical care.
study comparing the stem cell-based approach with the
best locally achievable treatment and follow-up, if the Recommendation 28: Informed consent is
local risk-benefit consideration allows. particularly challenging for clinical trials involving
highly innovative interventions.
Recommendation 26: Clinical research should
compare new stem cell-based therapies against (a) Patients need to be informed when novel
the best medical therapy currently available to the stem cell-derived products have never been
local population. tested before in humans and that researchers
do not know whether they will work as hoped.
6.2.5 Fair Subject Selection. The ISSCR supports the
ideal of fair access to well-designed clinical trials and (b) Cell-based interventions, unlike many
effective stem cell-based therapies without regard to pharmacological products or even many
patients’ financial status, insurance coverage, or ability implantable medical devices, may not leave the
to pay. In stem cell-based clinical trials, the sponsor body and may continue to generate adverse
and principal investigator have an ethical responsibility effects for the lifetime of the patient. The
to make good faith, reasonable efforts whenever possible irreversibility of a cellular transplant
possible to secure sufficient funding so that no person should be explained clearly.
who meets eligibility criteria is prevented from being
considered for enrollment because of his or her inability (c) Subjects should be informed about the source
to cover the costs of the experimental treatment. of the cells so that their values are respected.
Guidelines for the Clinical Translation of Stem Cells www.isscr.org14
(d) Ensuring subject comprehension must monitoring, and additional safeguards for
be done at each phase of the clinical trials ongoing patient privacy should be provided.
process. Ideally, the subject’s comprehension
of information should be assessed through a Recommendation 31: To advance scientific
written test or an oral quiz during the time of understanding, research subjects should be
obtaining consent. asked, in the event of death, for consent to the
performance of a partial or complete autopsy to
(e) Human subjects research committees obtain information about the extent of cellular
should ensure that informed consent implantation and its morphological and functional
documents accurately portray these consequences. Any request for an autopsy must
uncertainties and potential risks, and clearly consider cultural and familial sensitivities.
explain the experimental nature of the
clinical study. This is a delicate issue, but without access to post
mortem material, the information coming out the trial
Recognizing the potential value of stem cell-based will be substantially reduced to the detriment of future
therapies for subjects who are cognitively impaired, product/delivery refinements in the indication.
procedures should be developed and employed
allowing authorized representatives to be placed in Recommendation 32: Researchers should facilitate
decision-making roles and to monitor participation on the gathering of empirical data about socio-
behalf of potential subjects. It is important that such demographic characteristics of participants
subjects and their conditions are not excluded from in clinical trials, financial compensation levels
biomedical advances involving stem cells. At the same (if applicable), and the nature and extent of
time, such subjects should be recognized as especially any benefit and harm resulting from research
vulnerable, and steps should be taken to involve participation. Such data are crucial for health
guardians or surrogates who are appropriately qualified services researchers and policy-makers to improve
and informed to make surrogate research judgments the conduct of future clinical trials and to assess the
and to provide other protections. utility of the information obtained in these trials
for informing policy decisions such as approval and
6.3 Patient Monitoring and Adverse Event Reporting insurance coverage for cell-based interventions.
Recommendation 29: A data monitoring plan, 6.4 Publication of Research Results
which may involve an independent data safety
and monitoring process, is required for all clinical Publication of both positive and negative results and
studies, and aggregate updates should be adverse events is strongly encouraged to promote
provided to peer review committees on demand, transparency in the clinical translation of cell-based
complete with adverse event reporting and therapies, to ensure development of clinically effective
ongoing statistical analysis. and competitive stem cell-based therapies, and to
prevent participants in future clinical trials from being
The welfare of subjects should be carefully monitored subjected to unnecessary risk.
throughout the duration of stem cell-based clinical
trials, privacy must be respected, and subjects must be Recommendation 33: Researchers should publish
free to withdraw without penalty, as new information both positive and negative results and adverse
about the effect(s) of the intervention or the subject’s events. To ensure the integrity of scientific
clinical condition may change in the course of research. information and to promote the highest standards
of professional conduct, researchers should
Recommendation 30: Subject withdrawal from the present their results at professional scientific
research should be done in an orderly fashion to conferences or in peer-reviewed scientific journals
promote physical and psychological safety. Given before reporting their research to the lay media or
the potential for transplanted cellular products to to patient advocacy groups and associations.
persist long-term, and depending on the nature
of the experimental stem cell-based intervention,
patients may have to undergo long-term health
December 3, 2008 Guidelines for the Clinical Translation of Stem Cells15
7. Stem Cell-Based Medical Innovation Given the many uncertainties surrounding the infusion
of cells in ectopic locations and the significant challenges
Historically, many medical innovations have been to the processing and manufacture of cellular products,
introduced into clinical practice without a formal only in exceptional circumstances does the ISSCR believe
clinical trials process. Some innovations have resulted it would be acceptable to attempt medical innovations
in significant and long-lasting improvements in clinical involving stem cells and their direct derivatives. The
care, while others have been ineffective or harmful. In ISSCR anticipates that the following recommendation
contrast to the commercial purveyance of unproven will be applicable primarily for seriously ill patients who
stem cell interventions noted in Section 2, the ISSCR lack good medical alternatives.
acknowledges that in some very limited cases, clinicians
may be justified in attempting medically innovative Recommendation 34: Clinician-scientists may
stem-cell based interventions in a small number of their provide unproven stem cell-based interventions to
seriously ill patients. at most a very small number of patients outside
the context of a formal clinical trial, provided that:
In the case of medical innovations using stem cells
and their direct derivatives, unique considerations (a) there is a written plan for the procedure
justify a heightened level of caution. The diseases that includes:
which potentially could be targeted by stem cell-
based interventions are some of the most intractable i. scientific rationale and justification
diseases confronting clinicians – and interest in stem explaining why the procedure has a
cell research has resulted in the organization of patient reasonable chance of success, including
communities with high hopes for the prospect of future any preclinical evidence of proof-of-
stem cell treatments. Due to their relative novelty in principle for efficacy and safety;
science, stem cells and their direct derivatives could
behave more unpredictably when delivered to patients ii. explanation of why the proposed stem
than either drugs used off-label or modified surgical cell-based intervention should be
techniques. Some attempts at medical innovation using attempted compared to existing
stem cells and their direct derivatives may inadvertently treatments;
violate physicians’ ethical obligation to “do no harm,”
by producing more injury than benefit. iii. full characterization of the types of
cells being transplanted and their
Innovative medical care and clinical research aim characteristics as discussed in Section 4,
at different goals. The mere fact that a procedure Cell Processing and Manufacture;
is medically innovative does not qualify it as
clinical research. Clinical research aims to produce iv. description of how the cells will be
generalizable knowledge about new cellular or drug administered, including adjuvant
treatments, or new approaches to surgery. Notably, drugs, agents, and surgical procedures;
the individual patient’s benefit is not the focus and
of clinical research, nor is the individual patient’s
benefit the primary focus of the human subjects v. plan for clinical follow-up and data
research committees overseeing clinical research. In collection to assess the effectiveness
contrast, medical innovations do not aim to produce and adverse effects of the cell therapy;
generalizable knowledge but are aimed primarily
at providing new forms of clinical care that have a (b) the written plan is approved through a peer
reasonable chance of success for individual patients review process by appropriate experts who have
with few or no acceptable medical alternatives. Unlike no vested interest in the proposed procedure;
clinical research, then, the main goal of innovative care
is to improve an individual patient’s condition.
Although attempting medically innovative care is not
research per se, it should still be subject to scientific and
ethical review and proper patient protections. This is
especially true for stem cell-based medical innovation.
Guidelines for the Clinical Translation of Stem Cells www.isscr.org16
(c) the clinical and administrative leadership other medical institutions because of the conservative
supports the decision to attempt the medical nature of medical care. Strict application of the above
innovation and the institution is held criteria to many clinical interventions offered outside of a
accountable for the innovative procedure; formal clinical trial will identify significant shortcomings
that should call into question the legitimacy of the
(d) all personnel have appropriate purported attempts at medical innovation.
qualifications and the institution where the
procedure will be carried out has appropriate 8. Considerations of Social Justice
facilities and processes of peer review and
clinical quality control monitoring; While all research should be responsive to issues of
justice, there are additional reasons to consider justice
(e) voluntary informed consent is provided by in the context of stem cell translational research. First,
patients who appreciate that the intervention ethical arguments in support of stem cell research
is unproven and who demonstrate their depend in part on its potential for advancing scientific
understanding of the risks and benefits of the knowledge that may result in therapies or cures for
procedure; disease, other health benefits associated with advances
in scientific knowledge, or associated technological or
(f) there is an action plan for adverse events methodological developments. As such, governments,
that includes timely and adequate medical institutions, researchers, and providers have a
care and if necessary psychological support responsibility to attend to issues of public benefit and
services; specifically to ensure that the anticipated benefits
are genuinely and justly available. Second, stem cell
(g) insurance coverage or other appropriate research offers the potential to develop therapies that
financial or medical resources are available could be widely shared internationally. Choosing which
to patients to cover any complications arising applications to address for clinical development, and
from the procedure; and how, will necessarily require special attention to issues
of social justice.
(h) there is a commitment by clinician-
scientists to use their experience with Addressing issues of social justice at each stage of
individual patients to contribute to research and involving various entities – researchers,
generalizable knowledge. This includes: institutions, companies, funders, review bodies,
ethicists, and policy-makers – will require carefully and
i. ascertaining outcomes in a systematic locally adapted procedures.
and objective manner;
Recommendation 35: Regulatory and oversight
ii. a plan for communicating outcomes, agencies, (local, national and international) must
including negative outcomes and explicitly include the consideration of social justice
adverse events, to the scientific principles into their evaluations. Mechanisms
community to enable critical review include (a) involvement of community and patient
(for example, as abstracts to advocates in public discussions, committee
professional meetings or publications representation, and oversight board evaluation
in peer-reviewed journals); and procedures; (b) opportunity for open discussions
about ethical issues; (c) enforcement of social
iii. moving to a formal clinical trial in a justice considerations by appropriate agencies.
timely manner after experience with at
most a few patients. Researchers ought not to raise false hopes and must
deal honestly with serious issues of risk, harm, and
Not following such standards may exploit desperate chance. Similarly, opponents of research ought not to
patients, undermine public trust in stem cell research, raise unfounded alarms. Discussion must be transparent,
and unnecessarily delay better designed clinical trials. accurate, inclusive, interactive, critical, and fair.
Many who provide stem cell-based therapies may claim
that they offer innovative medical care not available in
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