FDA's Draft Guidance on Suicidality Monitoring

On September 8, the FDA issued its Draft Guidance “Suicidality: Prospective Assessment of Occurrence in Clinical Trials.” This guidance, which has a 10-year history in the making, clarifies the FDA’s stance in regard to “treatment-emergent suicidality.” Suicidality is described as encompassing both suicidal ideation and behavior.

The draft was issued by Dr. Thomas Laughren, Director of the Division of Psychiatry Products (DPP) and the assessment of suicidality is recommended for drugs in development for any psychiatric conditions, as well as neurologic drugs with central nervous system activity.

Guidances from FDA often cause a high-level of interest, if not concern, among the sponsor and CRO community because of changing or incremental requirements. In this case, the community was largely prepared for this Draft Guidance, according to Mark Ammann, Vice President, Regulatory Affairs, United BioSource Corp. “Industry really dealt with this a year-and-a-half ago,” explained Ammann. That was when DPP began communicating its thinking on suicidality assessment. The communication at that time, however, was informal to industry sponsors, not in the form of a public guidance. The broadness of the initial policy did cause widespread concern from pharmaceutical companies in early 2009. However, through the trade association (PhRMA), industry had an opportunity to provide input to Dr. Laughren which is reflected in the Draft Guidance. This guidance then, according to Ammann, is straightforward and expected.

The guidance does include one notable expansion from the initial communications from DPP. Prospective monitoring for neurologic drugs with CNS activity means drugs being studied under INDs from other divisions, such as the Division of Neurologic Products, will now apply.

“It is a fairly onerous requirement,” said Ammann, based on the reasoning that each subject in a trial is recommended to be evaluated at each visit. But he says the FDA has two reasons for insisting on the prospective assessment, which are: 1. To protect individual patients in clinical trials from potential risk of suicide and 2. To assess and ideally quantify whether there is a signal of concern for a product of an increased rate of suicidality in the intended treatment population (looking across the population treated in clinical trials)

While suicide as an actual adverse event is rare, FDA was concerned by a 2003 report suggesting an increased risk of suicidality among pediatric patients with a major depressive disorder taking Paxil. A 2004 label change was requested by FDA for all antidepressants prescribed to pediatric patients. In 2007, the labels for antidepressants were changed to reflect an increased risk of suicidality among young adults up to age 25.

The FDA in 2005 identified suicidality signals in meta-analysis of 199 placebo-controlled clinical studies of 11 antieplieptic drugs. This led to the FDA’s issuance of a boxed warning and medication guide for 23 of these drugs in December 2008.

More recently, in July 2009, the FDA issued a black box warning for the smoking cessation drugs Chantix and Zyban to include side effects of agitation, hostility, depressed mood, and suicidality. In fact, the Draft guidance says “there has been long-standing concern about a variety of drugs, including isotretinoin and other tretinoins, beta blockers (especially those entering the brain), reserpine, drugs for smoking cessation, and drugs for weight loss, for which possible signals of risk for suicidality have already been identified. Therefore, we recommend that prospective suicidality assessments carried out in all clinical trials for all drugs that are pharmacologically similar to [those drugs].”

The FDA recommends that sponsors use a suicidality assessment instrument that maps to the Columbia Classification Algorithm for Suicide Assessment (C-CASA), which lists and defines the nine codes to be used in coding the various levels of suicidality for data purposes.

While the FDA specifically mentions the Columbia Suicide Severity Rating Scale or C-SSRS as an acceptable instrument, Ammann says the guideline describes how sponsors may be able to qualify other instruments. Ammann acknowledged that, to date, C-SSRS has essentially been the “gold standard” for all intents and purposes.

As noted, industry has had time to prepare itself and has largely implemented steps to address suicidality assessment in clinical trials. For its part, as a services provider to pharma companies, UBC provides advice on how to implement the guidance into Phase I through III trials, as well as postmarketing assessments. One area in particular to concentrate is in the training and education of investigators and investigative site personnel in using the instrument. “Investigators may not necessarily be practicing pyschiatrists. They can be GPs or other allied health professionals and need help to understand and use the instrument,” explained Ammann.

Yesterday and today, the International Society for CNS Clinical Trials and Methodology’s Annual Meeeting in Baltimore will feature a variety of topics in CNS, including the guidance.