FDA spells out rules for reprints of articles about off-label drug use

Washington -- Physicians may see an uptick in the number of journal reprints coming their way from pharmaceutical firms interested in alerting them to information about an off-label use of one of their drugs or devices.

Sparking this increase are Food and Drug Administration guidelines released in early January to clarify when this approach is permissible.

Prescribing approved drugs for unapproved uses is a common practice. A 2006 study in the Archives of Internal Medicine found that unapproved uses accounted for 21% of an estimated 725 million scripts written in 2001 for 160 frequently prescribed drugs.

AMA Executive Vice President and CEO Michael D. Maves, MD, MBA, noted in comments in April 2008 regarding the FDA's then-proposed guidelines that it is important for physicians to have "timely access to accurate and unbiased information about unlabeled uses of drugs and medical devices."

And drug firms would agree. "Getting good, scientific information out to physicians about the latest uses of drugs is a good thing," said Alan Bennett, an attorney in Washington, D.C., who represents several large pharmaceutical firms.

But concerns have surfaced about the accuracy and impartiality of the journal articles that are to convey this information, Dr. Maves said.

For example, a 2008 study in the New England Journal of Medicine quantified a previously suspected problem of publication bias. The researchers found that although 94% of published studies on antidepressants were positive, an FDA analysis of all studies, including unpublished ones, showed that only 51% were positive.

Another 2008 article, this one published in the Journal of the American Medical Association, charged Merck with downplaying the risk of heart attacks and stroke carried by its now-withdrawn medication, Vioxx. A related piece in the same JAMA issue charged that the firm concealed the true authorship of articles by having them "ghostwritten" by unnamed authors. Merck called the charges false and misleading.

JAMA editors since have instituted numerous safeguards to avoid publishing studies that include manipulated data, inappropriate analyses and selective reporting of results.

But the author of the article on ghostwritten studies remains skeptical about using journal articles as unbiased conveyers of information. "I realize that journal articles do carry a semblance of authority and objectivity," said Joseph Ross, MD, assistant professor in the Dept. of Geriatrics at Mount Sinai School of Medicine in New York City, "but my experience with what I know of ghostwriting makes me very suspicious of a lot of the medical literature."

Another view

Some argue that the new guidelines clear up a murky area. "Companies will welcome the guidance because they would rather have a little restriction so long as they have a sort of safe harbor for what they are doing," said Scott Gottlieb, MD, a resident fellow at the American Enterprise Institute for Public Policy Research, a Washington, D.C., think tank. Dr. Gottlieb also was the FDA's deputy commissioner for medical and scientific affairs from 2005 to 2007 and notes that this issue was then under discussion.

Others note that off-label drug use is a common practice, which the directive aids.

"The FDA guidance supports the public health by helping to assure that medical professionals receive timely and accurate medical information prior to the lengthy process for inclusion in the FDA-approved labeling," said Ken Johnson, senior vice president of the Pharmaceutical Research and Manufacturers of America. PhRMA represents large pharmaceutical research and biotechology companies in Washington, D.C.

Distribution of journal reprints has long been practiced by drug firms. Until it expired in 2006, federal law required companies first to submit articles to the FDA for review and to file within certain time frames for approval of the new uses. Those requirements are not in the new guidelines.

Making the situation even murkier is the fact that it remains illegal for pharmaceutical companies to promote off-label drug use. Drug firms, as well as some physicians working for them, have run into well-publicized legal trouble over the practice. In one well-known case, Pfizer agreed to plead guilty and pay $430 million to state and federal authorities to settle allegations that the company, among other things, illegally paid physicians to research and promote Neurontin. Pfizer denied any wrongdoing.

Now, some physicians argue, the FDA has blurred the line between what is promotional and what is not.

"How can it not be promotional when a drug rep hands off that material?" said Erick Turner, MD, assistant professor of psychiatry and assistant professor of pharmacology at the Oregon Health & Science University. Dr. Turner was the lead author of the NEJM article on publication bias.

"The idea that industry would be permitted to use their scientific literature for off-label promotion is distressing and not in the interests of public health," said Bruce Psaty, MD, PhD, professor of medicine, epidemiology and health services at the University of Washington in Seattle. Dr. Psaty was the lead author of the JAMA article charging Merck with downplaying Vioxx's risk. He categorized the FDA's guidance as being "in the spirit of deregulation."

"Industry doesn't treat efficacy and safety in a symmetrical fashion as a physician would or as an independent scientist would. That's why we need a strong FDA to keep the industry honest about its reporting," he said.

Dr. Psaty would like a new FDA commissioner, still to be named by the Obama administration, to reverse the guidelines. Members of Congress have also decried the guidelines.