Part Two: The First Amendment: Physician education using off-label indications to ensure that patients receive the most effective treatment.
Jennifer Williams PhD, JD, MBA, RN, MS
Jennifer Williams, PhD, JD, MBA, MS, RN
Conflicts of Interest
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The First Amendment: Physician education using off-label indications to ensure that patients receive the most effective treatment.
Abstract: In today’s medical environment there is a two-fold element of risk that affects a medical device company. It is comprised on the one hand by the risk of improper treatment through the agent’s lack of scientific disease state knowledge, and on the other by the medical device company’s fiduciary duty to ensure patient safety, including the facilitation of proper education to the physician. The body of law that regulates the marketing of medical device products in the United States is the Drug and Cosmetic Act, which places a restriction on off-label marketing and advertising. To date, proponents have argued that off-label utilization is a First Amendment right necessary to ensure that patients receive the most effective treatment.
A treatment for cardiac arrest using Targeted Temperature Management (TTM) or Therapeutic Hypothermia (TH) Off-Label but it is a Standard of Care
Pharmaceutical and Medical device companies are prohibited from promoting the off-label use of their products, as is the case when a certain device is advertised for use with children when it is only indicated for adults (1). Sudden cardiac death is a leading cause of death among adults over the age of forty in the United States and other countries, but its treatment is considered an off-label use by some medical device and pharmaceutical companies (2).
For adult patients with out-of-hospital cardiac arrest (OHCA) from a shockable rhythm, Therapeutic Hypothermia (TH) is a standard of care (24, 25). This is a level one recommendation from the American Heart Association, which indicates that one or more randomized clinical trials wherein the lower limit of CI for treatment effect exceeded the minimal clinically important benefit. On the basis of the published evidence to date, the ILCOR ALS Task Force has made the following recommendations:
Unconscious adult patients with spontaneous circulation after out-of-hospital
cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the
initial rhythm was VF. Such cooling may also be beneficial for other
rhythms or in-hospital cardiac arrest.
An excellent source of standards for cardiac care is contained within the ACLS manual, a two-volume set of comprehensive guidelines for cardiopulmonary resuscitation (CPR) and the diagnosis and treatment of cardiac events (26). The first volume, subtitled “Certification Preparation,” deals with the essentials of running a code, including key algorithms for CPR, essential drugs, treatment modalities and basic arrhythmia interpretation, the essentials of airway and intravenous (IV) access, including management of the airway, ventilation and IV access, and the “perils and pitfalls” of providing basic life support, including administration of drugs, defibrillation, and arrhythmia interpretation (26).
A duty of care is a legal obligation imposed upon an individual that requires adherence to a standard of reasonable care while performing acts likely to harm others. Duty of care is the first element that must be established to proceed with an action in negligence. In an action alleging malpractice, the plaintiff has the burden of proving in light of the state-of-the-art technology existing at the time of the alleged malpractice that:
(a) The defendant, if a general practitioner, failed to provide the plaintiff with the recognized standard of acceptable professional practice or care in the community in which the defendant practices or in a similar community, and that as a proximate result of the defendant failing to provide that standard, the plaintiff suffered an injury.
(b) The defendant, if a specialist, failed to provide the recognized standard of practice or care within that specialty as reasonably applied in light of the facilities available in the community or other facilities reasonably available under the circumstances, and as a proximate result of the defendant failing to provide that standard, the plaintiff suffered an injury. [M.C.L. § 600.2912a(1); MSA 27A.2912(1)(1).] (15).
Physicians are experts in the field of medicine, and, concomitant with any such dutiful occupational, there exists a responsibility to put the welfare of one’s patients before all else. Off-label uses, however, limit the extent to which medical information, on behalf of the manufacturer, can be disseminated to these physicians. The most obvious negative consequence capable of arising from such restricted dissemination is the increased potential for negligent practices. The proponents of off-label use further argue that physicians are “best able to evaluate the information and insure that patients receive appropriate treatment,” a declaration supported by the American “learned intermediary” tort doctrine (27). The off-label proponents contend that the FDA prohibits dissemination of critical information that is medically valid; it is harmful not only to the physician and the patient but to the public interest as well (28). Manufacturers have an important duty to act in a manner that is medically and ethically appropriate, by communicating truthful, non-misleading scientific and medical information that supports sound
medical practice. And it is for this reason that they should not be subjected to civil or criminal liability (29).
Off-label use can not only exist in a manner that does not violate the standard of care, but, in many cases, it can actually constitute the standard of care as such. Plaintiffs have tried to incorporate tactics that make it seem as if the utilization of an off-label pharmaceutical or device constitutes medical malpractice per se. This type of claim, though, has not been successful. In fact, such claims have failed miserably: courts have not agreed with plaintiff’s claims that an off-label use may in itself violate the duty of care because such use is both legal and generally accepted as the FDA does not intend to regulate the practice of medicine. Wilhoit v. Boehringer Ingelheim Pharmaceuticals, Inc., 2009 WL 702007, at *3-4 (D. Minn. March 13, 2009).
Here are just two of several cases wherein accusation of off-label promotion to generate sales is a primary factor. The first concerns Parke-Davis, the unit of Warner Lambert which produces Neurotin (gabapentin), an FDA approved treatment for seizures associated with epilepsy. Parke-Davis employed technical medical writers, acting as ghostwriters, to compose the Neurontin drug profile. Physicians were then remunerated in exchange for placing their names on the publications as authors. This act of legerdemain was perpetrated in order to promote the drug for a multitude of off-label uses, including the treatment of pain, anxiety, and depression, none of which were approved for use in the series of treatments cited (31). Parke-Davis also employed “medical liaisons” to solicit physicians to prescribe Neurotin for other similar off-label indications. One of the participating physicians brought a qui tam action against the company alleging violations of false claims. Evidence that was subsequently confiscated in the case included various sales presentations which not only directed sales representatives to promote unapproved and off-label uses, but even went so far as to equate off-label use to “money” in a contemptible display of corporate cupidity (32). This allegation was settled for $430 million dollars (33).
Another pharmaceutical that was alleged for off-label use is Allergan. The makers, however, brought an action against the FDA and the Department of Justice (DOJ) in federal district court in Washington (34). This lawsuit was brought to determine if a number of FDA regulations are unconstitutional. The company asked for preliminary and permanent injunctions that would enjoin the government from taking civil or criminal action against Allergan on truthful and non-misleading speech. This was a unique case as it detoured from the path taken by similar cases in which the First Amendment had been used as a defense by companies accused of proliferating false and misleading information (34). To date, similarly intrusive governmental investigations have led to the pay-out of billions of dollars in criminal and civil penalties (14).
In December of 2013, the United States Court of Appeals for the Second Circuit reached the conclusion that the regulation and near total ban of off-label use is overly-broad and vacated the conviction of Alfred Caronia, who had been tried and convicted of an unlawful conspiracy to introduce a misbranded drug into interstate commerce in violation of the U.S. Food, Drug and Cosmetic Act (the “FDCA”) (35). Caronia was hired by Orphan Medical, Inc. as a special sales consultant and began to participate in the company’s speakers program. He enlisted practicing physicians to promote the drug Xyrem to other healthcare physicians (35). A government cooperator recorded conversations between Caronia and another physician hired as a promotional speaker, wherein the uses of off-label indications for the use of Xyrem in an unapproved patient population were referenced (36). Federal investigators found that Caronia was recommending Xyrem to physicians for patients with fibromyalgia, restless legs syndrome, and even chronic fatigue. Under the Federal Food Drug and Cosmetic Act, drug makers are prohibited from marketing drugs for unapproved uses. The government did not assert that the speech was either false or misleading, basing their claim, rather, on the promotion of off-label use (37). Caronia was charged and convicted of participating in an unlawful conspiracy that introduced a drug into interstate commerce within the meaning of the FDCA (38). On appeal to the second circuit court, Caronia argued that his right to free speech under the First Amendment was violated as his words were truthful and did not misrepresent the safety or efficacy of the drug, and, therefore, the government could not prohibit him from truthfully promoting the drug (35). In a 2-1 decision, the Second Circuit held that Caronia’s right to free speech under the First Amendment was indeed violated (35,39,40). This decision could have a far-reaching impact that positively effects a change in not only how free speech in this country is legally construed, but in how medical device companies market their products (31).
As defined by preceding case history, First Amendment protection does not provide a defense for false, fraudulent, or even unintentionally misleading speech. Moreover, the FDA has a substantial interest to protect the public from the unsafe or otherwise ineffective use of medical devices and pharmaceuticals by way of regulating the manufacturers that promote off-label promotion, see United States v. Caputo, 288 F. Supp. 2d 912, 921 (N.D. Ill. 2003); WLF I, 13 F. Supp. 2d at 69 (41). Thus, the question to be answered is: “is there a less-burdensome alternative that the government could implement in order to regulate the manufacturers of devices and pharmaceuticals?” If the answer is “yes,” then the current ban is overly-broad and yet too restrictive for the accomplishment of the government’s interests. This is evidenced by the ineluctable failure of the proscriptive test for commercial speech established by the Supreme Court in Central Hudson Gas & Electric Corp. v. Public Service Commission (42).
When the Second Circuit addressed the restrictions on Caronia’s speech under the four-part test established by the Supreme Court in Central Hudson Test, the Court determined that the first two prongs of Central Hudson were easily satisfied (42). The first prong dealt with whether or not the speech in question promoted off-label use of approved drugs and constituted a lawful activity that warranted First Amendment protection. The second prong focused on the possibility of the government having a substantial interest in drug safety and the restriction of protected speech. The third and forth prongs previously mentioned, as determined by the Second Circuit Court, could not be satisfied. The third prong concerned the requirement that the regulations at issue directly advance government interest. The Second Circuit stated that an off-label drug use itself is not prohibited, as it does not follow that the promotion of off-label use by a particular class of speakers would further the government’s goals in preserving the FDA’s drug approval process. Furthermore, reducing patient exposure to unsafe and ineffective drugs (35). Finally, the fourth prong of the Central Hudson test determined if the regulations could be more narrowly tailored to further said government interest. The Second Circuit determined that to impose this complete and criminal ban on off-label use would be more restrictive than is necessary to achieve the goal of furthering the government’s interest (35). Therefore, as a matter of law, the Second Circuit overturned and vacated Caronia’s conviction.
Off-label devices and uses frequently have therapeutic uses other than the FDA-approved indication. In re Schering Plough Corp. Intron/Temodar Consumer Class Action, 678 F.3d 235, 239 (3d Cir. 2012). The fact that the FDA has not approved labeling of a drug for a use does not necessarily establish it is medically and scientific appropriate.” Weaver v. Reagen, 886 F.2d 194, 198 (8th Cir. 1989). “The decision to prescribe such ‘off-label usage’ . . . is regarded as a professional judgment for the healthcare provider to make.” Nightingale Home Healthcare, Inc. v. Anodyne Therapy, LLC, 589 F.3d 881, 884 (7th Cir. 2009) (applying Illinois law). “[T]he lack of FDA approval for a drug or device for a particular use does not imply that using the drug or device for that use is either disapproved or improper.” Richardson v. Miller, 44 S.W.3d 1, 12 (Tenn. App.2000), appeal denied (Tenn. March 12, 2001). “[O]ff-label usage is not illegal or even disfavored under federal law. Rather, it is an accepted and indeed valuable part of the practice of medicine.” Riley v. Cordis Corp., 625 F. Supp.2d 769, 784 (D. Minn. 2009).
The American Medical Association supports the need for physicians to have access to accurate and unbiased information about unlabeled uses of drugs and devices while simultaneously ensuring that manufacturer-sponsored promotions remain under FDA regulation. AMA policy states that the association “supports the dissemination of independently derived scientific information about unlabeled uses by manufacturers to physicians, if the independent information is provided in its entirety, is not edited or altered by the manufacturer, and is clearly distinguished from manufacturer-sponsored materials” (12).
The conflict between the First Amendment and public health is certainly here to stay, but it has been effectively minimized by the Second Circuit Court’s stance on free speech. The current imposition of a near-complete and criminal ban on off-label speech is, considering its ability to potentially save a considerable number of lives, most definitely indicative of the government’s over-reaching and overly broad interpretation. The application of off-label uses has met a new frontier with the use of the Central Hudson four prong test, which has narrowed the government’s interest. This will perhaps lend a more transparent view of what is acceptable when speaking with physicians regarding off-label use. In today’s medical environment there is still a two-fold element of risk that affects a medical device company: the risk of improper treatment by way of the agent’s lack of scientific disease state knowledge, and the medical device company’s fiduciary duty to ensure patient safety by including proper education is facilitated to the physician. This seems curtailed by the body of law that was promulgated by the Second Circuit’s view on off-label use and the narrowing of the range of substantial government interest.
In a world where increasingly sophisticated technological advances in the field of health care and medicine such as Targeted Temperature Management are allowing people to live longer, more active, and significantly more fulfilling lives, even after life-threatening events and illnesses that would have formerly been regarded as irretrievably fatal, there remains the lamentable fact that certain limitations are impeding the course towards what could very well be the apogee of medical and legal progress. This is made all the more disconcerting by the fact that the most basic of our supposedly guaranteed Constitutional freedoms, that of free speech, is being restricted with regard to the off-label utilization of pharmaceutical drugs and medical devices. So while the world of health care continues to evolve at an unprecedented rate into a state of nearly unbelievable and even futuristic proportions, the state of the law that governs its applications appears to be sorely lacking to an extent that, at least relatively speaking, borders on the almost static and antediluvian. If society as a whole, and not just singular aspects of it like medicine and health care, is to reach a suitable state in the very near-future, one elevated to an extent directly proportional to the amount of progress made since its inception in other key areas, greater attention will need to be given not only to the more effective enforcement of current laws, but also to the laws themselves. Indeed it seems nearly paradoxical that legal aspects governing how potentially life-saving medications and devices are allowed to be, or not to be, put into practice in an off-label manner are allowed to exist where lives are at stake. Nevertheless, the debate between free speech and off-label promotion continues to linger on. In the scope of things, it seems a rather reasonable goal, especially given the context, that such a divergent argument should reach a suitable conclusion, one that upholds the basic tenets of the law while emphasizing to the utmost degree the importance that medical progress plays in the sustainment of human life. If the necessity of human life should prove incompatible to the legal aspects governing it, any further discourse or dialectic on this subject, or any other for that matter, shall be rendered unnecessary.
- Allison D. Burroughs, et al., Off-Label Promotion: Government Theories of Prosecution and Facts That Drive Them, 65 Food & Drug L.J. 555, 555-87 (2010) (discussing directions that FDA defined as adequate for laymen to follow regarding use of drugs).
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- Federal Food, Drug and Cosmetic Act, 21 U.S.C. §§ 301–399 (2006).
- Stafford, Randall, Regulating Off-Label Drug Use — Rethinking the Role of the FDA. N Eng J Med 2008; 358:1427-1429 April 3, 2008DOI: 10.1056/NEJMp0802107
- Buckman Co. v. Plaintiffs Legal Committee 531 U.S. 341, 351 & n.5 (2001).
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- Wyeth v. Levine, 129 S. Ct. 1187, 1202 (2009) (noting that manufacturers “have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge”); Citizen Petition Regarding the Food and Drug Administration’s Policy on Promotion of Unapproved Uses of Approved Drugs and Devices, 59 Fed. Reg. 59,820, 59,821 (Nov. 18, 1994) (“Scientific departments within regulated companies generally maintain a large body of information on their products.”).
- Osborn, John, Can I tell you the truth? A comparative perspective on Regulating off-label scientific and medical information. Journal of Health Policy, Law and Ethics summer Vol. 10, No. 299, 2010.
- Michael D. Green & William B. Schultz, Tort Law Deference to FDA Regulation of Medical Devices, 88 Geo. L.J. 2119, 2133 (2000) (noting that physicians are permitted to prescribe drugs for off-label uses). See also Luciana Gravotta, Why Doctors Prescribe Off-Label Drugs, Sci. Am., May 13, 2013, available at http://www.scientificamerican.com/article.cfm?id=why-doctors-prescribe-off-label-drugs.
- M.C.L. § 600.2912a(1); MSA 27A.2912(1)(1).
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- Wilhoit v. Boehringer Ingelheim Pharmaceuticals, Inc., 2009 WL 702007, at *3-4 (D. Minn. March 13, 2009)
- Natasha Singer, Medical Papers by Ghostwriters Pushed Therapy, N.Y. Times, Aug. 4, 2009, at A1 (regarding recent allegations related to this practice).
- John Ford, a Parke-Davis marketing manager, reportedly encouraged the company’s medical liaisons to promote Neurontin for off-label uses for which there was no apparent scientific or medical basis:
- I want you out there every day selling Neurontin…. We can’t wait for them to ask, we need to get out there and tell them up front…. That’s where we need to be, holding their hand and whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything.
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- See Press Release, Dep’t of Justice, Warner-Lambert To Pay $430 Million To Resolve Criminal & Civil Health Care Liability Relating to Off-Label Promotion (May 13, 2004), http://www.justice.gov/opa/pr/2004/May/04_civ_ 322.htm. In a more recent case, Eli Lilly was accused of illegally promoting its drug Zyprexa (olanzapine). Zyprexa, the first in a new class of so-called atypical antipsychotics, was approved by the FDA in 1996 for the treatment of schizophrenia and in 2005 for the treatment of bipolar disorder. Following FDA approval of the second indication, the record suggests that Eli Lilly shifted its marketing strategy such that its sales representatives would indicate to general practitioners that Zyprexa was appropriate for elderly patients suffering from depression or dementia. In announcing its settlement, the government emphasized the primacy of the FDA’s role, suggesting that any information provided by companies outside of the FDA-approved message would necessarily “undermine the integrity of the doctor-patient relationship and place innocent people in harm’s way.” Eli Lilly settled these allegations in early 2009 for $1.415 billion. Press Release, Dep’t of Justice, Eli Lilly and Company Agrees To Pay $1.415 Billion To Resolve Allegations of Off-label Promotion of Zyprexa(Jan.15,2009),http://ww.justice.gov/civil/ocl/cases/Cases/Eli_Lilly/Lilly%20Press%CC20Release%CC20Final%C-̈civ-038.pdf.
- Rockoff, Allergan Suit Seeks to Lift Botox Curbs, Wall St. J., Oct. 2, 2009, at B4; Natasha Singer, Botox Maker’s Suit Cites Free Speech, N.Y. Times, Oct. 3, 2009, at B3.
- United States v. Caronia, No. 09-5006-cr, 2012 WL 5992141, at *1 (2d Cir. Dec. 3, 2012).
- 36.Id. at *4. Xyrem is a “powerful central nervous system depressant,” which at the time of Caronia’s alleged misconduct had been approved by the U.S. Food and Drug Administration (“FDA”) solely to treat narcolepsy patients for cataplexy (a condition associated with weak or paralyzed muscles). Id. at *3. Soon thereafter, Xyrem was approved by the FDA to treat narcolepsy parties with excessive daytime sleepiness. Id.
- 37.Id. at *4.
- 38.Id. at **4-5. The government never asserted that Caronia’s statements about Xyrem were false or misleading. Id. at *13 n.11. Rather, the government’s claims were based entirely on the theory that Caronia had promoted or participated in promoting Xyrem for unapproved uses and/or patients populations. Id. at * 9.
- 39.Id. at **5, 7. Prior to trial, Caronia moved to dismiss the charges against him on the ground that the FDCA provisions at issue impermissibly and unconstitutionally restricted his First Amendment right to free speech. Id. at *6. The district court denied that motion, and the case proceeded to trial. Id. Orphan and the physician it hired as a promotional speaker were also charged under the misbranding provisions of the FDCA, and both pled guilty. Id.
- 40.Id. at *8.
- United States v. Caputo, 288 F. Supp. 2d 912, 921 (N.D. Ill. 2003); WLF I, 13 F. Supp. 2d at 69
- Central Hudson Gas & Electric Corp. v. Public Service Commission
- Schering Plough Corp. Intron/Temodar Consumer Class Action, 678 F.3d 235, 239 (3d Cir. 2012).
- Weaver v. Reagen, 886 F.2d 194, 198 (8th Cir. 1989).
- Nightingale Home Healthcare, Inc. v. Anodyne Therapy, LLC, 589 F.3d 881, 884 (7th Cir. 2009)
- Richardson v. Miller, 44 S.W.3d 1, 12 (Tenn. App.2000), appeal denied (Tenn. March 12, 2001).
- Riley v. Cordis Corp., 625 F. Supp.2d 769, 784 (D. Minn. 2009).
- U.S. Food and Drug Administration, Guidance for Institutional Review Boards and Clinical Investigators: “Off-Label” and Investigational Use of Marketed Drugs, Biologics and Medical Devices. 1998 Update. http://www.fda.gov/oc/ohrt/irbs/offlabel.html
- U.S. Food and Drug Administration, Guidance for Industry: Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared medical Devices. January 2009. http://www.fda.gov/oc/op/goodreprint.html