Despite Mandates, Few Study Results Are Reported

Despite Mandates, Few Study Results Are Reported

December 8th, 2011 // 3:10 pm @

Four years ago, the US began requiring researchers to register studies of prescription drugs and report results on ClinicalTrials.gov, the federal database. But a new study found that, while the mandate increased the number of trials that were registered, 39 percent were actually registered late and results for only 12 percent of completed trials were reported within one year, as required.

Another interesting finding: clinical trials that were funded by the pharmaceutical industry were more than three times as likely to report results than trials that were funded by the National Institutes of Health. The overall showing prompted the authors of the study, which was published in Health Affairs, to suggest tougher penalties to force industry, institutions and researchers into compliance.

Clinical trial disclosure, you may recall, has been a hot-button issue, especially in the wake of various scandals that revealed selective publication. To remedy the situation, the International Committee of Medical Journal Editors six years ago began requiring trial registration prior to patient enrollment as condition for publication.

And in 2007, the FDA mandated study sponsors or principal investigators register on ClinicalTrials.gov, although researcher are allowed to delay reporting results for up to three years for trials conducted before drugs are initially approved, and for studies of unapproved clinical indications for currently approved drugs. But no one has previously quantified the impact of the FDA requirement on the number of trials registered or the timeliness of registrations and reported results.

For this reason, the findings are “important because there is evidence of selective reporting even among registered trials,” the authors write. “Additional enforcement may be required to ensure disclosure of all trial results, leading to a better understanding of drug safety and efficacy. Congress should also reconsider the three-year delay in reporting results for products that have been approved by the Food and Drug Administration and are in use by patients” (here is the abstract).

To examine the impact of the FDA mandate and ICMJE requirement, the researchers looked at all Phase II, Phase III and Phase IV studies registered on ClinicalTrials.gov, and completed between October 2008 and May 2010. All totalled, there were 4,455 of these studies. They noted that there were 40,343 Phase II through IV trials registered between September 1999 and May 2010.

So what else did they find? All trials with a US study site or studies conducted under a US investigational new drug application must report results within one year, unless granted an exemption. However, one year after reporting completion, only 12 percent of all trials and only 14 percent of Phase IV trials had reported results. But it was unclear which studies may have been exempt.

Meanwhile, Phase III trials and Phase IV trials were more likely to report results than Phase II trials. And studies that had 101 to 500 enrollees or more than 500 enrollees were more likely to report results than trials with 100 or fewer enrollees.

There were increases in trial registration as a result of the ICMJE reqruiements and these persisted over the long term. But the added short-term impact of the FDA mandate suggests that many trials went unregistered despite the ICMJE requirement. And as more trials move overseas, the authors notes that the FDA requirement will have less force.

Monthly trial registrations with ClinicalTrials.gov spiked to 3,474, from the previous monthly average of 78, when the ICJME requirement went into effect in September 2005. Another spike of 755 registrations occurred in December 2007, when the FDA took effect. But by January 2010 the monthly number of registrations had fallen to the level seen before the federal mandate took effect.

What to do? The authors suggest Congress reconsider the three-year delay in reporting results for meds approved by the FDA. They also propoose stricter enforcement; currently, failure to comply with the FDA mandate to register studies and report results can result in civil penalties of up to $10,000 a day if violations remain uncorrected 30 days after being cited by the FDA. But as of February 2010, the authors found that no fines had been levied for noncompliance with the federal mandate.

They also argue that using Institutional Review Boards and informed consent documents as “points of leverage” would cncourage registration and reporting. And they maintain that making early registration and the posting of results requirements for publication in medical journals. “Our findings also suggest that regulatory authorities should apply stronger pressure to non-industry researchers. This could include enforcing the current federal mandate provision that allows the authorities to withhold funds from the NIH for failure to com- ply with other mandate provisions,” they add.

In the end, they explain their rationale this way: “Public disclosure in a registry is vital for at least two reasons. First, even if trials are registered, many studies remain unpublished, particularly those funded by industry. And second, there is evidence that the primary and secondary outcomes reported in journal articles are often different from those initially registered. Because of these concerns, public disclosure of all studies and all of their outcomes would make trial reporting both more balanced and more credible.”

“A complete database of all studies and their results would be immensely beneficial to patients and clinicians, as it would provide a wealth of data with which to examine important safety and efficacy questions,” lead study author Michael Law, an assistant professor in the Centre for Health Services and Policy Research at the University of British Columbia, in Vancouver, writes us. “The people running ClinicalTrials.gov have developed an excellent platform for information on clinical trials. The challenge now is to ensure we maximize the completeness and quality of data that it contains.”


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