FDA's draft guidance on suicidality screening focuses on eight drug classes, but the agency is seeking comment on whether all new drugs should be covered.

The drug classes covered by the draft are:

# All psychiatric drugs, not just antidepressants;

# Antiepileptic drugs. The recommendation comes despite an Aug. 5 article in the New England Journal of Medicine questioning whether a suicidality risk exists for this drug class (Health News Daily, Aug. 5, 2010);

# Other neurologic drugs with central nervous system activity;

# Isotretinoin (Roche's Accutane and generics) and other tretinoins;

# Beta blockers, especially those entering the brain;

# The blood pressure drug reserpine;

# Drugs for smoking cessation; and

# Drugs for weight loss if "possible signals of risk for suicidality have already been identified." The reason for this caveat on FDA's part is unclear, given the frequency with which a suicide signal pops up in this class; for example, a clinical trial of Sanofi-Aventis' rimonabant was shut down over such concerns (Health News Daily, Aug. 13, 2010).

"We recommend that prospective suicidality assessments be carried out in all clinical trials for all drugs that are pharmacologically similar to drugs in the above list," the draft says.

"The possibility that suicidality assessments should be conducted as part of essentially all drug development programs, even for drugs not yet recognized as having CNS effects, has also been considered," the agency notes, "but this guidance is not recommending that approach. Further experience may change our view on this issue and comments on this current recommended approach are welcome."

For drugs in the classes covered by the draft guidance, the agency is also recommending that prospective suicidality assessments be added to ongoing trials for such drugs, unless it is so late in the game that the protocol modification and institutional review board approvals this would entail would be impractical. However, in those cases the sponsor should notify the sites to be on the lookout for suicidal behavior, the draft says.

Examples of drugs in clinical development that may be affected by this recommendation are Biovail and Acadia Pharmaceuticals' 5-HT2A receptor antagonist pimavanserin, in Phase III trials for Parkinson's disease psychosis, and Takeda and Amylin's obesity candidates, including pramlintide/metreleptin.

C-CASA Is FDA's Case Method

FDA recommends sponsors use a suicidality assessment instrument such as the Columbia Suicide Severity Rating Scale or other validated method that can be "mapped" onto the Columbia Classification Algorithm for Suicide Assessment, which was developed to help the agency code suicidality data from clinical trials of antidepressants (Also see "As FDA Suicidality Reviews Become More Common, Firms Move Into C-CASA" - Pink Sheet, 4 February, 2008.).

Since the scale was designed for retrospective analyses, four codes that indicate insufficient information is available in the database can be omitted in prospective assessments. The remaining codes are for completed suicides, suicide attempts, preparatory actions toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without suicidal intent. It is possible for individual patients to experience more than one coded event, but any events that "remain indeterminate" do not need to be coded, the draft guidance says.

Some types of cognitively impaired patients, such as those with Alzheimer's disease, cannot form suicidal attentions and may not need to be assessed, but sponsors should check with FDA.

All clinical trials of drugs that require a suicidality assessment should include this assessment, even single-dose trials and Phase I studies in healthy volunteers, the draft says. "The full assessment of suicidality generally should involve a pooled analysis of all controlled trials, so it will not be possible to conclude that the suicidality question has been resolved until all data are in hand," the draft notes. Assessments should be performed at baseline and all visits involving a clinical evaluation.

Additional guidance or guidances on suicidality may follow this draft, for which comments are due Nov. 8. These will address "the complex analytic issues involved in the analysis of the suicidality data that will be derived from prospective assessments of suicidality," the draft says.

In addition, "detailed advice about the structure of data tables and other data recommendations for preparing a suicidality submission to the FDA will be discussed in a separate guidance, as well as analytic and statistical considerations."

- Martin Berman-Gorvine (m.berman-gorvine@elsevier.com)

Suicidality Screening For All New Drugs Still On The Table After Draft Guidance

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