{"id":66386,"date":"2016-06-24T11:49:50","date_gmt":"2016-06-24T15:49:50","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=66386"},"modified":"2016-06-24T12:29:34","modified_gmt":"2016-06-24T16:29:34","slug":"involuntary-honesty","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/06\/24\/involuntary-honesty\/","title":{"rendered":"involuntary honesty…"},"content":{"rendered":"\n

A Phase 3 Randomized Clinical Trial <\/font>[RCT<\/font>] of a medication isn’t really research. That’s already been done earlier. The RCT is product testing with two important elements – efficacy [does it work?] and safety [does it cause harm?] – and in either case, what is the strength of the effect?  Other things might become apparent along the way. Who knows? Maybe some day the secret of the universe might be serendipitously found in an RCT, but that’s still an incidental, exploratory finding – not why the trial is being done. <\/p>\n

<\/p>\n

Everything about a given trial is specified in two documents [often combined] – the Protocol<\/font> and the Statistical Analysis Plan<\/font> – prepared in advance [a priori<\/font><\/em>] and submitted to an Institutional Review Board <\/font>[IRB<\/font>]. After the Clinical Trial is approved and the blinded study is underway, no changes can be made except under unusual circumstances, and then only by an official amendment to the Protocol approved by the IRB<\/font><\/em>. <\/p>\n

Why so rigid? It’s obvious. There’s never any guarantee that the sanctity of the blind hasn’t been breached, informing any after·the·fact<\/font><\/em> changes. Anyone who has any experience with statistical analysis knows that with foreknowledge, one can have a field day with statistical testing. Shuffle some outcomes, select the right tests, ignore the negatives, etc. And that’s exactly what has happened – over and over. Weak signals without clinical significance have been turned into lucrative blockbusters. While it’s hard to prove, it can easily be prevented<\/font>.<\/p>\n

So some version of the proposal made by Dr. Carroll seems inevitable to me [see CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL<\/a> and out of this mess…<\/a>]. We’ve had decades of proof that the pharmaceutical industry isn’t going to self·<\/font><\/em>regulate. His suggestion is both feasible and goes straight to the heart of the matter: <\/div>\n

Our primary defense against such perversions of scientific reporting is fidelity to the registered IND protocol and plan of statistical analysis. The solution is not hard to see: We need independent analyses of clinical trials because we cannot trust the corporate analyses. In effect, we need something like the Underwriters Laboratory to verify the statistical analyses of clinical trials. Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators. Why treat the statistical analysis of drug trials any differently? It’s highly technical work. Who should assume that responsibility? Why not the FDA? After all, they alone see all the data. My specific proposal is for Congress to mandate that the FDA analyze all clinical trials data strictly according to the registered protocols and analysis plans. That requirement should apply to new drugs or to approved drugs being tested for new indications. It should apply also to publications reporting new trials of approved drugs. Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight. <\/p><\/blockquote>\n

Interestingly, this was the direction we were headed in fifty years ago when the RCTs were in their infancy [see Evolution of Psychopharmacology Trial Design and Analysis: Six Decades in the Making<\/a> and under fire I…<\/a>] <\/div>\n