Two researchers with significant experience in the pharmaceutical industry, Adriane Fugh-Berman, M.D., an associate professor in the GUMC Department of Physiology and Biophysics, and Douglas Melnick, M.D., a preventive medicine physician in the Los Angeles County Department of Public Health have published a report in the free online journal PLoS Medicine shedding light on risky and legally questionable practices that have become commonplace in the industry.
We think it’s definitely worth checking out in full, but here’s the rundown. As the researchers explain, companies seek approval for drugs for a particular indication. Research on the drug’s safety and effectiveness is centered on its use for the specific indication. Influencing the approval process is a relative balance of risks and benefits. Why and how is it “relative”? Certain side effects may be deemed within “the parameters of acceptable risks” for more serious diseases – liver toxicity risk in a cancer treatment, as the researchers say – but may not be found acceptable for less serious conditions (e.g. a drug approved specifically for cosmetic purposes).
Fairly extensive testing and review are required for the approval of drugs in this country (although the system is showing some cracks, as we’ve reported in the past). A different scenario comes into play when it comes to off-label use. As Dr. Fugh-Berman and Dr. Melnick explain, “Once a drug is approved for at least one indication, it may be prescribed off-label for a different condition, a different population, or in a different dose than what the drug is approved for.” And inherent in this off-label prescription process is the off-label promotion of course.
How does the off-label process begin? Oftentimes, as Fugh-Berman and Melnick describe, a pharmaceutical might show potential for a few medical conditions. Nonetheless, the company pursues regulatory approval for only one. (And, as the researchers point out, the choice of which condition to pursue is usually influenced by ease of approval rather than the primary medical benefit or big-picture marketing intention.) Once the drug is approved for the treatment of a particular condition, whatever research exists to support its use for other conditions may be publicized and promoted. However, Fugh-Berman and Melnick point out, whatever study and review is there isn’t comparable to that required for approval. There generally isn’t the same research depth or review rigor for these off-label uses – in terms of a drug’s effectiveness or its safety for the new condition or population.
Instead, as Fugh-Berman and Melnick explain, the research often consists of “industry-generated, non-peer-reviewed, covert promotional pieces” that are publicized by paid “key opinion leaders” (KOLs), physicians and researchers that work for (and are funded by) pharmaceutical related research and advocacy but aren’t technically employed by a particular pharmaceutical company. Because they are considered (however questionably) “independent,” they aren’t subject to off-label marketing regulations. And these promotion efforts, if they’re successful, may actually discourage the industry’s further investigation of an off-label use. Fugh-Berman and Melnick suggest that if enough “buzz” can be created in conferences and other “continuing education” programming, further studies that might dampen or undermine the new “successful” perception are avoided. The industry, in this way, glides along on (and handsomely profits from) a version of half-supported, suggestive scuttlebutt.
At this juncture, let us say once again that we’ve never been against the existence of the pharmaceutical industry. They’ve created medications that have legitimately saved countless people’s lives and significantly improved the quality of others’ lives. What we’ve taken issue with isn’t their business itself but their business practices – like focusing their experimental efforts on so-called blockbuster lifestyle drugs that are then ruthlessly marketed to the general public in underhanded, manipulative ways (See Mark’s commentary on this week’s statins “study.”) and like promoting the off-label use of drugs whose safety and effectiveness for these other conditions haven’t been reasonably assessed let alone proven.
We understand that there are circumstances when carefully targeted, informed off-label use of existing drugs can be of genuine use. In very aggressive or terminal conditions when patients show no signs of response to the gamut of usual treatments, going an experimental route may offer a patient and his/her family hope and (in some cases) medical progress in battling the condition.
The problem in this scenario is the slippery slope effect. The researchers point out that about 75% of pharmaceutical prescriptions in cancer treatment were off-label. In the case of rare medical conditions, this number is closer to 90%. In many situations, this practice may offer real benefit. In others, it may only further drain patients and their families financially and emotionally. A very well-intentioned physician may decide to try a drug off-label with his patient because she’s heard positive “buzz” about it, saw a poster session at a conference or read a “preliminary” report. However, as Dr. Fugh-Berman and Dr. Melnick suggest, there is very little and often incomplete research available to confirm the usefulness of the drug.
If your patient has a terminal diagnosis, it might be worth the gamble. But what if another drug would’ve made a more positive difference during that window of time? In a world of low standards for off-label research, how often are we being diverted from attention to and study of more promising therapies (sometimes fully conventional, sometimes complementary/alternative)? What if your patient isn’t “terminal” but suffers considerable side effects as a result of the off-label treatment – side effects that delay or interrupt other active (and legitimately beneficial) treatment therapies? When you add the elements of knowingly dubious marketing and company profit to this scenario, it leaves an uncomfortable knot in the stomach. Dr. Fugh-Berman and Dr. Melnick’s final analysis is this: “Allowing off-label promotion of drugs for untested, unproven benefits maximizes industry profits at the expense of public health. A risk-benefit ratio cannot be assessed without knowing whether benefits exist. Where no benefits exist, no risk is acceptable.”
As we’ve said in the past, the fault isn’t just with the pharmaceutical industry itself but with the oversight and approval system that is supposed to keep the industry in check. Underfunded, understaffed, caught in revisions that have compromised their impartiality, the system seems in dire straits, an especially scary scenario as increasingly more Americans take more medications for more conditions for longer periods of time (interactions, circumstances and time tables that were never studied in the original or subsequent research). Add to this the new wrinkle of growing off-label prescriptions, and we’re left questioning how much strategic manipulating and maneuvering within the system Americans and their doctors are willing to turn a blind eye to. How much risk are we willing to take – in some cases not for the sake of patient hope or tentative progress, but for the cause of profit?
What are your thoughts on this report and the light it sheds on the under-the-table promotion processes of the industry? How do you view the questions surrounding expanding medical possibilities versus self-serving gains in the industry? Thanks for your comments and insights.