Pharmaceutical companies that promote their products for off-label use continue to be the subject of intense regulatory scrutiny. But they are no longer alone. Recent statements by government prosecutors suggest an increased focus on the sales and marketing practices of device companies. The medical device industry should expect heightened scrutiny from the "usual" actors, including the Food and Drug Administration (FDA), the Office of the Inspector General (OIG) of the Department of Health and Human Services, the Department of Justice (DOJ) and U.S. Attorneys Offices, and state Medicaid fraud control units and consumer protection bureaus. Other parties, such as the Federal Trade Commission, the Securities Exchange Commission, Congress, whistleblowers, customers, shareholders, and competitors (via Agency "rat" letters), are also targeting device companies.
The consequences of promoting a product for off-label use could be significant. Allegations often include violations of the Federal Food, Drug, and Cosmetic Act, the False Claims Act, and the Anti-Kickback Statute. The underlying legal theory is based upon fraud -- if a company's improper off-label promotion causes a physician to prescribe a product for a non-approved use and obtains reimbursement through Medicare or Medicaid, the company has committed fraud against the government. Violative off-label promotion could result in FDA warning letters, civil penalties often totaling hundreds of millions of dollars, criminal penalties, Corporate Integrity Agreements and deferred DOJ prosecution, Congressional investigations, and product liability and shareholder lawsuits.
Recent settlements with federal and state authorities offer a roadmap for structuring a company's compliance program to avoid some of the common pitfalls associated with off-label promotion.
All company "labeling", such as advertisements, sales brochures, press releases, speeches, conference posters or boards, and website content, must be truthful and not misleading. This is particularly important when reporting clinical trial results. For example, in October 2006, InterMune, Inc. agreed to pay nearly $37 million to resolve criminal charges and civil liabilities in connection with its alleged illegal promotion and marketing of Actimmune. FDA approved Actimmune for the treatment of chronic granulomatous disease and severe, malignant osteopetrosis. The government alleged that InterMune promoted Actimmune for the treatment of idiopathic pulmonary fibrosis (IPF), a condition for which the company had not received FDA approval. The company conducted a clinical trial of Actimmune on the treatment of IPF, which failed to establish statistically significant evidence of benefit for either the primary or any of the secondary endpoints. The government alleges the company distributed a press release characterizing the clinical trial results as beneficial to patients suffering from IPF.
Reviewing postings on company websites is an easy method for regulatory officials to "catch" any violative promotion. On July 21, 2006, FDA sent a warning letter to Tyco Healthcare/Kendall regarding information posted on the company's website for the Kendall Dover® Silver Hydrogel Coated Silicone Foley Catheters (Dover Catheters). FDA cleared the Dover Catheters for use in the drainage and/or collection and/or measurement of urine. According to the letter, the website promoted the Doley Catheters for other clinical uses that were not cleared or approved by the FDA. In addition, FDA stated that although the company originally agreed not to promote the antimicrobial properties of the Dover Catheters, the website included such claims.
Sales strategies are another factor that regulators evaluate to determine whether a company is illegally promoting a product for off-label use. Potential warning signs include increased contact with medical professionals specializing in an area for which the product is not approved and the use of a large sales force to target a small market for an approved use. On January 15, 2009, DOJ announced that Eli Lilly and Company agreed to pay $1.415 billion to resolve allegations of off-label promotion of its drug, Zyprexa, which FDA approved for the treatment of schizophrenia and certain types of bipolar disorder in adults. The government alleged that from September 1999 through at least November 2003, Eli Lilly unlawfully promoted Zyprexa for the treatment of agitation, aggression, hostility, dementia, Alzheimer's dementia, depression and sleep problems, uses which were not approved by FDA, but are prevalent in the elderly population.
According to the government, Eli Lilly promoted Zyprexa in nursing homes and assisted living facilities primarily through the company's long-term care sales force, even though schizophrenia rarely occurs in elderly patients. Eli Lilly's executives allegedly then decided to market Zyprexa to primary-care physicians, even though the company knew that there was virtually no approved use for Zyprexa in the primary care market. To succeed in this campaign, the company allegedly trained its primary physician sales representatives to promote Zyprexa by focusing on symptoms, rather than on the drug's FDA-approved indications. They also allegedly trained their sales staff on how to respond to doctors' concerns about off-label uses of Zyprexa.
In addition to interactions with healthcare providers, company employees and representatives should discuss only FDA-approved indications during meetings with government officials, unless they are responding to questions regarding off-label uses. In one instance, FDA issued a warning letter to a company alleging off-label promotion of its drug. According to the Warning Letter, the challenged activity stemmed from a presentation to a committee within the Maryland Department of Health and Mental Hygiene to support the inclusion of the drug on the state's Preferred Drug List. The speaker provided the committee with a handout that FDA believed falsely suggested the drug was safe and effective for uses outside the scope of the product's FDA-approved indications. Later that year, the company agreed to settlements of more than $425 million to resolve federal and related state Medicaid investigations into its off-label promotion and sales marketing practices.
It should not come as a surprise that regulators will focus on the actual approval status of a product that is being marketed. Particular attention is paid to marketing of certain indications for which the FDA refused approval or clearance, the dissemination of information about any FDA-denied use (unless it discloses the denial and the underlying reason), and a company decision not to seek FDA approval or clearance for a product. Medical devices that are cleared by FDA through the premarket notification (510(k)) process should not be marketed as "approved" because such claims are authorized only for those medical devices for which a company submitted a PreMarket Approval (PMA) application and received FDA approval.
In 2007, Cell Therapeutics Inc. (CTI) agreed to pay $10.5 million to resolve allegations concerning the company's anti-cancer prescription drug Trisenox. The complaint alleged several violations, including that CTI falsely marketed Trisenox to doctors by suggesting the drug was FDA-approved and listed as medically accepted in the compendia for treating various types of cancers not specifically approved by the Agency. While Trisenox received FDA approval for only one type of cancer, it was not listed as a medically accepted treatment in the compendia for any other condition. Under the rules in effect at the time the alleged conduct occurred, the complaint asserted that Medicare paid only for anti-cancer drugs when prescribed for FDA-approved uses or uses that were determined to be medically accepted as published in the drug compendia.
The first step in devising a compliance program is the appointment of a compliance officer with disciplinary authority and direct access to management. Written compliance policy manuals and annual comprehensive training programs are necessary for all applicable employees, especially senior management and employees and contractors involved in sales, marketing, and product information distribution. The compliance department should review and approve all scripts used by sales representatives and periodically accompany sales representatives during meetings with physicians. It also should review and approve all materials and presentations provided by company employees and consultants during physician conferences and meetings with governmental agencies. Finally, companies should consult the Corporate Integrity Agreements that companies have entered into with OIG. While these agreements, which are posted at Corporate Integrity Agreements, may present a stricter compliance program than what would normally exist absent a governmental enforcement action, they provide a roadmap for identifying the salient elements of a compliance program.
James R. Ravitz is a partner at Arent Fox and practices within the firm's FDA and Health Groups . His well-rounded practice focuses on food and drug law and healthcare, consumer product safety, and advertising.
Ravitz is on the Editorial Advisory Boards of several industry publications such as FDANews Device and Diagnostics Letter, BNA Medical Device Law & Industry, and Medical Product Outsourcing. He has published and spoken on a wide variety of topics in the health products area. Some recent articles and speeches include:
Amy Swift Colvin is an associate in Arent Fox's food and drug group. She counsels manufacturers, distributors, importers, and specialty retailers on the requirements established by the Federal Food, Drug and Cosmetic Act, the Federal Hazardous Substances Act, the Consumer Product Safety Act and the Consumer Product Safety Improvement Act of 2008.