The website “ClinicalTrials.gov” has become the first stop for many of us who need to check on trial activity of a particular drug. All larger human Phase 2 – 4 trials are listed there in quite some detail. While companies sometimes shy away from publishing full entry criteria or primary study endpoints, there is plenty of information on timelines including expected study completion. There is also a section dedicated to reporting study results and the existence of a final publication.
Having worked in industry for many years, I am very familiar with the publication process. For large multi-author articles, the process of writing and finalizing the result interpretation can be a challenge. Nonetheless, after unblinding, a final manuscript should be ready for journal submission within 6 months. Occasionally it may take up to 12 months but any further delay is hard to justify.
In the US, submitting updated trial information on an ongoing basis is a federal requirement. Why then is it that so many large trials remain without publication and no results provided in ClinicalTrials.gov? I am not referring to abstracts, posters or oral presentations which investigators and companies are always eager and quick to produce. I am talking about full-fledged study write-ups which provide detailed methodology and primary study results.
This compliance issue is not new; it has come to the attention of the public several times already.
Jones[i] selected large trials (>500 patients per study) and found – embarrassingly enough – a lack of full publications for 29% of them. For most, the ClinicalTrials.gov site had no information on study results either. When publications existed, it took a median time of 27 months from study completion to publication.
Subtracting time for data cleaning and journal review and peer review process, approx. 18 months go by in the internal manuscript review process at the sponsor. This typically involves investigators, medical writers and several layers of company personnel, from Clinical to Drug Safety and Marketing.
Surprisingly, NIH sponsored trials did not fare any better. Ross[ii] reported a lack of publication in 32% of trials. When published, it took an average of 23 months.
Studies of this size are not sponsored by individual investigators. These are expensive, ergo well-designed trials and results – good or bad – matter. In the Jones paper, approx. 77% of trials without publication were industry sponsored, the remainder had government funding or support from organizations like NIH.
Prayle[iii] reviewed ClinicalTrials.gov for compliance with federally mandated reporting timelines and found that only 22% of trials were in compliance. The rest were not.
Vaccine trials follow the trend already outlined: rampant underreporting of results and delayed publication. Upon review of Clinicaltrials.gov information and other databases as well, Manzoli[iv] also found evidence of selective reporting (i.e., in favor of positive results) in industry studies.
While delays are bad, certainly lack of publication altogether is unacceptable and inexcusable. Who is holding the ‘stragglers’ accountable? Is there a ClinicalTrials.gov “webmaster” who reviews (and polices) the submitted information for gaps and identifies laggards?
FDAAA 801 clearly states that “results submission is required “. Indeed, there is a fairly stiff penalty for non-compliance.
In 2012, three US lawmakers took action and asked FDA commissioner Dr. Hamburg whether the assertions made in the BMJ articles were correct and what enforcement actions were taken by FDA [v]. I am unable to find Dr. Hamburg’s response but attempts to improve compliance and data transparency were made.
Unfortunately, the well-intended Trial and Experimental Studies Transparency (“TEST”) Act is currently stuck in the Subcommittee on Health and seems to be going nowhere.
Cui bono?
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[i] Non-publication of large randomized clinical trials: cross sectional analysis. BMJ 2013; 347
[ii] Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ 2012; 344
[iii] Compliance with mandatory reporting of clinical trial results on clinicalTrials.gov: cross sectional study. BMJ 2012;343
[iv] Non-publication and delayed publication of randomized trials on vaccines: survey. BMJ 2014; 348
[v] http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/02/bmj-article-on-clinical-trial-reporting-foments-discontent-on-capitol-hill-our-1500th-post.html
