Pressure Grows to Publish Data

The current regulations on the publication of clinical trial results require a major overhaul, according to a group of researchers from the German Institute for Quality and Efficiency in healthcare (IQWiG) in Cologne.

Beate Wieseler, PhD, lead author of "Finding Studies on Reboxetine: a Tale of Hide and Seek," and IQWiG's Deputy Head of the Department of Drug Assessment, noted in the British Medical Journal on October 12 that public access to regulatory databases containing trials of older drugs, more data sharing between regulatory authorities, re-evaluation of a drug if approval is declined elsewhere, and the legal obligation for manufacturers to supply all requested data to health technology assessment bodies without commercial restrictions to publication, are all necessary.

Implementation of these measures, which should cover trials of both drug and non-drug interventions, would close the information gaps for post-approval decisions and enable adequate decision making in healthcare, she wrote.

The Food and Drug Administration's Amendments Act of 2007 solves part of the problem over publication bias in drug research by requiring standardized data on protocol and results to be publicly posted at clinicaltrials.gov, except for Phase I. However, the act has loopholes, and does not cover trials completed before September 27, 2007 or trials of drugs that were never approved.

"Although comprehensive information will in the future be available on newer drugs, published information on older drugs will remain biased, resulting in an unfair comparison of old and new treatment options," she stated. "It also means that negative findings on drugs never approved may not be made public, even if the drug is approved elsewhere."

Furthermore, posting of results for trials of approved drugs tested in new, unapproved indications can be delayed for up to two years. Existing regulations are also insufficient to tackle the problem of reporting selected outcomes. Similar legislation to the FDA's Amendments Act is under way in Europe with the mandatory public disclosure of data from the clinical trials database, EudraCT. These laws should be expedited, and the loopholes must be closed, wrote Wieseler.

The Cologne group assessed the benefits and drawbacks of reboxetine compared with placebo or other antidepressants, such as serotonin reuptake inhibitors (SSRIs), for treating adults with major depression. They also measured the impact of potential publication bias in trials, analyzing the results of 13 trials, including eight previously unpublished trials from reboxetine's manufacturer, Pfizer. They found the overall quality of the trials was good, but the data on 74 percent of patients were unpublished. A further comparison of published and unpublished trials showed that published data overestimated the benefits of reboxetine, an ineffective and potentially harmful antidepressant.

Reboxetine was approved in several European countries in 1997. In 1999, the FDA granted preliminary approval on the basis of trials primarily conducted outside the United States, but after the results of later North American trials had been submitted, the FDA declined final approval in 2001 because of a lack of compelling evidence of efficacy.

In a second analysis in the BMJ, Robert Steinbrook, MD, adjunct Associate Professor of Medicine and of Community and Family Medicine at the Dartmouth Medical School, Hanover, New Hampshire, outlined the problems of trusting drug companies to provide the complete picture about the clinical trials they sponsor. Journals should define full access to all the trial data and require that investigators and journal editors have full access, he pointed out. Editors should take appropriate action if concerns about data arise after publication.

"Trust in the medical literature, not just in industry sponsored trials, is at stake," he concluded.

The BMJ's editors agree that the medical evidence base is distorted by missing clinical trial data and that urgent action is necessary to restore trust in existing evidence. It is important to re-evaluate the integrity of the base of research evidence, and it is time to demonstrate a shared commitment to set the record straight, they noted in an accompanying editorial.

—Philip Ward