The Dangers of Off-Label Drug Promotion

Once a drug is approved by the F.D.A. for a given use, it may be prescribed for any use that a physician sees fit. F.D.A.’s only restriction on that “off-label” use is that manufacturers cannot advertise or otherwise promote the drug to a physician for that use. Drug companies want that restriction lifted so that they can promote such off-label uses freely by giving physicians medical journals that discuss the off-label use. Indeed, drug sales experts describe the ability to promote a drug using journal articles as one of their most powerful sales tools. F.D.A. has opposed such promotion, instead urging that companies get new uses approved, after which the companies would be permitted to advertise the use.

As part of the F.D.A. reform legislation before the Senate (S. 830), negotiations are underway to permit drug companies to disseminate peer-reviewed journal articles discussing off-label uses directly to physicians, even if a given article’s findings are not subsequently borne out by further study, or are refuted by other studies.

The Danger:

• Drug companies could get approval for a drug for some narrow use and then heavily promote it for much broader uses that had not been adequately tested.
• Many journal articles, even in the most prestigious journals, present very preliminary findings — sometimes based on as few as a dozen patients.
• Journal articles may present an unbalanced view — often one positive article about a drug is contradicted by several opposite findings — but the manufacturer might only distribute the positive finding.
• There is an inherent conflict of interest — all studies of drug safety and efficacy are funded by manufacturers of those same products.
• The current system permits a company to advertise a new use once it has done the necessary studies and gained F.D.A. approval. Eliminating the requirement for F.D.A. review would eliminate the incentive to study the drug to determine whether the new use really works. The result would be a disincentive for further research and thus less information about the drug for patients and physicians.

The Dangerous Examples:

There are numerous examples of off-label uses that initially appeared to be valid but were subsequently determined to be dangerous, including:

Fenfluramine and Phentermine (Fen-Phen) were approved individually over 20 years ago by the F.D.A. for single-drug, short-term obesity therapy. In 1984 and again in 1992, published studies indicated that the drugs might be more effective in combination than singly, and perhaps with fewer side effects. This triggered a 100-fold increase in doctors prescribing those drugs in combination. No applications, however, were submitted to the F.D.A. requesting approval of this combination therapy, and as a result, the F.D.A. did not have the opportunity to review the drugs’ safety and effectiveness when used together over the long-term.

In a July 1997 letter to doctors, the F.D.A. warned against this unapproved use, citing reports of 33 cases of heart valve abnormalities in women who had been prescribed the drug combination (the numbers have now risen to at least 49). Researchers at the Mayo Clinic subsequently announced results of a study in which numerous cases of valvular heart disease were found in women who had been prescribed the drug combination. At least six of the women in the study required open heart surgery to repair the damage.

This dangerous combination of drugs has been promoted heavily by weight-loss clinics. This off-label provision, if it had been in effect for the last 13 years since publication of the first peer-reviewed medical journal article demonstrating the effectiveness and “safety” of fen-phen, would have allowed drug companies making fenfluramine or phentermine to send out hundreds of copies of these journal articles to physicians. This would have dramatically increased the number of people using the combination and, therefore, the toll of those suffering damage to their heart valves would likely have been more than 1,000 people.

Calcium channel blockers (CCBs) are F.D.A. approved and labeled as an effective treatment for patients with angina (crushing chest pain due to constriction of the arteries supplying blood to the heart muscle). They are not approved for use in patients who have had a heart attack but have no symptoms. While large, controlled studies indicated that CCBs are ineffective for post-heart attack patients, some publications could be interpreted as supporting this use and many physicians prescribe CCBs to post-heart attack patients.

Post-heart attack patients do, however, benefit from another class of drugs, beta-blockers, which are known to reduce mortality by 25-30% after heart attacks. Because beta-blockers generally should not be prescribed in combination with CCBs, post-heart attack patients are receiving CCBs in lieu of clearly life-saving beta-blockers. According to testimony of the F.D.A.’s Deputy Commissioner on Policy, many, possibly thousands, of lives are lost each year because a drug of no known benefit for treating post-heart attack patients is being substituted for a drug with proven value. Allowing for off-label promotion of CCBs would have dramatically increased this toll in lost lives.

Encainide and Flecainide are drugs that were approved by the F.D.A. for certain heart arrhythmias. In the late 1980s, based on only preliminary reports, physicians prescribed them widely for certain patients who had suffered heart attacks. The use became so widespread that the National Institutes of Health decided to study the effectiveness in these patients.

The NIH study demonstrated not only that the drugs were ineffective in reducing the risk of death, they were actually harmful in patients for whom it had been prescribed off-label. The sudden death rate among those receiving the drugs was two and a half times higher than that of those receiving a placebo. In testimony before Congress, the F.D.A.’s Deputy Commissioner for Policy estimated that if these unapproved uses had been heavily promoted by drug companies, thousands more unnecessary deaths would have occurred.

Anturane is a medication approved by the F.D.A. to treat gout, but early studies showed it also was an effective anticlotting drug. In 1980, a New England Journal of Medicine article reported a 74% reduction in sudden death in patients who had suffered a heart attack when using Anturane, and the drug manufacturer subsequently submitted a new drug application to the F.D.A. for this new use.

When the F.D.A. analyzed the actual data from the trial, however, it recognized that mistakes were made in how the causes of death were classified. After correcting for this design flaw and reanalyzing the data, the F.D.A. determined that Anturane had no effect in reducing the rate of sudden death in recent heart attack victims and the application was denied.

As this example shows, articles — even those from distinguished peer reviewed journals like the New England Journal of Medicine — may not contain enough information to allow peer reviewers or readers to determine whether the drug is safe and effective for the use the article addresses.