Peek behind the paper: How proven is a ‘proven intervention’?

Regenerative treatments, such as cell or gene therapies, have been explored as promising treatment pathways for a number of serious conditions. At the experimental phase, such treatments can be made accessible to patients only within the framework of clinical trials or, in special cases, outside clinical trials under so-called conditional-approval programs. These programs allow approval of experimental therapies on the basis of less robust evidence about their efficacy than otherwise required for the registration of new treatments. They make experimental treatments available to patients, albeit on the condition that more data about their effectiveness is collected in subsequent clinical research, following conditional approval. Such approval can, however, make rigorous treatment efficacy research difficult for a number of reasons. For instance, by making placebo-controlled trials (usually required to determine efficacy) less attractive for potential participants or by enabling ethical arguments against this study design if conditionally approved therapy starts to be considered as best-proven treatment, thus creating a vicious circle resulting in the inability to generate rigorous efficacy evidence. There are rules about when placebo controls can be used so that patients receiving them are not deprived of a proven treatment if such exists. When a treatment is made available to patients under a conditional approval pathway, it may become difficult to estimate whether a proven treatment exists and, thus, whether an experimental treatment can be compared with a placebo. Allowing ethically unjustifiable use of placebo comparators can result in serious harm to patients, that is why it is so important to get the correct picture of whether there exists a proven therapy for a particular disease. This paper discusses the difficulties of estimating (non)existence of best proven therapeutic intervention when regenerative experimental treatments are made accessible to patients under conditional approval programs.

When placebo controls are used in clinical trials, the scientific interest to generate new knowledge is weighed against trial participants’ need for medical care. This balance is often problematic and raises ethical concerns. On the one hand, placebo-controlled trials are needed to confirm or deny the efficacy of the therapy under investigation. On the other hand, an important concern is that patients randomized into a placebo group might miss a therapeutic benefit. Ethical guidelines, such as the Declaration of Helsinki, state that an experimental therapy has to be compared with a best-known proven therapy, where one exists. In my opinion, one of the greatest challenges can be to establish whether there is a therapy that can be considered as best proven for a particular disease and thus out-ruling the use of placebo comparators unless other conditions are met.

Although estimation of treatment efficacy can be difficult for many kinds of therapeutic interventions, it often is especially challenging in regenerative medicine for a number of reasons. Full information about the efficacy of e.g., cell or gene therapies is unavailable until a long-term follow-up (often outside the scope of a standard clinical trial) has been performed. Results from such follow-ups are often unavailable at the time of decision-making as to the ethical justification of placebo controls. Moreover, therapeutic approaches in regenerative medicine can often have different pathways toward the same goal (e.g., administered a varying number of times, with varying concentrations of cells and at varying intervals or at different stages of disease). It can be difficult to judge which of these therapeutic approaches should be considered the best-proven therapy. Moreover, patients considering regenerative therapeutic approaches often tend to be suffering from dangerous conditions for which other therapeutic alternatives have already been exhausted. The use of a placebo-control design can become especially controversial in cases where such patients participate in randomized controlled trials, and it is especially important to be able to make correct estimations as to the efficacy status of conditionally approved therapies.

Scientists have to be aware that approval does not automatically mean efficacy, that conditionally approved therapies may be unused in practice. Scientific and public debate about these issues has to be facilitated to raise awareness among researchers, physicians and patients. In practice, this debate should lead to clear information about the efficacy status (e.g., through appropriate labeling) both to patients, desperate to try something rather than nothing, and medical professionals, eager to find therapeutic solutions for their patients with unmet medical needs, when they are considering conditionally-approved therapies.

The shift toward conditional-approval programs allowing patient access to therapies on the basis of less robust evidence regarding their safety and efficacy than required before these programs were put in place necessitates a new ethical debate about the use of placebo controls. A debate that would take this context into consideration. My article lifts up the difficulties of treatment efficacy estimation in regenerative medicine, where it can become especially challenging, and proposes to debate how existing ethical guidelines about the use of placebo controls should be interpreted and applied in the context of changing requirements for evidence about treatment efficacy.

I expect that ethical and scientific debates on the subject will lead to the acknowledgment at the international level that efficacy evidence on which conditional approvals are granted, cannot be considered sufficient to provide continuous or long-term marketing of approved therapies if it is not obtained through rigorously conducted late-stage randomized-controlled trials. I also expect a public debate and public outreach to take place about the rationale behind conditional approval pathways and the dangers of abusing them.

In my future work, I hope to reflect on the ethical aspects of using other methodological approaches where randomized-controlled trials cannot be performed, e.g., due to a limited number of patients. If other approaches are used, such as single-arm studies, guidance on how to understand the role of nonrandomized evidence would be needed. The use of nonrandomized evidence would also necessitate an ethical analysis.