Over the past several years, the federal government and law enforcement agencies have increasingly investigated and prosecuted large pharmaceutical and medical device companies for off-label marketing. Various media outlets have covered these settlements and cases and others have even conducted their own investigations (e.g., ProPublica.
Consequently, a recent article from the Pacific Standard, written by Ford Vox, a rehabilitation physician at Shepherd Center, addressed an investigation conducted by The Washington Post that looked into off-label prescribing. Vox, who treats survivors of acquired brain injury and spinal cord injuries, noted that the kind of reporting conducted by the post will create “chilling implications for the practice of medicine in difficult populations.”
Background
In May 2013, in cooperation with the investigative journalism non-profit ProPublica, The Washington Post
published a high-profile expose into physicians’ prescribing habits. 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.
Vox noted that “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.'”
Why Off-Label Prescribing Benefits Patients
As a physician tasked with managing the care of patients suffering from the effects of acquired brain injuries, Vox asserted that he cares “a lot about off-label prescribing.” Vox said he prescribes “off-label every working day.”
He maintained that “Medicine does not always have the luxury of waiting until the mountains of needed research on any given problem are completed centuries from now. [Doctors] are tasked with treating real-world suffering today.”
Consequently, he challenged Capron on his belief that off-label prescribing is improper. Vox explained that “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.”
In Capron’s view, once “a physician finds a new off-label use helpful in more than two 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,” Vox writes.
The article then discusses ProPublica’s “Prescriber Checkup,” a searchable online database ProPublica compiled with their FOIA 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 website for the ProPublica database. 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.
Vox pointed out that the ProPublica reporters strategically highlighted certain doctors, such as Robert Morton, MD. The coverage noted that Morton writes prescriptions for a lot of memantine hydrochloride. “He prescribes it most often for patients under the age of 65, which suggests that he is not using the drug for its sole FDA-approved indication, Alzheimer-type dementia.”
“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.”
But as Vox points out, “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.” Instead, the anti-industry journalist group chose 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 NMDA receptor antagonist to calm problem behaviors in patients with autism, “an opinion from on high that appears to overrule what Morton is finding on the ground in Oklahoma.”
Vox also pointed out that “evidence has been building in support of another drug in the NMDA receptor antagonist class called amantadine, which appears to help accelerate the return of consciousness after severe acquired brain injury.” A good clinician working on the front lines might theorize that such a stimulant is worth trying, preferable to the heavier antipsychotics and benzodiazepines which are often used for the behaviors Morton identified, yet achieve their effects with a heavier toll on neural networks.
The nursing director of one of the facilities that Morton serves told reporters that the memantine has “worked wonders for mood behaviors in developmentally disabled patients.”
“I’m pleased to see that 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,” Vox wrote.
Consequently, Vox underscored the delicate balance that physicians must recognize in treating patients. He explained that “there is a natural struggle between the randomized controlled trial based medicine that spawns most FDA drug approvals and personalized medicine.” Practitioners of behavioral management must trend toward the latter view if we are to be of any use to our patients, he maintained.
Vox noted that “there is not a single FDA-approved drug for the treatment of cognition or behavior in acquired brain injury, and we have precious few classes of neuromodulatory drugs with which to work. All of these drugs can have unintended effects. Although the term is most often used these days to describe genetically targeted drugs, “personalized medicine” need not involve such biomarkers at all. It depends entirely on what you are treating as to what your best metric should be. When the problem is your patient slamming his or her head into a wall or striking his or her caregivers, the cessation of these behaviors is a more precise measure than any yet-to-be-developed gene assay.”
“I practice in a field in which the unexpected happens every day. One patient with severe TBI and with intraventricular hemorrhage may develop hydrocephalus, another may not; one penetrating brain trauma will lead to seizures, another will not. One patient with a thalamic hemorrhage may suffer debilitating central pain, others will not. One patient in a vegetative state perks up to minimally conscious with zolpidem, another does not. I sympathize with Morton when he told The Washington Post that he has not had time to write up his successes with memantine.”
Ultimately, Vox noted that one day he hopes to have the time and resources to document all of his successes and failures in treatment patients. But until that day, he is managing to help as many of his patients and their families as possible through the best skills and knowledge he has, including off-label prescribing. He notes that his greatest power as a rehab physician is not a pill, but “the interdisciplinary therapy program at my hospital.”
There are numerous variables that affect how physicians treat patients and treatment literature is not always certain. As Vox explains, the correct answer to “how much and how long” is always “a moving target based on an individual patient’s unique goals, resources, social setting, and evolving functional status.”
“Perhaps this experience is why, when I read about an Oklahoma psychiatrist prescribing off-label memantine to severely developmentally disabled patients, I was not scandalized. Perhaps this is why when I read about a bioethicist whose ethical prescription would box me out of using baclofen in stroke, trazodone for sleep, propranolol for storming, intrathecal baclofen within a year of brain injury, or Botox for lower limb spasticity, all non-FDA indications, I worry for my patients.”
“Physicians who treat patients with acquired and developmental brain injuries know that our patients do not attract many new large randomized drug trials or new drug indications. We are used to rapidly reaching the edge of known medical science, where our practical expertise begins to fill in for the dearth of research. In these cases, we are correct to draw from our knowledge of analogous conditions that often have a greater research base simply due to a more economically favorable population for pharmaceutical and device company investment.”
Vox noted that such physicians “have a duty to keep abreast of the latest information available about the treatments we offer and a duty to discuss innovative new treatment approaches with our colleagues. We have a duty to inform our patients and their caregivers about our level of confidence in the treatments we offer, and we should encourage their participation in weighing potential treatment effects versus possible adverse effects.”
He noted that “Such conversations should acknowledge that lower-risk treatments allow for more speculative and fewer evidence-based approaches, and more severe problems without standard approaches can justify greater risk taking under informed consent.”
Accordingly, Vox maintained that claims such as those propounded by the Washington Post “that this model of expertise-based and individual problem-oriented medical practice represents an ethical lapse deserve a strong response.”
“When will all the dedicated physicians tackling the toughest cases start to back away for fear a national newspaper will label us rogues experimenting on vulnerable populations?”
For a depressed patient with Irritable Bowel, primarily diarrhea, a constipating antidepressant may be what is needed. I tend to see all side effects of drugs as potentially therapeutic.
Consider topiramate (Topamax), originally approved for treatment of epileptic seizures. Patients taking it for its FDA-approved use who also suffered from migraine reported fewer, milder headaches; topiramate is now approved for migraine prevention. Once it started being used for the larger population of migraine sufferers, it became apparent the drug also promotes weight loss, for which it now is approved (in combination with phentermine, as Qsymia) for that indication. Not all pharmaceuticals that prove effective for non-FDA-approved indications will be approved for them, often because their use for the new purpose (unlike the situation with topiramate) will not be sufficiently profitable for the company to invest in expensive clinical trials.
I strongly agree with Dr. Vox. Considering the inordinate amount of time and substantial resources (often invested only where a significant monetary reward is anticipated) required for FDA approval, what seems far less ethical than prudent off-label prescribing, is the withholding of treatments that may offer the only chance of survival or a subjectively acceptable quality of life.
I find it of interest that NMDA receptor antagonists have arisen in this context. Consider ketamine, a drug long approved for anesthesia. It’s substantial benefits on refractory major depression were documented by Harvard researchers in the 1990’s and more recent studies have shown remarkable results. Yet very few clinicians will use it for this indication, even where suicide risk is high. It’s widespread availability awaits the completion of J&J’s clinical trials of a slightly altered version of the drug, and estimates put it’s release no earlier than 2017. I find it hard to see the ethics in that process.
More physicians like Dr Vox would need to stand up against the witch hunt of the media. Treating TBI ,strokes and CP I also know the daily prescribing off label. All I want to be able to practice at the best of my knowledge and conscience without some busy body know it all’s to interfere and create adversity. It is easy to be an ethicist when you have no responsibility to any patients .
I congratulate Dr Vox for his outstanding approach and am displeased with repetitive “investigational” reporting done with poor insight and ex catedra. As if RCT and meta analyses are the source of all medical wisdom. As Dr Vox puts is elequently-we treat our patients here and now one at a time with knowledge acquired from trials, FDA approval data, off-label use or word of mouth. Come to think of it medicine has worked this way well before FDA.