Fewer than one in five clinical trials of cancer treatments logged on the National Institutes of Health’s (NIH) public registry, ClinicalTrials.gov, were subsequently published in peer-reviewed medical journals, a US study has found. The publication rate for industry-sponsored trials was just 5.9%.

The analysis by Scott Ramsey of the Fred Hutchinson Cancer Research Center in Seattle and John Scoggins of the Department of Health Services at the University of Washington, Seattle will aggravate concerns about publication bias in oncology research in particular and clinical trials in general. Another finding was that, out of 341 published oncology trials where the researchers could judge whether the findings were positive or negative, 220 or 64.5% reported positive results.

Among the fewer than 6% of industry-sponsored trials that had been published, 75.0% reported positive results. And 78.8% of the results were positive for the higher proportion (27.3%) of NIH-sponsored trials that found their way into peer-reviewed journals. On the other hand, only 50.0% of published trials sponsored by oncology networks (i.e., international quasi-private medical research facilities) – where the publication rate was 59.0% – delivered positive results.

Ramsey and Scoggins isolated a total of 2,028 oncology trials that were registered on ClinicalTrials.gov and met the inclusion criteria for their study. Just 17.6% of these studies were published in journals listed by the US National Library of Medicine’s database, PubMed.gov.

Allowing for legitimate delays between manuscript submission and publication, it still appears likely that fewer than one quarter of all oncology trials registered with ClinicalTrials.gov are published in widely accessible journals, the researchers wrote in The Oncologist. They also suggested that, whereas 35.5% of the published studies could be considered negative, the proportion of negative findings in unpublished studies is likely to be much higher.

Unpublished studies may contain important information that could influence future research and current practice, Ramsey and Scoggins pointed out. Moreover, the publication of clinical trials with negative results “clearly has value to researchers and patients”.

Researchers “benefit from not repeating a negative trial, but they also benefit from what the negative trial implies regarding the conceptual relationship between the experimental treatment and outcomes”, the authors commented. “Negative trials compel researchers to reconsider hypotheses regarding how the study intervention and related approaches impact mechanisms of disease, patient or population behaviours, or other pathways between treatment(s) and outcome.”

These issues were especially pertinent to oncology, due to the toxicity and/or expensiveness of many therapies, Ramsey and Scoggins added.

Accrual problems

In an accompanying editorial, Drs Gregory Curt and Bruce Chabner – respectively, senior editor and editor-in-chief of The Oncologist (Curt also works for AstraZeneca) – noted that one important reason for trials not being published is failure to accrue patients. “So, while about one in five cancer trials is eventually published, equally sad is the fact that half of the published trials have failed to accrue and reach endpoints,” they wrote.

This in itself is “an indictment of the review process that allows poorly designed or low-priority trials to be initiated, or delays them past their point of relevance”. The US National Cancer Institute (NCI) Cooperative Groups, for example, “routinely take two years or more to bring a trial from concept to active accrual”.

Curt and Chabner also acknowledged that investigators and sponsors may have difficulty finding a journal willing to publish a negative, poorly designed or inadequately accruing trial, as “a journal filled with such data will not attract readership, citations, and advertisement”.

Among their suggestions for change were that the NCI, its granters and its Cooperative Groups need to focus their efforts on trials of the highest priority, streamline their study review process, and provide adequate reimbursement for trials. “In return, the publication record of the groups for both positive and negative trials, indeed for all trials, should be the major determinant of their continued funding,” Curt and Chabner wrote.

They also pointed to the commitment of leading pharmaceutical companies to place negative clinical trials in the public domain, while cautioning that “posting on a website is not the same as a peer-reviewed publication, and the potential for publication bias works as strongly against a sponsor as an academic investigator”.

In addition, The Oncologist is considering whether to publish a peer-reviewed, searchable journal for negative trials and has invited comments from readers on whether such a resource “would be worth the considerable effort and expense”.

Investigators and sponsors have an obligation “to publish in a peer-accepted public forum the results of trials to which cancer patients have contributed their precious time and well-being, and for some, their very lives, in the hope that such information will accelerate the research process and save lives in the future”, Curt and Chabner commented.