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 18.104.22.168: 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:
- Conducting informed consent discussions that include someone who is independent of the research team.
- 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.
- Addressing misconceptions and misestimations that derive from public representations of the field.
- 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.
- Requiring a period between consent discussions and acceptance of consent.
- Avoiding language that has therapeutic connotations, for example, using words like agent or cells or intervention rather than “stem cell therapy” or “treatment.”
- 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 22.214.171.124: 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.
Recommendation 126.96.36.199: 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 188.8.131.52).