Balancing Burdens and Benefits: Ethical Issues of Off‐Label Prescription Pharmaceutical Use

I remember when Botox (Allergen, Irvine, CA) was becoming all the rage in rehabilitation in the mid 1990s. As I recall, the only U.S. Food and Drug Administration (FDA) approved uses at the time were for spasmodic torticollis and blepharospasm. In a short period of time, however, Botox was the new treatment du jour for adults and children alike with spasticity from CP, traumatic brain injury (TBI), and stroke. I also remember feeling a bit queasy about it. Perhaps having recently completed a fellowship in clinical medical ethics colored my view. Images of thousands of people with limb deficiencies, the tragic consequence of the widespread and unregulated use of thalidomide, were fresh in my mind. Bioethicists and professional organizations were beginning to voice concerns about the perceived erosion of patient protections and professional norms between industry and medical practice. Some examples of these concerns included fast-tracking of new drug approvals with the FDA, the hefty finders fees for enrolling patients in pharmaceutical research studies, the elaborate gift giving by pharmaceutical companies to buy the loyalty of future prescribers; the marketing ploys of pharmaceutical-sponsored speakers bureaus, the ghost writing of pharmaceutical-sponsored research articles, and the surreptitious promotion of off-label uses 1-4. I wondered whether Botox would really be safe for our patients. Were the risk and expense worth the benefits? Did we really know enough about how to use it? Were we being a bit cavalier in risking the possibility that some day we might have a slew of patients experiencing unexpected harms from the wide-spread off-label use, as occurred with thalidomide? Fortunately, concomitant with the increasing off-label use, some conscientious physician-researchers did the work for us all and studied the drug for the populations we work with in rehabilitation. They provided us with much needed information on safety, efficacy, dosing, and risks that we can easily access through such excellent online tools such as the Cochrane Library (http://www.thecochranelibrary.com/view/0/index.html) (John Wiley and Sons, Hoboken, NJ) and UpToDate (http://www.uptodate.com/home) (Wolters Kluwer, Waltham MA), which provide quick access to high-quality expert and evidence-based medicine reviews to facilitate clinical decision making. The lack of FDA approval for indications other than the primary target populations do not necessarily infer that the use of a drug is unsafe. The decision whether to seek expansion of FDA approvals can be a complicated and expensive undertaking. Access to high-quality research is needed for both FDA expansion of indications and the safe and efficacious use of a drug off label, yet such research is often what is lacking. There may be orphan populations for whom researching the drug is unlikely to occur due to the minimal profit that could be realized by promoting the drug for a particular use. Practicing clinicians often do not have the time, skills, or resources to perform the needed research. Thus, off-label use of medications is a reality and will continue to pose a number of challenges that clinicians must learn to navigate. In the end, clinicians will need to balance ethical mandates to do no harm (nonmaleficence) with the need to try to do good and to alleviate suffering (beneficence). A discussion caught my eye recently on a bioethics listserv organized by the Medical College of Wisconsin about an article in The Washington Post 5. The article highlighted the opportunities that Medicare Pharm D programs now provide in tracking prescribing patterns of individual physicians, including high-volume narcotics, psychoactive medications, and off-label uses of medications. As an example, a physician in Oklahoma is profiled who liberally uses memantine for older children with autism. Alexander Capron, a professor of law and bioethics at the University of Southern California, responded that “when one moves beyond a single patient or maybe a couple of patients … you're basically saying, ‘I'm doing a study.’” Ford Vox, MD, a brain injury specialist and physiatrist from Shepherd Center challenged Professor Capron on this point and noted that this is an unrealistic and demanding standard for already stretched clinicians who are in the trenches treating “difficult” patients with distressing cognitive-behavioral symptoms, little research, and few drug options. In addition to autism, patients with brain injuries often fall into this group. Before you read further, I would encourage each clinician-reader to pause, reflect on your own prescribing practices and what you know about the FDA-approval status for the drugs you commonly use. You may want to check your knowledge against a list of drugs commonly prescribed for off-label use by perusing the Web site from Consumer Reports 6. As always, I welcome your comments, critiques, and suggestions for future columns. In May 2013, in cooperation with the investigative journalism nonprofit ProPublica (Pro Publica Inc, New York, NY), The Washington Post published a high-profile expose into physicians' prescribing habits 1. The article highlighted that, although the Centers for Medicare and Medicaid Services (CMS) should know the prescribing trends of its participating physicians, the agency has not used the trove of data at its fingertips to police member prescribers. ProPublica's enterprising reporters sought to prove the point that these data can be exploited with a mind toward keeping Medicare beneficiaries protected from suspicious clinicians. The reporters filed a successful Freedom of Information Act request that gave them access to prescription data of the CMS, then used the data to identify outliers who were prescribing certain psychiatric drugs. Two questionable assumptions drove the reporting by The Washington Post: (1) Medicare has the mandate to police physicians practicing legally and in their normal scope; and (2) there is something inherently suspect or dangerous about off-label prescribing. To back up the piece's implication that off-label prescribing carries unusual obligations, reporters turned to bioethicist Alexander Capron who advised, “when one moves beyond a single patient or maybe a couple of patients … you're basically saying, ‘I'm doing a study.” The reporters then pointed out that, in a “clinical study, patients or families would be informed about side effects and risks” 1. I believe the combination of Professor Capron's declaration and the contention that CMS should investigate outlying prescribers creates chilling implications for the practice of medicine in difficult populations. As a physician tasked with managing the care of patients suffering from the effects of acquired brain injuries, I care a lot about off-label prescribing. I prescribe off-label every working day. Thus invested, I engaged Professor Capron on the Medical College of Wisconsin's Bioethics listserv where he confirmed to me that The Washington Post quoted him accurately. He stood behind his remarks. Professor Capron believes that a physician who has found an off-label use of a medication to be helpful for a particular problem in a particular population has an ethical obligation to publish a research article reporting the findings to the world. He has even given a threshold outlining when the practice of medicine ends versus when the practice of unethical, non–institutional review board approved research begins. He states that once a physician finds a new off-label use helpful in more than 2 patients, he or she is engaging in unethical conduct if he or she continues treating further patients without setting up a research study. As a result, routine medicine becomes an impractical and unhelpful endeavor under these constraints which I do not consider ethical at all. The Washington Post story served to announce the debut of “Prescriber Checkup,” a searchable online database ProPublica compiled with their Freedom of Information Act data that allows the general public to learn the top drugs any Medicare-participating physician prescribes for Medicare patients (drugs with more than 50 prescriptions). One can see his or her own physician profile by going to the Web site for the ProPublica database (http://projects.propublica.org/checkup/). ProPublica hopes that one day every clinician's prescription history will be a matter of public record, whether or not a public insurance program is paying for the medications we are prescribing 2. The reporters knew what they were doing when they checked up on Robert Morton, MD, an Oklahoma psychiatrist whose medical license has twice been revoked due to an opioid addiction in the 1990s. They noted that Dr Morton, now legally back in practice, writes prescriptions for a lot of memantine hydrochloride. He prescribes it most often for patients under age 65 years, which suggests that he is not using the drug for its sole FDA-approved indication, Alzheimer-type dementia. Dr Morton informed his interviewers that he has found that memantine helps calm overstimulation behaviors, such as rocking and flapping, in the older children and adults with autism and developmental disability he treats in facilities across Oklahoma. The fact that a small amount of the literature that discusses memantine as a treatment for difficult behaviors in autism has been accruing since 2006 did not make it into ProPublica's story, in favor of a quote from a prominent psychiatrist who disclosed that he has no experience with the drug. The Yale psychiatrist stated that he is “dubious about the rationale” for giving an N-methyl-d-aspartate (NMDA) receptor antagonist to calm problem behaviors in patients with autism, an opinion from on high that appears to overrule what Dr Morton is finding on the ground in Oklahoma. It must be because I also try to help patients in desperate situations due to problematic behaviors that I did not read about Dr Morton's use of memantine with horror but rather with interest. The nursing director of one of the facilities that Dr Morton serves told reporters that the memantine has “‘worked wonders for mood behaviors in developmentally disabled patients.” I'm pleased to see that Dr Morton has found something that works in his similarly complex population of children and adults so impaired with harmful behaviors that they are residing in institutions rather than in the community. In practicing brain injury medicine, I know about this challenge all too well. Medicine does not always have the luxury of waiting the of needed research on any given problem are completed from are tasked with treating suffering It is in these most where clinicians to that no physician in history has doing no of us has every implication of any single or as any can the most in his or her medical must to a of with an in our as to where it may help and where it may and then we and practice medicine with such tools as we have to There is a between the medicine that most FDA drug approvals and of must toward the if we are to be of any use to our patients. There is not a single FDA-approved drug for the treatment of or in acquired brain and we have few of drugs with which to of these drugs can have the is most often used these to need not such at all It on what you are treating as to what your should the problem is your patient his or her into a or his or her the of these behaviors is a more than any I practice in a in which the unexpected every day. One patient with and with may may one brain will to will One patient with a may will One patient in a up to with does I with Dr Morton when he told The Washington Post that he has not time to up his with I a patient who was and who only when we turned her I have yet to up this I know there are that will one day the I see every a of research every day in this In the although I can what I see little than a on I managing to help of my patients and their families through the As a rehabilitation the treatment I is not a at all but the program at my could my for the we The literature has yet to even the most about the and of The to much and how is always a target on an individual and Perhaps this experience is when I read about an Oklahoma psychiatrist prescribing off-label memantine to developmentally disabled patients, I was not Perhaps this is when I read about a bioethicist whose ethical prescription would me out of using in for for a of brain or Botox for limb all I for my patients who patients with acquired and developmental brain injuries know that our patients do not new drug or new drug are used to the of medical where our to in for the of research. In these we are to from our knowledge of that often have a research due to a more population for pharmaceutical and have a to of the information about the we and a to new treatment with our have a to our patients and their about our of in the we and we should encourage their in treatment effects versus should that for more and evidence-based and more without standard can risk under informed that this of and individual medical practice an ethical a will all the physicians the to back for a will us on of drugs for uses other than the for which the FDA has approved their use use of a drug to a than the one for which it was or to a such as using a drug for children when it was only in is widespread and for at of all prescriptions 1. not all such uses the the ethical by the routine off-label use of a drug by a single physician when such use has been as safe and through as the general standard of care for the in I on this of off-label use rather than on a physician who uses a drug off as a of treating a particular patient who has not responded to other because it was the in The Washington Post article in which I was quoted 2. also are by the and by the even more in which physicians prescribe a drug for an off-label use that has been through published in or that has of the of most or all physicians without a example, in the physicians may be prescribing the drug without that they are using it in a that has not been and approved by the FDA or without really the implications of prescribing on and off off-label use of drugs is as to whether this is good as of the law is that is to that a that its drug is safe and for the use that will be on its a the a drug has been for and the FDA has no to how physicians use whether in with the or a physician with the to use a drug in a when he or she has to believe that doing so will provide the for a individual can be when a physician is with a medical for which no approved a A physician in such a must that he or she is using the drug for an that has not yet been by or approved by the Thus, the physician should the for the off-label use and the risks with the physician must the off-label of the treatment to the patient is medical for the such as the of a patients will be by the of their but the risks of with a treatment should be when the treatment with the of a with such an him or her to the off-label use for all patients with the the physician should that he or she has a not only to each of patients with their symptoms, and to are unlikely to be served by the but also to the as a to whether the works the the physician it will to use it to on an that is unlikely to any a physician who is to a treatment risks patients because own experience does not provide a for treatment In its which continues to provide the ethical commonly used by and review across the in and research with the for the of of and the of a between and practice of The that physicians must be to as needed in for their patients without being to the review board that are to research. The an to an to be and to or to it then a in a from standard or practice, the does in and of research. The fact that a is in the of or does not it in the of research. new of this however, be the of research at an in to whether they are safe and medical have to that be by being used and then be once used in a few 5. the the use of the drug to be or to have that its then the can be to an end, which may not for a when a uses a drug off with patients. however, the the of the then it can be into general use on the of and should a care to this on the of an such have been by other physicians on of by the it becomes of the of the and of an off-label use becomes difficult for both and ethical The widespread of off-label drug use is a to the of an for medical and to the in practice patterns the 6. A single physician may not have the time, or to a study. such a with from drug the of or the CMS, and through care by using of data about medicine as it is to help physicians and patients know what really works and what does not the in to out a of the does not a single physician whose routine use of a drug to an The need to conduct a is when the use of a drug from practice norms in the and a or should not be a who use, routine use of a drug off should with the the data that have him or her of the of such use. The of are then to such if it is and if an new of to and seek for a clinical of the drug for the new that are now paying for other for the are not or which have too should the research if the by the that there is not only no for that the off-label use works as the or the it is the should to continue to for the off-label drug and the fees of the physician who is using it. The physician with drugs for each and the physician ends with one drug for so much and so little is the that off-label use. use, is not a The problem is that off-label use the from care to when we about whether off-label use is the of its There are that a pharmaceutical may not seek FDA approval for evidence-based uses of a in the that we it is up to the to such a review if they seek an on the FDA The for patients, and is use that is beyond the and it so that most off-label use into this 1. should use drugs off when there is an balance the use in There are of these clinical A number of whether this balance has been including the of a the and of risks and of the the number of and treatment and the clinician's and patient these the of informed is where are to patients about the and risks and of there is no to believe that informed prescribers to when drugs are being used off a standard for informed is whether a would provide the information in yet the of information about the status of prescribed drugs is by no standard of practice. and in this have too little knowledge of the FDA to this information into clinical decision making. In a of primary care physicians and the the FDA-approval status of of the 2. In other a of a would have as which was for some example, the of physicians who prescribed for with the in it was FDA approved for this use, in has been FDA approved for this indication, at the time of our a for risk of to in patients with dementia. A that it is to the status as of any informed is that, by on the status rather than the it the for the of informed for prescription and the of any such should be on the balance of the rather than the status A of have been to the challenge by a prescription drugs in all too clinicians lack the information that they need about clinical reflect what is in rather than what is by the and may be a drug may not be for a of new drugs prescribed and in study, no were provided to patients for a of the prescribed each of these is to prescribers toward a more and some of them may also help to of off-label use. example, some have for off-label it is to any such could for a or more prescriptions that occur off in the have that mandate that prescribers provide a clinical for each although such and would be at any due to its would be for such or would be used to it? would be that may be expensive or have high of for off-label uses with the of further information about the or of such uses with may although this is most from an when to a number of 5. it to the with off-label there are no individual patients and there will a which the of of that the of new with and use of a small number of that one to know 6. and the opportunities in which the on in research that the and of off-label may be high such as the off-label use of expensive with and provide for further as as by and some the for through the FDA is than for In the of brain injury medicine, there are to evidence-based medicine, and further, to FDA There is a of to treatment in with to or example, the and of is an that is in need of evidence-based 1. has behind clinical practice for a number of it is a complex population in of of injury and are not always are clinical are and can be clinical brain is read as There are no to this some on of and from or work for a few treatment are by the individual of the The of often more of an than a use is off as a not as an FDA approval does not always research, if the drug is no under The FDA often appears to be more by and rather than the of patients, although that can be a One in the of is the use of the is a (NMDA) receptor with of including There is a for its use, to what we know of the of and the of of us in the of have used it off for on our own clinical experience and the although small and example, our was to a clinical that at in with that but the was and It was not a did the of a that we have a that the of in although this only from states in A of with that was for of in with that more than is an off and There is not much to it as a for an FDA-approved in of the