Disclosure of trial results - a continuing saga
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Incomplete disclosure of trial results is clearly a significant issue, but one that is often represented to the public as evidence of a pharma conspiracy to suppress negative data. In that context, it was refreshing to read balanced coverage of a new article (subscription required) and accompanying editorial in Journal of Clinical Oncology studying the reporting of oncology trial results in ClinicalTrials.gov and / or PubMed. From the editorial:
[The authors] found that almost one half of trials had no publically available results at 3 years after completion. In addition, compliance with the FDAAA requirement of outcome reporting within 12 months of study completion was even poorer, with only 13% of trials posting results within the legislated timeframe. Contrary to the notion that the pharmaceutical industry might have the most to lose from clinical studies which did report negative results, compliance with the FDAAA legislation was highest in trials with industry primary funding.
Despite some methodologic limitations (noted in the editorial), this study sheds new light on both the current state of affairs and the path forward toward more complete reporting of clinical trial results:
Need to focus on gap in "reporting" results - which is not the same as "publishing". This paper correctly looked at not just journal publications, but also reporting in ClinicalTrials.gov, for evidence of results reporting. ClinicalTrials.gov reporting is mandated under FDAAA for many (but not all) studies, and should therefore be the most comprehensive source for such results.* Many prior studies of publication bias have incompletely focused exclusively on publications in journals (see here for a recent meta-analysis), even though (a) journal publication is outside the law's scope, and (b) there may not necessarily be a suitable journal for every report of trial results, particularly if the findings are negative, confirmatory or inconclusive.
Need stronger internal policing by both industry and academia. Partly in response to FDAAA, many pharma companies have committed to publicly reporting trial results (see here and here, for example). If reporting of results from industry-sponsored trials is still suboptimal, we need to understand in more detail how these policies are performing (e.g., if there are differences in compliance between companies with and without strict internal guidelines) and how reporting of industry-sponsored studies can be improved across pharma. In contrast to pharma, to my knowledge most academic centers do not explicitly require investigators to adhere to FDAAA rules or actively monitor investigators' adherence. If the apparently lower reporting compliance rate for non-industry studies seen in this most recent study is validated, it is worth exploring whether academic institutions should increase enforcement - for example, by charging Institutional Review Boards that approve trials with the task of requiring submission of dissemination plans and enforcing compliance.
Need to address the time delay question. On its face, the time delay permitted by FDAAA between study completion and results filing is reasonable. If, as suggested in this study, there is a widespread inability of investigators and sponsors to comply with this requirement, we need to understand and quantify the possible contributors - including, for example, lack of resources, education or commitment among the various parties - in order to define the scope of the problem and address outstanding issues head-on.
There is a compelling argument that investigators must publicly report clinical trial results to fulfill their implicit moral agreement with study volunteers. To be sure, there are past examples in which industry sponsors violated this compact and withheld trial results, and these are indefensible. But with every passing year, these historical events are further away in the rear-view mirror, largely replaced with data-driven analyses that demonstrate that these rare occurrences do not reflect widespread malfeasance. Journalists, academics and even (especially) "pharmascolds" owe it to the public to focus on evidence instead of anecdotes to both describe the remaining challenges to dissemination of trial results and suggest solutions. Rigorous analyses of results disclosure and thoughtful, unbiased press reporting - as seen in this recent example - are an important step in this process.
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* Importantly, the relevant section of the FDA Amendments Act (FDAAA) that sets reporting requirements for ClinicalTrials.gov explicitly permits reporting of trial results to be delayed for investigational drugs until closer to regulatory approval, provided this rationale for delay is requested within one year of study close and documented in the database. In this paper, studies were classified as having released results if they provided this documentation, suggesting that the low FDAAA compliance rate is not due to permitted exceptions for unregistered agents.
(Full disclosure: From 2008 to 2012, I consulted extensively for the Medical Publishing Insights and Practices (MPIP) initiative, a multi-pharma consortium that aims to "elevate trust, transparency and integrity in publishing industry-sponsored studies", and co-authored several papers with that group. In addition, I am currently employed by a global pharma company.)