Off-Label Use Of Lilly's Evista Multiplies Risks

On October 24, 2002 the Cancer Prevention Coalition issued a press release that said women taking the osteoporosis drug Evista, marketed since 1997 by Eli Lilly, were at an increased risk of developing ovarian cancer.

"There is ample scientific evidence that Evista poses risks of ovarian cancer," wrote Samuel Epstein, MD, Chairman of the Prevention Coalition.

"Whether the large-scale treatment of women with Evista since 1997 has resulted in an increased incidence of ovarian cancer cannot yet be determined," Dr Epstein said, "as the latest NCI cancer incidence data are now two years old."

However, the data reveals "an 8 percent increased incidence of ovarian cancer in white females over 65, those most likely to be treated with Evista, from 1997 to 1999," he added.

"Lilly's own study, specifically designed to prove the drug's safety, found that the drug was shown to induce ovarian cancer in rats and, at doses well below the therapeutic, in mice," Dr Epstein said. He noted "the strong scientific consensus that the induction of cancer in well-designed studies in two species creates the strong presumption of human risk."

In addition, a study by University of Southern California researchers, presented at the July 2001 annual meeting of the European Society of Human Reproduction and Embryology provides further evidence of the drug's cancer risk. The study shows Evista increases the growth rate of ovarian cancer cells in laboratory studies, and may increase risks of recurrence of ovarian cancer, Dr Epstein advises.

He called Lilly's suppression of its own evidence about ovarian cancer risk "reckless and threatening to women's health and life."

In light of a recent $36 million dollar settlement agreement between Eli Lilly and the US Department of Justice, the number of women at risk of developing ovarian cancer as a result of using Evista is likely to be much higher than previously thought.

The DOJ criminal filing accuses Lilly of marketing Evista in 1998 for uses that had not been approved by the FDA after sales for its approved use of the treatment of osteoporosis were disappointing. In its first year on the market, Evista only generated sales of $120 million, far less than the company's original forecast of $401 million.

In December 2005, Lilly agreed to pay $6 million in criminal fines, a $6 million forfeiture to the Federal government, and $24 million in civil disgorgement to settle charges that the company illegally sold Evista for unapproved uses, including breast cancer prevention and the reduction of cardiovascular disease.

The unapproved-use campaign continued into 2000, the DOJ said, with physician seminars and one-on-one meetings with doctors, all aimed to boost Evista sales by increasing prescription rates for unapproved uses.

The settlement includes a permanent injunction and a consent decree under which Lilly agreed to not engage in illegal promotional and marketing practices.

Since Evista gained FDA approval for the treatment of osteoporosis, Lilly spent a fortune on creative methods of promoting the drug to women over 50 for daily life-long use. In 1998 alone it spent $39 million in direct to customer advertising according to Competitive Media Reporting.

"The surest route to high profits is the expensive drug that must be taken daily for years, preferably for life, out of fear of a disease that might create symptoms 10, 20, 30 years down the road," according to How to Read A Drug Ad by Maryann Napoli, associate director of the Center for Medical Consumers in New York City, December 2001.

Ms Napoli describes a Lilly Evista commercial as an example of this technique.

"Osteoporosis - Could you be at Risk" was the headline of a TV advertising campaign which purposely did not mention Evista, as a treatment for osteoporosis.

With the ad, instead of identifying a specific drug, Lilly sells the dangers of the disease because if a drug and its purpose appear together, the side effects of the drug must be included in the ad.

This particular ad also involved other marketing tricks. "Up to half of women over age 50 will break a bone due to osteoporosis in their lifetime," the ad warns. "And the risk increases when menopause ends," it said.

"The statement is true," says Ms Napli, "but choosing the age of 50 as the cut-off is guaranteed to instill fear."

The truth is that a woman's odds of having an osteoporosis-related hip fracture between the age of 50 and 70 are low. "Half of all hip fractures in women occur after the age of 80," Ms Napli points out.

Although the above ad may be legal, creating ways to intentionally avoid warning patients about a drug's dangerous side effects is certainly deceptive. But Lilly has been under fire for outright illegal marketing techniques in promoting Evista for years.

Back in March 1999, Zeneca Pharmaceuticals filed a lawsuit against the company alleging it had misled doctors in promoting Evista as a treatment for reducing the risk of breast cancer.

At the time, Zeneca, had FDA approval to market the drug Nolvadex to lower the risk of breast cancer with high-risk women. Zeneca said Lilly's promotion of Evista violated the Latham Act, New York Business Law and the common law of the State of New York.

According to the allegations in the lawsuit, Lilly's sales representatives "systematically and deliberately attempted to mislead doctors into believing that Evista has been proven to reduce the incidence of breast cancer and that Evista can now be prescribed as an alternative to Nolvadex."

The lawsuit further alleged that "as many as one in three oncologists surveyed have been detailed on Evista by Lilly, despite the fact that Evista has no indication for use in an oncologist's office."

Zeneca said the lawsuit is intended to "put an end to the risk to the public health caused by confusion among physicians and patients which Lilly has purposefully orchestrated."

The US District Court for the Southern District of New York determined that Lilly's statements were literally false and ordered the company to implement a training program to prevent the claims from being made in the future and granted Zeneca's request for an injunction against Lilly's continued dissemination of such claims.

In a 106-page opinion, the court accepted Zeneca's position that Lilly's dissemination of false information has created a "grave public health risk."

The court said since at least October 1998, Lilly representatives had been "systematically communicating to physicians that Evista has been proven to reduce the risk of breast cancer and that Evista is comparable or superior to Nolvadex in reducing the risk of breast cancer."

"These communications have been determined by the court to be approved and directed by Eli Lilly management and to be false," the court wrote.

In regard to whether calls to doctors by Lilly representatives constituted promotional activity, the court noted that "[c]ourts have consistently held that oral statements by a company's sales representatives concerning a product constitute 'commercial advertising or promotion' under the Lanham Act."

In 1999, a month before Zenaca filed its lawsuit, the FDA sent a warning letter to Lilly about its promotional materials. The agency said Lilly was overstating the benefits of Evista and implying that it was indicated for wider use than supported by the drug's labeling and pointed out that it was only approved for prevention of osteoporosis in postmenopausal women.

In 2002, the DOJ informed Lilly of its investigation and then in late March 2004, the US Attorney's office in Pennsylvania announced it was investigating Lilly's marketing practices for Evista.

But through it all, Lilly continued to make a fortune off Evista. According to Bloomberg News on March 26, 2004, the drug generated $922.1 million in sales in 2003.

The recent $26 million settlement marks the end of an exhaustive 3-year investigation that resulted in a number of specific findings on Lilly's illegal marketing activities. The DOJ said Lilly sales representatives were ''encouraged'' to send unsolicited letters to doctors to promote off-label uses, and they were ''trained to prompt or bait questions by doctors in order to promote'' off-label uses.

The company had also produced a videotape for use by sales representatives in which Lilly claimed Evista was "the best drug" for the prevention of osteoporosis, breast cancer and heart disease, according to the DOJ.

Lilly also trained representatives to promote Evista with a medical reprint that highlighted key results of the drug but told representatives to hide the disclosure page of the reprint that said: "All of the authors were either employees or paid consultants of Eli Lilly at the time this article was written," and the prescribing information portion that said: "The effectiveness of [Evista] in reducing the risk of breast cancer has not yet been established."

The DOJ also determined that Lilly organized "consultant meetings" for physicians who prescribed Evista during which unapproved uses were discussed; and then calculated "the incremental new prescriptions for doctors who attended Evista advisory board meetings in 1998."

"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," the DOJ noted.

In marketing surveys, doctors said they were told Evista might reduce the risk of breast cancer and the DOJ settlement information lists calls in Illinois, Texas, California, and Alabama, in which sales representatives promoted Evista for off-label use.

And finally, Lilly ran an advertisement in Prevention Magazine that said Evista "lowers cholesterol (and) addresses concerns about breast cancer," the DOJ said.

On December 21, 2005, Don Woodley, a principal with Woodley Ferra Manion Porfolio Management told the Washington Post: "This settlement is very reasonable and affordable. It's chump change for a company of Lilly's size."

$36 million is chump change considering that in October 2005, Lilly reported 3rd quarter global sales of Evista through September 30, 2005, of $770.8 million, compared to $755.4 million in sales for the same period the year before.