抗うつ剤の臨床試験結果公表の不透明さ医師の一分/ウェブリブログ

抗うつ剤の臨床試験結果公表の不透明さ

<< 作成日時： 2008/01/22 22:48 >>

　プロザックやパキシルのような抗うつ剤のメーカーは、認可をとるために、実施した臨床試験の1/3の結果を出版せずに、医師や消費者に対して真の有効性について誤解させている。公表された試験結果では、プラセーボの40%に比べ60%が有効であり有意に抗うつ効果があるとされた。しかし、効果が低い未発表の試験データを加えると有効性は低下する。効果ありとの研究結果は94%が印刷されたが、期待はずれ又は不明瞭な結果のものは14%しか印刷されなかった。
　薬剤の臨床試験がどのように報告されるかについて議論が沸いている。2004年に抗うつ剤の臨床試験で有効ではなかったものが出版されなかったという事実の後、公的なデータベースに登録されなかった臨床試験については出版しないと主要な医学雑誌グループは合意した。
　昨年議会は、国立医学図書館NLMの公開データベースclinicaltrials.gov に提出しなければならない臨床試験のタイプと情報内容について拡大する法案を通した。FDAのサイトで最近の臨床試験のレビューが一部見られるが、利用しにくいという。
---------------------------------------
Antidepressant Studies Unpublished
http://www.nytimes.com/2008/01/17/health/16cnd-depress.html?_r=1&ref=health&oref=slogin
http://www.nytimes.com/2008/01/17/health/17depress.html?_r=1&ref=health&oref=slogin

By BENEDICT CAREY
Published: January 17, 2008

The makers of antidepressants like Prozac and Paxil never published the results of about a third of the drug trials that they conducted to win government approval, misleading doctors and consumers about the drugs’ true effectiveness, a new analysis has found.

In published trials, about 60 percent of people taking the drugs report significant relief from depression, compared with roughly 40 percent of those on placebo pills. But when the less positive, unpublished trials are included, the advantage shrinks: the drugs outperform placebos, but by a modest margin, concludes the new report, which appears Thursday in The New England Journal of Medicine.

Previous research had found a similar bias toward reporting positive results for a variety of medications; and many researchers have questioned the reported effectiveness of antidepressants. But the new analysis, reviewing data from 74 trials involving 12 drugs, is the most thorough to date. And it documents a large difference: while 94 percent of the positive studies found their way into print, just 14 percent of those with disappointing or uncertain results did.

The finding is likely to inflame a continuing debate about how drug trial data is reported. In 2004, after revelations that negative findings from antidepressant trials had not been published, a group of leading medical journals agreed to stop publishing clinical trials that were not registered in a public database. Trade groups representing the world’s largest drug makers announced that members’ companies would begin to release more data from trials more quickly, on their own database, clinicastudyresults.org.

And last year, Congress passed legislation that expanded the type of trials and the depth of information that must be submitted to clinicaltrials.gov, a public database operated by the National Library of Medicine. The Food and Drug Administration’s Web site provides limited access to recent reviews of drug trials, but critics say it is very hard to navigate.

“This is a very important study for two reasons,” said Dr. Jeffrey M. Drazen, editor-in-cheif of The New England Journal. “One is that when you prescribe drugs, you want to make sure you’re working with best data possible; you wouldn’t buy a stock if you only knew a third of the truth about it.”

Second, he continued, “we need to show respect for the people who enter a trial.”

“They take some risk to be in the trial and then the drug company hides the data?” he asked. “That kind of thing gets us pretty passionate about this issue.”

Alan Goldhammer, deputy vice president for regulatory affairs at the Pharmaceutical Research and Manufacturers of America, said the new study neglected to mention that industry and government had already taken steps to make clinical trial information more transparent.

“This is all based on data from before 2004, and since then we’ve put to rest the myth that companies anything to hide,” he said.

In the study, a team of researchers identified all antidepressant trials submitted to the Food and Drug Administration to win agency approval from 1987 to 2004. The studies involved 12,564 adult patients testing drugs like Prozac from Eli Lilly, Zoloft from Pfizer and Effexor from Wyeth.

The researchers obtained unpublished data on the more recently approved drugs from the F.D.A.’s Web site. For older drugs, they tracked down hard copies of unpublished studies through colleagues, or using the Freedom of Information Act. They checked all of these studies against databases of published research, and also wrote to the companies that conducted the studies to ask if specific trials had been published.

They found that 37 of 38 trials that the F.D.A. viewed as having positive results were published in journals. The agency viewed as failed or unconvincing 36 other trials, of which 14 made it into journals.

But 11 of those 14 journal articles “conveyed a positive outcome” that was not justified by the underlying F.D.A. review, said the new study’s lead author, Dr. Erick H. Turner, a psychiatrist and former F.D.A. reviewer who now works at Oregon Health and Sciences University and the Portland Veterans Affairs Medical Center. His co-authors included researchers at Kent State University and the University of California, Riverside.

Dr. Turner said the selective reporting of favorable studies sets up patients for disappointment. “The bottom line for people considering an antidepressant, I think, is that they should be more circumspect about taking it, and not be so shocked if it doesn’t work the first time and think something’s wrong with them,” he said.

For doctors, he said, “They end up asking, ‘How come these drugs seem to work so well in all these studies and I’m not getting that response?’ ”

Dr. Thomas P. Laughren, director of the division of psychiatry products at the F.D.A., said the agency had long been aware that favorable studies of drugs were more likely to be published in journals.

“It’s a problem we’ve been struggling with for years,” he said in an interview. “I have no problem with full access to all trial data; the question for us is how do you fit it all on a package insert,” the condensed prescribing information that accompanies many drugs.

Dr. Donald F. Klein, an emeritus professor of psychiatry at Columbia, said drug makers were not the only ones who can be reluctant to publish unconvincing results. Journals, and study authors too, may drop studies that are underwhelming.

“If it’s your private data, and you don’t like how it came out, well, we shouldn’t be surprised that some doctors don’t submit those studies,” he said.

--------------------------------
Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy
Erick H. Turner, M.D., Annette M. Matthews, M.D., Eftihia Linardatos, B.S., Robert A. Tell, L.C.S.W., and Robert Rosenthal, Ph.D.
NEJM Volume 358:252-260 January 17, 2008 Number 3
ABSTRACT

Background Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased. Selective publication of clinical trials ― and the outcomes within those trials ― can lead to unrealistic estimates of drug effectiveness and alter the apparent risk–benefit ratio.

Methods We obtained reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients. We conducted a systematic literature search to identify matching publications. For trials that were reported in the literature, we compared the published outcomes with the FDA outcomes. We also compared the effect size derived from the published reports with the effect size derived from the entire FDA data set.

Results Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.

Conclusions We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Source Information

From the Departments of Psychiatry (E.H.T., A.M.M.) and Pharmacology (E.H.T.), Oregon Health and Science University; and the Behavioral Health and Neurosciences Division, Portland Veterans Affairs Medical Center (E.H.T., A.M.M., R.A.T.) ― both in Portland, OR; the Department of Psychology, Kent State University, Kent, OH (E.L.); the Department of Psychology, University of California–Riverside, Riverside (R.R.); and Harvard University, Cambridge, MA (R.R.).

Address reprint requests to Dr. Turner at Portland VA Medical Center, P3MHDC, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, or at turnere@ohsu.edu.