Off-base on off-label promotion
You might have caught the editorial published today on PLoS Medicine by Fugh-Berman and Melnick, which decries rampant, greed-driven off-label promotion by pharmaceutical marketers. They suggest that the US government step in with tighter reigns and resist “gutting” current restrictions against off-label promotion.
The authors make their argument without providing evidence that off-label use of drugs is net harmful (or, supporting their viewpoint, more net harmful than labeled drug use) or that drug companies routinely engage in, support, or condone off-label marketing. They also provide no evidence that further restrictions designed to combat off-label promotion are warranted.
I’ll paraphrase key points of their argument (italics) to illuminate my objections (plain text).
A drug should have risks commensurate with benefits. I agree.
The majority of off-label uses aren’t supported by the type (and, by implication, superior quality) of scientific evidence used to support for drug approval. It’s likely that most off-label uses of newer drugs aren’t supported by randomized, controlled studies, as the authors indicate. However, the authors seem to believe that the group responses reported from such “gold-standard” studies, can be used to determine appropriate therapy for an individual patient. But randomized, controlled studies cannot and were never intended to guide therapy for an individual patient. Let me be clear on this point, because it is often missed (and misused) by off-label critics. Approval studies are typically designed to demonstrate that a drug works as it is intended (claimed), with benefits exceeding risks on balance, for use in a given population. In order for the evidence from these types of investigations to be useful for individual prescribing, a prescriber must apply relevant evidence from the group responses to her unique patients, a cognitive task that goes well beyond mere reading of product labels requiring expert specifization, generalization, and abstraction. Certainly, the more evidence available to the prescriber the better, but too many “experts” put excessive much weight on the type of evidence from approval studies and not enough weight on other types of evidence, including the case reports that often support off-label uses. I believe it is exactly this point that Sir Michael Rawlins, Chair of UK’s NICE, made recently when he said that randomized, controlled trials “have been put on an undeserved pedestal.” So, to summarize, the authors assume that the weight of evidence supporting off-label use is inferior to labeled uses, but they provide no evidence to support this contention.
Off-label use of drugs has been associated with serious adverse effects. So has labeled use, and I’m not aware of any evidence that off-label use is associated with a relatively higher incidence of serious adverse effects than labeled use. The authors present none.
From a business standpoint, off-label use has its advantages and disadvantages viz. Avastin/Lucentis. And, your point would be?? Off-label use, like any use of a prescribed drug should be considered in advance of marketing. In certain cases, yes, it will work to the disadvantage of a manufacturer. In most cases it won’t.
The authors spend much of the editorial describing how the industry promotes off-label use surreptitiously via unaccredited and CME symposia, meeting abstracts, information letters, etc. I think they’re point is basically that off-label promotion is occurring all the time in the disguise of legitimate, nonpromotional activities. Call it what you want product promotion or information dissemination–but prescribers are grown ups who can make up their own minds. If information exists they have every right to hear/read/see it, and sponsors have every right to disseminate it. The US Supreme Court has ruled as much. If KOLs and other speakers who work for sponsors or compendia authors/journal publishers feel they’re are being manipulated they should stop taking sponsors’ money. If prescribers feel they are being manipulated they should stop attending events supported by sponsors.
Off-label use should be undertaken with care because it subjects patients to an “uncontrolled experiment.” This argument would be comical if it weren’t intended to be taken seriously. The authors obviously chose the word “uncontrolled” to connote a chaotic situation. Uncontrolled experiments when there is only one test subject are the norm in patient practice, and I’d argue that every first-time drug use, labeled or otherwise, is an uncontrolled experiment. Finally, it should be obvious to all physicians, nurses, and pharmacists that any drug prescription should be made with care, regardless of the evidence accumulated from other patients.
“Truly useful off-label benefits of drugs will not remain a secret.” Surely they jest. Important off-label uses escaped notice for years until finally documented;. Hell, there would be no newly flourishing drug re-purposing industry if this were not the case. Truly useful off-label uses are more likely to escape notice in disease conditions where the indicated use is rare or when the off-label benefit occurs on a highly prevalent disease background (e.g. reduction of heart disease), in an asymptomatic condition, or in a symptomatic condition with a long latency (e.g. most cancers). It’s safe to say that we’re only capturing a small part of all the potentially “truly useful” uses of existing drugs. We should be doing much more to capture and disseminate them, not less!
Pharma shouldn’t be expected to police its own reps. Of course it should, with appropriate oversight from FDA. Explicit off-label promotion should not be tolerated. Pharma is best equipped to police its own reps, and FDA is best equipped to police Pharma. If FDA needs more personnel to carry out its oversight responsibilities, then they should get more people. Stiff fines for off-label promotion shouldkeep Pharma honest, and I could live with financial incentives for whistle-blowers if that will help quell the industry critics. If states want to join FDA to police Pharma reps because they’re worried about footing the bill for expanded off-label uses among Medicaid patients that’s fine too. But if they’re smart (Mass. apparently isn’t) they will keep the red-tape to a minimum, because for every dime pharma spends helping the policemen do their job, it’s a dime more they’ll charge those same patients/payers down the road for new medicines or a dime they’ll remove in R&D or manufacturing dollars from their tax coffers.
