Indianapolis, INThe revelations that Eli Lilly concealed the side effects of Zyprexa and promoted the drug for unapproved uses is not newly discovered misconduct. It is a persistent pattern of conduct indicative of a nasty habit that needs breaking.
After the secret company documents were leaked to the press last month by attorney, Jim Gottstein, the focus has been on Zyprexa; but a year ago it was Evista, and before that it was Prozac.
In the case of Evista, approved for treating post-menopausal women with osteoporosis, Lilly concealed data that showed an increased risk of cancer. On October 24, 2002, the Cancer Prevention Coalition issued a press release that said Lilly suppressed evidence that women taking the drug were at an increased risk of developing ovarian cancer.
"There is ample scientific evidence that Evista poses risks of ovarian cancer," said Dr Samuel Epstein, MD, Chairman of the Prevention Coalition.
The data revealed "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 said.
"Lilly's own study," Dr Epstein wrote, "found that the drug was shown to induce ovarian cancer in rats and, at doses well below the therapeutic, in mice."
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."
Dr Epstein also cited a 2001 study by the University of Southern California that found Evista increases the growth rate of ovarian cancer cells in laboratory studies, and may increase risks of recurrence of ovarian cancer.
He called Lilly's suppression of its own evidence "reckless and threatening to women's health and life," and the FDA's approval of Evista without the cancer warning "equally reckless."
Also in 2002, the US Department of Justice began looking at Lilly's off-label marketing of Evista, and in March 2004, the US Attorney's office in Pennsylvania announced it was investigating the company's marketing practices for Evista, Zyprexa and Prozac.
The DOJ's three-year investigation found that Lilly illegally marketed Evista for the prevention of breast cancer and heart disease. The DOJ noted that sales reps sent letters to doctors to promote unapproved uses and that Lilly produced a videotape in which the company claimed Evista was "the best drug" for the prevention of osteoporosis, breast cancer and heart disease.
In December, 2005, Lilly agreed to pay $36 million to settle criminal and civil charges related to the illegal marketing of Evista. The company paid a $6 million criminal fine, a $6 million forfeiture to the federal government, and $24 million to settle a civil lawsuit.
Lilly's settlement agreement also included the standard, but useless, permanent injunction and consent decree in which Lilly agreed not to engage in illegal marketing and promotional practices.
In the case of the antidepressant, Prozac, a selective serotonin reuptake inhibitor (SSRI), Lilly's concealment of the increased risk of suicide and violence associated with the drug is legendary.
FDA approved in 1988, Prozac was promoted off-label for everything from shyness to eating disorders to low self esteem. Within three years, annual sales of the drug were nearly $800 million. Newsweek put a Prozac pill on its cover with a headline calling it a breakthrough drug. Even healthy people were asking for Prozac, the magazine noted.
But with the massive off-label sales, so came the less newsworthy adverse events. The reporting system for prescription drugs in the US is called Medwatch. Within 10 years of Prozac's arrival on the US market, there were 39,000 adverse events submitted to Medwatch, a number said to represent only between 1% and 10% of the actual number.
"So, if we get 39,000 adverse event reports about Prozac, the number of people who have actually suffered such problems is estimated to be 100 times as many, or roughly four million people," investigative journalist Robert Whitaker explained in an interview for Street Spirit in August 2005.
"This makes Prozac," he said, "the most complained about drug in America, by far."
"There were more adverse event reports received about Prozac in its first two years on the market than had been reported on the leading tricyclic antidepressant in 20 years," he added.
On December 18, 2003, Lilly sent letters to healthcare professionals in the UK, saying that Prozac was not recommended for children for any use, but issued no warning to doctors in the US.
In a situation similar to the Zyprexa document case, a couple years ago, the British Medical Journal received a series of internal Lilly documents and studies on Prozac from an anonymous source. The BMJ sent the documents to authorities, including US Congressman Maurice Hinchey and the FDA.
Congressman Hinchey sent the materials to psychiatrist, Dr Peter Breggin, author of Talking Back to Prozac, and The Anti-Depressant Fact Book, who reviewed the documents and issued a January 12, 2005 report.
After examining the documents, Dr Breggin confirmed their authenticity as those that he had evaluated in the early 1990s when he served as an expert for the combined Multi-District Litigation concerning Prozac. He in fact testified about the documents during a trial in 1994 after which, he says, they seemed to just disappear.
One group of documents he examined, contained a study by the FDA on the increased post marketing reports of "hostility" and "intentional injury" by patients on Prozac. For this study, the FDA compared patients using the antidepressant, trazodone, with Prozac patients, and found a 24-fold relative increase of reports of hostility and intentional injury per prescription of Prozac compared to trazodone.
The documents Dr Breggin reviewed also contained graphs showing a 40-fold relative increase in reports of suicide attempts, overdose, and psychotic depression in patients on Prozac compared to patients on trazodone.
An August 6, 1989, Lilly document says that doctors should be warned that Prozac patients were at a higher risk of suicide unless they receive a sedative, stating: "The counterindication because of acute suicidality should become a warning whereby the physicians should be advised that in the absence of sedation, the risk of higher suicidality should be taken into account."
A June 13, 1990, letter to Lilly from a concerned doctor states: "There appears to be growing concern that Prozac may somehow trigger a suicidal preoccupation in a small subset of patients and that their families should be warned of this potential risk. It is certainly possible that some of the cases reported are "coincidence" in that the depressed person may have attempted suicide independently of Prozac. However, some of these cases appear to be in patients taking Prozac for reasons other than depression."
Yet two months later, on August 31, 1990, Lilly sent out a Dear Doctor letter assuring health care professionals that there is no "causal relationship between Prozac and suicidality (ideation or acts)."
The hidden Prozac documents have come back to haunt Lilly. On January 14, 2005, a class action lawsuit was filed in Canada with claims that Lilly withheld information on the safety of Prozac. The plaintiffs contend that the reason Lilly failed to disclose the documents was because they showed a drastic increases in suicide attempts and other violent acts in patient using Prozac when compared to four other drugs.
Throughout the 1990s, while swearing publicly that Prozac did not increase the risk of suicide or violence, Lilly quietly settled lawsuits out of court and was able to keep the incriminating evidence hidden by obtaining court orders to seal the documents, just as it had been doing with Zyprexa until the latest batch of documents was leaked to the press.
Since the FDA was placed on permanent vacation when George W Bush took up residence in the White House, these days litigation appears to be about the only means available for unearthing hidden studies that show a drug's adverse effects.
In the case of Zyprexa, Lilly has so far settled with an estimated 26,000 plaintiffs, at a cost of over $1 billion. The incriminating documents leaked to the press last month, came to light during litigation with these plaintiffs but even after the litigation was settled, they were kept under seal with a court order.
Since the documents were made public, Lilly's legal team has spent about every other day in court trying to silence the messengers, Dr David Egilman and Jim Gottstein, and get the incriminating evidence back under seal, albeit without much success.
In a January 15, 2007, legal filing, a Lilly attorney quotes a comment by Judge Brian Cogan in a previous court hearing who said, Mr Gottstein had "deliberately and knowingly aided and abetted Dr. David Egilman's breach of CMO-3."
A responsive filing from Mr Gottstein should say that by issuing a protective order to suppress these documents to begin with, the court deliberately and knowingly aided and abetted Lilly in the off-label sale of Zyprexa by concealing the drug's side effects from tens of millions of consumers and prescribing physicians.
The secret documents show that Lilly concealed information about Zyprexa's link to severe weight gain, high blood sugar, and diabetes for a decade and because Lilly promoted Zyprexa off-label for so many uses, more than 20 million people have taken the drug. It is Lilly's best-selling product, with sales of about $30 billion since its arrival on the market in 1996, according to the January 20, 2007, New York Times.
In the latest development in the Zyprexa saga, last week Illinois and Vermont joined a coordinated five-state investigation of Lilly's marketing practices.
"The states are investigating whether Lilly tried to hide Zyprexa's risk of causing weight gain and other risks associated with diabetes and whether the company promoted Zyprexa for use in patients who do not have schizophrenia or bipolar disorder," the Times reports.
The larger question would seem to be, were the roughly 26,000 plaintiffs who entered into out-of-court settlements aware of the contents of the hidden documents and did they understand that by settling out of court Lilly would be permitted to keep the information secret knowing full well that more victims would be injured or killed by Zyprexa?