ClinicalTrials.gov, Inhaled Loxapine, and Safety Issues

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In a recent article in the New England Journal of Medicine, Dr Maria Makrides makes the following statement: “[Ms X] should not start prenatal fish oil supplements on the basis of the results of a single study. Clinical practice decisions are best made in accordance with practice guidelines based on well-conducted systematic reviews, preferably of several randomized, controlled trials.”1 I wholeheartedly endorse this axiom and would add one of my own: When it comes to establishing the clinical value of any therapeutic intervention, the replication of seminal findings is an essential step. It is my view that, in general, a single positive outcome should provide the impetus to do further work on a hypothesis and to make continued efforts to refute it. I realize that there are exceptions to both of these axioms, especially for treatments of some rare or orphan diseases. The use of historical controls may also suggest an overwhelming benefit from a new, targeted therapy of a life-threatening or otherwise devastating condition.
How is a practicing clinician going to know how the efficacy of any newly marketed therapy was established? The concerned practitioner can and should read the information provided in the product's label—also called the patient package insert (PPI). Better still is a thorough literature search on the product. Unfortunately, it is common knowledge that some positive outcome trials are not published, and even more importantly, most negative trials are not published. The clinician may never discover that, although the agent was approved because of two positive controlled studies, there were also two, perhaps even more, negative trials. It is always possible that there may be good reasons for negative outcomes, but the PPI may not explain them. Issues include sample size, inadequate dosages, or adherence—to cite a few common reasons.
Another important and underused source of information is ClinicalTrials.gov (CTg). It is a website maintained by the National Library of Medicine; the National Library of Medicine is an institute within the National Institutes of Health (NIH). ClinicalTrials.gov is intended to serve as a registrational site for clinical trials in humans and as a repository for trial results and protocol amendments. A newly revised set of CTg guidelines went into effect on January 18th of this year. These guidelines, developed jointly by the Food and Drug Administration (FDA) and the NIH, are discussed and elaborated in a document entitled “Clinical Trials Registration and Results Information Submission.” It can be downloaded from http:federalregister.gov/d/2016-22129/.2 It details how protocols, analysis plans, and collected data and results are to be presented. Several points are worth reiterating: (1) no patient-specific data submission is required—I understand this as a means of privacy protection, but it limits any ability to better understand more than results from cohort mean values; (2) data must be submitted in tabular form—summarizing patient flow, demographic and baseline characteristics, primary and secondary outcome measures, unwanted treatment effects, and most importantly, the deposition of results from any scientifically appropriate statistical tests; and (3) trial results must be submitted no later than 1 year after study completion (also referred to as the “primary completion date”), defined as the date of final data collection for the primary outcome measure. Examination of the CTg website in December 2016 suggests that sponsors rarely provide all of these pieces of information.3 Calling these “requirements” may improve adherence to those expectations, but it is not at all clear how they will be enforced or what penalties will be imposed.
The Final Rule, also called FDAAA 801 and the NIH Policy on Clinical Trial Reporting, defines which clinical trials are covered by this newly published document.
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