Protecting Participants in Clinical Trials
The Research Ethics Blog by Bernard Lo, MD
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Meta-analyses of clinical trials of antidepressants have found a trend towards increased suicidality in children and adolescents receiving selective serotonin reuptake inhibitors (SSRIs). These meta-analyses raised concerns about conflicts of interest because published trials showed that the drugs were effective and safe in these circumstances, but when unpublished studies carried out by the manufacturers were also considered, the drugs were shown to be ineffective and possibly unsafe. The report Conflict of Interest in Medical Research, Education, and Practice provides other examples of failure to publish negative results or serious adverse events in industry-sponsored clinical trials. See summary (PDF 304KB). Here we discuss another ethical issue: How to protect participants in clinical trials if their condition worsens?
It is no surprise to clinicians that some patients experience worse depression despite treatment. Moreover, because they are depressed, participants may not appreciate that their condition is worsening or be able to seek help. For example, many persons with mental illness have poor access mental health care. At various stages of a clinical trial, steps might be taken to protect such participants.
During review of the trial: Many trials of antidepressants are designed by drug companies and do not undergo external scientific peer review. What should be responsibility of the IRB be with regard to the potential for suicidality in trial participants?
At enrollment: What exclusion criteria for participants might reduce the risk that patients may become suicidal or, if they do so, have a poor outcome? How should concerns about poor access to psychiatric care be addressed in the exclusion criteria?
In real time during the trial: What procedures should the protocol specify for indentifying and responding to participants who become suicidal? What “safety-net” measures should be in place? How should the development of suicidality be handled as an endpoint? (Note that the usual endpoints in depression clinical trials are change in symptom scales and the percentage of patients in remission.)
After cases are identified: If cases of suicidality are identified, how should the medical monitor or the Data and Safety Monitoring Board be notified? What steps should they take when evaluating such cases? Note that there are several issues to consider. One is whether the response of the investigators was adequate to minimize the risks to participants, and another is whether such cases are more common in one arm of the trial.
However, such protections for participants may have undesirable consequences for the trial. IRBs rarely carry out in-depth scientific review. Excluding persons at increased risk for suicide may compromise the power, efficiency, or generalizability of the trial? (Note that antidepressants may have greater effectiveness in persons with more severe symptoms.) Putting in place safety-net measures may increase the complexity and cost of the trial. In your view, what steps should researchers and sponsors take in clinical trials of antidepressants to protect participants whose condition worsens during the trial?