ACC: Major Clinical Trials Get Double Exposure by Journals and Meetings

NEW ORLEANS, March 23 -- Among the blizzard of clinical trials to be presented at the American College of Cardiology meeting here over the next four days are 11 singled out for special treatment -- simultaneous online publication in peer-reviewed journals.

Over the past decade the evolution in electronic publishing has fueled this "two-bites of the apple" approach to reporting clinical trial results -- a featured spot in the meeting program and concurrent publication in a first-tier journal. Starting as a rarity, this approach is now an expected element of major meetings.

At the ACC meeting, three trials will be presented with simultaneous publication in the New England Journal of Medicine, six papers will have simultaneous publication in the Journal of the American Medical Association, and two papers will have simultaneous publication in the Journal of the American College of Cardiology. In the journals, there will also be five editorials that were given expedited review to go with the simultaneous publications.

This trend is generally greeted as a welcome one, according to interviews with current and former journal editors, meeting organizers, and researchers.

A lingering question is whether journals cut corners to get research peer-reviewed in time for the simultaneous publication, with its undeniably enhanced visibility, but the journals believe they have developed a secure system that prevents this. If the research or the reviews -- sometimes condensed to as little as 48 hours -- aren't up to snuff, the simultaneous publication is abandoned, they argue.

"We think it's great," said Timothy Gardner, M.D., who served as program chair at the American Heart Association meeting last November.

Dr. Gardner, a cardiothoracic surgeon at the Christiana Care Health Services in Wilmington, Del., said that a major goal of scientific meetings is the dissemination of "important, potentially practice-changing" trial findings to the research and clinical practice community as well as to the general public.

From that perspective, the appeal of a published paper that would permit those findings to presented as complete, well-vetted research versus the intriguing -- but often incomplete -- snapshot of data reported in an abstract or a 10-minute oral presentation is undeniable.

Phil B. Fontanarosa, M.D., M.B.A., executive editor of JAMA, said JAMA embraced the fast-track publishing route in 1999 when it formalized the process by launching JAMA-EXPRESS --EXpedited Peer Review and Editorial System for Science.

In the editorial that announced JAMA-EXPRESS, Dr. Fontanarosa and co-author Margaret A. Winker, M.D., said that the online publication was created to "provide rapid, rigorous peer review and editorial evaluation, revision, release, and publication of papers of great scientific or public health importance."

Among the papers that might fit that description, they wrote, would be major "potentially practice-changing studies reporting the full results of abstracts scheduled to be presented at upcoming scientific meetings."

Coordination of meeting presentation and JAMA EXPRESS publication would, they wrote, "facilitate complete and thorough reporting of major findings, minimize the constraints authors feel regarding prepublication publicity, enhance consistency between abstract presentations and published reports, and ensure that the results presented in abstract form are available and published in full."

Dr. Fontanarosa said that over time the JAMA editors have evolved a process for selecting the JAMA EXPRESS candidates. Generally, the papers chosen for expedited review are "large randomized trials" but there have been exceptions. For example, JAMA-EXPRESS published an early observational study on the anthrax attacks in 2001.

And while a paper's inclusion in a late-breaking clinical trials session at a meeting may help it make the cut for expedited publication, that alone is not enough to guarantee selection.

Dr. Gardner said the MAGIC trial (Myoblast Autologous Grafting in Ischemic Cardiomyopathy) was a good example of trial featured in a late-breaking session that didn't make the cut for expedited publication.

He said the study was terminated early because it appeared that the treatment-injecting myoblasts into damaged heart muscle-was not effective. But a more complete analysis found "that there was a really significant improvement-a 12% to 13% reduction in left ventricular volume--and it was a important finding," Dr. Gardner said.

That example also illustrates one of the difficulties for both investigators who seek expedited review and the journal editors whose job is to evaluate that request. It's tough to pitch the significance of a study on the basis of an abstract and the news that a trial has been designated a late-breaking clinical trial by meeting organizers. It's tougher still to judge a trial's merit when given only an abstract.

"We need to see a good, solid draft," Dr. Fontanarosa said. That draft allows the journal editors to quickly judge whether the paper is a good candidate for expedited review or if "it should be considered for our normal print publication process, or if it is, perhaps, not a JAMA paper at all."

When medical journals embraced electronic publishing with expedited review and coordinated meeting release, it paved the way for more media coverage of the trial findings, as credentialed medical journalists are routinely given access to the papers days before they are presented at a scientific meeting and published online. In exchange for this early access journalists agree to hold off on reporting the findings until this embargo lifts, usually at exact time of the meeting presentation.

That agreement often improves the likelihood of the findings ending up getting featured coverage in newspapers, web-based news services, and on the evening news, which makes this coordinated coverage extremely attractive to the trial's sponsors. These can be government entities like the National Institutes of Health or Britain's National Health Service, but often the sponsors are companies that make and market the drugs and devices tested in the studies.

It's that industry influence that both Sidney Wolfe, M.D., of Public Citizen and Jerome Kassirer, M.D., a former editor of the NEJM, said makes these critics wary of the practice.

Dr. Kassirer, now a professor at Tufts University School of Medicine, said he has no problem with expedited review and early online publication of studies that have a major impact on public health, but was not a fan of the practice of timing study publication to coincide with meeting presentations.

Noting that coordinated release was "not done in my time as NEJM editor," he said the practice suggested that "important results are either rushed into publication or held simply to get two bites at the apple."

Dr. Wolfe said that he had no objection to releasing a fully peer-reviewed study at the same time as the data are reported at a meeting, but he objected when the practice was used to "promote off-label uses of drug" or when the study was simply a trial that compared a new, more expensive drug with an older, cheaper drug.

For example, a study that compared an angiotensin receptor blocker to a thiazide diuretic might demonstrate that the ARB achieved a greater or faster reduction in blood pressure than the diuretic, but with no observable difference in clinical outcome. According to Dr. Wolfe there is no public health benefit in showcasing such findings, but there is a potential benefit to the drug maker. That, he said, was an inappropriate use of expedited review.

Elliott Antman, M.D., a senior editor of Circulation, Journal of the American Heart Association, said that sometimes head-to-head trials of new versus old medications provide results that "are practice changing" and in such cases physicians and patients are well served by coordinating the presentation.

Dr. Antman noted that Circulation did not have any fast-track publications at this year's ACC meeting, but he said that the journal has already accepted some of the late-breaking trials for regular print publication.

Dr. Antman has a unique perspective on coordinating expedited review with data presented at meetings. As an editor he has been the one who received investigations requested for expedited review, and as reviewer for several journals, he has been asked to perform expedited reviews.

And he was the principal investigator of ExTRACT-TIMI 25, which was reported as a late-breaking clinical trial at ACC's 2006 meeting and simultaneously published in NEJM.

He said there is another important reason to quickly publish "clinically important, potentially practice-changing findings" by coordinating with the meeting or publishing soon after-practice guidelines and scientific statements.

"It is AHA and ACC policy to only use published clinical trial results to drive guideline determination," he said. That means a trial that "could have a major impact on clinical practice will not be considered by guideline committees until the trial is published or we have received from the authors a copy of the acceptance letter from a peer-reviewed journal."

ExTRACT-TIMI 25was typical of the papers selected for expedited review. One of these was a large randomized study, which had been "anticipated" by cardiology researchers.

Dr. Fontanarosa acknowledged that often the JAMA editors are well aware of the progress of major trials and may express interest in trials long before the trial is completed. In those cases it is may be the journal editors, not the investigators, who suggest an expedited review.

"Often when we are contacted by authors seeking expedited review we will come back to the author with specific requests for additional analysis," Dr. Antman said. Those additional requests are often time consuming and can "mean that we cannot complete a full review within the very tight timetable needed for expedited review."

The review process for papers accepted for print publication usually takes two to six weeks, but expedited review is typically done in 48 hours, according to journal editors. During those two days the "full content, statistical, and editorial review is completed," said Dr. Fontanarosa. "Nothing is compromised or left out."

If a problem is discovered during review the study may "be taken off the expedited review tract and placed on the regular print publication tract or might be determined that it is not a paper for JAMA," Dr. Fontanarosa said.

At the ACC meeting, NEJM will also be releasing two editorials that address the three papers it has slated for early release and JAMA-EXPRESS has three editorials to go along with the five studies it earmarked for early release.

Dr. Fontanarosa said he thinks the editorials are an important part of the expedited review process because "they put the findings into context for the clinician."

Because the papers selected for the expedited review process tend to be high profile "highly anticipated" trials, Dr. Fontanarosa said it was usually easy to find an expert in the field to provide that necessary context. "Sometimes, but not always, a reviewer will write an editorial," he said.

As an example of the acceptance of early release-papers at ACC, is the unique position of ACC president Steven Nissen, M.D., of the Cleveland Clinic.

Dr. Nissen is first author of two early-release, late-breaking clinical trials-one getting simultaneous publication in JAMA and one in NEJM.