United States v. Caronia: Some Preliminary Thoughts on the Second Circuit’s Decision Invalidating the Ban on Off-Label Promotion
Earlier this week, the Second Circuit Court of Appeals at last issued its decision in United States v. Caronia and it is momentous (and predicted to be heading to the Supreme Court). A two-judge majority of the Circuit Court held that Alfred Caronia, a pharmaceutical sales representative, “was convicted for his speech – for promoting [the central nervous system depressant Xyrem] for an off-label use – in violation of his right of free speech under the First Amendment.”
The majority’s decision begins with a threshold question. Was Caronia convicted for conspiracy to misbrand Xyrem because he engaged in off-label promotion qua off-label promotion, that is, for his speech? Or, was his speech simply “evidence that the ‘off-label uses were intended ones for which Xyrem’s labeling failed to provide [the required] directions[,]” as the government argued on appeal? The former would implicate the First Amendment, but the latter would not. The Supreme Court has held that “[t]he First Amendment … does not prohibit the evidentiary use of speech to establish the elements of a crime or to prove motive or intent.” As the Caronia dissent (colorfully) explained, “Abby and Martha [do not have] a First Amendent right to offer arsenic-laced wine to lonely old bachelors with the intent that they drink it. … And any statements Abby or Martha made suggesting their intent—even if all of the statements were truthful and not misleading—would not be barred from evidence by the First Amendment…”
The majority found that Caronia was convicted for his speech alone, pointing to the lower court’s instructions to the jury and to a number of statements that the government made at trial including “[Caronia] conspired through some act of misbranding, and that act of misbranding … was the promotion on October 26th and November 2nd[,] marketing [a] drug for unapproved uses.” Caronia’s conviction must therefore be vacated, the majority concluded. The Food Drug and Cosmetic Act does not “criminaliz[e] the simple promotion of a drug’s off-label use because such a construction would raise First Amendment concerns.” The majority did not disagree with the general proposition that speech may be used as evidence of intent, and it expressly declined to decide the specific question whether the FDCA violates the First Amendment by “defin[ing] misbranding in terms of whether a drug’s labeling is adequate for its intended use, and permit[ting] the government to prove intended use by reference to promotional statements made by drug manufacturers or their representatives.” Even if the Second Circuit’s decision stands, then, the government may be able to argue that Caronia is a case about an erroneous jury instruction with limited practical effect
The majority went on to hold that a ban on off-label promotion qua off-label promotion—like the Vermont law barring drug companies from using physician-specific prescribing data to craft physician-specific sales pitches at issue in the Supreme Court’s 2011 decision in Sorrell v. IMS Health (which I discussed on this blog here)—is unconstitutional regardless of whether strict or intermediate scrutiny applies. The majority gave short shrift (no shrift, really) to the argument that the ban on off-label promotion is necessary to preserve the integrity of the FDA’s drug approval process, suggesting that the government could “minimize … manufacturer evasion of the approval process” by imposing “ceilings or caps on off-label prescriptions.”
The majority did not elaborate on how ceilings or caps on off-label prescriptions would work, on the grounds that the First Amendment puts the burden on the government to demonstrate that they would not. Here, too, there may be an opening for the government, to make a stronger case to the Supreme Court than it did before the Second Circuit (in its briefs or at oral argument) that ceilings or caps would not be “administrable, feasible, or otherwise effective” and that the ban on off-label promotion therefore provides a direct, narrowly-tailored, and crucial incentive to clinical research into already-approved drugs. As the dissent suggested, “[a] ceiling on off-label prescriptions would require collecting data from countless numbers of doctors and patients and, given the medical uncertainties involved, could needlessly (and simultaneously) result in the denial of some effective treatments and the overprescription of ineffective and even dangerous ones.”
In Case you missed it: Research Fellow & Lecturer in Law, Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, Kate Greenwood, on American Law Journal TV regarding Pharmaceutical Off-Label Marketing and Free Speech. A regular blogger here at HRW, Kate Greenwood appeared along with attorneys Hope Freiwald of Dechert, LLP and Brian J. McCormick, Jr., of Sheller, P.C.
As predicted, in the wake of the Supreme Court’s decision in Sorrell v. IMS Health pharmaceutical companies have raised First Amendment challenges to the ban on off-label promotion on a number of fronts. Most recently, Par Pharmaceutical sued to invalidate the ban to the extent that it “criminalize[s] Par’s truthful and non-misleading speech to healthcare professionals concerning the FDA-approved use of its FDA-approved prescription drug.” How is it that the ban on off-label promotion could be interpreted to bar the on-label promotion in which Par wishes to engage? At the heart of Par’s dispute with the government are the “call plans” that pharmaceutical companies develop using the prescriber-specific prescription data at issue in Sorrell.
Call plans set forth which physicians pharmaceutical sales representatives should visit and how often. In an article in the current issue of Next Generation Pharmaceutical magazine, Matthew Linkewich and Jay Margolis of IMS Health explain that a “properly conceived and configured … call plan directs reps to those physicians whose practice characteristics, constellation of prescribing behaviors and attitudes are conducive to supporting the brand goals.” Because call plans embody “brand goals,” the government has focused on them as evidencing companies’ intent to engage in off-label promotion.
For example, in a December 15, 2010 press release announcing a $214.5 million settlement with Elan Corporation, the Department of Justice highlighted the fact that Elan’s “off-label marketing efforts” for its anti-epilepsy drug Zonegran “targeted non-epilepsy prescribers.” A January 28, 2011 press release announcing the formal sentencing of Novartis in a case involving off-label promotion of its anti-epilepsy drug, Trileptal, similarly noted that the company “decided to market and promote Trileptal as a treatment for [two off-label indications, bipolar disease and neuropathic disease] and directed its sales force to visit doctors who would not normally prescribe Trileptal due to the nature of their practice.” Novartis’ plea agreement explains that while epilepsy is treated by epileptologists and neurologists, the company’s call plan included psychiatrists and pain doctors.
The corporate integrity agreement that Novartis entered into as part of the settlement of the Trileptal-related claims against it provides for independent review of “the bases upon which [health care providers] and [health care institutions] belonging to specified medical specialties are included in, or excluded from, the Call Plans based on, among other factors, expected utilization of Government Reimbursed Products for FDA-approved uses or non-FDA-approved uses[.]“ The corporate integrity agreement requires a similar review of the company’s sampling strategy and goes so far as to bar the company from delivering samples to health care providers identified by the company as “belong[ing] to a specialty group that is unlikely to prescribe” the sampled product on-label.
Currently, Par Pharmaceutical’s call plan for its appetite stimulant Megace, which is FDA-approved for the treatment of AIDS-related wasting, does not include oncology practices or long-term care facilities. With the help of an outside consultant, Par determined that physicians in those settings “reasonably may encounter patients suffering from AIDS-related wasting, and thus may have occasion to prescribe [Megace] for its on-label use,” but all agree that they would be much more likely to prescribe the drug off-label to treat wasting in cancer and geriatric patients. In the concluding paragraphs of Par’s complaint, it explains that the U.S. Attorney’s Office for the District of New Jersey, which is investigating the company’s marketing practices, has informed the company that before it promotes a drug for its on-label use to doctors who prescribe the drug off-label it must “confirm that there are presently a sufficient number of patients being treated for whom the drug could be prescribed on-label.”
As Par points out, the government has offered no guidance regarding the number of on-label patients that a doctor must treat before he or she can be included in a company’s call plan. On the one hand, this is to be expected because the call plan is only one factor that the government considers in determining a company’s intent. On the other hand, it leaves companies like Par without a clear course to follow and, after Sorrell, likely to sue.
Distribution Controls: A Potentially Powerful Weapon Against Inappropriate or Dangerous Off-Label Use
When supplies of sodium thiopental dried up earlier this year, states turned to other drugs to carry out executions by lethal injection. The anti-seizure drug pentobarbital, marketed as Nembutal, is one such drug. An estimated two-thirds of the thirty-four states with the death penalty have switched or considered switching to Nembutal; states that have made the switch include Georgia, Ohio, Oklahoma, South Carolina, and Texas. As of earlier this month, Nembutal had been used in eighteen executions this year.
Like sodium thiopental, Nembutal is an off-patent drug that serves a relatively small market. The sole company licensed to manufacture Nembutal in the United States, the Danish firm Lundbeck Inc., has been the target of a public relations and investment campaign by human rights activists calling for the end to the use of the drug in executions. Lundbeck has never sold Nembutal directly to prisons, however, and initially the company said that there was nothing it could do to control the drug’s re-sale. As a spokesperson explained:
We can’t withdraw the product because it is used for treating severe epilepsy and sometimes it’s the only treatment option. All we can do is write to the prisons urging them to stop misusing using our product which was designed to help sick people. It’s a really unfortunate situation.
Earlier this month, Lundbeck announced that it had determined that there were steps it could take beyond letter writing. The company considered ceasing production of the drug altogether–it represents less than one percent of the company’s sales and is, in the company’s words, “economically insignificant”–but decided against doing so in light of survey evidence that the fifty million doses of the drug it sells in the United States each year are important for treating epilepsy that is severe and refractory (that is, unresponsive to other drugs).
Lundbeck decided instead to distribute Nembutal through Cardinal Health’s Specialty Pharmaceutical Services on a “drop-ship” basis, directly to hospitals. Less than ten percent of drugs are distributed directly to end-user customers in this way, typically “cancer treatments that are expensive, difficult to make, or not in high demand.” Lundbeck will review each Nembutal order and deny those from “from prisons in states currently active in carrying out death penalty sentences.” Every purchaser will be required to represent in writing “that the purchase of [Nembutal] is for its own use and that it will not redistribute any purchased product without the express written authorization of Lundbeck.” Lundbeck’s CEO has warned that the company will take unspecified “legal action” against any purchaser who violates these terms.
Lundbeck’s decision to use a drop-ship program and purchaser agreements to take responsibility for the off-label uses to which its product is put once it leaves the company’s control raises the question whether other companies could or should be asked to do the same. In some cases, issues of scale will foreclose such an approach. In other cases, a company and/or regulators may have concerns about inappropriate or dangerous off-label use but not be able to link it to an easily identified class of would-be purchasers like “prisons in states currently active in carrying out death penalty sentences.” (Note that even in Lundbeck’s case the agreements are overbroad to the extent that they deny access to Nembutal to prisoners in death penalty states who need the drug to treat severe, refractory epilepsy.) In still other cases, however, taking control of distribution will be a feasible, and powerful, compliance tool. The Risk Evaluation and Mitigation Strategy (REMS) for Lazanda (fentanyl) Nasal Spray, recently posted to the Food and Drug Administration website, which provides that would-be distributors enroll in the REMS program and agree to limit their distribution to specially-certified pharmacies which are also enrolled in the program, is just one example.
Off label prescribing has become fairly common practice for many medical professionals. Once a drug has been approved by the Food and Drug Administration (FDA) for a specific purpose, physicians are given the freedom to prescribe the approved drug “off label” for other beneficial uses of the drug. There is a great interest for physicians to retain this autonomy of prescribing drugs off label as the practice expands treatment options. Both the American Medical Association and the FDA have recognized that physicians are in the best position to determine the method of treatment for their patients.
However, the practice of off label prescribing has not been without controversy. Many politicians and regulators view off label prescribing as a way to avoid clinical testing and FDA approval process. In addition, studies have shown that many physicians prescribe off label with little or no scientific rationale. According to the Daily News Central, an example can be found in a particular study: “in all, the study estimated that 1 in 7 prescriptions were written [by doctors] without good medical evidence that they would work.”
A LA Times article has recently highlighted the problems of off label prescriptions. In the article, it has come to light that the off label use of statins, one of the world’s most prescribed medication, may not have the efficacy that many doctors had previously thought. The LA Times reports,
Statins were initially approved by the Food and Drug Administration for the prevention of repeat heart attacks and strokes in patients with high cholesterol who had already had a heart attack. And used for that purpose — called “secondary prevention” — the drugs are powerful and effective medications, driving down patients’ risk of another heart attack or stroke by lowering their levels of LDL (or “bad”) cholesterol.
Then physicians came to believe statins could also reduce the risk of a first heart attack in people who have high LDL cholesterol but are nonetheless healthy. This use of statins — called “primary prevention” — has driven the growth in the market for statins over the last decade.
Statins certainly decrease rates of heart attack in people who have clear signs of cardiovascular disease but it’s not so clear they work that way in people who are healthy. In spite of that uncertainty, statins’ use for primary prevention has sky rocketed.
One wonders how so many physicians came to believe that statins could also reduce the risk first time heart attacks. Dr. John Abramson, from Harvard Medical School, attributes statins’ off label growth to a “conspiracy of false hope.” He states, “[t]he public wants an easy way to prevent heart disease, doctors want to reduce their patients’ risk of heart disease and drug companies want to maximize the number of people taking their pills to boost their sales and profits.”
So, with all these interests pushing for statins’ off label use, it should not be a great surprise that extensive research has not been performed regarding statins’ primary preventive effects– and conflicting results have emerged. The LA Times reports,
In the first of three studies published in the Archives last month, medical researchers found that, contrary to widely held belief, statins do not drive down death rates among those who take them to prevent a first heart attack. A second article cast significant doubt on the influential findings of a 2006 study, called JUPITER, that has driven the expansion of statins’ use by healthy people with elevated blood levels of C-reactive protein, a measure of inflammation. A third article suggested potential ethical, clinical and financial conflicts of interest at work in the execution of the JUPITER study and concluded the widely hailed trial was “flawed” and raises “troubling questions concerning the role of commercial sponsors.”
Potentially, new findings regarding the efficacy (or lack thereof) of statins can have seismic effects. If it is found that statins’ primary preventative effects are overstated or nonexistent, this would amount to what has been a tremendous amount of healthcare waste (time, money, and effort) due to the popularity of the drug. According to IMS Health, U.S. patients filled 201.4 million prescriptions for statins last year alone.
While there is a strong interest for physicians to retain their autonomy when assessing the best treatment for the patient, due to the potential of healthcare waste, there may be an equal or if not stronger interest for some regulation regarding the practice of prescribing off label drugs. As to industry funding of research, there seems little incentive for a pharmaceutical company with a blockbuster off label hit to do anything which would upset the apple cart– or should I say money cart?