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Archived Comments for: Extent of publication bias in different categories of research cohorts: a meta-analysis of empirical studies

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  1. Clarification - Regulatory cases

    Fujian Song, University of East Anglia

    31 August 2010

    Thanks Dr. Eric Turner (Portland VA Medical Center) for sending me (Fujian Song) an email to explain US FDA regulatory process. I found it very helpful. After obtaining Eric's agreement, this clarification is pasted as below for other readers of the article:

    "Fujian, I was just looking back at the paper you first-authored in BMC Research Methodology and noticing Figure 1. It shows regulatory authorities first receiving information on a clinical trial after inception and after the data have been analyzed and written up. That's *partly* true. In the US, the FDA gets involved at two points in time, once before inception, and once after trial completion.

    The before-inception stage is called an IND application (which stands for Investigational New Drug). Before a drug company can begin recruiting its first patient, it has to submit the protocol to the FDA for review. The FDA then has a chance to put it on clinical hold and forbid the sponsor from doing the trial. Assuming the FDA does not object to the trial as laid out in the protocol, the sponsor can then proceed. At that time, the sponsor will have its sites submit to their IRBs for local approval.

    The later time point at which the FDA gets involved comes about with the NDA, or New Drug Application. After all the data has been collected and analyzed, and assuming they have some hope that they have some decent results, the sponsor drug company sends in all the data, both summary data and raw patient-level data, which the FDA statistician analyzes according to statistical methods laid out in the original protocol.
    The sponsor cannot at this stage pretend a trial never happened, because the trial would have been registered with the FDA at the IND stage, before they had any way of knowing it would turn out to be negative.

    I've attached an essay I wrote in PLoS Med in 2004 (only their second issue, I believe) describing this. In the title I tried to make the point that the FDA functions as both a registry (data from IND stage) and a results database (data from NDA stage).

    There is a "loophole" in this that would allow things to operate as shown in Figure 1, i.e. where the FDA would learn about a trial only after the data are all collected, analyzed, and written up: That would be for the drug company to do a bunch of trials overseas and then, perhaps years later, approach the FDA and try to do the entire clinical trial program based on the overseas data. That would, of course, allow for some "cherry picking" of trials and selective submission of trial data.

    But what happens then is that the FDA often requires that some of the data be collected from US sites, and that would follow the full procedure outlined earlier."

    Competing interests