Unproven Cell Products
This page assembles the sections of the Guidelines that specifically address the premature commercialization and unproven use of cellular products. Other sections of the Guidelines may be relevant to this issue (e.g., Chapter 4. Communications).
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.
3.5 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.
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:
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.
- The written plan is approved through a peer review process by appropriate experts who have no vested interest in the proposed procedure.
- 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.
- The patient is not eligible for an existing stem cell-based trial for this indication.
- 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.
- 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.
- Voluntary informed consent is provided by patients according to the ISSCR Informed Consent Standard (see Appendix 6).
- There is an action plan for addressing adverse events that includes timely and adequate medical care and if necessary psychological support services.
- Insurance coverage or other appropriate financial or medical resources are provided to patients to cover any adverse events arising from the intervention.
- 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.
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.
Substantial evidence to establish effectiveness for market approval
Recommendation 126.96.36.199 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.