Abstract: In today’s medical environment, a two-fold element of risk affects a medical device company. This risk is comprised of the risk of improper treatment through the agent’s lack of scientific disease-state knowledge, as well as the medical-device company’s fiduciary duty to ensure patient safety through facilitating proper education for the physician. The Food, Drug, and Cosmetic Act serves as the body of law that regulates the marketing of medical-device products in the United States, which restricts 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.
What is off-label use?
Off-Labeling involves anything a company or an employee produces or presents in a promotional message that is not consistent with the approved product designation, regardless of whether it is truthful, accurate, and reflective of good medical practice (1). The use of any drug or treatment that incorporates a medical device is considered to be off-label if it is false or misleading, or if it does not have an indication for specific uses (1). Pharmaceutical and medical-device companies are prohibited from promoting the off-label use of their products, such as advertising a certain device for use with children when it is only indicated for adults (1).
Abundant examples exist for the reality of this predicament. Sudden cardiac death is a leading cause of death among adults over the age of 40 in the United States and other countries, but its treatment is considered an off-label use by some medical-device and pharmaceutical companies (2). Despite occurring at an average of 60 years of age, it continues to claim the lives of people during their most productive years. Similarly, Temperature Management is a new treatment option available in most hospital systems that may not only mitigate brain damage resulting from anoxic encephalopathy after Sudden Cardiac Arrest (SCA) but may also control fever in several disease states (3). Utilization in this capacity, however, is regarded as off-label by Temperature Management companies in the United States. This may constitute a compliance issue on behalf of the medical-device company, one with a potentially vast array of consequences insofar as the promotion of off-label education to physicians and other healthcare practitioners is concerned.
When SCA occurs, blood stops flowing to the brain, the heart, and the rest of the body, causing the person to collapse. In fact, SCA renders the victim clinically dead, a state during which time, in the absence of immediate assistance, the body and brain will be subject to serious and perhaps irreversible harm (4). Each year, 424,000 people in the U.S. (more than 1,000 per day) experience EMS-assessed, out-of-hospital, non-traumatic SCA, and nine out of ten of these victims die. This is roughly equivalent to the combined number of people who die from Alzheimer’s disease, assault with firearms, breast cancer, cervical cancer, colorectal cancer, diabetes, HIV, house fires, motor-vehicle accidents, prostate cancer, and suicides. In fact, the incidence of sudden cardiac death is nearly ten times higher than the incidence of death from breast cancer (4-7).
The U.S. Federal Drug Administration restricts off-label promotion—which includes print media, brochures, websites, lectures, and face-to-face communication—by employees of a medical-=device or pharmaceutical company when there is no indication for use (8). The statutory framework under the FDA regulates sales and marketing by a series of statutory provisions, as interpreted by the FDA through the Food, Drug, and Cosmetic Act of 1938 (FDCA) (9). Physicians may only prescribe off-label medications and devices if the physicians are not employed by the medical or pharmaceutical companies in question. Even if the physician is an agent of the company, any verbalization of accurate and truthful information regarding off-label use provides grounds for the prosecution and conviction of a federal crime (8). In this review, the term “off-label” will be used to convey specific indication as well as false or misleading promotion.
Physicians who practice in a hospital have a choice regarding the prescription of off-label uses for medical devices; this choice can bestow certain important advantages (8). First, it allows greater innovation in clinical practice, particularly when other approved treatments have failed. An example of such an occurrence might take place after a stroke patient has been administered Tylenol or a similar medication for the control of fever. If this treatment should prove ineffective, the off-label employment of a fever-control device could provide the necessary relief. This form of action is imperative, given the deleterious effects that inadequately controlled states of fever can exert upon the neurological recovery of patients (3). Although this example is hypothetical, the off-label use of certain treatments is nevertheless invaluable because it offers patients and physicians access to potentially lifesaving options that might be dismissed otherwise. This could enable physicians to adopt new practices based on emerging evidence, rendering off-label usage—unlike other treatment options—devoid of stasis due to its adaptability. Moreover, treatment options of this variety are the only ones available for “orphan” conditions (10).
At the same time, however, off-label use can produce negative consequences, most of which result from the lack of systematic evaluation. This is the case when evidence from one clinical situation is applied to another presumptuously. The expectation is, of course, that since safety and efficacy have been fully evaluated in the case of the former, the same results can be expected for the latter, regardless of the disease state involved. Clearly, these notions are erroneous. When newer, more expensive options are used in an off-label manner, it increases healthcare costs by de-incentivizing manufacturers to perform due diligence in designing and participating in clinical studies, encouraging them instead to seek approval for secondary indications for which clinical trials are less complicated and less expensive (10). Currently, the general legality and value of off-label uses is integral for medical practice. Any ambiguity related to the matter was removed by the decision of the Supreme Court in Buckman Co. v. Plaintiffs Legal Committee, which states that “[O]ff-label use is generally accepted” in medicine, and under the law, “[p]hysicians may prescribe drugs and devices for off-label uses” (531 U.S. 341, 351 & n.5, 2001). However, manufacturers are limited as to what they may give to physicians as educational resources (8).
Physicians may benefit from proper education provided by the company that directly manufactures the device. Since it is the fiduciary duty of the company to ensure patient safety, proper education should be offered to the physician (10). Other educational resources of particular benefit are medical and science journals, newsletters, seminars, websites, and peer influence on behalf of colleagues. It can be difficult, if not altogether improbable, for a single physician to keep up with the hundreds of publications written each year (12). The direct link for up-to-date information would be the source itself, namely the company that manufactures a specific device (13). But how is this to be accomplished when FDA policy bans all speech relating to the subject, regardless of whether it is false or misleading in nature? (8). It has been stated that the greatest threat to the medical and pharmaceutical industry in the domestic United States may be its own policy environment, a dilemma undoubtedly brought about by the restriction of truthful dialogue with physicians about their product (14).
The authority of the FDA, however, does not extend to the practice of medicine, and the regulations it imposes do not prohibit physicians from prescribing approved devices and drugs to treat conditions for which they believe the products are indicated (15). Here the issue of negligence becomes a relevant topic, as the probability of inadvertent patient harm increases when physicians lack the proper knowledge and training for the application of off-label medications and devices. Without understanding either the physiological changes that occur with individual disease states or the potential ramifications of the treatments prescribed for them, the physician places the patient in an unnecessarily precarious position that can lead to claims of negligence in the event that the patient is harmed (16). Such harm arises because of the direct link that exists between off-label indication and the absence of education from the manufacturer.
The next section explains several organizational goals that ensure compliance with FDA guidelines for the distribution of off-label information and material by manufacturers. The use of field representatives is a fundamental component of the medical-device or pharmaceutical sales models. Yet interactions between the field representatives and healthcare practitioners (HCPs) often pose compliance risks for manufacturers, such as the risk of off-label promotion and the provision of perceived kickbacks. Monitoring, both retrospectively and in real-time, identifies the risks inherent in these interactions and serves as part of a risk-mitigation strategy (17, 18).
Scientific Dialogue vs. Marketing:
There are a few exceptions to the proverbial rule by which the FDA permits the distribution of off-label information by manufacturers. The first of these, known as the “bona-fide scientific dialogue” (hereafter BFSD), deals with promotional activity accomplished by marketing. As its title implies, the BFSD permits manufacturers to discuss information regarding the off-label use of its products through a scientific dialogue or an exchange of information that is not conducted in a promotional setting. The second exception occurs as a response to unsolicited requests for information about unapproved uses. Manufacturers in these cases may distribute information concerning off-label use “in response to unsolicited requests for scientific information from health care professionals,” so long as the response is characterized by balanced, scientific material that is non-promotional (19). The initial inquiry, moreover, must not have been prompted through a sales or marketing effort made to encourage, target, or otherwise solicit a physician with questions or requests regarding off-label use (19).
Standard of Care and Legal Theories: Potential Third-Party Consequences
Underlying the off-label argument is a fiduciary responsibility and an obligation for individuals who are trusted to act in the best interest of their clients. Theoretically speaking, the responsible party should be transparent in its dealings and personally accountable for its results. Physicians often fail to think of themselves in this role (that is, as constituents of the responsible party). Nevertheless, the generation of income through unnecessary medical services is substantial evidence of an improper purpose. (see Scott, 107 N.M. at 122, 753 P.2d at 901 (20)). From the manufacturer’s standpoint, soliciting the off-label use of a product to increase profits is a violation of false-claims policy (19).
As soon as the physician-patient relationship comes into existence, the physician can be held liable for an intentional refusal of care or treatment under the theory of Abandonment. (Abandonment is an intentional act; negligent lack of care or treatment is medical malpractice.) When a treatment relationship exists, the physician must provide all necessary treatment to a patient unless the relationship is terminated by the patient or by the physician himself, provided that the physician gives the patient sufficient notice to seek another source of care. Most doctors and hospitals routinely ensure that alternative sources of treatment are made available for patients whose care is being discontinued (21). As previously mentioned, the arguments for and against off-label use constitute a diverse dialectic with no general consensus. This is even more problematic since off-label use is capable of bringing innovation to clinical practice, especially when other approved treatments have failed (10).
One potential issue of abandonment in a patient’s care is the denial of prescribed medication. In numerous cases in most conceivable contexts, this may constitute the standard of care (Layzer v. Leavitt, 770 F. Supp.2d 579 (S.D.N.Y. 2011)). Layzer involved Medicare coverage of an off-label use in a recurrent context, namely that of a rare disease for which no on-label treatment existed because the small market size did not justify the costs associated with undertaking the studies the FDA requires to support a labeled indication. Medicare denied coverage in this case because the particular off-label use fell outside of the government’s definition; it was neither on-label, nor apparent in any of the specific compendia of compensable off-label uses. The court held, as a matter of law, that the government’s position (including regulation) concerning what was “medically accepted” was invalid (770 F. Supp. At 587).
Off-label uses offer significant benefits to patients by allowing greater access to potentially valuable treatment options. Physicians also stand to be impacted positively. Through the adoption of new practices based on emerging evidence, physicians can avail themselves of a greater wealth of conceivable treatment resources, an accomplishment which can only enhance the prosperity of ailing patients (10). Proponents of off-label use argue that medical-device companies are in the best position to ensure patients receive the most effective treatment by educating the physician in the mitigation of potential risk (23). At the same time, off-label use has potentially negative consequences. Uses of this nature have not been evaluated systematically, and evidence provided for one clinical situation may not apply to others. As a result, expectations regarding safety and efficacy are undercut (10). Despite these concerns, off-label prescribing is a necessary practice of medicine (14).
The conflict between the First Amendment and public health is certainly here to stay, but it has been minimized effectively 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 potential to save a considerable number of lives, most definitely indicative of the government’s overreaching and overly broad interpretation of policy. 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 to what is acceptable when speaking with physicians regarding off-label use. In today’s medical environment, a two-fold element of risk affects medical-device companies: (A) the risk of improper treatment through the agent’s lack of scientific disease-state knowledge, and (B) the medical device company’s fiduciary duty to ensure patient safety by providing proper education for the physician. This seems curtailed by the body of law promulgated by the Second Circuit’s view of off-label use and the narrowing of the range of substantial government interest.
In a world where increasingly sophisticated technological advances in healthcare and medicine such as Targeted Temperature Management are allowing people to live longer, more active, and more fulfilling lives—even after life-threatening events and illnesses that would have formerly been regarded as irretrievably fatal—certain limitations impede the course towards what could be the apogee of medical and legal progress. This is made all the more disconcerting by the restriction of the most basic of our Constitutional freedoms, free speech, with regards to the off-label utilization of pharmaceutical drugs and medical devices.
While the world of healthcare 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 lacking to an extent bordering on the static and antediluvian. If society as a whole, instead of singular aspects like medicine and healthcare, is to reach a suitable state in the near future, one elevated to an extent directly proportional to the progress made in other key areas since its inception, greater attention must be given not only to the more effective enforcement of current laws, but also to the status of laws themselves. Indeed, it seems nearly paradoxical that legal aspects governing the practice of potentially life-saving medications and devices in an off-label manner are allowed to exist where lives are at stake. Nevertheless, the debate between free speech and off-label promotion lingers. In this context, it seems a reasonable goal that this 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 with the legal aspects governing it, any further discourse or dialectic on this subject 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).
- Sudden Cardiac Arrest Foundation statistics. (visited July 10, 2014) http://www.sca-aware.org/donate
- Greer D, MD, MA; Funk S, MBA; Reaven N, MA; Ouzounelli M, MD; Uman G, RN, PhD Impact of Fever on Outcome in Patients With Stroke and Neurologic Injury A Comprehensive Meta-Analysis
- AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2014 update: A report from the American Heart Association, Circulation. Published online December 18, 2013
- CDC National Vital Statistics Report, Vol. 60, No. 3, Dec. 29, 2011.
- CDC Fire Deaths and Injury Fact Sheet
- 7. 520 deaths from breast cancer were projected for 2011. U.S. Breast Cancer Statistics, breastcancer.org, retrieved July 2, 2014.
- Conko, Gregory, Hidden truth: The perils and promotion of off-label drug and medical device promotion. Health Matrix: Journal of Law Medicine Vol. 21, No. 149, 2011.
- 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).
- AM. MED. ASS’N, ANNUAL MEETING OF THE AMERICAN MEDICAL ASSOCIATION: REPORTS OF THE COUNCIL ON SCIENTIFIC AFFAIRS, available at http://www.ama-assn.org/ama1/pub/upload/mm/443/csaa-97.pdf.
- 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).
- 21 U.S.C. §301 et seq
- 42 U.SC. § 1320a-7b(b)
- Scott, 107 N.M. at 122, 753 P.2d at 901
- Abandonment https://lsms.org/legal/terminationofrelationship.asp
- Layzer v. Leavitt, 770 F. Supp.2d 579 (S.D.N.Y. 2011)
- Margaret Z. Johns, Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest, 58 Hastings L.J. 967, 980 (2007)
- Peberdy MA , Callaway CW , Neumar RW , et al ; American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for CardiopulmonaryResuscitation and Emergency Cardiovascular Care [published corrections appear in Circulation. 2011;124(15):e403 and Circulation. 2011;123(6):e237] . Circulation. 2010 ;122 ( 18 suppl 3 ): S768 – S786.
- Neumar RW , Nolan JP , Adrie C , et al . Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, Inter American Heart Foundation, Resuscitation Council of Asia, and the resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council . Circulation .2008 ; 118 ( 23 ): 2452 – 2483.
- Advanced Cardiac Life Support, Ken Grauer and Daniel L. Cavallaro, Mosby Lifeline, St. Louis, MO.
- Johns, supra note 109, at 981.
- Robert Steinbrook, Gag Clauses in Clinical-Trial Agreements, 352 New Eng. J. Med. 2160, 2160 (2005) (“Sponsors with a financial interest in the outcome of clinical research can suppress negative results.”).
- Stafford, supra note 13; see also Donna T. Chen et al., U.S. Physician Knowledge of the FDA-Approved Indications and Evidence Base for Commonly Prescribed Drugs: Results of a National Survey, 18 Pharmacoepidemiology & Drug Safety 1094 (2009).
- 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.
- 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.
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