To introduce a new drug or medical device into interstate commerce, manufacturers must first demonstrate to the satisfaction of the Food and Drug Administration (FDA) that it is safe and effective for each intended use and patient population. In the case of new drugs, the review process includes “examination of the proposed drug labeling, which specifically cites, among other things, the conditions and population the drug has been approved to treat.” Once a drug has been approved, any promotional materials used or distributed by the manufacturer must be consistent with, and are limited to, the information contained in the approved labeling. A drug’s approved and intended uses are contained in the package insert summary. Once approved, the drug company may not market or promote the drug for “off-label” use – that is, for an unapproved use outside of the approved product label.
Gathering storm of enforcement activity
Over the past decade, off-label promotional activities by drug and device manufacturers have come under increased scrutiny by the US Department of Justice (DOJ). The government enforces the prohibition against off-label promotion by bringing cases under the Food, Drug and Cosmetic Act, the Anti-Kickback Statute, and the False Claims Act (FCA).
Specifically, the qui tam  provisions of the FCA have been instrumental in the government’s efforts against off-label promotion. These so-called “whistleblower” cases allow company insiders, former disgruntled employees of drug and device companies, and others with knowledge of inappropriate promotional activity to bring civil fraud lawsuits on behalf of the federal government against drug and device companies, and to collect a reward based on the amounts ultimately recovered by the government. Sales representatives and other company insiders are encouraged both by the government and private plaintiffs’ attorneys to come forward with information about suspected fraud. Once a qui tam complaint is filed, the government then has the option of taking over the case on behalf of the private citizen – often after conducting a lengthy and expensive investigation of the underlying allegations.
- In 1999, the government settled one of the first off-label promotion cases with a drug company for $50 million. Since then, the DOJ’s efforts have continued unabated and the dollar amounts have grown significantly:
- May 2004: $430 million off-label settlement to resolve criminal and civil liabilities related to a synthetic human growth hormone.
- August 2006: $435 million settlement to resolve criminal and civil charges involving off-label promotion of two cancer drugs.
- May 2007: $634.5 million settlement to resolve criminal and civil charges related to the misbranding of a prescription pain relief medication.
- January 2009: $1.415 billion to resolve allegations of off-label promotion of an anti-psychotic drug.
- January 2009: $2.3 billion to settle a federal investigation involving off-label promotion of a prescription painkiller.
Given the size of these settlements (which are typically based on sales volume), it is no surprise that the government is continuing to target drug and device companies. On Feb. 19, the Justice Department announced that it had intervened in two whistleblower suits against a drug manufacturer and its parent company, alleging that the companies marketed a cardiac drug for scheduled, serial outpatient infusions for patients with less severe heart failure – a use not included in the FDA-approved label – and thereby caused false and fraudulent claims to be submitted to federal healthcare programs.
Another recent complaint was unsealed on Feb. 25 against a New York pharmaceutical company for FCA violations arising from the company’s alleged marketing of antidepressants for unapproved pediatric use and for paying kickbacks to induce physicians to prescribe the drugs. Despite the FDA’s denial of a pediatric indication, according to the complaint the company actively promoted pediatric use of the drugs and misled physicians and the public by failing to disclose the negative results of a clinical study.
Off-label promotion vs. off-label use
Although off-label promotion is illegal, it is important to note that the government does not regulate treatment decisions by physicians. Once a drug or medical device has been approved or cleared by the FDA, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product’s approved labeling (or the product’s statement of intended uses, in the case of devices).
The fact that it is perfectly legal for a doctor to prescribe a drug for an off-label use is of course what tempts drug companies to increase sales by promoting the drug for that use. What constitutes actual “promotion,” however, has been the subject of much debate and discussion. The distribution of medical literature to physicians, suggesting that a drug may have merit for an unapproved use, is one practice that is potentially fraught with peril for drug manufacturers.
During calendar years 2003 through 2007, the FDA issued 42 regulatory letters citing companies for off-label promotion. The United States Government Accountability Office’s (GAO) analysis of the 42 regulatory letters indicates that half of the improper promotional activity was targeted towards physicians and other medical professionals, as shown in the Figure. 
The FDA has long recognized that the dissemination of truthful and non-misleading medical journal articles and publications regarding unapproved new uses of drugs is important to advancing the cause of public health. On Jan. 13, the FDA issued final guidelines to explain when manufacturers may distribute copies of medical journal articles that describe unapproved uses, without running afoul of the rules against off-label promotion.
The FDA guidance contains helpful suggestions for manufacturers. Articles published in peer-reviewed journals that are generally available in bookstores or through other independent distribution channels exemplify the type of article considered most appropriate by the FDA for distribution to physicians. Also, scientific or medical information that is distributed should be:
Accompanied by the approved labeling for the drug or medical device,
Distributed separately from information that is promotional in nature [and]
In the form of an unabridged reprint, copy of an article, or referenced publication.
The FDA also gives examples of publications that, in its view, are not scientifically rigorous enough and/or independent – publications which, in its view, would not be consistent with “good reprint practices.” These include things such as letters to the editor, abstracts of a publication, and reports of Phase 1 trials in healthy subjects.
It is important to note, however, that sales representatives should never be entrusted with the dissemination of even appropriate reprints. The job of responding to unsolicited requests for information about off-label uses of drugs is typically the responsibility of designated Medical Liaisons – specialists who typically have some scientific training or background and no sales responsibility. When sales representatives are calling on physicians and asked about potentially off-label uses for a drug, they should refer the physicians to the appropriate scientific personnel at the pharmaceutical company.
How a pharmaceutical company can arm itself
Government attorneys have long cautioned companies that they will be better off in any off-label investigation if they had a robust compliance program in place at the time, even if the program did not ultimately detect or deter the improper sales or marketing activity. The message to companies is clear: ignorance is not a defense.
This advice is consistent with the position taken in HHS OIG’s 2003 Compliance Program Guidance for Pharmaceutical Manufacturers in which companies are urged to adopt comprehensive and effective compliance programs. Specifically, the compliance program guidance for pharmaceutical manufacturers contained seven specific elements that pharmaceutical manufacturers should consider when developing and implementing an effective compliance program. At a minimum, a comprehensive compliance program should:
- Implement written policies and procedures
- Designate a compliance officer and compliance committee
Conduct effective training and education
Develop effective lines of communication between the compliance officer and all employees
- Conduct internal monitoring and auditing
Enforce standards through well-publicized disciplinary guidelines
Respond promptly to detected problems and undertake corrective action.
Given the government’s continued scrutiny of the sales and marketing practices of drug and device companies, it is imperative that companies adopt clear policies regarding off-label promotion and that they train and monitor their sales force to ensure compliance with those policies. The recent guidance provided by the FDA offers companies a good opportunity to revisit their policies and offer supplemental training and guidance to both the field and their Medical Liaisons, to minimize the risk of inappropriate conduct and better protect the company in the event that an employee crosses the line.
In addition, the vast majority of off-label cases involve situations where companies had inadequate controls over, and tracking of, the information disseminated to physicians and other healthcare providers. Companies should, at a minimum, ensure that in addition to training employees about what is appropriate promotional activity, they also implement systems to track, monitor and control what is disseminated to healthcare providers, both at the field level and by their Medical Liaisons. PC
The opinions expressed in this article are intended for general guidance only. They are not intended as recommendations for specific situations. As always, readers should consult a qualified attorney for specific legal guidance.
1 21 U.S.C. 331(d).
2 Government Accountability Office, Prescription Drugs FDA’s Oversight of the Promotion of Drugs for Off-Label Uses, July 2008, GAO-08-835. pg. 7. Available at: http://www.gao.gov/new.items/d08835.pdf. Accessed March 19, 2009.
3 21 CFR § 202.1(e)(4).
4 21 U.S.C. § 331.
5 42 U.S.C. § 1320a-7b.
6 31 U.S.C. §§ 3729, et seq.
7 Qui tam is short for the Latin phrase “qui tam pro domino rege quam pro se ipso in hac parte sequitur” meaning “who as well for the king as for himself sues in this matter.”
8 Settlement amounts may include penalties for offenses not involving off-label promotion.
9 U.S. Department of Justice. United States Joins Suits Against Scios and Johnson & Johnson. No. 09-138. February 19, 2009. Available at: http://www.usdoj.gov/opa/pr/2009/February/09-civ-138.html. Accessed March 19, 2009.
10 U.S. Department of Justice. United States Files Complaint Against Forest Laboratories for Allegedly Violating the False Claims Act. No. 09-163. February 25, 2009. Available at: http://www.usdoj.gov/opa/pr/2009/February/09-civ-163.html. Accessed March 19, 2009.
11 Government Accountability Office, Prescription Drugs FDA’s Oversight of the Promotion of Drugs for Off-Label Uses, July 2008, GAO-08-835. pg.19. Available at: http://www.gao.gov/new.items/d08835.pdf. Accessed March 19, 2009.
12 Government Accountability Office, Prescription Drugs FDA’s Oversight of the Promotion of Drugs for Off-Label Uses, July 2008, GAO-08-835. pg. 20. Available at: http://www.gao.gov/new.items/d08835.pdf. Accessed March 19, 2009.
13 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 U.S. January 2009. Available at:
http://www.fda.gov/oc/op/goodreprint.html. Accessed March 19, 2009.
14 OIG, Compliance Program Guidance for Pharmaceutical Manufacturers, 68 Fed. Reg. 23731. May 5, 2003. Available at: http://www.oig.hhs.gov/authorities/docs/03/050503FRCPGPharmac.pdf. Accessed: March 10, 2009.
15 OIG, Compliance Program Guidance for Pharmaceutical Manufacturers, 68 Fed. Reg. 23731. May 5, 2003. Available at: http://www.oig.hhs.gov/authorities/docs/03/050503FRCPGPharmac.pdf. Accessed: March 10, 2009.
ABOUT THE AUTHORS
Sheila W. Sawyer (LEFT) and Tanielle D. Henriques are attorneys at the law firm of Waller Lansden Dortch and Davis, LLP.