Date Published: October 28, 2008
Publisher: Public Library of Science
Author(s): Adriane Fugh-Berman, Douglas Melnick
Abstract: Adriane Fugh-Berman and Douglas Melnick describe techniques by which pharmaceutical companies covertly promote off-label drug use even where such promotion is illegal.
Partial Text: For prescription drugs, demonstrated benefits define the parameters of acceptable risks. For example, liver toxicity may be acceptable in a drug approved for cancer, but unacceptable in a drug approved for acne. Government regulatory bodies review laboratory, animal, and human data to confirm that a drug has the claimed efficacy and safety prior to approving its release in the market for specific approved (“labeled”) uses.
Off-label use is sometimes unavoidable; three-quarters of marketed prescription drugs have no labeling indications for children, a population only recently included in clinical trials . Pregnant women are also routinely excluded from studies, so most drug treatment during pregnancy is off-label.
From a business standpoint, increased off-label use means larger revenues from larger user populations, especially for products with narrow indications. For example, a company that knows that an approved leukemia drug reduces facial wrinkles could fund an efficacy trial in people with wrinkles in order to garner a new indication. However, clinical trials are expensive, and the results could decrease sales by showing that the drug is ineffective, or has significant safety problems. A company-funded long-term trial that tested the efficacy of Vioxx (rofecoxib) for colon polyps turned up cardiovascular risks that eventually resulted in the drug being withdrawn .
One of us (DM) worked in the pharmaceutical industry as a physician in medical affairs, supporting marketing, for over five years, and both authors have current contacts within the industry. Any unreferenced material that follows is from our personal experience, contacts, or information available in public fora such as industry discussions and presentations at trade shows.
In the pharmaceutical industry, there are two ways to market an approved drug for a new use: the “indication” route—performing studies necessary for regulatory approval—or the “publication” strategy, which stimulates off-label prescribing by using research “to disseminate the information as widely as possible through the world’s medical literature” .
Posters and abstracts presented at medical meetings create buzz, especially if a press release garners media attention. Meeting abstracts and posters are considered cutting-edge, but the information is almost always incomplete and usually lacks peer review. While abstracts must be submitted six months before meetings, posters can be altered, without review, up to the day of the meeting. Poster reproductions are made available to meeting attendees, and are an ideal form of stealth marketing.
Publications and posters provide the foundation for the medical education programs that are key for promoting off-label uses [12,13]. “Medical education drives this market!” stated a Parke-Davis business plan revealed in a legal case regarding off-label promotion . MECs know that accredited CME programs funded by unrestricted grants must favor marketing messages. The easiest way to accomplish this goal is to use company speakers trained for unaccredited (non-CME) promotional presentations.
In the US, although pharmaceutical representatives are not supposed to detail doctors on off-label uses, representatives are rated, and compensated, based on sales. As one industry consultant quoted in Medical Marketing and Media stated, “Let’s say the sales goal [for a drug] is larger than if every patient over 60 is already on it. Divide that down to territories, and everybody has to meet it. The message is, sell off-label.” A pharmaceutical industry attorney quoted in the same article stated, “Before engaging in off-label promotion, companies should ascertain the risk profile, safety, efficacy, and potential commercial benefits of the use—without committing that last bit to print” . In other words, illegal promotion may be cost-effective if potential profits trump potential fines.
Compendia are compilations of drug information that include both on-label and off-label uses. Medicare, Medicaid, and many other insurers will cover off-label uses of reimbursable drugs included in major compendia, including the American Hospital Formulary Service–Drug Information (American Society of Health-System Pharmacists), the US Pharmacopoeia–Drug Information (Micromedex, a division of the Thomson Publishing Company), and DRUGDEX. Pharmaceutical companies strive to establish good relationships with compendia staff, and may assign an employee as the designated compendia contact. The pharmacists who write compendia listings are very busy, and are usually delighted to receive organized packets of scientific articles, abstracts, and contact information. Using company-provided articles (which always contain marketing messages) saves time; all of the company’s assertions for off-label use may be transferred intact to the final product. Companies celebrate new compendia listings because expanded insurance coverage ensures more sales.
While off-label use is sometimes necessary, it should be undertaken with care and caution due to the uncontrolled experiment to which a patient is being subjected. Valuable off-label uses should be discussed by unbiased researchers in bona fide medical journals. Promising therapies should be tested in clinical trials. Truly useful off-label benefits of drugs will not remain a secret.