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

No part of this document may be produced in any form without written permission of The International Society for Stem Cell Research.

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 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 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.