Thursday, October 09, 2008

Did Pfizer Marketers Suppress and Manipulate Clinical Studies of Neurontin?

Here we go again. Multiple media sources reported on allegations that Pfizer Inc, the world's largest pharmaceutical company, attempted to manipulate and suppress clinical research results unfavorable to one of its products. Per the Wall Street Journal,

Pfizer Inc. marketers urged the suppression of medical studies that reached unfavorable conclusions about the effectiveness of the company's big-selling drug Neurontin [gabapentin], according to internal Pfizer documents submitted in a lawsuit against the company.

In 2004, Pfizer's Warner-Lambert unit pleaded guilty to felony charges that it promoted Neurontin for uses not approved by the Food and Drug Administration, including bipolar disorder and chronic nerve pain. The FDA originally approved the drug as an antiseizure treatment for epilepsy and in 2002 for one kind of pain related to shingles.

Pfizer paid $430 million to resolve the charges and reimburse state Medicaid programs for unapproved, or off-label, uses of Neurontin. Pfizer said it made sure there was no improper marketing after it purchased Warner-Lambert in 2000. Pfizer has booked about $12 billion in Neurontin sales since then and, though the drug is now subject to generic competition, it remains a strong seller.

Documents and emails released this week in the case in U.S. District Court in Boston suggest Pfizer's marketers influenced the drug's scientific record to boost sales at least until 2003 by declining to release or altering the conclusions of studies that found no beneficial effect from Neurontin for various off-label conditions.

Here are the details about how one study of gabapentin was allegedly suppressed.

According to documents in the Boston case, a European study done in the late 1990s by Warner-Lambert to measure Neurontin's use for diabetic nerve pain produced consternation at Pfizer after it failed to find a significant effect. 'I think we can limit the potential downsides of the ... study by delaying the publication for as long as possible,' wrote Michael Rowbothan, then Neurontin's marketing team leader, in a 2000 email sent after Pfizer bought Warner-Lambert. He added that 'it will be more important to how WE write up the study.'

The study's scientific manager, Beate Roder, wrote in an email to employees after Pfizer agreed to buy Warner-Lambert that she had been instructed "that we should take care not to publish anything that damages Neurontin's marketing success." Neurontin has been widely prescribed for diabetic nerve pain, according to market researchers.

In 2002, Angela Crespo, then Neurontin's senior marketing manager, emailed an outside firm that was contracted to write up the study's results: "We are not interested at all in having this paper published because it is negative!!" Pfizer declined to make the three employees in the emails available for interviews.

The company's writeup of the study was subsequently rejected by two medical journals. Some of the reviewers for these journals said the company was putting too rosy a spin on the results, the court documents show. The paper was never published, although Pfizer later summarized some of the study's results in a broad review published in 2003 in an obscure medical journal, Clinical Therapeutics.

The New York Times had some more detail,

In one example, the experts concluded that Pfizer had deliberately delayed release of a study that showed the drug had little effect against pain that is a complication of long-term diabetes, even as the outside researcher who was a lead investigator for the study, Dr. John Reckless of Bath, England, pushed to publish the unflattering findings on his own. Dr. Reckless’s office said Tuesday that he could not be reached for comment.

According to one September 2000 e-mail message by a Neurontin team leader at Pfizer, “The main investigator in the U.K. (Dr. Reckless) is keen to publish but this will have several ramifications.” The team leader later wrote, “I think we can limit the potential downside of the 224 study by delaying publication for as long as possible.”

Another series of e-mail messages had the subject line “Spinning Serpell,” a reference to an investigator on the study, Dr. Michael Serpell of Glasgow, Scotland. In the e-mail exchange a senior marketing manager for Pfizer and a professional medical writer discussed how to cast the results in a more favorable light for a poster presentation at a medical conference, the experts concluded.

“If Pfizer wants to use, present and publish this comparative data analysis in which two of the five studies compared make the overall picture look bad, how do we make it sound better than it looks on the graphs?” the medical writer asked.

In summary,

One of the experts who reviewed the documents, Dr. Kay Dickersin of the Johns Hopkins Bloomberg School of Public Health, concluded that the Pfizer documents spell out “a publication strategy meant to convince physicians of Neurontin’s effectiveness and misrepresent or suppress negative findings.”

Dr. Dickersin, the Johns Hopkins expert, said that of 21 studies she reviewed, five were positive and 16 negative, meaning they did not prove the drug was effective. Of the five positive studies, four were published in full journal articles, yet only six of the negative studies were published and, of those, two were published in abbreviated form.

This case is important in that it reveals the extent of involvement of Pfizer marketers in the how and whether clinical research is reported, and the effects of that involvement in terms of how often negative studies are suppressed. The specific tactics pushed by the marketers appeared to have included having professional ghost writers spin the data so that a negative study will "sound better than it looks," delaying unfavorable results, and when all else fails, suppressing the most unfavorable studies entirely. In the case of gabapentin, which does not seem to be a very good drug, this meant suppressing about two-thirds of the negative studies, which outnumbered the positive studies by a three to one ratio.

This unfortunately is another blow to the current paradigm of evidence-based medicine. The EBM paradigm calls for physicians to make optimal decisions for individual patients based on their knowledge of the clinical context, the patients' values and wishes, and a critical review of the best relevant evidence from clinical research. For the paradigm to work, the assumptions are that all relevant research can be found, and that the research studies, while imperfect, were not intentionally designed or reported to deceive the reader. Yet the case of gabapentin adds to fears that relevant evidence that is unfavorable to the interests of the drug, device, or biotechnology company which sponsored the work is likely to be suppressed by that sponsor, and that commercially sponsored research is often deliberately manipulated to make its results appear more favorable.

Also, as Professor Dickersin noted (reported by the WSJ), "in exchange for being experimented upon in trials, patients are told they are contributing to human knowledge. To withhold negative results from the public breaks that ethical obligation to such patients...."

The practical lessons:
- As we have said many times, physicians, patients, and policy-makers need to be extremely skeptical about the clinical research evidence base.
- On a policy level, if providers of health care goods and services are to continue to be allowed to sponsor clinical research that evaluates their products, no one from their marketing departments should be allowed any influence on such research
- However, since it may be impractical to prevent such influence, a more draconian but effective approach would be to ban such commercial firms from any direct involvement in human research meant to evaluate their products.


InformaticsMD said...


Due to the repeated issues we are agggregating regarding biomedical research, I think it's fair to say:

EBM is dead where recent pharmaceuticals are concerned, and probably regarding medical devices as well.

Anonymous said...

This issue occured and was addressed with Franklin v. Parke Davis, 1996, regarding the study issue and improper promotion of neurontin.

Pearly Home Remedy said...

Pfizer continued with the medical marketing firms and planted marketing messages in journal articles that Neurontin was effective while they knew that their own clinical trials had failed to demonstrate it was effective