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WASHINGTON, D.C. - American pharmaceutical manufacturer Warner-Lambert has agreed to plead guilty and pay more than $430 million to resolve criminal charges and civil liabilities in connection with its Parke-Davis division's illegal and fraudulent promotion of unapproved uses for one of its drug products, Associate Attorney General Robert D. McCallum, Jr. and Massachusetts U.S. Attorney Michael J. Sullivan announced today. The drug Neurontin was approved by the Food and Drug Administration in December, 1993 solely for adjunctive or supplemental anti-seizure use by epilepsy patients.
OFFICIAL PRESS RELEASE
However, it is estimated that about 80% of users turn to the drug not to curb seizures but to treat other conditions for which it is NOT approved, including: bipolar disorder, neuropathy, attention deficit disorder (ADD), restless leg syndrome, migraines, neuralgia, and drug and alcohol withdrawal seizures. Neurontin's maker, formerly called Parke-Davis but now a division of pharmaceutical giant Pfizer marketed the drug for these unapproved uses. The illegal conduct occurred prior to Pfizer's acquisition of Warner-Lambert/Parke-Davis. But Pfizer recorded about $3 billion in Neurontin sales over the short term of two years, 2000 and 2001.
Under the provisions of the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to the FDA. Once approved, the drug may NOT be marketed or promoted for sole called "off-label" uses, any use not specified in an application and approved by the FDA.
However, Warner-Lambert's strategic marketing plans, as well as other evidence, show that Neurontin was aggressively marketed to treat a wide array of ailments for which the drug was not approved.
Warner-Lambert promoted Neurontin even when scientific studies had shown it was not effective. For example, the company promoted Neurontin as effective for use as the sole drug (monotherapy) for epileptic seizures, even after solo use had been specifically rejected by the FDA. Similarly, the pharmaceutical company falsely promoted Neurontin as effective for treating bipolar disease, even when a scientific study demonstrated that a placebo worked as well or better than the drug.
"This illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision making, thereby putting patients at risk," stated U.S. Attorney Michael Sullivan. The drug giant profited from such conduct by subjecting the poor, elderly and other persons to experimental drug uses, which had not been determined to be safe or effective.
As a consequence of the unlawful promotion scheme, patients who received the drug for unapproved and unproven uses had no assurance that their doctors were exercising their independent and fully-informed medical judgment, or whether the doctor was instead influenced by misleading statements made by, or inducements provided by, Warner-Lambert. Potential problems that can arise from off-label use without the benefit of careful FDA oversight include the occurrence of unforeseen adverse effects because the drug was not studied in the type of patient it is being used for off-label and the appropriate dosage and course of treatment have not been established. The problem with this is that it is not only illegal, but it is also dangerous. Neurontin has been reported to cause suicidal thoughts, suicidal ideation, anxiety, hostility, paranoia and psychosis.
Warner-Lambert used a number of tactics to achieve its marketing goals, including:
1. Encouraging sales representatives to provide one-on-one sales pitches to physicians about off-label uses of Neurontin without prior inquiry by doctors. The company's agents also made false or misleading statements to health care professionals regarding Neurontin's efficacy and whether it had been approved by the FDA for the off-label uses. Warner-Lambert also utilized "Medical Liaisons," who represented themselves (often falsely) as scientific experts in a particular disease to promote off-label uses for Neurontin.
2. Warner-Lambert paid doctors to attend so called "consultants meetings" in which physicians received a fee for attending expensive dinners or conferences during which presentations regarding off-label uses of Neurontin were made. These events included lavish weekends and trips to Florida, the 1996 Atlanta Olympics and Hawaii. There was little or no significant consulting provided by the physicians.
3. The pharmaceutical company implemented numerous tele-conferences in which physicians were recruited by sales representatives to call into a pre-arranged number where they would listen to a doctor or a Warner-Lambert employee speak about an off-label use of Neurontin.
4. The company also sponsored purportedly "independent medical education" events on off-label Neurontin uses with extensive input from Warner-Lambert regarding topics, speakers, content and participants.
Warner-Lambert mislead the medical community beforehand about the content, as well as the lack of independence from the company's influence, of many of these educational events. In at least one instance, when unfavorable remarks were proposed by a speaker, Warner-Lambert off-set the negative impact by "planting" people in the audience to ask questions highlighting the benefits of the drug.
5. Warner-Lambert paid physicians to allow a sales representative to accompany the physician while he or she saw patients, with the representative offering advice regarding the patient's treatment, which was biased towards the use of Neurontin.
These tactics were part of a wide-spread, coordinated national effort to implement an off-label marketing plan. At the same time, Warner-Lambert decided not to seek FDA approval for any of the new uses because it was concerned that approval for any of the non-epilepsy uses would allow generic competitors of Neurontin, which was expected to go off-patent soon, to compete with a "son of Neurontin" drug that Warner-Lambert hoped to have approved by the FDA for both epilepsy and non-epilepsy uses.
Neurontin was launched into the marketplace in February, 1994; from mid-1995 to at least 2001, the growth of off-label sales was tremendous. While not all of these sales were the consequence of Warner-Lambert's illegal marketing, the marketing scheme was very successful in increasing Neurontin prescriptions for unapproved uses.
Documents filed in the government's lawsuit against the pharmaceutical company show that the company deliberately formed a plan to persuade doctors to prescribe Neurontin for bipolar disorder, diabetic neuropathy, migraine, pain disorder and other conditions - all in the name of profit.
Unsealed documents in the case indicate that Parke-Davis undertook this strategy for two reasons:
1. Neurontin was approved only for add-on use in epilepsy, and only up to 1,800 mg dosage. There are about 2 million people in the U.S. with epilepsy - a relatively small market.
2. To have obtained FDA approval for other uses of Neurontin would have been expensive and time consuming, with approval possibly not coming until the patent ran out - at which time generics would become available and the profits would drain away.
Dr. Paul Keck, in a September 2002 article, "Clinical Management of Bipolar Disorder," reported that "in two studies, a placebo-controlled cross-over monotherapy trial and a placebo-controlled, parallel group, adjunctive treatment trial, Neurontin treated patients did not display significantly greater improvement in manic symptoms than patients receiving placebo."
One such study was paid for by Parke-Davis and concluded: "The findings of this study did not demonstrate that Neurontin (Neurontin) is an effective adjunctive treatment when administered to outpatients with bipolar disorder."
FULL STORY
The court papers offer a remarkable insight into the ethics (or lack thereof) of a major multi-national pharmaceutical company. A senior marketing executive at Parke-Davis was quoted during a tele-conference as saying to medical liaisons:
"Pain management, now that's money. Monotherapy, that's money. We don't want to share these patients with everybody, we want them on Neurontin only. We want their whole drug budget, not a quarter, not half, the whole thing. . . . That's where we need to be holding their hand and whispering in their ear: 'Neurontin for pain, Neurontin for monotherapy, Neurontin for everything' ... I don't want to hear that safety crap either, have you tried Neurontin, everyone of you should take one just to see there is nothing [that the drug is safe] it's a great drug."
Parke-Davis' concocted uses for Neurontin turned the drug into a "blockbuster." A blockbuster is the Wall Street description for any drug that sold $1 billion per year or more. In 2000, the company reported that Neurontin had earned $1.3 billion. As much as 78% of these sales were for uses without evidence that Neurontin was safe and effective. In 2001, a market research firm estimated that Neurontin sales totaled $1.7 billion.
FULL ARTICLE
The company may also reap a long term benefit from sales of the drug. Physicians' prescribing practices, also known as prescribing habits, are not likely to be cured of the Neurontin habit just by some negative press. As of March 28, 2002 the National Library of Medicine listed 729 English language articles published in the medical literature on Neurontin use in humans. Of course, not all these articles are corporate creations but the disturbing point is that there may not be any attempt to purge the medical literature of these company-contrived studies, leaving patients, even years from now, at risk of exposure to Neurontin for inappropriate uses.
The 11 illegally promoted unapproved uses for Neurontin (Gabapentin) as outlined in the court documents are:
1. Bipolar Disorder. Psychiatrists were told that early results from trials evaluating Neurontin in the treatment of bipolar disorder indicated a 90 percent response rate when the drug was started at 900 milligrams per day and increased to 4,800 milligrams per day. No such results existed. In fact, the only type of clinical trial being conducted at the time was a pilot study. According to the court documents, Parke-Davis was in possession of clinical data indicating that increasing the dose did not increase Neurontin's effect. The FDA-approved dosage for Neurontin in adults is 900 to 1,800 milligrams per day.
Any data regarding Neurontin in bipolar disorder was anecdotal and of unclear scientific value. Most of the published reports on the use of Neurontin in bipolar disorder had been written and sponsored by Parke-Davis, a fact that was hidden. Medical liaisons of the company were trained to tell psychiatrists that there were no reports of adverse reactions with Neurontin when used in psychiatric illness. In fact, such reports had been given to Parke-Davis by health care professionals but the company attempted to hide this information from physicians.
2. Pain Syndromes, Peripheral Neuropathy, and Diabetic Neuropathy. Parke-Davis medical liaisons were trained and instructed to report that "leaks" from clinical trials demonstrated that Neurontin was highly effective in the treatment of a number of pain syndromes and that a 90 percent response rate in the management of pain was being reported. No such evidence existed. Medical liaisons were trained to claim support for these findings as a result of inside information despite the fact that no such information existed. The only basis for these claims were anecdotal evidence of minimal, if any, scientific value. Many of the published case reports, according to the court papers, had been created and sponsored by Parke-Davis in articles that frequently hid the company's involvement in the creation of the article. The company's payment for the creation of these case reports was also concealed.
3. Treatment of Epilepsy alone (as monotherapy). In 1997, the FDA rejected the company's application for approval of Neurontin as monotherapy in the treatment of seizures. However, medical liaisons were strongly encouraged to push neurologists to prescribe Neurontin as the only drug to treat epilepsy, in spite of the fact that studies found it safe and effective only when used in combination with other seizure drugs. Neurologists were told that substantial evidence supported the company's claim that Neurontin was effective when used alone for seizures. In fact, at the time the court papers were filed, Parke-Davis knew that clinical trials using Neurontin alone in seizure were inconclusive. One of Parke-Davis' clinical trials showed that Neurontin alone was not effective. The vast majority of patients in the study taking Neurontin were unable to continue with Neurontin alone. In the same study, there was no significant difference between doses of 600, 1,200 or 2,400 milligrams. Nevertheless, Parke-Davis continued to urge doctors to use higher doses than approved by the FDA.
4. Reflex Sympathetic Dystrophy (RSD). Physicians were informed that extensive evidence demonstrated the efficacy of Neurontin in the treatment of RSD, a condition of pain and tenderness following traumatic injury to a limb. Again, the only evidence was in anecdotal reports of little or no scientific value. The Parke-Davis medical liaisons were trained to imply that case reports, most of which had been created or sponsored by the company, were actually studies.
5. Attention Deficit Disorder (ADD). Pediatricians were told that Neurontin was effective for the treatment of ADD. No hard data to support this claim existed--only occasional anecdotal evidence. Parke-Davis medical liaisons were trained to report that large numbers of physicians had success in treating ADD with Neurontin, when no such case reports existed.
6. Restless Leg Syndrome (RLS). This is another condition in which company medical liaisons were trained to refer to a growing body of evidence relating to the RLS, when no such scientific data existed. The only reports were anecdotal, the majority of which had been sponsored or created by Parke-Davis.
7. Trigeminal Neuralgia. The company represented Neurontin as a treatment for trigeminal neuralgia, a syndrome of severe bursts of facial pain, when no scientific data supported this claim; only occasional anecdotal reports. No evidence was available that Neurontin was as effective as currently available less expensive painkillers.
8. Post-Hepatic Neuralgia (PHN). This is a syndrome of severe pain following a herpes virus infection. Physicians were told that 75 to 80 percent of all PHN patients were successfully treated with Neurontin. Again, no clinical trial data supported such a claim.
9. Essential Tremor Periodic Limb Movement. No scientific data supported Parke-Davis' claim that Neurontin was effective for this disorder, just anecdotal reports of dubious scientific value.
10. Migraines. Claims that Neurontin was effective in the treatment of migraine headaches were made by company medical liaisons and were alleged to be based on early results from clinical trials. Pilot studies had been suggested and undertaken, but no early results existed to support these claims. The data were purely anecdotal and most case reports were either created or sponsored by Parke-Davis.
11. Drug and Alcohol Withdrawal Seizures. It was suggested by the company that Neurontin be used in the treatment of drug and alcohol withdrawal seizures despite the lack of any evidence supporting the use of the drug for these conditions.
The drug giant's ability to implement a coordinated national effort for an off-label marketing plan has mislead the medical community and may have greatly impacted the number of adverse effects suffered by Neurontin patients receiving the prescription based on false claims. The illegal and fraudulent promotion scheme has been putting Neurontin patients at risk for adverse side effects.
The $430 million settlement will not cure all the ills created by the illegal promotion of Neurontin. More importantly, it does nothing to help the patients who took the drug for unapproved uses.
Of the $430 million settlement, over $150 million will be divided among federal and state medicaid programs for losses suffered as a result of Warner-Lambert's fraudulent drug promotion and marketing misconduct. $240 million will be paid as a criminal fine for violation of the Food, Drug and Cosmetic Act, the second largest criminal fine ever imposed in a healthcare fraud prosecution. Another $38 million will be paid to settle civil liabilities to the 50 states and the District of Columbia for harm caused to consumers. This part of the global settlement was negotiated by the Consumer Protection Divisions of the 50 State Attorneys General.
However, none of the $430 million will be paid to the many patients who took Neurontin for the unapproved, off-label uses for which the drug was not determined to be either safe or effective.
References:
U.S. Department of Justice News Release, May 13, 2004.
http://www.usdoj.gov/opa/pr/2004/May/04_civ_322.htm
Suit: Neurontin Marketed Illegally for Bipolar Disorder.
http://www.bipolar.about.com/
Neurontin (Gabapentin) - The Illegal Corporate Creation of a Blockbuster Drug.
www.citizen.org/eletter/articles/neurontin.htm
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