A new draft guidance released by the US Food and Drug Administration (FDA) addresses suicidal thoughts and behavior occurring in clinical trials and how to proactively assess the risks during drug development stages.
FDA's 14 August 2012 draft guidance, Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials, focuses on pharmaceutical and biological products, and in particular on psychiatric and nonpsychiatric drugs.
FDA explains the draft guidance is the result of several studies on both pediatric and adult populations showing an increased risk of suicide when patients are taking antidepressants, though it noted the studies were not sufficient enough to show causation. Other drugs, too, have shown similar tendencies toward suicidal ideation and behavior.
"In view of the wide range of drugs involved, it is reasonable to consider whether prospective assessments for suicidal ideation and behavior should be included in clinical trials involving at least selected drugs for nonpsychiatric indications," FDA explains in the draft guidance. The addition of this assessment category stands to benefit patients involved directly in the study and allow for better and more complete data collection in the event that suicidal ideation or behavior does ultimately occur.
Clinical Trial Requirements
FDA notes this would be, "Important whether or not a particular drug is known to be associated with treatment-emergent suicidal ideation and behavior," though it recommends assessment be conducted for any drug intended to treat a psychiatric condition.
"Therefore, other than the exceptions noted in section III.C., prospective suicidal ideation and behavior assessments should be carried out in all clinical trials involving any drug being developed for any psychiatric indication, as well as for all antiepileptic drugs and other neurologic drugs with central nervous system (CNS) activity, both inpatient and outpatient, including multiple-dose phase 1 trials involving healthy volunteers," FDA explained.
The additional requirements could add additional time to the development of CNS drugs-a class already defined as taking more than 22 months on average for FDA to review.
All drugs that are "pharmacologically similar" to isotretinoin, tretinoins, beta blockers, reserpinem, smoking cessation drugs and weight loss drugs will also be required to conduct the suicidal ideation and behavior assessments, though FDA said this was a "minimum" requirement and might be broadened to include any drug acting on the CNS.
FDA said it wants sponsors to use the Columbia-Suicide Severity Rating Scale (C-SSRS)-a scale of suicidal ideations and behaviors that range from passive to active. Regulators said the test was accurate and "performed well relative to other instruments" measuring similar behavior.
- active: nonspecific (no method, intent, or plan)
- active: method, but no intent or plan
- active: method and intent, but no plan
- active: method, intent, and plan
- completed suicide
- suicide attempt
- interrupted attempt
- aborted attempt
- preparatory actions toward imminent suicidal behaviors
Self-injurious behavior, no suicidal intent
The use of the C-SSRS test instead of others will allow sponsors to avoid duplicative and time-intensive reclassification procedures, FDA noted, with the entire procedure typically taking approximately 10 minutes to conduct and presenting "little burden."
Sponsors will be allowed to use other validated methods to assess suicidal ideation and behavior, FDA added.
For drug products where it has been deemed necessary to assess patients for their risk of suicide, sponsors should assess a number of factors known to be relevant. FDA notes dosing can have an impact on suicidal thoughts and actions, though concedes these rarely happen in healthy volunteers taking low-doses of medication, and is extremely unlikely to occur in microdose trials.
Some patient populations may be difficult to assess for suicidality, particularly if they suffer from dementia, Alzheimer's disease or other cognitive impairments. Sponsors should obtain permission with FDA's review division before omitting these patients from review.
Sponsors should also pool data from all ongoing trials to allow for advance signals of suicidality without needing to wait until the conclusion of the trial. A separate guidance document is forthcoming on this particular issue, FDA noted.
Long-term, ongoing clinical trials will also be required to comply with the guidance, explained regulators.
For drugs with a long half-life, assessments of patients should ideally continue even after the clinical trial has ended. For those drugs with a more normal half-life, regular assessments should occur consistent with the evaluation of other vital signs, particularly if the patient is enrolled in an inpatient trial.