Marks Daily Apple
Serving up health and fitness insights (daily, of course) with a side of irreverence.
13 Nov

Off-Label Pharmaceutical Promotion

74417883 0f585a5f4bWhat can we say? We’ve got Pharma on the mind this week! On Monday Mark offered commentary on the latest “study” being spun to further promote statins to the general population. It seemed like an opportune time to bring you news of a recent report on the “unofficial” business of off-label pharmaceutical marketing and the clever manipulation of drug approval rules and research dissemination.

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.

massdistraction Flickr Photo (CC)

Further Reading:

The Beginning of the End? – Statins for Children

Health Engagement – Where Do You Find that Personal Touch?

The High-Tech, High-Risk State of Maternity Care

You want comments? We got comments:

Imagine you’re George Clooney. Take a moment to admire your grooming and wit. Okay, now imagine someone walks up to you and asks, “What’s your name?” You say, “I’m George Clooney.” Or maybe you say, “I’m the Clooninator!” You don’t say “I’m George of George Clooney Sells Movies Blog” and you certainly don’t say, “I’m Clooney Weight Loss Plan”. So while spam is technically meat, it ain’t anywhere near Primal. Please nickname yourself something your friends would call you.

  1. Mark- Thank you so much for this very informative article. I think one of the things that scares me the most is not knowing the long-term effects of many of the commonly used drugs. Many have just been on the market for a couple of years – what are the final effects in 10, 20, or 30 years?

    Lucy wrote on November 13th, 2008
  2. Again, another great post! Thanks so much for educating me further on BigPharma. So eye opening I want to learn more.

    If a doctor fills out a prescription and its off label, is he/she required to tell the patient? It makes me uncomfortable to think I might forever be second guessing what my physician tells me.

    Conny wrote on November 13th, 2008
  3. If a doctor decides to give someone a off-label prescription, the doctor should give just one days supply. When the supply is done (the next day!) the doctor needs to see the patient again to check on progress. This all needs to be carefully documented, all side effects noted, and recovery rate. Once treatment is done this data must be entered into a common place where all doctors and researchers can examine it. (This means the patient better not have privacy concerns about sharing personal data – some will)

    If the doctor is playing drug researcher, he should act like one. While the doctor may not have enough patients to do a proper double-blind test. Even the non-blind, non-scientific nature of this single “study” when combined with hundreds of others latter can be helpful for a researcher who can see if there are results that are better than chance. (results covers both side effects and cures) If this results in a drug failing the test, then the drug is no longer off-label it is not allowed for that treatment.

    Henry Miller wrote on November 13th, 2008
  4. Hey Mark,

    To be honest with you, I’m torn. A part of me believes that all business at it’s root is meant to be self serving with regards to maximizing profits. It’s their nature. However, while I believe that when health is involved certain regulations must be provided to ensure the safety of consumers, I also don’t think that the government should get too involved.

    The answer could very well be educating people through forums such as blogs. Maybe by providing a little more exposure to varying points of view on the subject we could provide people with the information that they would need to decide the proper course of action for themselves.

    In any case, thank you for the great post!

    All the Best,

    Andrew R

    Andrew R wrote on November 13th, 2008
  5. In an ideal world with limitless money/time/resources, of course it would be wonderful to make sure that all off-label prescriptions had “tested, proven benefits.” But with the wide variety of rare medical conditions that occur, providing all patients with all medical conditions no-risk medications at a low cost is a case of wanting-to-have-the-cake-and-eat-it-too.

    While pharmaceutical companies certainly employ dubious marketing, I believe off-label pharmaceuticals are actual a great benefit to our current health care system. Even if we have to deal with a few biased studies.

    Steven wrote on November 13th, 2008
  6. Andrew, of course I agree that business is self-serving and profit-motivated. But when businesses lie in matters concerning life and death, and when government health regulations are put into place on the basis of special interests or lobbying efforts, the system fails. I’m actually all for people using whatever drugs they want…as long as they take full responsiblity for whatever goes wrong. The problem, of course, is that they can’t possibly know what can go wrong. Furthermore, they have come to trust the docs and the FDA as looking out for them, but neither one can effectively do that under the current system.

    Mark Sisson wrote on November 13th, 2008
  7. Mark,

    You are on fire right now. That was another great post and a topic that is not discussed nearly enough. I will do my very best not to get on my soap box and go on a rant. Just suffice it to say that I work in health care and think all the “off label” practicing went off the deep end quite some time ago.

    primalman wrote on November 13th, 2008
  8. Mark,

    You must be joking man. Big Pharma has a long a torrid history of distorting clinical studies (the statin push being the most recent), lying to consumers, threatening critics, burying negative evidence and all the while heavily promoting the drug to physicians and consumers. These companies are knowingly harming patients just so they can keep selling dangerous drugs to a population that’s generally too uninformed to know any better. And most conventional physicians just kept on prescribing the drug, oblivious to the true causes of disease or health. The drug industry, taken as a whole, hurts 10 times as many patients as they help. Hows that sit with you?

    Michael wrote on November 13th, 2008
  9. Mark,

    I see your point. The part you mentioned that I really agree with is for people to “take full responsibility” for what happens. But is that too much to ask of people on a large scale?

    I’m really interested in picking your brain on this one. If you’ve got a second, walk me through what you think would be an effective change made by the FDA that would help bring back that feeling of trusts between doctors and patients. Or better yet, maybe a future post? I would love to read a post on that!

    Thanks for the feedback

    All the Best,

    Andrew R

    Andrew R wrote on November 13th, 2008
  10. Isn’t off labels cheaper? I wander if insurance companies would rather Dr.’s prescribe name brand prescriptions which is more expensive.

    Donna wrote on November 14th, 2008
  11. Donna,

    You are confusing off-label with generitc.

    Off-label means the drug is known good for something other than what you are taking it for. Generics are drugs that are cheaper because they are not name brand.

    For example if you take Asprin for aches and pains you are taking a generic, Bayer makes the brand name. If you take Bayer asprin cancer, you are taking it for an off-label use as Asprin isn’t approved for cancer (I picked a bogus example here – Asprin is not useful for cancer – but your doctor could tell you to try)

    Henry Miller wrote on November 14th, 2008
  12. Hi Henry,
    I do know what “off label” means. I also know what generic means. I know a Dr. has the right to prescribe something that is not FDA Approved, but approved by the Drug Co. When i say it’s cheaper, what i mean is that it’s cheaper for the Drug Co. not to pay the FDA to spend money for them to approve it and “label” it that’s it’s good for this or that. That’s the Dr.s right to approve “off label”(not labeled…not approved by the FDA)But EVEN THOUGH it’s NOT labeled, the Dr. knows “what” he “can” prescribe. Generic means it’s the cheaper other than name brand with same ingredients, i know that, too.

    Donna wrote on November 15th, 2008

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