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Off-Label Use of Prescription Drugs

A recent survey of 599 primary care physicians and 600 psychiatrists found that:

The adjusted response rate was 47%, respondents were similar to non-respondents, and physicians commonly prescribed the drugs examined. The average respondent accurately identified the FDA-approval status of just over half of the drug-indication pairs queried (mean 55%; median 57%). Accuracy increased modestly (mean 60%, median 63%) when limited to drugs the respondent reported having prescribed during the previous 12 months. There was a strong association between physicians’ belief that an indication was FDA-approved and greater evidence supporting efficacy for that use (Spearman’s 0.74, p < 0.001). However, 41% of physicians believed at least one drug-indication pair with uncertain or no supporting evidence (e.g., quetiapine [Seroquel®] for dementia with agitation) was FDA approved.

These results are interesting, but deserve to be dissected a bit further. Taken at face value they indicate that physicians need better education regarding the FDA indications and (more importantly) the evidence-base for commonly prescribed drugs. This is an uncontroversial recommendation, and I personally strongly advocate more thorough physician continuing medical education.

Of course, at SBM we have to also dissect the weaknesses of any study we examine. This was a voluntary survey with a 47% response rate, which opens the door for significant responder bias. The survey does not broadly represent different specialties and therefore its relevance beyond primary care and psychiatry is uncertain. The details of the study may also have greatly influenced the outcome.

For example, one of the drug-indication pairs was gabapentin for diabetic peripheral neuropathy. Gabapentin is not specifically indicated for diabetic neuropathy, but it is indicated for post-herpetic neuralgia. Both conditions are forms of neuropathic pain, and it is highly scientifically plausible for a treatment of one condition to also be effective for the other. In fact, there is strong evidence that gabapentin is effective for diabetic neuropathy, and it is commonly prescribed for this condition (in fact insurance companies often require that it is first line treatment as it is now available generically and is therefore less expensive than newer drugs that are indicated specifically for diabetic neuropathy). In other words, this was one of the easiest mistakes to make.

The most cautionary result of this survey is the fact that 41% of responders belief in a drug-indication pair that is not evidence-based. But the example given (to put it into perspective – quetiapine for dementia with agitation) is not indicated not because quetiapine is not used for that type of problem but because it should not be used in patients with dementia. This is the kind of detail a prescriber should know.

So how do we put the results of this survey into perspective? I think they do indicate the need for better physician education regarding the drugs they prescribe -and to put that information at their fingertips at the point of patient care. However, the drug-interaction pairs assessed involved a mixture of subtle but important distinctions and insignificant ones.

It is important to recognize that off-label use of medication is not the same as non-evidence-based used of medications. In fact, the gabepentin-diabetic neuropathy example is my personal favorite to make this point. Some argue that physicians are better off knowing the evidence-base for a drug rather than the FDA regulations – which are about marketing, not about use (the FDA regulates the marketing of drugs, but once on the market the FDA does not regulate how physicians prescribe drugs). On the other hand, knowing that a drug is approved for a specific indication is a reliable indicator that it has passed the rather high bar of evidence for safety and efficacy required by the FDA.

Off label use of medications is not uncommon. A 2001 review indicates that 21% of prescriptions are for off-label use. Actually, I thought the number was higher – 21% seems quite reasonable to me. But what is more important is the evidence base for this off-label use. The same article indicates that 73% of off-label use has little or no scientific support. That is high – however, there are many assumptions hidden in this number.

Much of off-label use includes prescribing a drug for an approved indication but not in an approved population. For example, this includes prescribing drugs studied in adults only to a pediatric population. If the drug has not been studied in children this can be considered without scientific support.There are very real concerns about how to apply the literature to the pediatric population, and this does highlight the need for more research in children – but it should not be confused with prescribing a drug for an indication for which there is no evidence.

Off-label prescribing also includes prescribing a class of drugs for a class of disorders – such as prescribing a sodium-channel blocker for neuropathic pain (rather than a specific sodium-channel blocker for a specific cause of neuropathic pain). It can be reasonably debated how to assess the evidence base for such class use of drugs.

There are risks and benefits to off-label use of drugs. Dr. G. Caleb Alexander summarizes them here:

Disadvantages of off-label use

* May diminish public expectation that drugs will be evaluated for safety and efficacy before use
* Blunts industry incentives to perform studies required for FDA label changes
* Drugs used off label may have unrecognized safety and efficacy problems
* Promotes use of drugs in populations (e.g., children, the elderly) for which they have not been tested

Advantages of off-label use

* Allows for clinical innovation, especially for patients who do not respond to standard treatments
* May be only available option for uncommon conditions or for patient populations that have not been studied
* Allows physicians to anticipate growing evidence of efficacy prior to formal evaluation
* Increases return on investment for pharmaceutical firms

I would add under advantages that off-label use of drugs allows for evidence-based options for which (for economic reasons) the pharmaceutical company did not seek FDA approval. Some of these uses may be life-saving.

Conclusion

In my opinion, focusing on FDA indications for a drug is a bit of a distraction. The real issue is the evidence for safety and efficacy for any specific application of a pharmaceutical (or any intervention, for that matter). FDA approval is all about marketing, not about the appropriateness of use. Knowing what a drug is indicated for is a useful shortcut to knowing that it is safe and effective for that indication. It is also essential to be familiar with the FDA package insert – which contains information on side effects, contraindications, and drug-drug interactions.

And as I stated above, while physicians are generally familiar with the drugs they most prescribe, there is room for improvement in terms of physician education and access to information at the point of patient care. Technology is helping with the latter issue, but other steps may be required to improve physician knowledge, such as more effective use of continuing medical education requirements.

Focusing too myopically on the issue of off-label use, however, is misleading and not constructive.

Posted in: Pharmaceuticals

Leave a Comment (22) ↓

22 thoughts on “Off-Label Use of Prescription Drugs

  1. Scott Young says:

    Nice, succinct discussion.

  2. Harriet Hall says:

    Thanks for this, Steve.
    This is a topic that comes up frequently in discussions with critics of conventional medicine, and now we have a link to send them to so we don’t have to try to explain it anew each time.

  3. iamthebrillo says:

    Thanks for this discussion. As a fourth-year medical student just starting to learn about treatments and prescriptions, I had this image of “off-label use” being equivalent to some back-alley, “the government doesn’t want me to do this, but let’s keep it between you and me” type of thing. It’s helpful to see the distinction between “FDA-approved” and “evidence-based” spelled out like this.

  4. halincoh says:

    When I saw this topic I thought, “uh oh.” I thought you were going to heavily criticize us for using meds off label. But you didn’t. As always, you presented a balanced approach.

    I think the essence of off label use is based on two components of science based medicine: plausibility and the evidence. The plausibility, of course, is based on does this make sense from a biochemical, pharmacokinetic, and pathophysiologic basis and the evidence , in this case, is based on like, but not identical, compounds.

    For example, ACEs and ARBs are used in diabetics as first choice blood pressure agents. The ACES are most rigidly studied ( double blind , random ) in type 1 diabetics and the ARBs are most rigidly studied ( double blind, random )in type 2s, yet, time after time, thought leaders at ADA and EASD meetings use these two similar classes interchangebly, especially when discussing treatment of microalbuminuria with regards to prevention of full blown diabetic nephropathy ( where evidence for using ACEs in type 2s are more based on interesting, but much less valuable meta analysis, whereas evidence for ARBs are usually based on random, double blinded on this specific topic ). Yet most of us use ACES as the first line to prevent diabetic nephropathy. Why? Cost effectiveness. They are cheap. Why else? Though anecdotal, we see consistant ( though nothing is ever 100% effective ) decreases in microalbuminuria.

    Since these meds are generic it is unlikely that any pharmaceutical company will perform a rigid study looking for non inferiority when comparing effectiveness of ACES and ARBS with regards to decreasing microalbuminuria. Only the NIH may consider such a study. But that too is unlikely.

    So, we consider plausibility, we consider sister evidence in ARBs and we consider the less strong meta analysis and it seems to work.

    On the other hand, gabapentum was heavily promoted for bipolar maintence years ago, but the research was shotty at best. It was used off label by some and disgarded quickly. Why? Anecdotally, it didn’t work.

    Though science and evidence must always lead us clinically, sometimes our clinical experience force us to reconsider the evidence. Science is about reproducing results. Occasionally in medicine we consider treatments before they are reproduced, especially for off label use. Gabapentum and efficacy in bipolar was never reproduced. Perhaps ( I do not know for sure ) it was the failed clinical experience that forced new studies that revealed it’s ineffectiveness.

    We practice art and science in medicine. Science gives us our brushes and paints. Sometimes we use then in novel ways. Ideally, science should then re-test. If not … sigh … there’s always meta analysis.

    Reviews/Commentaries/Position Statements:
    Zachary T. Bloomgarden
    Angiotensin II Receptor Blockers and Nephropathy Trials
    Diabetes Care October 2001 24:1834-1838; doi:10.2337/diacare.24.10.1834

    Reviews/Commentaries/ADA Statements:
    Jorge L. Gross, Mirela J. de Azevedo, Sandra P. Silveiro, Luís Henrique Canani, Maria Luiza Caramori, and Themis Zelmanovitz
    Diabetic Nephropathy: Diagnosis, Prevention, and Treatment
    Diabetes Care January 2005 28:164-176; doi:10.2337/diacare.28.1.164

  5. mckenzievmd says:

    Nice article. I appreciate the clear distinction between off-label use and non evidence-based use. As a vet, the majority of my prescription drug use is off label sicne the economic incentives for pursuing an FDA label are quite a bit smaller than in human medicine. While this means I rarely have the quality of evidence I would like to justify the use of various drugs, it does not mean that such off-label use is equivalent to the use of herbs, homeopathy, and other CAM methods for which there is much lower plausibility or supporting evidence, and often even clear evidence against their use.

    As Dr. Hall pointed out, it is nice to have a cogent article to refer people to when makingt his point.

    SkeptVet
    http://www.skeptvet.com
    http://skeptvet.com/Blog

  6. Zetetic says:

    How is “Compounding” related to this issue? I have an old Navy buddy, now retired, who is a pharmacist working in a designer “Compounding Pharmacy” in San Diego. His firm compounds ANY combination of medications requested. I often wonder if this fits in the realm of “Off-Label” as these combinations have never been thoroughly evaluated via FDA standards.

  7. qetzal says:

    My attention was caught by the caught by the claim that “73% of off-label use has little or no scientific support.”

    Happily, that review is available as free full-text on line (linked in Dr. Novella’s post above). From the Methods section:

    An indication was considered to be scientifically supported if, according to DRUGDEX, its effectiveness has been shown in controlled trials or observed in clinical settings.22 All other indications that lacked FDA approval or that did not meet the criteria for having scientific support were considered to be off-label with little or no scientific support.

    Based on that, I’d say “little or no scientific support” is a rather unfortunate and misleading phrase. A better phrase might be “little or no published clinical evidence.”

    IMO, if a drug is known to work in adults, that’s more than a little scientific support for the idea that it would work in children, even if there are no controlled trials or published clinical data in kids. Same goes for extrapolating between drugs of the same class.

  8. Wholly Father says:

    “Some argue that physicians are better off knowing the evidence-base for a drug rather than the FDA regulations – ”

    I strongly agree. Knowing the evidence-base for a drug/indication pair requires a much deeper and clinically relevant understanding of the state of the art than knowing the FDA status.

  9. Quick comments:

    The FDA states, although probably without the power to enforce it, that

    Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.

    What the FDA has successfully done is to stop practitioners from using drugs for contraindicated practices, as in this example; and to prosecute practitioners for mislabeling or ‘misbranding’ drugs for off-label uses, if the drug has arrived via interstate commerce, as in this case. Note that in the latter instance the court found that claims made in pamphlets intended for patients, but distinct from the drug’s package, constituted mislabeling.

    Some compounding pharmacies are involved in mischief. Look here.

  10. Alaskan says:

    Spouse wants to reply…

    >(the FDA regulates the marketing of drugs, but once on the market the FDA does not regulate how physicians prescribe drugs).

    Not quite true in the veterinary world…AMDUCA (ELDU) prohibits us from prescribing a drug that might be more convenient, cost-effective, therapeutically effective, etc. if a FDA approved drug is available for that specific use. That certainly impacts how I prescribe drugs.

    Nice article otherwise, thank you for it.

  11. hokieian says:

    “IMO, if a drug is known to work in adults, that’s more than a little scientific support for the idea that it would work in children, even if there are no controlled trials or published clinical data in kids.”

    Sorry I disagree – kids are not just “little adults”. There are many differences in metabolism and physiology that can effect PK/PD parameters, leading to changes in efficacy and safety between adults and children.

    While a drug’s mechanism of action may be similar, it can’t be automatically assumed that it will work the same or have similar side effects in kids..

  12. weing says:

    Give tetracycline to a young child and see what happens to their permanent teeth once they come out.

  13. qetzal says:

    @ hokieian & weing,

    I agree that we can’t “automatically” assume that drugs for adults will work in kids. I never said otherwise, and certainly didn’t intend to imply as much.

    My point was to disagree with the claim that 73% of off-label uses has little or no scientific support. That makes it sound like MDs are just trying stuff off-label with no good reason at all. It’s the kind of claim that CAM artists love to quote as evidence for how bad conventional medicine supposedly is.

    I stand by my previous statement. If a drug works in adults for a given condition, that is significant scientific support for the idea that it may work in kids for the same condition. It’s not as good as having clinical evidence in kids, but it’s a far cry from “little or no scientific support.” The fact that certain drugs (like tetracycline) work in adults but not in kids does not invalidate the general idea.

  14. halincoh says:

    As both a pediatrician and an internist I can assure you, over and over again, it is emphasized that kids are not little adults. And they are not.

    One example – I used to give a lecture on pediatric dyslipidemia. That was about 12 years ago. The lecture quickly became obsolete, because once the subject became better studied, the future predictions was not as predictable and the topic has since been significantly revised.

    Sometimes there is an overlap between adults and kids. Sometimes it’s not. It’s important for the science to confirm this because the risk, damaging a child, is simply too high to rely on off label.

    Finally, the medicolegal risk would be too great to chance.

  15. qetzal says:

    As both a pediatrician and an internist I can assure you, over and over again, it is emphasized that kids are not little adults. And they are not.

    Completely, fully, absolutely agreed.

    Sometimes there is an overlap between adults and kids. Sometimes it’s not.

    Would you agree that if a drug works for X in adults, the chance that it also works for X in kids is much higher than some other drug that doesn’t work for X in adults? Assuming you do agree, why is that not significant scientific support?

    Basically, I’m just objecting to the inappropriate conflation of scientific evidence and clinical evidence.

  16. halincoh says:

    “Would you agree that if a drug works for X in adults, the chance that it also works for X in kids is much higher than some other drug that doesn’t work for X in adults? Assuming you do agree, why is that not significant scientific support?”

    More importantly, with regards to children is does the risk now outweight the benefit. Aging is a major risk factor when it comes to end point complications of disease. Thus the same drug, while possible efficacious, may not be warranted because the benefit is minimized. One simply needs to be more certain when it comes to children because the consequences of being wrong could be greater than when it comes to treating adults.

  17. qetzal says:

    halincoh,

    You do realize that nothing in your response actually addresses my questions, right?

  18. halincoh says:

    Then I simply don’t understand your question. My apologies.

  19. Harriet Hall says:

    The question was “Would you agree that if a drug works for X in adults, the chance that it also works for X in kids is much higher than some other drug that doesn’t work for X in adults?”

    The answer is that most drugs that are tested in adults are likely to work in children but we can’t make that assumption because there are exceptions. And even if they do work, the proper dose for children needs to be determined. And it depends on the age of the child – newborns are far more different from adults than school-age children are.

  20. halincoh says:

    I guess I DID understand the question, Harriett. :)

  21. qetzal says:

    No, I’m virtually certain you did not.

    You seem to think that I’m arguing it’s OK to prescribe drugs off-label to kids, based only on known efficacy and safety in adults. I’m not.

    My point was much simpler. As I said two comments back:

    I’m just objecting to the inappropriate conflation of scientific evidence and clinical evidence.

    The 2001 review that Dr. Novella linked claimed that 73% of off-label drug use is based on “little or no scientific support.” As Dr. Novella himself implied, that’s misleading. In fact, the review should have stated that 73% of off-label drug use is based on little or no clinical support.

    Scientific support is a much broader thing than clinical support. In fact, that’s a key point made by the very first post on this blog, and the reason for the blog’s name:

    EBM is a vital and positive influence on the practice of medicine, but it has its limitations. Most relevant to this blog is the focus on evidence to the exclusion of scientific plausibility.

  22. halincoh says:

    I re-read your comment – “would you agree that if a drug works for X in adults, the chance that it also works for X in kids is much higher than some other drug that doesn’t work for X in adults? Assuming you do agree, why is that not significant scientific support?” – slowly and carefully.

    Yes, I agree that this is scientific support … but only to a point.

    The trepidation is expressed in two comments. The first made by Dr Hall:

    “The answer is that most drugs that are tested in adults are likely to work in children but we can’t make that assumption because there are exceptions. And even if they do work, the proper dose for children needs to be determined. And it depends on the age of the child – newborns are far more different from adults than school-age children are.”

    And the second made by myself, which is simply an extension of Dr Hall’s comment:

    “One simply needs to be more certain when it comes to children because the consequences of being wrong could be greater than when it comes to treating adults.”

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