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3.4.2 Standards for Clinical Research Conduct

Risk-Benefit Analysis
Recommendation 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 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 At a minimum, this review should consist of a synthesis of a systematic search of published and unpublished studies testing the intervention in animal systems.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 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 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 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 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 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

Recommendation 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 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.