Recently, Eli Lilly agreed to plead guilty and to pay $36 million in connection with its “illegal promotion” of the drug Evista, which is approved by the FDA for the prevention and treatment of osteoporosis in post-menopausal women (see DOJ December 12, 2005 press release).

The case, brought by the Department of Justice (DOJ), reveals a few tactics that Lilly employed to skirt the prohibition by the FDA of “off-label promotion” of prescription drugs (see PMN Glossary Definition). What Lilly did, according to documents from the DOJ, was to promote the use of Evista for the treatment of heart disease and breast cancer in women.

Off-label promotion is seen by some — including the Washington Legal Foundation (WLF), an organization that continually confronts the FDA concerning commercial free speech issues — as a First Amendment issue:

According to the WLF: “The core question is whether a manufacturer can be prohibited from discussing or promoting drugs that are being legally prescribed in an ‘off-label’ manner by physicians.” (See “OFF-LABEL” SPEECH: UNCERTAINTY REIGNS FOR DEVICE AND DRUG MAKERS“.)

Reviewing the evidence in the Lilly case, it is obvious that the core question is really the role that pharmaceutical companies play in urging physicians to prescribe off-label in the first place. BTW, in case you did not know it already, off-label use of drugs by physicians is perfectly legal. A physician can prescribe any drug for any purpose, except where fear of malpractice suits may restrain the practice.

According to the information provided by DOJ, unrealized Evista sales forecasts spurred Lilly’s new off-label promotion business plan.

“…the first year’s sales of Evista in the U.S. were disappointing compared to Lilly’s original forecast. According to the information, in October of 1998, the company reduced the forecast of Evista’s first year’s sales in the U.S. from $401 million to $120 million.” [DOJ press release]

So, it appears that prior to October, 1998, physicians may not have been doing much prescribing of Evista at all, let alone off-label prescribing.

According to DOJ information, which includes a lot of quotes from Lilly brand team e-mail messages, Lilly — with some input from an “independent communications consultant” — realized that to solve the problem it was essential to “elevate the efficacy image of Evista” and talk to physicians about not just the prevention osteoporosis, but also prevention of “cardiovascular complications, prevention of breast cancer.” (See DOJ Information submitted to US District Court in Indianapolis.)

Thus begins the slippery slope of illegal off-label promotion of Evista by Lilly, which used the following tactics (according to the DOJ):

Prompting Doctors to Ask for Off-label Information
One-on-one sales pitches by sales representatives promoting Evista to physicians about off-label uses of Evista. Sales representatives were trained to prompt or bait questions by doctors in order to promote Evista for unapproved uses. [DOJ press release]

The FDA allows companies to distribute off-label information such as might appear in peer-reviewed medical journal articles to a doctor only if specifically solicited by the doctor. This is where the WLF has a problem with the law as a First Amendment issue. I also have some qualms about not allowing pharma companies to freely distribute some off-label information, especially information published in peer-reviewed literature.

Be that as it may, it is very hard to prove that sales reps engage in this kind of activity unless documentation is found. The DOJ information refers to “medical letters” that sales reps were encouraged to send unsolicited to doctors. The letters “go beyond what we are able to discuss with our customers,” according to an e-mail sent by a Lilly District Manager to his sales reps.

Just a little side note regarding eDetailing. The ability of live sales reps to “wink and nod” while conversing with docs and thereby skirt some regulations to promote off-label use of drugs is something that could never be accomplished through eDetailing. As long as off-label use is critical for a brand, eDetailing will never be a good technique for that brand to employ. eDetailing is a tool for a more perfect world (i.e., a world where drug sales are based solely on FDA-approved use).

Lack of Transparency
Training sales representatives to promote Evista for the prevention and reduction in the risk of breast cancer by use of a medical reprint in a way that highlighted key results of Evista and thereby promoted Evista to doctors for an unapproved use. Some sales representatives were instructed to hide the disclosure page of the reprint which noted, among other things, that “All of the authors were either employees or paid consultants of Eli Lilly at the time this article was written,” and “The prescribing information provides that ‘The effectiveness of [Evista] in reducing the risk of breast cancer has not yet been established.’ ” [DOJ press release]

It is one thing to say that pharma companies have a First Amendment right to distribute off-label information, but pharma reps should not have the right to edit and manipulate that information in order to deceive the physician. I should think this goes without saying. It seems to me, based upon this kind of evidence, that if WLF wins its case against the FDA, and pharma companies gain the right to distribute off-label materials, they are likely to abuse the right and engage in the sort of practice that Lilly has been accused of.

The ROI Dilemma
Calculating the incremental new prescriptions for doctors who attended Evista advisory board meetings in 1998. The advisory board meetings included discussion of unapproved uses for Evista. By measuring and analyzing incremental new prescriptions for doctors who attended the advisory board meetings, Lilly was using this intervention as a tool to promote and sell Evista. [DOJ press release]

Measuring physician prescribing patterns and new prescriptions is a tried and true way of determining the effectiveness — i.e. return on investment (ROI) — of pharmaceutical marketing (see, for example, “The New Written Prescription: Leveraging Technology to Measure Change in Physician Behavior as it Occurs“, a Pharma Marketing News reprint).

Measuring the success of pharma-sponsored medical education, on the other hand, is more problematic because US regulatory authorities take a dim view of using prescribing behavior as a measure of ROI (see, for example,”Provider/Pharmaceutical Partnerships – Are They Possible Without Conflict of Interest?“, a Pharma Marketing News reprint). The use of “advisory board” meetings by Lilly is a case in point.

Other market research cited by the DOJ indicated that Lilly’s tactics — only a few of which are described above — were successful. Twenty-four percent (24%) of doctors surveyed recalled receiving the message from Lilly sales reps that Evista may reduce the risk of breast cancer. Six months earlier, before Lilly’s new off-label campaign, there had been no indication that doctors recalled that Evista may reduce the risk of breast cancer.

There’s no disputing that off-label promotion works. But can it be done legally and with transparency?