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©2021 by The International Society for Stem Cell Research. All rights reserved.

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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. 

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