E-mails suggest Pfizer tried to suppress study on drug

Suits say company misled on Neurontin

By Liz Kowalczyk
11 oct 2008--Top drug company marketing executives suppressed a large European study suggesting their blockbuster medication Neurontin was ineffective for chronic nerve pain, and they privately strategized about how to silence a British researcher who wanted to go public with the data, according to newly filed documents and e-mails that are part of a Boston court case.
During the same period of several years, Pfizer Inc. launched an advertising blitz promoting the purportedly positive findings of a smaller Neurontin study it had published in a major medical journal - including showing a video to airline passengers before their in-flight movie.
The widespread promotion of Neurontin turned what had been a relatively minor epilepsy drug into one of the fastest-growing blockbuster drugs in the world, one that generated more than $2 billion a year in US sales for Pfizer before a generic competitor entered the market in 2004.
Taken together, the e-mails and other internal Pfizer documents produced as part of a potential class action lawsuit against the company represent one of the most detailed looks yet at how a drugmaker controls what physicians and consumers know about a drug.
In the case of the European study, called 224, the full findings were never published as a stand-alone paper; data from the study were pooled into results from several other Pfizer studies and published in a minor journal in 2003.
"We must delay publication of 224, as its results were not positive," wrote Pfizer marketing executive John Marino in a September 2000 e-mail to Angela Crespo, senior manager of major markets for Neurontin.
Later that month, Michael Rowbotham, Neurontin team leader, e-mailed Crespo about the problem of Dr. John Reckless, an investigator on the study who was pressing Pfizer to publish the results for ethical reasons. Along with delaying publication for as long as possible "it will be more important how WE write up the study," Rowbotham wrote. "We are not allowing him to write it up himself."
A dozen researchers and physicians reviewed thousands of documents for the plaintiffs' attorneys; their conclusions included that Pfizer controlled the information available to doctors and consumers by suppressing or delaying negative studies about Neurontin's effectiveness for certain types of pain, migraine headaches, and bipolar illness, and by manipulating other studies before they were published to make the results look more positive.
"They created the illusion of Neurontin's efficacy in the scientific literature," said lead plaintiff attorney Thomas Greene of Boston. "Pfizer's scientific misconduct and unethical behavior caused physicians to write tens of millions of ineffective prescriptions for serious and debilitating conditions resulting in billions of dollars in profit for Pfizer at the expense of patients and insurance companies."
Pfizer denied the plaintiffs' charges in a written statement released yesterday. "Pfizer is committed to the communication of medically or scientifically significant results of all studies, regardless of outcome," company officials said. "Company policy also requires that, in all cases, study results are reported by Pfizer in an objective, accurate, balanced, and complete manner, with a discussion of the strengths and limitations of the study, and are reported regardless of the outcome of the study or the country in which the study was conducted."
Pfizer, which said it stopped actively marketing Neurontin in the United States in 2004, also cited in its statement several other negative studies whose publication it supported.
In the case of study 224, Pfizer said, the company submitted the study to at least two medical journals, which both rejected it.
But according to a 2002 e-mail from Diabetic Medicine editor Dr. Simon Heller to Pfizer officials, his journal's reviewers rejected the study partly because of "many areas of company bias."
Reckless, the British researcher, did not return messages.
One common strategy, according to court documents, was "ghost-writing," in which Pfizer executives, or firms hired by Pfizer, wrote articles for submission to journals, rather than allowing outside researchers to write them.
"Not only did they fail to publish studies, but they twisted the truth in studies that were published," Kay Dickersin, director of the Center for Clinical Trials at Johns Hopkins School of Public Health, said in an interview. She reviewed thousands of documents and Neurontin studies for the plaintiffs.
Meanwhile, at medical education conferences, dinners, and in hospitals, Pfizer spent millions marketing the drug to thousands of doctors for these conditions, none of which were uses approved by the US Food and Drug Administration, according to the plaintiff's specialists. Doctors are allowed, however, to prescribe drugs for unapproved, or "off-label," conditions.
The company's strategy appeared to be a success; in 2001, Neurontin was the fourth-fastest growing blockbuster drug in the world. Prescriptions for chronic nerve, or neuropathic, pain nearly doubled between 1999 and 2001, even though Reckless's study of 325 patients in 1998 and 1999 found that Neurontin did not lessen the pain for diabetic patients with this type of discomfort in their arms, hands, legs, and feet.
Even the positive chronic pain study - funded by Parke-Davis, which was purchased by Pfizer in 2000, and published in the Journal of the American Medical Association in Dec. 1998 - is now being questioned.
Nicholas Jewell, a biostatistics professor at the University of California at Berkeley, who reanalyzed the data for the plaintiffs, said Neurontin actually had no benefit for diabetic patients with nerve pain, when he adjusted the results to exclude patients who discovered during the trial that they were on Neurontin and not a placebo. That knowledge could have affected patients' perception of their pain. Another study published in the same issue showed Neurontin improved another less common type of pain called postherpetic neurophathy, or shingles. The FDA approved the drug for this use in 2002.
A growing body of research and documents produced in court cases are illuminating how pharmaceutical companies have biased studies of the effectiveness and safety of their drugs. In an article in the New England Journal of Medicine in January, researchers found that 36 of 37 positive studies about antidepressants were published. But only 3 of 22 negative studies were published, while another 11 negative studies were published in such a way as to make the outcome seem positive.
Lawsuits against Merck & Co. over its painkiller Vioxx have produced reams of internal company documents, and researchers who reviewed them said the company selectively reported mortality data for Alzheimer's patients taking the drug, they reported in JAMA in April.
In the Boston case, attorneys for Neurontin users and insurers are suing Pfizer for consumer fraud and unjust enrichment, saying the company promoted Neurontin for medical conditions and doses for which it knew the drug wasn't effective. A year ago, US District Court Judge Patti B. Saris denied the plaintiffs' request to certify the case as a class action, but she allowed the attorneys to try again.
In a related case, Pfizer pled guilty to criminal conduct and paid $430 million in fines in 2004 to resolve charges that it illegally marketed Neurontin for "off-label" uses, ranging from manic depression to hiccups. In that case, Pfizer produced internal documents from the 1990s. In this new case, the company produced e-mails and documents mostly from the early and mid-2000s.
Other documents show that Pfizer intensively promoted the drug for neuropathic pain, despite advice from the company's consultants that it didn't work and an opinion from the FDA that the agency would not approve the drug for that purpose without further evidence.
During a meeting with company executives on Sept. 6, 2001, at the Crowne Plaza Hotel in Ann Arbor, Mich., Pfizer's consultants said "the evidence is not convincing to support a broad neuropathic pain claim. New analysis/data not only do not support a broad claim, they provide evidence to the contrary to a broad indication," according to court documents.
The following month, the company developed its 2002 operating plan for Neurontin. Aside from strengthening the drug's position in epilepsy, the company outlined a strategy for promoting the drug for neuropathic pain, which it said represented a significant opportunity, including a global market of $2 billion.
In its 2003 operating plan, Pfizer describes Neurontin as the gold standard for treating neuropathic pain in the United States, according to court documents.
"The only way to make Neurontin a blockbuster drug was to market it for things for which it was not effective," said Dr. John Abramson, a Harvard Medical School instructor and author of Overdosed America, an examination of the pharmaceutical industry published in 2004, who also reviewed documents for the plaintiffs. "The distinctive feature of this case was how marketing trumped science."

Gabapentin (Neurontin) Eases Chronic Pain in Fibromyalgia

CINCINNATI, June 13 -- For treating the chronic pain and other symptoms of fibromyalgia, the anticonvulsant gabapentin (Neurontin) proved safe and effective, researchers here reported.
In a 12-week randomized, double-blind clinical trial, patients taking gabapentin displayed significantly less pain, better sleep, and less fatigue than placebo controls, Lesley M. Arnold, M.D., of the University of Cincinnati, and colleagues reported in the April issue of Arthritis and Rheumatism.
However, the drug had no effect on acute pain points or depression, the researchers reported.
Although gabapentin, which was used off-label for fibromyalgia, has little, if any, effect on acute pain, it has shown a robust effect on pain caused by a heightened response to stimuli related to inflammation or nerve injury in animal models of chronic pain syndromes, Dr. Arnold said.
Studies have also found the drug to have a substantial analgesic effects on diabetic neuropathy, postherpetic neuralgia, migraine, and other neuropathic pain conditions, as well as beneficial effects on sleep and restless legs syndrome. On the basis of these findings, the researchers suspected that gabapentin might also ease fibromyalgia pain.
The study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, included 150 mainly white fibromyalgia patients (90% women). Of these, 75 took gabapentin at dosages of 1,200 to 2,400 mg daily for 12 weeks, while there were 75 placebo controls.
The study was conducted at three outpatient research centers in the U.S., from September 2003 to January 2006.
The mean pain severity scores, measured by the Brief Pain Inventory (BPI), decreased in both groups but more so among the gabapentin patients (P = 0.015). The estimated difference between groups at week 12 was - 0.92 (95% confidence interval -1.75, -0.71).
Of the gabapentin-treated patients, 51% achieved a response at the endpoint compared with 31% of the placebo patients (P= 0.014).
Gabapentin compared with placebo also significantly improved the BPI average pain interference score, as well as a series of other scores. These included the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity Improvement, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS), the Sleep Problems Index, and the MOS Short Form 36 vitality score.
However, the drug had no effect on acute pressure-point pain or depression (the Montgomery Asberg Depression Rating Scale), the researchers reported.
Overall, the drug was well-tolerated. Of the 150 patients, 19 dropped out due to adverse events, with no significant difference between the treatment groups.
The gabapentin patients reported dizziness, sedation, lightheadedness, and weight gain significantly more often that did the placebo-treated patients. Notably, the researchers said, there was no significant difference in weight change in the two groups as measured in the clinic, although edema may have explained some of the patients' perceptions. Most treatment adverse events, they reported, were mild to moderate in severity.
The pathophysiology of fibromyagia is unknown, but evidence suggests that it is associated with aberrant central nervous system pain processing, the researchers said.
The drug appears to be effective in reducing abnormal hypersensitivity induced by inflammatory responses or nerve injury. Yet unlike many other pain syndromes, there is no physical evidence of inflammation or CNS damage.
One possible explanation, Dr. Arnold said, is that gabapentin's effects involve binding to a specific subunit of voltage-gated calcium channels on neurons. This binding, she said, reduces calcium flow into the nerve cell, which reduces the release of some signaling molecules involved in pain processing.
In discussing the study's limitations, the researchers said that because the study was short, the results may not generalize to longer treatment periods, and long-term efficacy should be studied in future clinical trials.
Also, because the study was relatively small, they said it may have lacked the power to detect potentially relevant differences between the groups. Finally, they wrote that the results may not apply to patients with some comorbid psychiatric disorders, such as bipolar disorder, or to patients with other painful musculoskeletal disorders.
"In this, the first randomized, placebo-controlled study to evaluate gabapentin in the treatment of fibromyalgia, the results demonstrated that gabapentin, taken for up to 12 weeks, is effective and safe in the treatment of pain and other symptoms associated with fibromyalgia," Dr. Arnold concluded. Primary source: Arthritis and RheumatismSource reference: Arnold LM, et al "Gabapentin in the Treatment of Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial" Arthritis Rheum 2007; 56: 1336-1344.