Last week the US Food and Drug Administration ruled that the pharmaceutical industry could promote drugs for uses that haven’t been cleared by the regulatory body.  The new FDA guidelines permit the “dissemination of medical journal articles and medical or scientific reference publications on unapproved uses of drugs and medical devices.”

In order to be prescribed to treat a certain disease, a drug needs to be formally assessed and approved for this use by the FDA. The practice of ‘off-label prescribing’ entails doctors using a drug to treat a particular disease regardless of whether the FDA has confirmed that the drug is a safe and effective treatment for the disease in question.  As the FDA puts it, “Once a drug or medical device has been approved or cleared by FDA, generally, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product’s approved labeling”.

Off-label prescribing is reasonably common, even though you may not have heard it described this way.  An article published in Archives of Internal Medicine in 2006 reported that more than 20% of prescriptions in the US during 2001 were for off-label uses of a drug. One example of off-label prescribing is the use of the drug Avastin – approved by the FDA for the treatment of metastatic colorectal cancer and breast cancer – to treat the condition wet macular degeneration, an age-related eye disease that can lead to vision loss.

The FDA highlight the importance of off-label prescribing, stating that “These off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care”.  Such practices permit innovation and allow physicians to use their own judgment on the basis of their personal experience prescribing a drug.

The new FDA guidelines sound like good news for the pharmaceutical industry. By promoting off-label uses of already approved drugs, companies can squeeze more profit out of ‘old’ drugs and can ease off the lengthy and expensive process of investigating novel drugs.  But what’s to stop such companies ruthlessly promoting dubious off-label uses for established drugs and risking the health of patients by encouraging doctors to use drugs when there’s not adequate evidence of their efficacy for a certain disease?

Well, the new FDA guidelines include a lot of restrictions as to exactly how off-label uses can be promoted to doctors.  For starters, the guidelines discuss the use of journal articles or medical publications to promote off-label prescribing, meaning that pharmaceutical sales reps will be handing out genuine research that has been conducted by independent groups, not self-penned marketing material.

The guidelines also include lots of important limitations on what type of journal articles, or reprints, can be handed out, including that the articles must:

• Be published in a peer-reviewed journal that has experts on the subject on the editorial board
• Not be part of a publication or supplement that is funded in whole or in part by the company that wishes to use the article
• Be in the form of an unabridged reprint, copy of an article, or reference publication
• Not be marked, highlighted, summarized, or characterized by the manufacturer in any way
• Be disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use
• Be distributed separately from information that is promotional in nature. For example, if a sales representative delivers a reprint to a physician in his office, the reprint should not be physically attached to any promotional material the sales representative uses or delivers during the office visit and should not be the subject of discussion between the sales representative and the physician during the sales visit

So the FDA have done their best to tie up pharmaceutical companies in such a way as to ensure that doctors receive the most accurate and unbiased information possible on off-label drug uses.

Having said that, bias and conflict of interest is an important problem here – of course sales representatives are going to do their best to only hand out journal articles that show the off-label use of their drug in a positive light.  You can bet that pharmaceutical companies won’t be providing doctors with the full body of evidence when it comes to use of their drug for a particular disease, as cumulatively such research could be more ambivalent about the benefits of an off-label use.

Also, in many cases even the total body of evidence doesn’t show that an off-label use is effective.  Indeed, the aforementioned Archives of Internal Medicine paper showed that three-quarters of off-label uses were not backed up by scientific evidence.  There is an argument that the clinical trials process and the publication procedure lags behind real life, and that although there are no trials showing that an off-label use is effective, many doctors will have prescribed a drug this way and seen the beneficial results for themselves.  Fair enough, to a degree, but this undermines the whole issue of the pharmaceutical industry giving out published research on off-label uses anyway, so will be of little interest to such companies.

Finally, how on earth is the FDA going to police their restrictions?  They can insist that the pharmaceutical industry follows their rules, but there is plenty of evidence that such regulations are regularly flouted.  For example, despite the new guidelines, the straightforward marketing of a drug for uses not cleared by the FDA is still illegal.  Global pharmaceutical company Eli Lilly used catchy slogans to persuade doctors to prescribe the antipsychotic agent Zyprexa for unauthorized use in elderly patients and has this month been fined $1.5 billion for doing so.

I’m not the only one with misgivings about these well-intentioned but ultimately flawed guidelines.  California senator Henry Waxman told Medscape that the new FDA decision “fundamentally undermines the requirement that companies prove to the FDA that each new use is safe and effective” and makes it easier for drugmakers to promote potentially risky medical practices.  Over on Nature Network, research scientist Craig Rowell proclaimed that “Alarm bells should be ringing” – despite his support of off-label prescribing, Craig is still deeply skeptical that pharmaceutical companies will stick faithfully to the restrictions.

What’s the bottom line for patients here?  Many will benefit from by off-label prescribing, or at least not be harmed, and doctors will be better able to prescribe off label if they are thoroughly informed about such practices.  The sticking point is whether the pharmaceutical industry can be relied on to accurately and fairly disseminate information about off-label uses; experience suggests probably not.  Whether the FDA has made a shrewd move in getting pharmaceutical companies to do this promotion for them, or a big mistake, remains to be seen.

• The Pharma Marketing blog has an interesting post on this issue, which discusses policing of the new guidelines and the efficacy – or not – of off-label prescribing.