Washington Report -- May 2008

FDA Intensifies Focus on Psychiatric Adverse Effects

The March 27 announcement from the FDA that it is looking into a possible connection between Merck's biggest seller, Singulair (montelukast sodium) and suicidality once again raises questions about whether the agency is requiring close enough scrutiny during clinical trials of possible connections between new drugs and psychiatric effects. The FDA said it had received postmarketing communications, presumably from patients and physicians, about the medication, which was approved in 1998 for asthma and allergy symptoms. Merck had added a label warning about suicide in 2007. But the new FDA analysis, which could take 9 months to complete, could lead to stronger actions such as a black box warning on package inserts or information sheets for health care professionals and patients, or it might even force Merck to take the drug off the market, although this is unlikely.

However, seemingly cascading allegations about adverse effects of currently marketed pharmaceuticals have supercharged the political environment. The New York Times got it only partly right when it said that the FDA has responded to political pressure by beginning a formal effort to require drug companies to look at suicidality and other psychiatric events for both new and existing drugs. The agency is taking a more aggressive approach in some drug classes, reflected in the "public communications" issued on Singulair and, at the end of January, about potential suicidality with anti-epileptic drugs used to treat epilepsy, bipolar disorder, migraine headaches, and other conditions. That warning was based on the FDA's retrospective review of suicidality reports from placebo-controlled studies of 11 anti-epileptic drugs, which demonstrated that patients taking these drugs have a risk of suicidal thoughts and behaviors twice that of patients receiving placebo (0.43% vs 0.22%).

However, the Times alluded to a new FDA "rule" requiring assessment of all prospective new drugs to look for suicidality during clinical trials but wrote that this would not be announced publicly "since the FDA's oversight of experimental medicines is done in secret." Crystal Rice, an FDA spokesperson, told Psychiatric Times that no such rule exists, nor is one contemplated. "While FDA is taking a proactive approach to better data collection for possible psychiatric adverse effects for certain types of drugs, there is no requirement that this be done in all clinical trials," she explained. "Again, such requests occur on a case-by-case basis. We're asking for the information selectively-in cases where other drugs in that class have been linked to suicidality (such as antidepressants, obesity drugs, antiseizure drugs), and in certain other drugs where the clinical trial data suggest psychiatric side effects."

The FDA does appear to be toughening its clinical trial requirements for psychiatric drugs. A spokesperson for the agency's division of psychiatry products said, "We have been looking at suicidality within psychiatric drug development programs for most indications for a long time, based on spontaneous reports of suicidality, because most psychiatric disorders have an increased background risk for suicidality. However, we are now considering adding more specific measures for assessing for suicidality for antidepressants and likely for other psychiatric drugs as well. Our policy on this matter is evolving. It's not a secret, but we obviously can't release proprietary information about specific companies and their drugs."

Nor will the FDA discuss exactly which Singulair studies it will be looking at over the next 9 months.



 

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Gaps in Defense Department/VA Research on PTSD

The substantial shortcomings of clinical trials of medication and psychotherapy for patients with posttraumatic stress disorder (PTSD)-especially combat veterans-stepped front and center at an April 1 hearing in the House Veterans' Affairs Subcommittee on Health. David Matchar, MD, a psychiatrist at the Center for Clinical Health Policy Research, Duke University Medical Center, reprised the findings of the Institute of Medicine's (IOM's) Committee on Treatment of Posttraumatic Stress Disorder, which were published last October. The IOM committee concluded that although several drugs and psychotherapies are used to treat PTSD, many of the studies have problems, particularly methodological flaws; as a result, they do not provide a clear picture of what works and what does not.

Rep Michael Michaud (D, Maine), chairman of the health subcommittee, asked Col Charles W. Hoge, MD, about those gaps. Hoge is director, division of psychiatry and neuroscience, at the Walter Reed Army Institute of Research. Hoge agreed with Matchar that there are "huge gaps" in PTSD research, especially related to the effectiveness of pharmacological agents and psychotherapy. He noted that Congress had provided $300 million in fiscal 2007 for PTSD to fund the US Army Medical Research and Materiel Command's Office of Congressionally Directed Medical Research Programs. He said some of that $300 million would go for clinical trials, but he did not know how many. "That 2007 funding allocation will, hopefully, fill some of those gaps, but gaps will remain," Hoge stated.

Asked whether Hoge discussed how the Army would incorporate the IOM recommendations into that new clinical research, Matchar, in an e-mail sent after the hearings, said he had heard nothing specific on that score.