3. Clinical Translation of Stem Cell-based Interventions

Return to TOC | 2021 Guidelines for Stem Cell Research and Clinical Translation

This section highlights 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.

The rapid advances in stem cell research and genome editing technologies have created high expectations for the promise of regenerative medicine and gene- and cell-based therapies. As the field advances, it is important to balance the excitement from patients, scientists, clinicians, and the media over the growing number of clinical trials for serious diseases with the requirement to rigorously evaluate the safety and effectiveness of each potential new intervention. There have been instances where some clinical applications and clinical trials occurred far in advance of what is warranted by sound, rigorous, and dispassionately assessed preclinical evidence. Clinical experimentation is burdensome for research subjects and expensive; therefore, new interventions should only advance to clinical trials when there is a compelling scientific rationale, a plausible mechanism of action, and an acceptable chance of success. Furthermore, the safety and effectiveness of new interventions must be demonstrated in well-designed and expertly-conducted clinical trials with approval by regulators before the interventions are offered in direct-to-consumer settings to patients or incorporated into standard clinical care. Finally, any premature clinical testing of a promising new technology may jeopardize its further development if some adverse event emerges due to inadequate trial design or product manufacturing. Stem cell science is best positioned to fulfill its potential by adhering to a commonly accepted and robust set of guidelines for evidence-based therapy development.

• 3.1 Classifying Stem Cell-, Cell-, and Tissue-based Interventions

  Recommendation 3.1.1: Stem cells, cells, and tissues that are substantially manipulated or used in a non-homologous manner must be proven safe and effective for the intended use before being marketed to patients or incorporated into standard clinical care.

  The therapeutic use of substantially manipulated stem cells, cells, or tissues or minimally manipulated stem cells, cells, or tissues for non-homologous treatments is complex, speculative, and has been shown to have risks to recipients. These products should be thoroughly tested in preclinical and clinical studies and evaluated by regulators as drugs, biologics, and advanced therapy medicinal products.

  Minimally Manipulated Stem Cells, Cells, and Tissues

  Minimally manipulated cells and tissues, such as, in some cases, fat tissue transferred from one part of the body to another, are generally subject to fewer regulatory requirements. When a stem cell-, cell-, or tissue-based intervention is claimed to be minimally manipulated and exempt from regulatory oversight on this basis, the responsibility rests on the clinician to invite independent scrutiny of their process of manipulation, such that scientific and regulatory experts can determine the proper level of regulatory oversight. When there is uncertainty or disagreement about the regulatory status of particular interventions, it is best to contact legally authorized regulatory bodies and seek their guidance concerning how specific interventions are classified. The US Food and Drug Administration, European Medicines Agency, Australian Therapeutic Goods Administration, Japanese Ministry of Health, Labour, and Welfare, and other regulators have released detailed standards to delineate when manipulation of cell-based products can no longer be considered minimal or their use homologous, and must therefore be subject to regulatory oversight as an advanced therapy product.

  Substantially Manipulated Stem Cells, Cells, and Tissues

  Substantially manipulated stem cells, cells, and tissues are subjected to processing steps that alter their original structural or biological characteristics. These processes can include isolation and purification processes, tissue culture and expansion of the cells, genetic manipulation, or other steps. For example, the extraction of cells from adipose tissue using enzymatic digestion, ultrasonic cavitation, or other means involves processing steps that can alter the original function of the cells imbedded in the tissue. The safety and efficacy profile of such an intervention needs to be determined for its particular indication using rigorous research methods. Safety and efficacy cannot be assumed because the composition of the intervention may differ from the original source tissue. Demonstration of safety and effectiveness will depend on the particular intervention and the specific condition targeted. Both to protect patients from risks and to help ensure that promising interventions are studied, it is critical that cells and tissues that have been substantially manipulated are evaluated by national regulators as drugs, biologics, and advanced therapy medicinal products.

  Non-homologous Use of Stem Cells, Cells, and Tissues

  Non-homologous use occurs when the stem cells, cells, or tissue are repurposed to perform a different basic function in the recipient than the cells or tissue originally performed prior to being removed, processed, and transplanted or otherwise delivered. For example, delivering adipose-derived stromal cells into the eye with the intent to treat macular degeneration would be a non-homologous use because the basic function of adipose tissue is not the trophic support of the retina. As with substantially manipulated cells and tissues, the non-homologous use of stem cells, cells, and tissues has potential benefits but can also pose serious risks. In the case of using adipose-derived stromal cells to treat macular degeneration, for example, there are well-documented reports of vision loss (Kuriyan et al., 2017). Such reports serve as a reminder that cells and tissues, depending on how they are administered, can cause serious harm. The benefit-risk ratio for non-homologous uses will depend on the particular intervention and the specific use. To protect patients from risks, and to ensure that necessary research is conducted, it is important that the safety and effectiveness of non-homologous uses be rigorously evaluated by regulators following the completion of well-designed and carefully controlled preclinical and clinical studies.

• 3.2 Cell Processing and Manufacture

  In most jurisdictions, the use of cellular products for medical therapy is regulated by governmental agencies to ensure the protection of patients. Although some stem cell-based products have now been approved for use in humans, a growing number of novel cellular products are being tested for a wide range of disease indications and present new challenges in their processing, manufacture, and pathways for regulatory approval. Given the variety of potential stem cell-based interventions, these guidelines emphasize that cell processing and manufacture of any product be conducted with scrupulous, expert, and independent review and oversight, to ensure the integrity, function, and safety of cells destined for use in patients. Manufacture of cells outside the human body introduces an additional risk of contamination with pathogens, and prolonged passage in cell culture carries the potential for accumulating mutations and genomic and epigenetic instabilities that could lead to altered cell function or malignancy, especially as such cells may outgrow others in the cultures. While many countries have established regulations that govern the culture, genetic alteration, and transfer of cells into patients, optimized standard operating procedures for cell processing, protocols for characterization, and criteria for release remain to be refined for the products of emerging technologies such as genome editing and novel derivatives of pluripotent cells and many attendant cell therapies.

  Given the unique proliferative and regenerative nature of stem cells and their progeny and the uncertainties inherent in the use of this therapeutic modality, stem cell-based therapies present regulatory authorities with unique challenges that may not have been anticipated within existing regulations. The following recommendations involve general considerations for cell processing and manufacture.

  3.2.1 Sourcing Material

  Donor Consent

  Recommendation 3.2.1.1: Donors of cells for allogeneic use should give written and legally valid informed consent that covers, where applicable, terms for potential research and therapeutic uses, disclosure of incidental findings, potential for commercial application, and issues specific to the type of intervention under development.

  Researchers should ensure that potential donors or their legally authorized representatives adequately understand the stem cell-specific aspects of their research participation. For a list of donor informed consent discussion points, see Section 2.3.2 and Appendix 3.

  The initial procurement of tissue from a human donor may or may not require good manufacturing practice (GMP) certification depending on the jurisdiction, but this should always follow regulatory guidelines related to human tissue procurement and maintain universal precautions to minimize the risks of contamination, infection, and pathogen transmission.

  Donor Screening

  Recommendation 3.2.1.2: Donors and/or the resulting cell banks developed for allogeneic stem cell-based interventions should be screened and/or tested as applicable for infectious diseases and other risk factors, in compliance with applicable regulatory guidelines (see Recommendation 2.4.3).

  Tissue procurement for generating stem cell-based interventions is similar to procurement of cells/tissues for other potential clinical purposes and should be governed by the same policies. However, an important distinction between tissue donation and stem cell generation that increases the importance of screening is that, while tissues and organs other than blood are usually distributed to a limited number of recipients, somatic or pluripotent cells derived from allogeneic cells or tissues can potentially be implanted into a large number of patients. Donor screening should include medical examination, collection of donor history and blood testing. This process mitigates the risk of potential transmission of adventitious agents from the donor to patients receiving the stem cell products. Regulatory agencies such as the (FDA; https://www.fda.gov/) and the European Medicines Agency (EMA; https://www.ema.europa.eu/) have issued guidance regarding donor testing and screening. If high-specificity tests are available for adventitious agents, direct testing of the donated cells and tissue can mitigate the need to screen for such agents. However, this type of testing strategy should be prospectively discussed with regulatory authorities to ensure appropriate risk mitigation.

  In some cases, in may not be possible to screen donors. For example, the donation of human embryos for the derivation of hESCs often occurs years after the harvesting of gametes and generation of the embryos, consistent with ethical and regulatory standards. Therefore, screening of the donors at the time of gamete harvest is not appropriate. In these cases, the hESC cell bank can be thoroughly tested to ensure the absence of adventitious agents. However, there still remains the risk of pathogens for which validated tests are not available.

  3.2.2 Manufacture

  Cellular derivatives generated from stem cells and tissues are considered manufactured products and are subject to various regulations to ensure their quality (consistency, purity, and potency) and safety.

  Quality Control in Manufacture

  Recommendation 3.2.2.1: All reagents and processes should be subject to quality control systems and standard operating procedures to ensure the quality of the reagents and consistency of protocols used in manufacturing. Manufacturing should be performed under GMP conditions when possible or mandated by regulation. However, in early-stage clinical trials it is understood that GMPs may be introduced in a phase appropriate manner in some regions.

  The variety of distinct cell types, tissue sources, and modes of manufacture and use necessitate individualized approaches to cell processing and manufacture. The maintenance of cells in culture for any period of time places selective pressures on the cells that are different from those in vivo. Cells in culture age and may accumulate both genetic and epigenetic changes, as well as changes in differentiation behavior and function. Scientific understanding of genomic stability during cell culture and assays of genetic and epigenetic status of cultured cells are still evolving. Guidance documents from the FDA and EMA, as well as other documents, provide a roadmap for manufacture and quality control of cellular products. However, given that many cellular products developed in the future will represent entirely novel entities with difficult-to-predict behaviors, scientists must work with regulators to ensure that the latest information is available to inform the regulatory process. An important goal is the development of universal standards to enable comparisons of cellular identity, purity and potency, which are critical for comparing studies and ensuring reliability of dose-response relationships and assessments of mechanisms of toxicity.

  Processing and Manufacture Oversight

  Recommendation 3.2.2.2: The oversight and review of cell processing and manufacturing protocols should be rigorous, and consider the manipulation of the cells, their source and intended use, the nature of the clinical trial, and the research subjects who will be exposed to them.

  Stem cells can proliferate in culture for extended periods of time. This proliferative capacity carries risks. When maintained in culture for prolonged periods of time, cells may acquire mutations, grow and differentiate into inappropriate cellular phenotypes, form benign or malignant outgrowths, and fail to mature. Appropriate tests must be devised to maximize safety of stem cell derived products.

  Factors that are common to many stem cell products include the cells’ proliferation and differentiation potentials, source (autologous, allogeneic), type of genetic manipulation, if any, homologous versus non-homologous or ectopic use, their persistence in the recipient, and the anticipated integration of cells into tissues or organs (versus, for example, encapsulation). Culture composition and purity of desired phenotype vs. extent of residual undifferentiated progenitors should be carefully evaluated. In order to mitigate the risk associated with these factors, stem cell-based interventions should be thoroughly tested in safety and efficacy preclinical studies. Given that each stem cell therapy is a unique product, the evaluation of each product should be informed by the characteristics of the cell product and the risk/benefit associated with the clinical indication.

  Assays available for genetic and epigenetic assessment of stem cell-based products are evolving. Researchers should be aware of the limitations of these assays in predicting clinical outcomes. For cryopreserved or otherwise stored products, any impact of short- or long-term storage on product potency and stability must be determined. Human or xenogeneic materials associated with elevated risk (for example, human allogeneic and pooled source materials or xenogeneic reagents such as fetal bovine serum) should be stringently tested for safety and quality.

  Components in Culture or Preservation of Cells

  Recommendation 3.2.2.3: Human or chemically defined components should be used in the culture or preservation of cells whenever possible.

  Cells are likely to be expanded in culture and might be exposed to xenogeneic materials before transplantation. Components of non-human animal origin present risks of transferring pathogens or unwanted biological material and can be quite variable in composition and bioactivity. As such the risk of transmission of viruses and other infectious agents is proportionately greater when using xenogeneic materials. Researchers can mitigate this risk by properly sourcing xenogeneic reagents from regions reasonably assumed to be clear of known pathogens. If xenogeneic components cannot be reasonably removed, researchers should demonstrate the lack of feasible alternatives and document favorable risk/benefit in using animal-based components. These risks can be mitigated by using reagents in which the manufacturers have included pathogen reduction steps which remove pathogens (such as viral inactivation), or testing cell lines (such as CHO lines), used in the manufacture of these reagents. In addition, adventitious agent testing of the cells should include testing for appropriate xenogeneic pathogens; these requirements are specified in guidance documents published by the FDA, EMA and other regulatory agencies. Careful adherence to regulations and tracking of cells and reagents and the development of a risk mitigation plan is crucial to translation and uptake of cell-based therapies.

  Recommendation 3.2.2.4: All reagents used in manufacturing stem cell-derived therapeutics should be of the highest quality available.

  In order to ensure the safety of stem cell products, the reagents and raw materials used in manufacturing should be manufactured under GMPs, whenever possible. It should be noted that while manufacturing under GMPs ensures product consistency and purity, it does not necessarily assure absence of adventitious agents. Therefore, a risk mitigation assessment and adventitious agent testing plan should be performed that address risks associated with all reagents used in manufacturing.

  In some cases, GMP grade reagents may not be available. In these cases, it is recommended to use reagents that comply with compendial requirements (e.g., USP, British Pharmacopoeia) and which were manufactured using the highest level of controls possible. It may also be necessary to clarify the appropriateness of reagents and raw materials with regulatory agencies if there are doubts about whether reagents that are not made under GMPs are of a sufficiently high enough quality for human use. It is essential that documentation including lot numbers and certificates of analysis and certificates of origin be retained for every reagent used in the isolation, expansion, and manipulation of stem cells that will eventually be used in the generation of therapeutic products.

  Release Criteria

  Recommendation 3.2.2.5: Criteria for in process and release specifications should be developed during the regulatory review process. Culture-acquired genetic abnormalities may be a significant risk and should be part of in process and/or final product testing for stem cell products that have undergone extensive expansion in vitro.

  The genetic and epigenetic stability of pluripotent stem cell-derived products warrants careful scrutiny. During manufacturing, it will be important to test cytogenetic abnormalities, as well as additional genetic and epigenetic parameters as defined by the protocol review process. The limitations of any such tests will be assessed and weighed against the risk /benefit and patient population for any given case.

  Recommendation 3.2.2.6: Criteria for release of cells should include the assessment of off-target cells, using the most sensitive assays possible.

  Release criteria for stem cell-based interventions should utilize qualified or validated assays that assess the identity, purity, sterility, activity, and potency of the product. Because stem cell products may consist of heterogeneous populations of cells, it is important to include assays that detect and quantify the target cells responsible for the bioactivity of the product as well as other “off-target” cell populations.

  The off-target cells may be cells from different lineages, cells from the same lineage, partially differentiated cells, or undesirable cells such as undifferentiated stem cells. For pluripotent stem cell-derived products, there is concern about residual undifferentiated pluripotent stem cells that may remain in the product. Given the nature of pluripotent stem cells and their innate capacity to form teratomas, there is a particular concern for the potential tumorigenicity of stem cell-based interventions. Therefore, the development of sensitive assays to detect contaminating undifferentiated pluripotent stem cells in the final product is critical, especially when delivering large cell doses. Further, the sensitivity of these assays should be documented in regulatory submissions. Some techniques (such as FACS analysis) may be suitable for doses of millions of cells but for doses in the 108-109 range more sensitive assays may need to be developed.

  In summary, all stem cell-based interventions should be defined with their constituents as completely as possible, including at a minimum the proportion of therapeutic (on target) cells within the final cell product as well as minimizing the cells capable of causing major side effects, including tumor formation.

• 3.3 Preclinical Studies

  The purpose of preclinical studies is to (a) provide evidence of product safety and (b) establish proof-of-principle for therapeutic effects. International research ethics policies, such as the Declaration of Helsinki (1964) and the Nuremberg Code (1949), strongly encourage the performance of non-human animal studies prior to clinical trials. Before initiating clinical studies with stem cell-based interventions in humans, researchers should have persuasive evidence of safety and the potential for clinical utility in appropriate in vitro and/or animal models. These preclinical studies must be rigorously designed and have been subject to regulatory oversight and reviewed independently prior to the initiation of clinical trials. This helps ensure that trials are scientifically, medically, and ethically warranted.

  Cell-based interventions offer unique challenges for preclinical studies. In some cases, homologous cells in the same species are unavailable. Immune-suppressed animal models, while useful, do not permit an understanding of the effect of the immune system on transplanted cells, or, more often, they may not share all the same biological properties of their human counterparts. Since transplanted cells are considerably more complex and can change after transplantation in unpredictable ways, extrapolating cell therapies in an animal model to humans is even more challenging than for small molecule therapeutic candidates.

• 3.3.1 General Considerations

  Animal Welfare

  Recommendation 3.3.1.1: Preclinical research into stem cell-based interventions involving animals should adhere to the principles of the three Rs: reduce numbers, refine protocols, and replace animals with in vitro or non-animal experimental platforms whenever possible.

  This recommendation is not incompatible with performing replication experiments or achieving adequate statistical power (see: www.nc3rs.org.uk). Indeed, these are key steps for ensuring that animal experiments support robust conclusions. This recommendation should also not be interpreted as suggesting that in vitro or non-animal platforms are sufficient for supporting clinical investigations. For most stem cell therapies safety testing should be performed in vivo. However, recent developments in organoid systems suggest that efficacy testing in vitro may by suitable in some circumstances.

  Preclinical Study Objectives

  Recommendation 3.3.1.2: Early phase human studies should be preceded by a rigorous demonstration of safety and efficacy in preclinical studies. These preclinical studies can include in vitro and in vivo modeling.

  Preclinical efficacy studies help provide the scientific rationale for proceeding into human trials. Stringent design and reporting standards should be demanded where planned trials involve invasive delivery approaches or where the cell product presents greater risk and uncertainty. However, prudent use of scientific resources means that even when risk is modest, studies should rest on sound scientific evidence of expected efficacy.

  The development of stem cell-based products generally includes a period of process development in which the manufacturing process is optimized. This may include exchanging research grade reagents with reagents manufactured under GMP and removing xenogeneic reagents from the process. Because these changes can affect the cellular composition and bioactivity of the final product, it is important that preclinical efficacy studies use stem cell product manufactured using processes intended for clinical applications, whenever feasible.

  Study Validity

  Recommendation 3.3.1.3: All preclinical studies testing safety and efficacy should be designed in ways that support precise, accurate, and unbiased measures of potential clinical utility. In particular, studies designed to inform trial initiation should have high internal validity; they should be as representative as possible of clinical scenarios they are intended to model, and they should be replicated.

  Preclinical experiments confront many sources of bias and confounding factors, including selection bias. For decades, clinical researchers have sought to minimize the effects of bias and confounding by using techniques like randomized allocation, blinded outcome assessment, or power calculations. Such rigor should also apply in preclinical studies intended to support trials. Numerous groups have articulated standards for designing preclinical studies aimed at supporting trials (Fisher et al., 2009; Henderson et al., 2013; Landis et al., 2012; Kimmelman et al., 2014). Key design principles include:

  Researchers should reduce bias and random variation by ensuring their studies have adequate statistical power, use appropriate controls, randomization, and blinding, and, where appropriate, establish a dose-response relationship.

  Critical or definitive safety and efficacy studies should be performed with prospective protocols and should have independent quality oversight.

  Researchers and sponsors should ensure preclinical studies model clinical trial

  settings. Researchers should characterize disease phenotype at baseline, select animal models that best match the human disease, use outcome measures that best match clinical outcomes, and provide evidence supporting a mechanism for treatment effect.

  Researchers and sponsors should ensure effects in animals are robust by replicating findings, ideally in an independent laboratory setting.

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

  Sex as a Biological Variable

  Recommendation 3.3.1.4: Preclinical studies should assess both male and female animals in safety and efficacy testing unless there is a scientifically valid reason not to do so.

  Males and females can respond differently to medical treatments as well as to the incidence of diseases, which can reflect distinct underlying pathways and mechanisms, due to chromosomal makeup and effects of gonadal hormones. Therefore, it is important to include both male and female animals in preclinical efficacy and safety studies. Of particular importance is the inclusion of both sexes in long-term safety studies, which is typically a mandatory requirement from many funding and regulatory agencies. In vitro model systems should, whenever possible, also be derived from male and female cells.

• 3.3.2 Safety Studies

  Human cells should be produced under the conditions discussed in Section 3.2, Cell Processing and Manufacture. Depending on the laws and regulations of the specific region, biodistribution and toxicity studies should be performed using good laboratory practice (GLPs). It is recommended that these studies be performed by a third party, such as a Contract Research Organization (CRO).

  Cell Characterization

  Recommendation 3.3.2.1: Cells to be employed in clinical trials must first be rigorously characterized to assess potential toxicities through studies in vitro and, where possible, for the clinical condition and tissue physiology to be examined in animal models.

  Outside of the hematopoietic, stratified epithelia, and various stromal cell systems there is little clinical experience with the toxicities associated with infusion or transplantation of stem cells or their derivatives. In addition to known and anticipated risks (for example, acute infusional toxicity, immune reactions, and tumor development), stem cell-based interventions present risks that will only be discovered with experience. As non-human animal models may not replicate the full range of human toxicities associated with stem cell-based interventions, particular care must be applied in preclinical analysis. This section defines toxicities that are likely to be unique to stem cells or their progeny.

  Tumorigenicity Studies

  Recommendation 3.3.2.2: Risks for tumorigenicity must be rigorously assessed for any stem cell-based product, especially if cells are extensively manipulated in culture, genetically modified, or when derived from a pluripotent source.

  Assessing tumorigenicity is a critical part of determining the safety profile of stem cell products. These studies can be challenging, as they usually require assessment of the human cell product in xenogeneic models. Further, these studies usually include long-term time points that can be several months to years. Therefore, immunocompromised animals, usually rodents, are often the animal model of choice.

  All stem cell derived products should be tested for tumorigenicity, see Recommendation 3.2.2.5. Long-term animal studies are necessary to demonstrate that the persistence of any remaining undifferentiated cells in the final product do not result in tumors.

  It is understood that assessing tumorigenicity in animal models is complicated by implantation technique, composition of the test article (percentage of undifferentiated cells versus the percentage of cell product), and various other parameters. Because of this complexity, tumorigenicity studies may benefit from additional in vitro studies. These would include examining rates of proliferation, observing if faster dividing subclones tend to take over the cultures, and looking for expression of oncogenes or loss of tumor suppressor gene activity. However, while these tests may add to in vivo studies, they cannot substitute for them.

  Positive tumor-generating controls and negative controls assessing background tumorigenesis should be run in parallel in these studies to validate results. Specifically, this informs whether the site of implantation and other delivery parameters are permissive to tumor formation, allowing interpretation of a negative result. In these studies, it is important to deliver the cell product to the intended clinical site, if feasible. Further, assessment of the clinical dose is also important. In cases where the human dose includes very large quantities of cells, this can be quite challenging, and it is critical to work with regulators to ensure that proposed study designs are appropriate. For example, in cases where it is not feasible to deliver a human-sized dose into an immunocompromised animal model, the risk from residual undifferentiated cells in the product may be assessed by spiking the largest feasible animal dose of the therapeutic product with the highest number of undifferentiated cells that might be present in the human-sized dose (based on the sensitivity of the assay used for measuring their presence in the clinical dose).

  The plan for assessing risks of tumorigenicity should be reviewed and approved by regulators before initiation of definitive preclinical studies and clinical trials. For additional guidance on specific techniques that may be of utility for genome edited interventions, see Appendix 5.

  Biodistribution Studies

  Recommendation 3.3.2.3: For all stem cell-based products, whether injected locally or systemically, researchers should perform detailed and sensitive biodistribution studies of cells.

  Because of the potential for cells to persist or expand in the body, investigators must seek to understand the nature and extent by which cells distribute throughout the body, lodge in tissues, expand and differentiate. Careful studies of biodistribution, assisted by ever more sensitive techniques for imaging and monitoring of homing, retention and subsequent migration of transplanted cell populations is imperative for interpreting both efficacy and adverse events. These studies should whenever feasible, include delivery of the cell product using the intended clinical route and site of delivery.

  Additional histological analyses or banking of organs for such analysis at late time points is recommended. Depending on the laws and regulations within specific jurisdictions, biodistribution and toxicity studies may need to be performed in a good laboratory practice (GLP)-certified animal facility.

  Distinct routes of cell administration, local or systemic, homologous or non-homologous/ectopic, can lead to different adverse events. For example, local transplantation into organs like the heart or the brain may lead to life-threatening adverse events related to the transplantation itself or to the damage 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), care must be exercised in assessing the possibility of local, anatomically specific and systemic toxicities.

  Ancillary Therapeutic Components

  Recommendation 3.3.2.4: Before launching high-risk trials or studies with many components, researchers should establish the safety and optimality of other intervention components, like devices or co-interventions such as surgeries.

  Cell-based interventions may involve other materials besides cells, such as biomaterials, engineered scaffolds, and devices. There may also be co-interventions like surgery, tissue procurement procedures, and immunosuppression. Additional components added to the cellular product, or delivery device can interact with the stem cell product and each other. In these cases, safety and efficacy studies should include the assessment of the final combination product. Many subjects in cell-based intervention studies may be receiving immunosuppressants or drugs for managing their disease. These can also interact with the implanted cell product. Safety and efficacy studies should include assessment of possible interactions between the cell product and these types of medications, in vitro or in vivo.

  Long-term Safety Studies

  Recommendation 3.3.2.5: Researchers should adopt practices to address long-term risks in preclinical studies.

  Given the likelihood for long-term persistence of cells and the irreversibility of some cell-based interventions, testing of the long-term effect of cell transplants in animal models is encouraged.

  Application of genetic alteration and genome editing technologies to stem cell products

  Recommendation 3.3.2.6: Researchers should comprehensively investigate the type, extent and genomic distribution of introduced genetic alterations as well as their potential adverse effects on the genome and the biological properties of the treated cells at short and long-term time points.

  Genetic alteration and genome editing technologies can be coupled to stem cell therapies or applied directly in vivo to resident tissue cells for a variety of therapeutic purposes.

  Gene replacement approaches have made substantial progress and advances into clinical testing, either performed ex vivo on hematopoietic stem cells, lymphocytes or epidermal stem cells or in vivo targeting the liver, retina or CNS, with a growing number of therapies approved for market access. Targeted genome editing strategies are still in the early stage of clinical development, although there is constant progress and early clinical testing is showing safety and some efficacy, at least for ex vivo based strategies.

  Considering the likelihood for long-term persistence, expansion and broad clonogenic output of many stem cell types and the irreversibility of any genetic alteration introduced by integrating gene transfer or genome editing, the type, extent and genomic distribution of the introduced genetic alteration, including on- and off-target events, should be comprehensively investigated as well as their potential adverse effects on the genome and the biological properties of the treated cells both in the short- and long-term. This is particularly important following genome editing when this has involved double strand breaks in DNA; the analysis of manipulated cells should include an assessment of incorrect on- and off-target events, and whether these pose any risk. Whenever possible and scientifically appropriate, such testing should include cell transplants in suitable xenogeneic hosts for long-term observation.

  Potential of Stem Cells for Toxicology

  Recommendation 3.3.2.7: Researchers, sponsors, and regulators should take advantage of the potential for using stem cell-based systems to enhance the predictive value of preclinical toxicology studies.

  Stem cell science offers the prospect of testing toxicology in cell-based systems or artificial organs that more faithfully mimic human physiology than animal models. Such approaches, though unlikely to ever completely substitute for in vivo testing in animals, hold substantial promise for reducing burdens imposed on animals in safety testing and improving the predictive value of preclinical safety studies.

• 3.3.3 Efficacy Studies

  Given the therapeutic goals of stem cell-based interventions, preclinical studies should demonstrate evidence of therapeutic effect in a relevant animal model for the clinical condition and the tissue physiology to be studied. Mechanistic studies utilizing cells isolated and/or cultured from animal models or human tissues, both diseased and controls, are critical for defining the underlying biology of the cell-based interventions. However, a complete understanding of the biological mechanisms at work after stem cell-based intervention is not a prerequisite to initiating trials, especially when trials involve serious and untreatable diseases for which efficacy and safety have been demonstrated in relevant animal models and/or in conclusive human studies with the same cell source. Further, in rare cases, appropriate animal models may not exist. In these cases, in vitro studies may be used to support the rationale for potential efficacy.

  Efficacy Evidence for Initiating Trials

  Recommendation 3.3.3.1: Trials should generally be preceded by compelling preclinical evidence of clinical utility in well-designed studies. Animal models suited to the clinical condition and the tissue physiology should be used, unless there is evidence of efficacy using similar products against similar human diseases, or if it is not feasible to establish appropriate or predictive animal models.

  Rigorous preclinical testing in animal models is especially important for stem cell-based approaches because cell therapies have distinctive pharmacological characteristics. Before clinical testing, preclinical evidence should ideally provide the following:

  Mechanism of action. Preclinical studies should establish evidence connecting a cell-based intervention’s therapeutic activity in animal models to a pathophysiological process. These studies establish the localization of transplanted cells and provide evidence that the predicted localization is tied to the proposed mechanism of action.

  Optimal conditions for applying the stem cell-based intervention (for example, dose, co-interventions, delivery).

  Ability to modify disease or injury when applied in suitable animal systems, and under conditions that are similar to expected trials (see design principles under Section 3.3.1.3, Study Validity).

  Sufficient magnitude and durability of disease modification or injury control to be clinically meaningful.

  In cases where an intervention is substantially similar to one that has already been tested in humans, trial evidence may reduce the demand for preclinical evidence.

  Animal Studies

  Recommendation 3.3.3.2: Appropriate animal models should be selected which allow the assessment of efficacy and safety of the stem cell-based intervention. Safety testing should include assessment of the delivery procedure or surgical technique used for implantation of the cells.

  Immune-deficient rodents or those manipulated to have humanized immune systems can be especially useful to assess human cell transplantation outcomes, engraftment in vivo, stability of differentiated cells, and cancer risk. Many small animal models of disease can faithfully reproduce aspects of human diseases, although there are considerable limitations. Small animal studies should also attempt to correlate cell number and potency required for large animal studies and subsequent trials.

  Large animals may better represent human physiology as they are often genetically outbred, maintained in more diverse environments, and anatomically more similar. They may provide the opportunity to test co-interventions used in trials (for example, adjunctive immunosuppressive drug therapy) methods of introduction or the compatibility of surgical devices and cell products. They also may be essential to evaluate issues of manufacturing scale up, or anatomical factors that are likely to mediate a therapeutic effect (for example, bone, cartilage, or tendon in a load-bearing model). Trials involving risky or novel approaches should generally be supported by evidence from large animal models in cases where such models better recapitulate human disease and human anatomy (e.g., cardiomyocyte transplantation).

  The need for invasive studies in non-human primates should be evaluated on a case-by-case basis, performed only if trials are expected to present high risk, and where non-human primates are expected to provide information about cell-based interventions not obtainable with other models. All studies involving the use of non-human primates must be conducted under the close supervision of qualified veterinary personnel with expertise in their care and their unique environmental needs. Particular care should be taken to minimize suffering and maximize the value of studies by using rigorous designs and reporting results in full.

• 3.3.4 Transparency and Publication

  Recommendation 3.3.4.1: Sponsors, researchers, and clinical investigators should publish preclinical studies in full and in ways that enable an independent observer to interpret the strength of the evidence supporting the conclusions.

  The publication of preclinical studies serves many ends. It enables peer review of clinical research programs, thus enhancing risk/benefit ratios in trials, respects the use of animals and reagents by disseminating findings from studies, enables more sophisticated interpretation of clinical trial results, and makes possible the evaluation of preclinical models and assays, thus promoting a more effective research enterprise. However, many studies show biased patterns of preclinical publication (Sena et al., 2010; Tsilidis et al., 2013). Preclinical studies—at least those that are aimed at confirming the hypotheses motivating a development program—should be reported in full regardless of whether they confirm, disconfirm, or are inconclusive with respect to the hypothesis they are testing. These guidelines recognize that publication may reveal commercially sensitive information and therefore acknowledge that a reasonable delay is permissible to secure appropriate protection of intellectual property. Nevertheless, preclinical studies supporting a trial should be published before the first report of trials. Animal studies should be published according to well-recognized standards, such as the ARRIVE (Animal Research: Reporting In Vivo Experiments) criteria, that have been endorsed by leading biomedical journals (Percie du Sert et al., 2020).

• 3.4 Clinical Research

  The rights and welfare of human subjects participating in clinical trials must be protected in any clinical research, including trials involving stem cell-based interventions and novel reproductive technologies. Clinical research should be designed to generate scientifically rigorous information that will be used to guide important decisions for patients, clinicians, clinical investigators, sponsors, and policymakers.

  Sponsors, investigators, host institutions, oversight bodies, and regulators bear responsibility for ensuring the ethical conduct of clinical trials. In addition, members of the broader research community have a responsibility for encouraging ethical research conduct. As with all clinical research, clinical trials of stem cell-based interventions must follow internationally accepted principles governing the ethical design and conduct of clinical research and the protection of human subjects (Department of Health, and Education and Welfare, 1979; European Parliament and Council of the European Union, 2001; World Medical Association, 1964; Council for International Organizations of Medical Sciences 2016). Key requirements include having adequate preclinical data, a rigorous research design that minimizes risk, independent oversight and peer review, fair subject selection, informed consent, research subject monitoring, auditing of study conduct, and trial registration and reporting. Ideally this should include the involvement of the relevant patient/carrier groups.

  Some interventions and conditions present challenges for standard trial designs. Nevertheless, research in such settings should similarly involve a pre-specified protocol, independent review for scientific merit and ethics, and a plan for reporting. Translational research on novel assisted reproductive technologies ideally combines both specialized oversight process (see Section 2.1) and human subjects review.

  What follows in this section pertains to clinical trials as well as innovative care pathways and observational studies.

• 3.4.1 Oversight

  The overarching goal of research oversight is to ensure that the research is safe, protects human subjects, has scientific and medical merit, and is designed and carried out to yield credible data and enhance scientific and medical understanding.

  Prospective Review

  Recommendation 3.4.1.1: All research involving clinical applications of stem cell-based interventions must be subject to prospective review, approval, and ongoing monitoring by independent human subjects research review committees.

  Independent prospective review and monitoring are critical for ensuring the ethical basis of research with human subjects, regardless of funding source. A competent review will be predicated on the absence of conflicts of interest (both financial and non-financial) that can bias assessment of the research design, maximize the alignment of the goals of the research with the subjects’ rights and welfare, and promote valid informed consent.

  Additional independent evaluation of the research may occur through other groups, including granting agencies, peer review, the specialized oversight process (see Section 2.1), regulators, and data and safety monitoring boards. Of crucial importance is that these groups collectively have the scientific, medical, and ethical expertise to conduct necessary review and oversight. To initiate stem cell-based clinical research, investigators must also follow and comply with local and national regulatory approval processes.

  Expert Review of Clinical Research

  Recommendation 3.4.1.2: The review process for stem cell-based clinical research should ensure that protocols are vetted by independent experts who are competent to evaluate (a) the in vitro and in vivo preclinical studies that form the basis for proceeding to a trial and (b) the design of the trial, including the adequacy of the planned endpoints of analysis, statistical considerations, and disease-specific issues related to human subjects protection.

  Peer review as well as institutional review boards/research ethics committees should also judge whether the proposed stem cell-based clinical trial is likely to lead to important new knowledge or an improvement in health. Comparing the relative value of a new stem cell-based intervention to established modes of therapy is integral to the review process. Peer review should be informed, where feasible, by a systematic review of existing evidence supporting the intervention including a review of its utility against other therapies that already exist for that condition. If decisions must be made based solely on expert opinion because no relevant literature is available, this should be described explicitly in the recommendations regarding a particular trial.

• 3.4.2 Standards for Clinical Research Conduct

  Risk-Benefit Analysis

  Recommendation 3.4.2.1: Risks should be identified and minimized, unknown risks acknowledged, and potential benefits to subjects and scientific understanding estimated. Sponsors should be able to justify research with human subjects in terms of likely risk and benefit based on evidence from preclinical studies and the published literature.

  Efficient designs that minimize risks and include the minimum number of subjects required to properly answer the scientific questions at hand should be employed. Eligibility criteria in prelicensure stages should be designed to minimize risks with consideration of potential comorbidities that may increase risk or modify the risk/benefit ratio. Correlative studies should be performed to ensure that the maximum possible information is obtained on the safety and efficacy of the approach being tested, provided that such assessments do not pose an undue burden for the subject.

  Systematic Appraisal of Evidence

  Recommendation 3.4.2.2: Initiation of clinical trials should be supported by a systematic appraisal of evidence supporting the intervention and the current unmet need for treatment of the disease or disorder.

  Decision-making about whether to proceed with a given research effort should be supported by a systematic review of available scientific evidence. At a minimum, this review should consist of a synthesis of a systematic search of published and unpublished studies testing the intervention in animal systems. For early-phase clinical trials, the systematic review will mostly involve synthesizing basic and preclinical investigations, while for late phase studies the systematic review should include clinical evidence. The systematic review should also be informed by accessing and synthesizing findings involving the testing of similar intervention strategies as well as current standard of care. Trial brochures should summarize the information gathered from systematic review without any bias.

  Objectives of Trials

  Recommendation 3.4.2.3: Stem cell-based interventions must be aimed toward being clinically competitive with existing therapies or meeting a unique therapeutic demand. Being clinically competitive necessitates having reasonable evidence that existing treatments are less than optimal or pose burdens that may be overcome should the stem cell-based intervention prove to be safe and effective

  The rationale for developing a new stem cell-based intervention is that it can work better or as well as existing treatments with less morbidity and a favorable cost benefit analysis. Simply being able to make a therapy for a condition is not sufficient for going to a clinical trial if effective treatments already exist for patients, which have been shown to have a major clinical impact, and cost-effective therapies are already widely used. Clinical trials should only proceed when a sound argument around its ultimate competitive advantage in a given medical/surgical condition is clearly articulated.

  Subject Selection

  Recommendation 3.4.2.4: Individuals who participate in clinical stem cell research should be recruited from populations that are in a position to benefit from the results of this research. Groups or individuals must not be excluded from the opportunity to participate in clinical stem cell research without rational scientific justification. Unless scientifically inappropriate, trials should strive to proportionally include women, as well as men, and members of all ethnic groups.

  Well-designed clinical trials and effective stem cell-based therapies should be accessible to patients without regard to their financial status, insurance coverage, or ability to pay. In stem cell-based clinical trials, the sponsor and principal investigator should make reasonable efforts to secure sufficient funding so that no person who meets eligibility criteria is prevented from enrollment because of their inability to cover the costs of participation.

  Assuming that a particular condition is not thought to adversely affect decision-making capacity, clinical research should generally seek to enroll those who have a capacity to provide consent rather than those who are unable. In some cases, first-in-human trials might be started in children because they are the only disease-affected individuals who might benefit from the intervention. When conducting late-phase or post-approval trials, investigators should generally plan, design, analyze, and report trials to examine relationships between treatment response and age, sex/gender, or self-selected ethnic group.

  Informed Consent

  Recommendation 3.4.2.5: Informed consent must be obtained from potential human subjects or their legally authorized representatives. Reconsent of subjects must be obtained if substantial changes in risks or benefits of a study intervention are identified or alternative treatments emerge during the research.

  Culturally and linguistically appropriate counseling and voluntary informed consent are necessary components in the ethical conduct of clinical research and the protection of human subjects. Subjects should be made aware that their participation is voluntary. Patients who decide not to participate in clinical research should be reassured that they will continue receiving ongoing clinical care. In addition, consent discussions should emphasize that once the stem cell intervention is provided, it cannot be removed and that subjects must be free to withdraw consent for follow up without penalty at any point. Subjects should be informed that the investigational stem cell intervention may prevent them from receiving other therapies or participating in future clinical studies. Specific consent challenges in early phase trials are discussed below.

  Recommendation 3.4.2.6: When human research participants lack the capacity to provide valid informed consent, when no other reasonably effective options exist, and the risks from study procedures should be limited to no greater than a minor increase over the minimal risk unless the risks associated with the intervention are exceeded by the prospect of therapeutic benefit. A legally authorized representative or substitute decision-maker should help make decisions that are in the patient’s interest.

  Stem cell-based clinical trials may involve populations, such as children or persons with advanced neurological disorders, who may lack knowledge, comprehension and decision-making capacity required to provide informed consent. Because such individuals cannot make their own decisions and protect their own interests, they require extra protection from research risk. Most jurisdictions provide guidance concerning which legally authorized representatives or substitute decision-makers should be approached when prospective research participants lack decision-making capacity. This recommendation pertains to risks that lack a therapeutic justification, for example, tissue biopsies to test biodistribution, sham procedures, or withdrawal of standard treatments to monitor response during unmedicated periods. Such procedures should not exceed a minor increase over the minimal risk when trial populations lack capacity to provide valid informed consent. In addition, in this setting, the assent of the research subject should be obtained where possible even when informed consent cannot be obtained. Because definitions of minimal risk vary by jurisdiction, researchers should adhere to policies defined by local human subjects review committees.

  The issue of obtaining informed consent and assent from children for research is not unique to stem cell research. Accordingly, research conducted with children, as with other individuals who lack the capacity to provide valid consent, should adhere to recognized ethical and legal standards for this research.

  Assessment of Capacity to Consent

  Recommendation 3.4.2.7: Prior to obtaining consent from potential adult subjects who have diseases or conditions that are known to affect cognition, their capacity to consent should be assessed formally.

  Subjects who lack decision-making capacity or have medical conditions that can adversely affect decision-making capacity should not be excluded from potential biomedical advances involving stem cells. At the same time, patients who lack capacity should be recognized as especially vulnerable. Conclusions that individuals lack decision-making capacity should only be reached after formally assessing their capacity to provide consent. When individuals are deemed to lack decision-making capacity, as permissible by law and following established ethical guidelines, steps should be taken to involve legally authorized representatives who are qualified and informed to make surrogate research judgments. See also Recommendation 3.4.2.6.

  Privacy

  Recommendation 3.4.2.8: Research teams must protect the privacy of human subjects.

  Privacy is an important value in clinical settings. Moreover, there are longstanding professional obligations and legal duties to maintain confidentiality in medical care and research. Given the high profile of many stem cell-based intervention trials, it is particularly important for research teams to take steps to protect the privacy of research subjects. For instance, research data should be maintained in a secure manner with access restricted to study staff, oversight bodies, and agencies who have a legitimate right and have undergone training in management of private data to review these data as would be the case in any clinical trial.

  Patient Sponsored and Pay-to-Participate Trials

  Recommendation 3.4.2.9: Patient-sponsored and pay-to-participate trials pose challenges for ensuring scientific merit, integrity, and priority as well as fair selection of study participants. Accordingly, charging individuals to participate in clinical trials should only be permitted when such studies are compliant with applicable national regulations and are approved and supervised by a rigorous independent review body, such as an institutional review board.

  As a general rule, study participants should not be charged to access investigational products or to participate in clinical studies. Exceptions to this rule should be subjected to close scrutiny by responsible parties such as institutional review boards and national regulators. The review process for pay-to-participate trials should ensure compliance with the principles outlined in these guidelines regarding the integrity of the research enterprise, transparency, and patient welfare. The process should consider all fees study participants are expected to pay and determine whether there is any credible basis for charging fees to individuals enrolled in the clinical trials. With studies that require authorization or clearance by national regulators, such regulators should be informed that study participants will be charged. They must then determine whether any and all fees charged to study participants comply with ethical, legal, and scientific standards. The potential liabilities of patient-sponsored and pay-to-participate research should be managed by requiring that protocols considering the use of such arrangements undergo independent expert review for scientific rationale, priority, and design. While input from patient communities can greatly enhance the research process, independent oversight is essential to ensure the responsible conduct of research and its reporting. Oversight bodies such as institutional review boards and research ethics committees must examine ethical, scientific, and legal features of pay-to-participate studies, ensuring they comply with applicable regulations and contemporary standards for research ethics.

  Whereas patient advocacy and disease groups interested in funding clinical studies may have a strong research orientation and have the capacity required to carefully assess ethical, legal, and scientific issues related to designing and conducting clinical trials, individual patients seeking trial access may not have the resources or background needed to evaluate the ethical and scientific implications of charging research participants for access to investigational products administered in clinical studies. Consequently, patient payers, however well-intentioned, may press for studies that are poorly justified, are not well designed, or blur the lines between treatment and research and promote therapeutic misconception or other misunderstandings that undermine meaningful informed consent. Pay-to-participate research also raises questions of selection bias given that only those with access to resources may be able to enroll in trials and bias for participation in the treatment vs. the placebo group.

  Patient-sponsored trials present opportunities for individuals and groups of patients to directly engage in the research process and fund work that public and industry sponsors are unwilling to undertake. Nevertheless, they present serious ethical and policy challenges that need to be addressed. Patient sponsors may press for study designs that eliminate elements such as randomization to a comparator arm and eligibility criteria that are critical for promoting scientific validity and patient welfare. Patient sponsors may also lack the expertise to distinguish meritorious protocols from those that are scientifically dubious. Further, there may be confusion over the intellectual property rights associated with successful interventions. Finally, they can also have the effect of diverting prospective study participants from studies that are well-designed and have the potential to generate meaningful safety and efficacy data to trials with serious methodological shortcomings.

  Pay-to-participate studies also raise ethical concerns that are not confined to the study subjects who wish to enroll in such trials. By potentially coopting research teams from pursuing research endeavors that have received support through more traditional peer-reviewed mechanisms, pay-to-participate studies can result in outcomes that may unfairly disadvantage patients who lack the financial resources to set research agendas. In addition, patient-sponsored trials may divert resources such as study personnel from research activities that advance more promising research avenues.

  Finally, because patients transact directly with those offering trial participation, direct payment for participation supports a business model whereby patients might be charged for receiving unproven and ineffective stem cell-based interventions and feel under pressure to accept such interventions from those “selling” it.

• 3.4.3 Transparency and Reporting of Research Results

  Registration

  Recommendation 3.4.3.1: All trials should be prospectively registered in public databases.

  Registration offers transparency regarding promising stem cell-based interventions so that patients, regulators, and the scientific community can monitor these efforts and incorporate them into future efforts, thereby minimizing risk and maximizing benefits of clinical trials. Registration also promotes integrity in scientific research, such as ensuring that scientists do not change primary endpoints after studies commence or otherwise take steps that might compromise the quality of research data. In addition, registration promotes access to clinical trials for patients who might not otherwise have a means of knowing about them. However, having a trial listed on public databases does not necessarily mean that the trial has been vetted by regulators or is in compliance with these guidelines. Prospective patients or their representatives should always confirm that trials are authentic before enrolling.

  Adverse Event Reporting

  Recommendation 3.4.3.2: Investigators should report adverse events, including their severity and potential causal relationship with the experimental intervention.

  Knowing the safety profile of stem cell-based interventions is critical for effective translation. Timely analysis of safety information is also crucial for reducing the uncertainties surrounding stem cell-based interventions. Unfortunately, many studies report deficiencies in adverse event reporting for novel therapeutics (Saini et al., 2014). Researchers should report adverse events associated with cells, procedures, and all other aspects of the intervention. Most if not all national regulatory agencies mandate the reporting of such events, as they would for any clinical trial, and thus trials of stem cells should do the same at all trial phases.

  Publication

  Recommendation 3.4.3.3: Researchers should promptly publish results regardless of whether they are positive, negative, or inconclusive. Studies should be published in full and according to international reporting guidelines, including registration in the public databases.

  Publication of all results and analyses, regardless of whether an agent is advanced to further translation or abandoned, is strongly encouraged to promote transparency in the clinical translation of stem cell-based therapies, to ensure the development of clinically effective and competitive stem cell-based therapies, to prevent individuals in future clinical trials from being subjected to unnecessary risk, and to respect research subjects’ contribution (Fung et. al 2017). As such, reporting must be timely and accurate with the ambition to report long term follow up as well for those therapies where the agent is predicted to survive long term. Publication of data without paywalls is encouraged. Researchers should also consider ways to share individual research subject data, provided that adequate privacy protections for research subjects can be assured. A U.S. Institute of Medicine Report offers principles on sharing clinical trial data (Institute of Medicine, 2015). Researchers, sponsors, and others should adhere to these principles. Additional information is also available from the AllTrials initiative (https://www.alltrials.net), which the ISSCR supports.

  If a particular project can be described according to internationally recognized reporting guidelines, this format should be used. For example, researchers should report all randomized trials according to the CONSORT statement recommendations (Consolidated Standards of Reporting Trials; http://www.consort-statement.org/). Journal editors should accommodate publication of inconclusive and disconfirmatory findings. See also Section 4, Communications. Publications should also be included in the clinical trial registries to allow easy access to the outcome of the trial.

• 3.4.4 Issues Particular to Early Phase Trials

  Early phase trials provide the first opportunity to evaluate the methods and effects of promising stem cell-based interventions in humans. They also represent the first occasion where humans are exposed to an unproven intervention. All preclinical study results, including negative and neutral studies, should be considered before first in human trials are started. Because early phase studies of stem cell-based interventions involve high levels of uncertainty, investigators, sponsors, and reviewers may have very different views about the adequacy of preclinical support for trial initiation.

  Consent in Early Phase Trials

  Recommendation 3.4.4.1: Consent procedures in any prelicensure phase, but especially early phase trials of stem cell-based interventions, should work to dispel potential research subjects’ overestimation of benefit and therapeutic misconception.

  Early phase trials involving stem cell-based interventions may enroll research participants who have exhausted standard treatment options. In some cases, trials enroll individuals who have just experienced a life-altering medical event, such as spinal cord injury. Such individuals may be prone to overestimating the likelihood or degree of benefit of the experimental intervention (“therapeutic misestimation”). Individuals may further perceive research procedures as having a therapeutic benefit (“therapeutic misconception”). Both therapeutic misestimation and misconception may lead individuals to inadequately weigh risks of study participation, including health, social, logistic, and economic risks. Both may derive from overly optimistic reporting on stem cell research in traditional and new/social media. Accordingly, investigators should adopt a position of therapeutic equipoise, be aware of media/public representations of their field and make particular efforts to ensure that informed consent is valid in this setting (Benjaminy et.al 2015). Approaches that might be considered include:

  1. Conducting informed consent discussions that include someone who is independent of the research team.

  2. Explaining that major therapeutic benefits in early phase studies are exceedingly rare and that there may be unknown side effects given that the intervention has not been tried in people before.

  3. Addressing misconceptions and misestimations that derive from public representations of the field.

  4. Testing the comprehension of prospective participants about risks and benefits before accepting their consent to allow for the relevant data to be read and understood with the opportunity to ask questions about it.

  5. Requiring a period between consent discussions and acceptance of consent.

  6. Avoiding language that has therapeutic connotations, for example, using words like agent or cells or intervention rather than “stem cell therapy” or “treatment.”

  7. Supplementing consent forms with additional educational materials.

  Resources for drafting consent forms in early phase trials can be found at the National Institutes of Health Office of Biotechnology Activities (National Institutes of Health, 2014).

  Sequence of Testing

  Recommendation 3.4.4.2: In general, initial tests of a novel strategy should be tested under lower-risk conditions before escalating to higher risk study conditions even if they are more likely to confer therapeutic benefit.

  The approach of risk escalation enables researchers to refine and test techniques before advancing towards more aggressive strategies. It also helps to minimize the prospect of catastrophic events that might undermine confidence in development of stem cell-based interventions. Investigators should generally begin at lower doses, use less risky delivery procedures, use less aggressive co-interventions, and stagger treatment but also not use doses that are unlikely to have any therapeutic effect for the patient. Staggered treatment provides the opportunity to carefully review experiences and results prior to posing risk to additional subjects. A clear plan on how this will be done is needed in terms of the process by which a decision on dose changes will be undertaken. Researchers should, in general, validate safety and techniques in research subjects with advanced disease before testing their products in research subjects with more recent disease onset. There may nevertheless be situations where, because of delivery or disease target, a cell product is not suitable for initial evaluation in individuals with advanced disease.

  Maximizing Value

  Recommendation 3.4.4.3: Researchers should take measures to maximize the scientific value of early phase trials.

  Many interventions tested in early phase trials do not eventually show efficacy. However, even unsuccessful translation efforts return a wealth of information for developing stem cell-based interventions. Researchers should take several steps to maximize what is learned in early phase trials. First, where possible they should design studies that identify dose effects and mechanisms of action. These help researchers to determine whether cells have worked in the way anticipated. Second, they should seek to use standardized assays, endpoints, and methods. This enables researchers to synthesize results from individual, statistically underpowered trials (see Recommendation 5.1). Third, researchers should publish trials, methods, and sub-analyses in full. Studies show that many aspects of early phase studies are incompletely reported (Camacho et al., 2005; Freeman and Kimmelman, 2012). Last, where resources permit, and with appropriate consent, researchers should bank tissues and approach research subjects or families for permission to perform an autopsy in the event of death (see also Recommendation 3.4.6.3).

• 3.4.5 Issues Particular to Late Phase Trials

  Late phase trials are aimed at providing decisive evidence of clinical utility. They do this by using clinical measures of benefit, typically in larger numbers of participants, and by monitoring response over a longer, more clinically relevant period. Late phase trials generally use randomization and comparator arms to protect the ability to draw valid conclusions about clinical benefit. The choice of comparator presents some distinctive ethical challenges in the context of stem cell-based interventions. When designing late phase clinical trials, researchers should select objective and measurable primary endpoints (clinical and validated surrogate endpoints).

  Choice of Comparators

  Recommendation 3.4.5.1: Clinical research should compare new stem cell-based interventions against the best therapeutic approaches that are currently or could be made reasonably available to the local population.

  Stem cell research is an international endeavor where local standards of care differ dramatically. Due consideration should be given to achieve the best care in a given country, taking into consideration legitimate factors that affect the quality of care available locally. Trials should not be conducted in a foreign country solely to benefit patients in the home country of the sponsoring agency. Similarly, trials should not be conducted in a foreign country solely due to less stringent regulation. The test intervention, if approved, should realistically be expected to become available to the population participating in the clinical trial through existing health systems or those developed on a permanent basis in connection with the trial. In addition, research should be responsive to the health needs of the country in which it is conducted. For example, clinical trials with comparator arms should compare new stem cell-based interventions against the best therapeutic approaches that are currently available to the local population.

  Placebo and Sham Comparators

  Recommendation 3.4.5.2: Where there are no proven effective treatments for a medical condition and stem cell-based interventions involve invasive delivery, it may be appropriate to test them against historical controls, placebo, or sham comparators, assuming early experience has demonstrated the feasibility and safety of the particular intervention.

  Once early phase trials appear to demonstrate feasibility and tolerability/safety, the next phase 2/3 trials should be designed to show safety and efficacy, as well as superior treatment to standard of care for the respective disease or at least equivalence with a safety and a cost-effective advantage. In order for this to be done, stem cell-based interventions should be tested as for any other therapeutic agent and include control subjects. In some cases, historical data from the subject or the patient population may be suitable. If historical data does not provide a suitable control, including a placebo or sham arm or in exceptional circumstances, a therapeutic comparator may be justified. In all such cases, the choice of a control arm should be explicitly justified. For the cellular products that require surgery to be administered, it is important to investigate the feasibility of blinding carefully, taking into account invasiveness and ethics of sham surgery. If blinding of sham surgery is unfeasible, considering other strategies to enhance blinding, such as blinding the evaluators, is essential.

  Obviously, some sham procedures are not without risks, e.g. surgery. However, the use of sham comparators might be needed to assess the therapeutic potential of the intervention, but this can only be realistically done when issues around dosing and delivery have been resolved and felt to be optimized. In addition, researchers should ensure that the validity and advantages of sham procedures are not undone by factors that could unblind research subjects or investigators. Maintaining blinding can be particularly challenging in an era when research participants are able to use social media platforms to locate one another and communicate about their experiences as study subjects.

  Researchers should also take particular care explaining the use of placebos or sham procedures during the informed consent process and ensure patients understand and agree that they may receive a treatment with no anticipated clinical benefit and that this may tie them into a trial for years.

• 3.4.6 Research Subject Follow-up and Trial Monitoring

  Data Monitoring

  Recommendation 3.4.6.1: A data-monitoring plan is required for clinical studies. When deemed appropriate, aggregate updates should be provided at predetermined times or on-demand. Such updates should include adverse event reporting and ongoing statistical analyses if appropriate. Data monitoring personnel and committees should be independent from the research team.

  The risk/benefit balance can change over the course of clinical research, as safety and response are observed, recruitment wanes, or as new treatments become available. This is especially true for stem cell-based intervention trials, which are characterized by high uncertainty and rapidly evolving science. The welfare of subjects must be carefully monitored throughout the duration of stem cell-based clinical trials, the study interrupted if the risk/benefit balance becomes favorable or unfavorable, and subjects informed of new information about themselves, the trial, or the intervention that might materially affect their continued participation in a study.

  Long-term Follow-up

  Recommendation 3.4.6.2: Given the potential for transplanted cellular products to persist indefinitely and depending on the nature of the experimental stem cell-based intervention, subjects should be advised to undergo long-term health monitoring. Long-term follow-up is mandated in some countries, often for the use of gene therapies or xenotransplants. Additional safeguards for ongoing research subject privacy should be provided. Subject withdrawal from the research should be made in an orderly fashion to promote physical and psychological welfare.

  Long-term follow-up provides an opportunity to monitor the emergence of late adverse events and the durability of benefit. Given the practical realities, conducting long-term follow-up may be challenging. Investigators should develop and adopt measures to maintain contact with research subjects. In addition, funding organizations should be encouraged to develop mechanisms for supporting long-term follow-up. Since the length of appropriate follow-up is impossible to specify in the abstract, the decisions about this should be clearly articulated by investigators and reviewed by independent peer-reviewers and oversight bodies. If subjects withdraw from a study after the product has been delivered, investigators should continue long-term follow-up to monitor the emergence of adverse events if subjects concur.

  Autopsy

  Recommendation 3.4.6.3: To maximize the opportunities for scientific advance, research subjects or surviving next of kin in stem cell-based intervention studies should be asked for consent to a partial or complete autopsy in the event of death to obtain information about cellular implantation and functional consequences at some point in the trial. Requests for an autopsy must consider cultural and familial sensitivities and be conducted in a respectful and compassionate manner. Researchers should strive to incorporate a budget for autopsies in their trials and develop a mechanism to ensure that these funds remain available over long time horizons.

  Though a delicate issue, access to post-mortem material substantially augments the information coming out of trials and enables future product or delivery refinements in the treated condition. Since consent for autopsy is typically obtained from the family members of someone who has died, investigators should facilitate discussion of this issue among subjects and appropriate family members well ahead of any anticipated terminal event.

• 3.4.7 Issues Particular to Genome Editing of Somatic Stem Cells

  Recommendation 3.4.7.1: The clinical use of genetically altered (including genome-edited) somatic stem cells should be reserved for the treatment or correction of severe disease and disability. Due to the inherent risks, these products should comply with established policies and regulations for genome editing and cell-based products.

  Potential clinical applications of genetically altered somatic stem cells should be evaluated for potential risks and benefits of serious medical diseases and conditions. Uses of genetic alteration for non-serious conditions or for enhancement of body performance or features, such as to give an advantage in sports, should be discouraged: the potential benefits are marginal and cannot offset the risks at this time; they are unlikely to have public support; and they could bring the field into disrepute. The current risks associated with the methods also make it inadvisable to use them in attempts to confer disease resistance.

  The genetic alteration of cells provides a potential long-term/lifetime treatment for certain diseases. However, there are risks associated with this approach that include:

  1. Off-target effects from the insertion of exogenous DNA in gene replacement applications.

  2. Incorrect on-target and off-target genetic events in genome editing applications.

  3. Large-scale chromosomal rearrangements/inversions due to multiple DNA cleavage events when using targeted nucleases in genome editing.

  4. Unwanted immune response to the virus or nucleic acids from the viral vector carrying the DNA or exogenous DNA.

  A detailed discussion of these and other issues around clinical trials with genome-edited stem cells can be found in Appendix 5.

• 3.4.8 Clinical Research that Involves Heritable Changes to the Human Genome

  Mitochondrial Replacement Techniques

  Recommendation 3.4.8.1: Mitochondrial Replacement Techniques (MRT) should be offered only in the context of clinical investigation that is subject to strict regulatory oversight, limited to patients at high risk of transmitting serious mitochondrial DNA-based diseases to their offspring, when no other treatments are acceptable, and where long-term follow-up is feasible. International data sharing arising from initial uses is essential to help inform the field and ensure its appropriate use.

  Initial applications of MRT should continue to be restricted to cases in which the probability of transmission of pathogenic mitochondrial DNA is very high, where preimplantation genetic testing is unlikely to identify embryos suitable for transfer, and where procedures are conducted in the context of clinical investigation that can contribute to generalizable knowledge about this currently unproven and experimental technique. Preclinical research in human embryo-derived stem cells following MRT indicated the possibility of levels of maternal mitochondrial DNA increasing with extended passaging, but the clinical relevance of these data is unclear. Concerns have also been expressed about the possibility of mito-nuclear interactions being disrupted by MRT, though these remain theoretical. Research on embryonic stem cells derived from embryos after MRT or on the embryos themselves maintained in vitro would help explore these issues. These experiments could only proceed in jurisdictions where the creation of embryos for research is allowed, and only where they have been permitted following review by a specialized oversight process (see Section 2.1).

  Recommendation 3.4.8.2: There are inadequate clinical and preclinical data to justify the use of MRT to treat unexplained infertility associated with poor oocyte/embryo quality in women; therefore, it is recommended that this not be an intervention at this time.

  MRT has been used in the clinic as a speculative treatment for infertility (Zhang et al 2016). Given the risks entailed and the absence of clear mechanisms and compelling rationale for the use of MRT for unexplained infertility, additional preclinical and clinical experience are required to establish safety and efficacy. In one reported pilot trial of MRT, embryonic development and pregnancy rates in patients of advanced maternal age did not increase (n= 30), and it was advised that such patients should not undergo MRT (Mazur, 2019). Data from another small (non-randomized) trial of MRT (n= 25), in women under 40 with previous multiple failures of IVF (Costa-Borges et al, 2020), suggest that further controlled trials and follow-up are required. Research conducted in vitro to understand the mechanism by which application of the techniques may help unexplained infertility (which might not involve mitochondria) should be conducted, notably because this may lead to alternatives that both circumvent the use of technically challenging methods and avoid any risks associated with heteroplasmy or disrupted mito-nuclear interactions.

  Heritable Genome Editing

  Recommendation 3.4.8.3.1: Substantial preclinical research is needed to minimize the potential harm associated with clinical applications involving heritable genome editing; therefore, any attempt to modify the nuclear genome of human embryos for the purpose of reproduction is premature and should not be permitted at this time (see Section 2.2.3A, Category 3A, a).

  Any decision to proceed with heritable genome editing, where modified human embryos are transferred into a uterus or otherwise allowed to develop in utero, must be preceded with adequate preclinical research to minimize the potential harms from intended and unintended edits (see Recommendation 2.1.4). The first-in-human clinical uses should only be considered for the most favorable balance of potential harms and benefits and this will be most clearly defined for diseases and patients for which there are no viable alternatives. This may include prospective parents for whom there are no or very limited available alternatives for preventing transmission of diseases and conditions for which mortality is high and morbidity is severe. Other options for having a healthy child, including adoption, gamete or embryo donation, and preimplantation genetic testing, should be considered with appropriate counselling prior to any decision to proceed.

  Recommendation 3.4.8.3.2: If the technical and safety challenges associated with human heritable genome editing are resolved (see Recommendations 2.1.4 and 3.4.8.3.1), any applications for the initial clinical use of human heritable genome editing should be evaluated on a case-by-case basis. This evaluation needs to consider not just the scientific methods, but also the societal and ethical issues associated with the proposed use.

  The decision to proceed with first-in-human clinical uses needs to be taken openly with robust consideration of informed public opinion generated through meaningful public engagement. In addition, and critically, any experimental use of heritable human genome editing should only proceed in jurisdictions with appropriate and robust regulations and oversight.

  A key consideration of potential uses of heritable genome editing is whether the prospective parents have feasible options for conceiving a genetically related child who does not inherit a serious genetic disease, such as preimplantation genetic testing and selection of embryos. The initial uses should be confined to prospective parents who lack reasonable alternatives.

  It is important that the biological consequences of the intended genome edit are well understood, both for the immediate offspring and for future generations who might inherit it, in order to minimize the potential for an intended edit to have unintended deleterious consequences (on its own, via genetic interactions with other loci, or via environmental interactions). At present, the best way to achieve this goal is to use editing to change a known pathogenic genetic variant to one that is present in unaffected family members, common in the relevant population, or known not to be disease-causing.

  Recommendation 3.4.8.3.3: A comprehensive regulatory and ethical framework for overseeing heritable genome editing must be established before any first-in-human clinical applications are considered. This framework should build on the existing regulatory frameworks for new biotechnologies, the practice of medicine, and the principles outlined in these guidelines (see Section 3.3 and 3.4).

  The regulatory framework for heritable genome editing must ensure that there is robust multi-generational follow-up to identify adverse reactions that may occur due to inherited genome alterations. However, this needs to be done in such a way as to protect the confidentiality of the prospective parents and any children born. The framework must ensure that there is a robust informed consent process that builds on the informed consent process discussed in these guidelines (see recommendations 3.4.2.5 and 3.4.4.1) and includes a discussion of potential alternative treatments (if any) and the multigenerational risks and benefits of pregnancies involving the implantation of germline genome edited embryos, including those derived from genetically modified gametes.

  Recommendation 3.4.8.3.4: Regulators, research funders, and academic and medical societies should seek to prevent the premature or unethical clinical uses of heritable genome editing unless and until the safety, ethical, and societal issues associated with the clinical use of heritable genome editing are resolved.

  It is incumbent upon the entire biomedical research community to monitor for potential unethical and premature clinical uses of human heritable genome editing technologies. Researchers are strongly encouraged to report potential unethical uses to regulators, funders, licensing bodies, and academic societies to evaluate potential unethical uses of this technology.

• 3.4.9 Clinical Research that Involves in utero Stem Cell and Genome Editing Interventions

  In utero administration of a stem cell-based or gene-based intervention (whether based on gene replacement or genome editing) may offer several advantages, including 1) early intervention before tissue damage is established and when the tissue/cells have the highest growth and regeneration potential; 2) more effective bio-distribution of the intervention within the intended tissue while interstitial diffusion is facilitated, tissue barriers are still immature, and more comprehensive modification of the target cell population is possible because of its smaller size; and 3) low risk of eliciting immune response to the stem cell-based or gene product, because of the incomplete development of the adaptive immune system.

  Considerations for in utero Genome Editing Interventions

  While there may be therapeutic advantages, in utero genome editing interventions may also exacerbate some safety concerns, particularly those associated with genetic interventions. Early and more comprehensive exposure to gene transfer/editing techniques may increase the risk of genotoxicity, because of the high rate of cell proliferation and tissue growth and increased proportion of self-renewing progenitors. The broad biodistribution of the therapeutic product may also reach unintended tissues or cell populations that are otherwise shielded at older ages, such as germline cells. Finally, any acute or delayed toxicity triggered by the administered cell/gene product at the target and off-target tissues may have far more damaging consequences than observed when genome editing is performed at later stages of life, including teratogenicity. Ad hoc comprehensive studies should thus be designed in surrogate small and large animal models to assess these risks and investigate any long-term consequences of the intervention.

  Recommendation 3.4.9.1 Clinical research involving in utero stem cell-based interventions or genome editing involves risks to both the pregnant woman and the future child, and should be undertaken only when it offers the prospect of a benefit greater than that of post-natal interventions, does not pose excessive risk to the pregnant woman, and where there is institutional capacity for autopsy (in the case of miscarriage or stillbirth) or follow-up (in the case of live birth).

  Clinical research involving in utero genome editing or stem cell-based interventions should only be performed in centers with personnel trained for in utero surgery and with existing guidelines or practices regarding the treatment of extreme preterm births or births of children with devastating/life-threatening conditions. Research protocols for experimental in utero interventions must be reviewed and approved by a research oversight committee prior to recruiting patients. The interventions should be conducted as early in pregnancy as medically appropriate in case termination is unexpectedly needed due to risks to maternal health or the prospect of miscarriage, stillbirth or neonatal condition inconsistent with survival. While there is a risk of pregnancy complications after fetal intervention, the anticipated prospect of benefit from the intervention should be greater than the risk of complications in experienced hands.

  Furthermore, the pregnant woman should be competent and able to voluntarily choose or refuse the intervention. The consent process should include a full discussion of alternative post-natal therapeutic interventions, as well as the possibility that even if this prenatal intervention is successful, there might nonetheless be a miscarriage, a stillbirth, or a child born with serious health problems. If permitted by the pregnant woman or required by law, the intended rearing partner should be consulted. 

• 3.5 Unproven Stem Cell-based Interventions and Medical Innovation

  The ISSCR condemns the administration of unproven stem cell- and other cell- and tissue-based interventions outside of the context of clinical research or medical innovation that is compliant with the guidelines in this document (see recommendation 3.5.2), particularly when it is performed as a business activity. Scientists and clinicians should not administer unproven interventions outside of clinical research or medical intervention as a matter of professional ethics. For the vast majority of medical conditions for which putative “stem cell therapies” or “regenerative therapies” are currently being marketed, there is insufficient evidence of safety and efficacy to justify routine or commercial use. Serious adverse events subsequent to such interventions have been reported and the long-term safety of most stem cell-, cord blood-, bone marrow-, and other cell-based interventions (i.e., mesenchymal stromal cells) remains undetermined. The premature commercialization of unproven stem cell interventions, and other cell-based interventions inaccurately marketed as “containing,” “acting on,” “derived from,” or “like” stem cells, not only puts patients at risk but also represents a serious threat to legitimate stem cell research. Widespread marketing and clinical use of unproven cell or tissue-based interventions reduces the number of individuals able to participate in credible clinical studies, risks jeopardizing the reputation of the field and causes widespread confusion about the actual state of scientific and clinical development.

  Recommendation 3.5.1: The clinical use of unproven stem cell-based interventions should be limited to well-regulated clinical trials and medical innovations compliant with these guidelines (Recommendation 3.5.2) and local laws, policies, and regulations. Government authorities and professional organizations should establish and strictly enforce policies and regulations governing the commercial use of stem cell based medical interventions.

  Historically, many medical innovations have been introduced into clinical practice without a formal clinical trials process. Some innovations have resulted in significant and long-lasting improvements in clinical care, while others have subsequently been demonstrated to be ineffective or harmful. Stem cell-based interventions typically entail complex manufacturing protocols that should rarely, if ever, be developed outside a formal clinical trials process. Nonetheless, in some very limited cases, clinicians may be justified in attempting medically innovative stem cell-based interventions in a small number of seriously ill patients. Although attempting medically innovative care is not research per se, it should not be embarked upon unilaterally. It is incumbent upon the clinician to obtain scrutiny by external experts through peer review, institutional oversight, and presentation of observations and data in peer-reviewed medical publication so that the knowledge can benefit all. Such limited attempts at medical innovation contrast with the advertisement, sale, and administration of unproven stem cell interventions.

  Hospital Exemption

  Regulators in some countries provide a “hospital exemption” to enable individualized care for patients. This exemption from requirements for regulatory evaluation of safety and effectiveness is only appropriate when the risks of the intervention are low and consistent with the risks typically associated with conventional surgical or medical procedures. Furthermore, the existence of such narrow exemptions should not be used as a vehicle for providing unapproved stem cell-based interventions or avoiding regulatory oversight, as occurs when cell-based interventions requiring pre-marketing authorization are inaccurately promoted as being exempt from regulatory scrutiny and approval requirements. Given the potentially serious risks associated with substantially manipulated tissues and cells and non-homologous uses, and the need to study their effectiveness, it is important that such interventions and uses be ineligible for these regulatory exemptions. In jurisdictions that provide hospital exemptions and have not established well-defined criteria that limit the scope of the exemption, regulators are urged to narrowly define them as including only low risk, minimally manipulated cells and tissues for homologous use.

  Surgical Procedure Exemption

  Regulators also often provide a narrow “same surgical procedure exemption,” excluding tissue- and cell-based interventions from certain regulatory requirements when cells or tissue are collected from, and delivered to, the same patient during the same procedure. These exemptions should be narrowly crafted to allow common surgical procedures like skin grafts, while excluding tissue and cell preparations that have been substantially manipulated or are being provided for a non-homologous use. This pathway should not be used to provide experimental and unapproved stem cell-based interventions.

  Stem Cell Based Medical Innovation

  Recommendation 3.5.2: Given the many uncertainties surrounding medical innovations involving stem cells and their direct derivatives, this pathway is rarely ethically and scientifically justifiable and should be limited to a very small number of patients and restricted to a) the off-label use of authorized therapies (see Recommendation 3.5.3), b) unproven interventions provided through expanded access pathways (see Recommendation 3.5.4), or c) minimally manipulated stem cell based interventions for homologous uses. Such interventions should only be provided to patients according to the highly restrictive provisions outlined in this section and the other referenced recommendations.

  The written plan for the procedure must include:

  1. Scientific rationale and justification explaining why the procedure has a reasonable chance of success, including any preclinical evidence of proof-of-principle for efficacy and safety. Explanation of why the proposed stem cell-based intervention should be attempted rather than existing treatments. Description of how the cells will be administered, including adjuvant drugs, agents, and surgical procedures.

     Plan for clinical long-term follow-up and data collection to assess the effectiveness and adverse effects of the cell-based interventions.

  2. The written plan is approved through a peer review process by appropriate experts who have no vested interest in the proposed procedure.

  3. The written plan is approved by an independent oversight body after evaluating the risks and benefits for patients. In the academic context this would be routinely done through an institutional review process for human subjects research.

  4. The patient is not eligible for an existing stem cell-based trial for this indication.

  5. The clinical and administrative leadership of the healthcare institution supports the decision to attempt the medical innovation and the institution is held accountable for the innovative procedure.

  6. All involved personnel have appropriate qualifications and training, and the institution where the procedure will be carried out has appropriate facilities and processes of peer review and clinical quality control monitoring.

  7. Voluntary informed consent is provided by patients according to the ISSCR Informed Consent Standard (see Appendix 6).

  8. There is an action plan for addressing adverse events that includes timely and adequate medical care and if necessary psychological support services.

  9. Insurance coverage or other appropriate financial or medical resources are provided to patients to cover any adverse events arising from the intervention.

  10. There is a commitment by clinician-scientists to use their experience with individual patients to contribute to generalizable knowledge. This includes:

      Ascertaining outcomes in a systematic and objective manner

      A plan for communicating outcomes, including negative outcomes and adverse events, to the scientific community to enable critical review (for example, as abstracts to professional meetings or publications in peer-reviewed journals).

      Initiating a formal clinical trial for the intervention in a timely manner after experience a very small number of patients.

  Off-label Use

  Recommendation 3.5.3 Off-label uses of stem cell-based interventions should be employed with particular care, given uncertainties often associated with off-label uses generally and associated with stem cell-based interventions specifically.

  Physicians generally may use approved drugs and biologics for indications or patient populations other than those for which they have been shown to be safe and effective. This practice is commonly known as providing products on an “off-label” basis. Such off-label applications, distinct from administering products for the purposes for which they have been studied and approved, as specified on their prescribing information and package labels, constitute a common aspect of medical practice. Nevertheless, they present distinct challenges for stem cell, tissue or cell-based interventions.

  First, depending on the jurisdiction, some stem cell-based interventions are not authorized for a specific use due to exemption from premarketing approval requirements. This can limit physicians’ access to reliable information on validated uses. Second, the complex biological properties of living cells and the limited clinical experience with cell-based therapies present uncertainties about long-term safety and effectiveness. Physicians should therefore exercise particular care when administering stem cell-based interventions on an off-label basis. As a rule, off-label use should only be offered when supported by high quality evidence or in situations consistent with current scientific knowledge, applicable regulations and institutional policies, and the standards of the international medical community. Patients must be informed in advance if a proposed off-label use has not been evaluated for safety and efficacy with respect to their specific medical condition. Off-label use of stem cell products is likely to increase as more stem cell therapies obtain pre-marketing authorization for particular indications. Providing such interventions on an off-label basis will need to be done with great caution, attentiveness to the available evidence base, and with the informed consent of potential recipients.

  As a general principle, physicians should conduct controlled, supervised studies to establish safety and efficacy for new applications of products or interventions that have been approved in a distinct clinical setting. As evidence of safety and efficacy accumulates, regulatory bodies are provided with the data they require to consider expanding the indications that fall within the scope of product labeling.

  Pre-approval Non-trial Access to Experimental Stem Cell-based Interventions

  Recommendation 3.5.4 Pre-approval access to experimental stem cell-based interventions should be limited to well-regulated programs that require prior authorization from national regulators.

  Patients understandably sometimes seek experimental interventions when there are no established and approved treatments for serious or terminal diseases and conditions. Regulatory authorization for pre-approval non-trial access programs (often described as “expanded access”) provides important checks and balances to ensure patient safety, facilitates drug development, and preserves the integrity of clinical trials. In particular, national regulatory bodies sometimes have access to important information about risks associated with particular investigational interventions that is not always available to individual patients or institutional review boards.

• 3.6 Clinical Application

  Clinical translation continues after a product is taken into clinical practice. Realizing the full potential of a product requires gathering additional safety and efficacy evidence, controlling applications that lack complete evidentiary footing, and pricing products in a way that delivers value for patients and healthcare systems.

• 3.6.1 Regulatory Approval

  The regulatory review and approval process for stem cell-based interventions must rigorously evaluate each potential intervention to ensure the quality, safety, and efficacy of new treatments. Regulators should require substantial evidence from well-designed clinical trials to demonstrate that new products provide a clinically meaningful benefit for the target indication. The premature commercialization of stem cell-based interventions threatens the development of safe and efficacious evidence-based therapies and places unnecessary economic burdens on healthcare systems and the public.

  Substantial evidence to establish effectiveness for market approval

  Recommendation 3.6.1.1 The introduction of novel products into routine clinical use should be dependent on the demonstration of substantial evidence of effectiveness in appropriately powered, well-controlled clinical trials, with statistically significant findings.

  Regulatory approval for commercialization represents a key pivot point in a product’s translation. National governments and regulatory authorities should maintain rigorous review pathways to ensure that stem cell-based products conform to the highest standards of evidence-based medicine. Early interactions and advice during the product development process may support the accelerated development of safe and effective new therapies.

  Even after clinical studies of the highest standard have demonstrated safety and efficacy and regulatory approval pathways have been cleared, close attention must be paid to ensuring the safety and effectiveness of interventions that have entered routine or commercial clinical use. Further, the fairness of access should be consistent with local legal requirements and standards and the standards of ethical, evidence-based medicine. These standards include ongoing monitoring of safety and outcomes and ensuring accessibility by those who have the most pressing clinical need.

  Accelerated Approval Pathways

  Recommendation 3.6.1.2 When evaluating new interventions for rare diseases or life-threatening medical conditions, regulators should consider the acceptable balance of risk and clinical benefit appropriate to the medical condition and patient population for which new treatments are designed. All approval pathways should require substantial evidence of safety and effectiveness before products are marketed to patients.

  Many countries already have well-defined accelerated approval pathways that can be adapted for stem cell-based products. These pathways may allow for the more regulatory interactions with product developers and the faster approval of products based on surrogate or intermediate endpoints that are reasonably likely to predict a meaningful clinical benefit.

  Conditional Marketing Authorizations

  Recommendation: 3.6.1.3 In jurisdictions with conditional approval mechanisms, regulators must ensure there is a robust post-market surveillance system whereby regulators have the capacity and power to remove products from the market as appropriate.

  Regulators may need to make decisions about stem cell products based on limited safety and efficacy data (Bubela et al 2015). In terms of safety, the goal of many cell therapies is long-term engraftment, thus, side effects may only become apparent many years after the conclusion of clinical trials. For stem cell products targeting rare diseases, clinical trial size and duration may be inadequate to determine efficacy. Furthermore, randomized controlled trials for risky and invasive therapies may be prohibitively expensive and unethical from the perspective of participants enrolled in the control arm. Therefore, international regulators have made provisions for conditional marketing authorization and post approval studies to confirm safety and predicted efficacy. While post approval studies have the potential to provide additional data on safety and efficacy, product developers must continue to collect, analyze, and report safety and efficacy data to identify adverse events and confirm any therapeutic benefit of conditionally authorized products. When post approval studies are required, regulatory oversight bodies need to ensure they are conducted.

  Considerations for Rare Diseases

  Recommendation 3.6.1.4 In jurisdictions with existing approval pathways for orphan or rare diseases, those pathways should be used to facilitate the development of stem cell-based interventions.

  Many jurisdictions have orphan disease designations for regulatory approval, because it is often difficult to ensure adequate statistical power in clinical trials for rare diseases. These pathways may accelerate access to approved stem cell therapies that have demonstrated safety and efficacy. In establishing orphan disease regulatory standards, jurisdictions should consider: the definition of orphan disease based on incidence (e.g., Japan – fewer than 50,000 patients in Japan; US – fewer than 200,000 in the US; Europe – prevalence is less than 5 in 10,000 Europeans). Jurisdictions generally limit the designation to serious, life-threatening, chronically debilitating disease, and unmet medical needs (no satisfactory authorized products). Further, in Europe and the US, it must be unlikely that the marketing of the product would generate sufficient returns to justify investment in its development. Jurisdictions provide a set of incentives that may include: tax credits for clinical testing, a voucher for accelerated approval for a different product, scientific advice and protocol assistance from regulators, a reduced fee for applications, priority review, potential coordination amongst regulators, internationally and extended periods of market exclusivity. Some jurisdictions may seek to recapture financial incentives if the therapy becomes highly profitable.

  Bio- and Pharmacovigilance

  Recommendation 3.6.1.5 Developers, manufacturers, providers, and regulators of stem cell-based interventions should continue to systematically collect and report data on safety, efficacy, and utility after they enter clinical use.

  Stem cell-based interventions can remain biologically active for long periods and thus may present risks with long latencies. Additionally, stem cells and their derivatives can exhibit a range of dynamic biological activities and therefore be potentially difficult to predict and control. These may lead to pathologies including tumorigenesis, hyperplasia, and the secretion of bioactive factors that may exert secondary effects on physiological processes such as inflammation or immune response. Some types of stem cells are capable of migration after transplantation, meaning there is a risk of off-target effects and inappropriate integration. Further, tracking the locations of transplanted cells may be difficult using current technologies.

  For these reasons, monitoring patients’ overall health status over the expected duration of the therapeutic benefit is critical and plans for the funding and conduct of long-term monitoring should be incorporated into study protocols early in the development of new interventions. These monitoring activities may include systematic post-market studies, event and outcome reporting by clinicians and patients, patient registries, and/or economic analyses of comparative effectiveness. The results of such monitoring activities should be promptly reported to regulatory authorities and the medical community.

  Patient Registries

  Recommendation 3.6.1.6 Registries of specific patient populations should be used to provide valuable data on the natural history and progression of diseases that can support the development of meaningful endpoints, biomarkers, and outcomes measures to facilitate the development of new products. Furthermore, patient registries are useful tools for monitoring adverse events after regulators have approved a product for routine clinical use. However, registries should not be substituted for well-regulated randomized controlled clinical trials designed to evaluate the safety and efficacy of complex products like stem cell and gene-based interventions.

  Stakeholders in stem cell-based therapeutics, including researchers, physicians, regulatory bodies, industry, and patient and disease advocacy groups, should cooperate in developing disease history registries to facilitate the development of stem cell and gene-based products. Because these therapies are novel and may have some increased risk, continued surveillance of patient outcomes after the commercial launch of the cell or gene products is recommended. To this end, registries should be established to collect additional safety, efficacy, and durability data on stem cell and gene-based interventions after they have been approved for clinical use. As valuable as they are, such registries should complement randomized controlled trials and not be used as a substitute for them.

  Biohacking

  Recommendation 3.6.1.7 Provision and use of equipment and commercial kits for cell and gene-based interventions in humans should be limited to settings with an appropriate level of regulatory oversight to ensure their safe and responsible use.

  Alongside the development of gene- and stem cell-based therapies has been an increased interest in self-administration and ‘do-it-yourself’ kits and equipment. Such “DIY” interventions are often promoted as a means of using “biohacking” to make improvements to personal health and well-being with little acknowledgment of risks posed by their use. Regulators and commercial providers should ensure that genetic alteration kits and equipment carry a warning that they are not approved for self-administration (e.g., SB-180, California State Legislature, 2019). Leaders in the emerging do-it-yourself biology movement are encouraged to continue to develop codes of practice based on these guidelines and other standards to inform best practice standards.

• 3.6.2 Access and Economics

  Support for stem cell research depends, in part, on its potential for advancing scientific knowledge, which may result in the development of clinical applications. As such, institutions, researchers, and providers in both the public and private sectors have a responsibility to promote public benefit, and specifically to ensure that research findings are accessible to the international scientific community and, importantly, equitable access to safe and effective therapies for those who need them. For these reasons, research, clinical, and commercial activities should seek to maximize affordability and accessibility.

  Developer Consideration of Value

  Recommendation 3.6.2.1: Stem cell-based interventions should be developed to deliver health and economic value to patients, payers, and healthcare systems.

  Consideration of value and access should be built into research and development pipelines early to enhance the probability of market access in addition to regulatory market authorization. Following market authorization, product developers still need to seek positive coverage decisions from public and/or private payers. Many make coverage decisions based on health technology assessments (HTA). HTA is the process of considering synthesized evidence to arrive at a decision on whether a specific technology should be included in the portfolio of technologies provided by a specific health care system or covered by a specific health care payer. The recommendations are based on clinical and pharmacoeconomic evidence, cost-effectiveness or comparative-effectiveness data, patient perspectives, as well as ethical and implementation considerations. Most importantly, however, HTA recognizes opportunity costs within a payer’s health care budget. This means that money spent on one technology or service is not available to be spent on other technologies or services.

  Many public health systems consider cost effectiveness, based on an incremental cost-effectiveness ratio (ICER). ICERs are comparative between existing and new therapies and are dependent on direct healthcare costs and changes in quality-adjusted life years (QALYs: life expectancy in years X quality of life). The level of the ICER threshold varies between countries and/or payers. Some payers have a differential ICER threshold for complex and specialist health care, which include Orphan Drugs.

  Reimbursement and Payer Considerations

  Recommendation 3.6.2.2: Payers, and healthcare systems should work with developers of stem cell interventions, patients, and regulators to establish processes to evaluate their health and economic value, including conditional pathways.

  Recognizing the challenges in evidence generation faced by stem cell-based therapies, especially for rare diseases, payers in some jurisdictions are considering coordination of conditional reimbursement models with conditional regulatory approval models. These models rely on expanded powers of regulators for post-market oversight and infrastructure and systems for post-market surveillance, since evidence generation is shifted to varying extents to the post-market period. These approaches will rely heavily on the availability and quality of post-marketing data, and the associated analytic capacity. Further, alternative payment plans that amortize payments over time are under consideration, such as technology leasing arrangements or refunds, rebates or discounts if the technology does not provide the promised benefits, is effective for a shorter period-of-time than expected, or requires re-administration. Such complex funding arrangements are pre-determined; they are negotiated and enforced via managed access agreements.

  The development and provision of clinical interventions are based on decisions made by patients, healthcare professionals, and payers. Key factors that influence such decisions include the known risks and benefits of available treatment options, individual preferences on the part of patients and treatment providers, and comparative availability and cost. Developers, manufacturers, and providers of stem cell-based interventions should recognize that, along with safety, efficacy, and accessibility, economic value is an important measure of the overall utility of any therapeutic. They should thus participate in studies intended to assess comparative effectiveness, particularly in countries in which such studies are legally mandated. Such studies involve the systematic comparison of currently available therapies for their full range of benefits and provide important information for medical decision-making.

  Pricing

  Recommendation 3.6.2.3: Developers, funders, providers, and payers should work to ensure that cost of treatment does not prevent patients from accessing stem cell-based interventions for life-threatening or seriously debilitating medical conditions.

  Sponsors of research aimed at the development of stem cell-based interventions targeting seriously debilitating or life-threatening medical conditions should seek to support access to safe and efficacious therapeutics to any patient in need, irrespective of financial status. Post-trial access for individuals who participated in clinical research leading to the development of a licensed stem cell therapy is a particular priority.

  Private firms seeking to develop and market stem cell-based interventions should work with public and philanthropic organizations to make safe and effective products available on an affordable basis to disadvantaged patient populations. Developers, manufacturers, and patient groups should engage with government regulators and health care funders to develop mechanisms for prompt and sustainable adoption of stem cell interventions for life-threatening or seriously debilitating medical conditions. Such mechanisms should balance the needs of those patients who will benefit with the responsibility of payers to the communities they serve and strengthen the evidence base for the safety, effectiveness, and long-term value of those therapies.

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