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Re: News - Antidepressants Vindicated? linkadge

Posted by Larry Hoover on September 12, 2007, at 10:25:34

In reply to Re: News - Antidepressants Vindicated? jhj, posted by linkadge on September 11, 2007, at 18:16:47

> GSK has chosen to be fully honest about disclosing clinical trial informaiton, including those from failed clinical trials, but other companies are not being so open as they know how it will affect public preceptions of drugs.

I did some very detailed analyses of a number of paroxetine trials from that database, for example, and what I discovered was that there were some very poorly conducted trials, particularly in the early years. They really didn't know how to do them, early on, and some of the data was simply of poor quality. You cannot attribute a failed statistical outcome to the medication having failed, when methodology was so poor. GIGO. Garbage in, garbage out.

> They likely have failed trials that they are not disclosing. And the FDA does not require that failed trials be used to calculate the overall effectivness of a drug.
> Publication bias also affects the viewpoints of the public. Simply put, effective trials get the attention.

Of course they do. That's the whole point of publishing. But aren't you ignoring the fact that the drugs are approved? Have you ever read a set of briefing notes for an FDA approval? It is far from a rubber stamp process. All data are considered.

> A meta analysis of placebo effect in 19 clinical trials.

I can show you a Preskorn reference that has SSRIs as a group better than placebo at P < 10^-40. Table 4.4.

I'm sure your reference was not free from selection bias, also.

> Also from:
> In a soon to be published study, Dr. Arif Khan, a psychiatrist at the Northwest Clinical Research Center in Washington, analyzed the Food and Drug Administration's database of 52 clinical trials in depression, involving nine new antidepressants, conducted from 1985 to 2000. ***Since the agency requires drug companies to report all data from all studies for drugs under development, the database can give a more accurate picture of a new drug's efficacy than the medical journals***, where positive findings are far more likely to be reported than negative ones.

But all data are considered in the FDA analysis. That's why they require their submission.

You'll also note that the data go back to 1985. Which means the studies were sometimes initiated much earlier than that. They didn't know what they were doing back then. Clinical trial procedures were in their infancy, and no one had any idea that the process of conducting a clinical trial would produce such a robust placebo effect. I've taken part in clinical trials, and let me assure you, the standard of care received in one is far, far superior to what I have received from my own family physician. Moreover, as a Canadian, I do believe my physician's care is superior to that received from "treat 'em and street 'em" "you've got five minutes, what do you want" HMO doctors in the U.S. Clinical trials do not represent real life.

> Dr. Khan found that in only 48 percent of the 52 clinical trials was the antidepressant superior to the placebo.

I prefer to present Khan's own words.

(Me: It's important to emphasize that subjects receiving placebo pills in antidepressant trials are *not* untreated.)

From the referenced article:
"The less-than-impressive results in these and other studies also calls to mind the fact that patients assigned to placebo treatment in clinical trials are not "getting nothing." The capsule they receive is pharmacologically inert but hardly inert with respect to its symbolic value and its power as a conditioned stimulus. In addition, placebo-treated patients receive all of the commonly employed treatment techniques: a thorough evaluation; an explanation for their distress; an expert healer; a plausible treatment; expectation of improvement; a healer's commitment, enthusiasm and positive regard; and an opportunity to verbalize their distress. "

(Me: He goes on to include a very important warning about the interpretation of the data arising from antidepressant clinical trials. Note particularly the concluding statement of the second paragraph.)

"A cautionary note is indicated about the generalization of these data to the clinical management of depressed patients. The less-than-impressive difference between drug and placebo in this and other studies of clinical trials does not speak directly to the effectiveness of antidepressants in clinical practice. Participants in antidepressant clinical trials are a highly select group and are not representative of the general population of depressed patients. They are not actively suicidal, they are almost always outpatients who are moderately rather than severely or mildly depressed, and they are free of comorbid physical or psychiatric illness. They are likely to have a higher placebo response rate than more severely ill depressed patients. "

"Furthermore, the primary aim of these studies is not to assess the optimal effect of antidepressants, but rather to rapidly assess efficacy of new drugs so they can be brought to the market. Therefore, dose, duration and diagnosis in clinical trials are not necessarily ideally suited to identify the optimal effects of antidepressants. Accordingly, clinical trials may identify the lower bound of the effect size compared to placebo. "

I'd also like to add that it is a fallacy to conclude that the absence of significant difference between groups in a clinical trial means there is no true difference. The absence of evidence (of a difference) is not evidence of the absence (of a difference). It only means that one was not found, in the limited and selected population under study, under the artificial constraints of the study methodology. It is incorrect to generalize from a null finding. Period.





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