You Really Can Report Safety Data

A new study concluded that the combination of sertraline (Zoloft) and cognitive-behavioral therapy (CBT) worked better than either treatment alone for children with anxiety disorders. There was even a nonsignificant trend for Zoloft to outperform CBT, which was quite surprising to me. But that's not really the point of this post. The study can be read at the New England Journal of Medicine website.

I'd like to commend the researchers on doing something that is exceedingly rare in psychopharmacology and psychotherapy trials -- they gave a detailed report of adverse events. And we find that a greater percentage of kids showed suicidal ideation on... CBT. It was not a statistically significant difference, but it was nonetheless surprising. Zoloft, however, was related to significantly more disinhibition, irritability, restlessness, and poor concentration than CBT. This may have been a fluke, but two participants on Zoloft had "homicidal ideation" compared to none on CBT. I have bitched several times about missing/mysterious data on adverse events in psychiatric drug trials, and some have also complained that psychotherapy trials do a poor job of tabulating adverse event data. Again, kudos to the study authors for reporting adverse events; imagine if reporting safety data in such a manner was commonly practiced.

Source: J. T. Walkup, A. M. Albano, J. Piacentini, B. Birmaher, S. N. Compton, J. T. Sherrill, G. S. Ginsburg, M. A. Rynn, J. McCracken, B. Waslick, S. Iyengar, J. S. March, P. C. Kendall (2008). Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety New England Journal of Medicine DOI: 10.1056/NEJMoa0804633

Burying Data, Chapter 317

In the sad yet unsurprising category, Ed at Pharmalot has two reports (1, 2) on Pfizer burying negative data about Lipitor. How would they do such a thing? Well, Pfizer conducted a study comparing Lipitor to Zocor and found positive results. Naturally, a favorable press release was issued, which opened by stating...

A retrospective analysis of a large U.S. managed care database showed that patients who took Pfizer's cholesterol-lowering medicine Lipitor® (atorvastatin calcium) Tablets had a significant 14 percent reduction in the risk of cardiovascular events, including heart attacks and strokes, compared with patients who took simvastatin.

An "independent" academic was also featured in the press release, stating...

"This analysis is important for physicians, employers and formulary directors at managed care companies who are making real-world treatment decisions for patients," said Dr. Robert Vogel, an author of the study and professor of medicine at the University of Maryland. "This further supports the cardiovascular benefits previously seen with Lipitor."

Well, turns out the analysis was wrong. The difference between Lipitor and Zocor was not statistically significant -- someone made an error during data analysis. No big deal that someone screwed up the analysis in my book -- it happens from time to time. Ed noted that, of course, there was no press release accompanying the new, less favorable data analysis. Though Lie-Zer, er, Pfizer has issued platitudes regarding its commitment to transparency, this behavior does not exactly engender faith in their commitment to honesty, eh? Here's Ed Silverman's rant...

So Jeff [Kindler, Pfizer CEO], what happened? If the marketing team is no longer in charge of everything, why hasn’t Pfizer gotten around to issuing that bad news press release? Your company has had 11 days to correct its mistake. Will that happen, or are accountability and transparency just convenient buzzwords?

Well said. I'd like to ask similar questions regarding the convenient release of study results that found Zoloft was ineffective for posttraumatic stress disorder ten years after the study was conducted, yet positive trials for Zoloft in PTSD took much less time to get published. How Pfizer handled other data regarding Zoloft is also dubious.

Convenient Honesty and Zoloft

Recently, a study was published which cast doubt on the efficacy of sertraline (Zoloft) for PTSD, finding that the drug was no better than a placebo.

The kicker is that the patent has expired for Zoloft, which is why the data are now flowing more freely. I’ll make the case here that data were buried until they would no longer hurt sales to any meaningful extent, at which point data were published, at least partially as a public relations move to show just how “honest” the companies are with sharing both positive and negative results with the psychiatric community.

The Research: The latest study, which appears in the May 2007 Journal of Clinical Psychiatry, showed no benefit for drug over a 12-week period. Placebo tended to outperform Zoloft on the majority of outcome measures, though the differences were of a small and statistically insignificant degree. Patients were significantly more likely to drop out of treatment on Zoloft. It was unclear if there were any serious adverse events (e.g., suicide attempts, notable aggression, etc.) because the article did not mention them at all. Patients started this study between May 1994 and September 1996. The original draft of the study was received by the journal in March 2006. Nearly 10 years passed between study completion and writing up the data for publication.

Two prior studies found positive results found positive results for Zoloft and were published quickly, while these negative results languished until the Zoloft patent had expired. One earlier positive study did not list the dates during which the study occurred, but it seems clear that it was rushed to publication much quicker than the negative study. Another positive study was conducted between May 1996 and June 1997 and was published in 2000. It’s quite obvious why the positive studies were rushed to press and the negative study languished, is it not?

Do keep in mind that the magnitude of positive effect for Zoloft over placebo, even in the positive studies, was small to moderate. When even the positive news for antidepressants in treating PTSD show only modest improvement relative to placebo, one should tread cautiously.

Change of Heart: Drug companies have been criticized widely for failing to disclose clinical trial data (1, 2). In an effort to shore up the support of the medical community and the public at large, what could possibly make more sense than publishing negative trial results? Gee, look at how honest we are – we share the good news and the bad news! Of course, when the positive results are published as quickly as possible and the negative results are published after a 10 year delay, well after the negative results can pose any threat to corporate profits, I’m not impressed by their newfound dedication to transparency.

Note: If you are a journalist, this is the kind of story that would merit a broad audience. The plot is pretty simple to follow and it reeks of corporate malfeasance, a subject that is not new to Pfizer and its former cash cow antidepressant.