NEJM Reviewer leaked Avandia study to drug firm
GlaxoSmithKline told early of diabetes blockbuster's links to heart attacks.
Published online 30 January 2008 | Nature 451, 509 (2008)
A peer reviewer for The New England Journal of Medicine (NEJM ) broke confidentiality and leaked a damaging report about the blockbuster diabetes drug Avandia to the drug's manufacturer weeks ahead of publication, Nature has learned.
Avandia (rosiglitazone) came under heavy scrutiny after 21 May 2007, when the NEJM published online a meta-analysis1 of other studies into the drug's efficacy and safety. The results showed that the drug increased the risk of heart attack by 43% in people who took it for at least 24 weeks. The report garnered widespread media attention, prompted the Food and Drug Administration (FDA) to issue a safety alert, and cut the stock price of Avandia's manufacturer, GlaxoSmithKline (GSK), by 13%.
But 17 days earlier, the reviewer, diabetes researcher Steven Haffner of the University of Texas Health Science Center at San Antonio, had faxed his copy of the article to Alexander Cobitz, a GSK employee whom Haffner knew from working on an earlier clinical trial of the drug. "Why I sent it is a mystery," Haffner told Nature . "I don't really understand it. I wasn't feeling well. It was bad judgement." Haffner says that Cobitz did not ask to see the draft and was "probably a bystander".
"Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgement."
Nancy Pekarek, a spokeswoman for GSK, says that the company did not offer any input to Haffner on the meta-analysis, and that she was not aware of anyone at GSK informing the NEJM of the confidentiality breach.
Haffner had earlier served on the steering committee of a GSK-sponsored clinical trial of Avandia. He says that he has given many talks for the company, although he declined to say how much he had earned from them. "I've got a considerable amount of money. I didn't do it to raise my income or anything like that," he says.
After publication of the meta-analysis, GSK vigorously contested the study's methodology and "strongly disagreed" with its conclusions. Then on 5 June, again in the NEJM online, GSK-sponsored researchers published an interim analysis2 of the company's RECORD trial of Avandia, a prospective study launched in 2001 to monitor adverse cardiac events. The June report referenced the May study and said that the new RECORD data "were insufficient" to determine whether Avandia increased the risk of a heart attack.
The interim RECORD analysis was published just 15 days after the damaging meta-analysis. Pekarek says that the FDA had previously asked to see the RECORD data, but that the company's inside knowledge of the meta-analysis "added an additional sense of urgency" that drove the swift publication.
Karen Pederson, a spokeswoman for the NEJM , says that the journal's policy is not to discuss specific peer reviewers. But she adds that any reviewer who breaks confidentiality is banned from future reviewing and from contributing editorials and review articles. Last April, the journal imposed such penalties on a prominent cardiologist, Martin Leon of the Cardiovascular Research Foundation in New York, after he talked about an embargoed study at a meeting.
In November, after being ordered to do so by the FDA, GSK added a black-box warning on Avandia packaging. The lengthy warning describes the meta-analysis and its findings, but also says that "the available data on the risk of myocardial ischemia are inconclusive".
In the third quarter of 2007, sales of Avandia were down 38% from a year earlier worldwide and down 48% in the United States.
On Wednesday Chuck Grassley, a Republican senator from Iowa who is also the ranking member on the Senate finance committee, asked Christopher Viehbacher, president of US pharmaceutical for GSK, for detailed information regarding the leak.
Senate Investigates Doctor Accused of Avandia NEJM Leak to GSK
By STEPHANIE SAUL
Published: January 31, 2008
A leading member of the Senate said Wednesday that a prominent diabetes expert had leaked an unpublished and confidential medical journal article to GlaxoSmithKline last year, tipping the company to the imminent publication of safety questions involving the company's diabetes drug Avandia.
The expert, Dr. Steven M. Haffner of the University of Texas Health Science Center in San Antonio, faxed the article to the drug maker after agreeing to read it as part of the peer-review process for The New England Journal of Medicine, according to a statement Wednesday by Senator Charles E. Grassley, Republican of Iowa.
"The most troubling aspect of this situation is that the integrity of another aspect of the scientific process is called into question - scientific peer review," Mr. Grassley's statement said. The peer-review process, he said, is meant to ensure "that other scientists will judge a study's quality before it is made public."
Mr. Grassley, the ranking Republican on the Finance Committee and a longtime critic of business dealings between doctors and drug companies, also released a copy of a letter he sent to GlaxoSmithKline in which he asked what action the company took after receiving the letter.
Dr. Haffner did not respond to phone calls and e-mail messages seeking comment on Wednesday.
An article on the matter published online Wednesday by the journal Nature quoted Dr. Haffner as saying: "Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgment."
A spokeswoman for GlaxoSmithKline, Nancy Pekarek, said that Dr. Haffner sent the article to the company on May 3, more than two weeks before the article was published in the journal.
He "expressed concerns and questions regarding the methodology of the analysis, and sent the article to GSK for advice from experienced statisticians," she said.
But Ms. Pekarek said the company did not provide comments or any other information. "We believe GSK acted appropriately and responsibly in responding to the situation."
Under The New England Journal's rules, reviewers are prohibited from disclosing an article's contents before publication, as a way of protecting the exclusivity of the journal's material and protecting the intellectual property of scientists who submit articles.
A spokeswoman for The New England Journal of Medicine said the journal was aware of the allegations against Dr. Haffner. "Any breach of ethics by a reviewer would be taken very seriously by the editors, but would be handled as a private matter," The Journal said in an e-mailed statement.
Besides violating The New England Journal's rules, disclosing a pending article would also be considered a breach of professional ethics, according to Dr. Jerry Avorn, a professor of medicine at Harvard Medical School. Dr. Avorn said that he was not familiar with the specific allegations against Dr. Haffner.
The University of Texas Health Science Center issued a statement Wednesday saying that it had just learned of the accusations and would investigate. "Once the facts are understood, we will take swift and appropriate action," the statement said.
Dr. Haffner has previously disclosed that he has conducted research and served as a paid speaker for Glaxo. Mr. Grassley said that Dr. Haffner had received $75,000 in consulting and speaking fees from GlaxoSmithKline since 1999.
As part of its normal prepublication review process, The New England Journal asked Dr. Haffner last year to vet the article, which had been submitted for publication by Dr. Steven E. Nissen of the Cleveland Clinic. The article, a pooled analysis of Avandia studies, was published in late May and suggested that the diabetes drug increased the risk of heart attack by more than 40 percent.
Dr. Nissen, the chief of cardiovascular medicine at the clinic, said Wednesday that he was disappointed in Dr. Haffner's decision to send the article to GlaxoSmithKline.
"The integrity of the scientific review process is really very important in medicine," Dr. Nissen said. "The last thing I would have ever expected was that a respected reviewer for a prestigious journal would have, within hours of receiving a review, given it to a pharmaceutical company."
The article led to criticism of the drug and was followed by a Food and Drug Administration order that a black-box warning be placed on the drug's label. Those developments have helped drive down Avandia's sales by more than half from their level in 2006, when sales exceeded $3 billion worldwide.
Receiving an early copy of the article could have given GlaxoSmithKline time to mount a campaign to rebut its findings. Within days of the publication of Dr. Nissen's article, the company began citing the interim results of another study, called Record, that did not support his findings.
But Ms. Pekarek said that even before receiving the Nissen article from Dr. Haffner, the company had been weighing whether to look at preliminary results of the Record study, which was still under way. Those internal deliberations, she said, were based on the company's own findings of an increased heart attack risk from Avandia.
Ms. Pekarek said the additional knowledge that an article critical of the drug's safety was soon to be published increased the urgency of looking at the interim Record results.
Dr. Haffner, who had been involved in a clinical study that found Avandia worked better at controlling blood sugar than two other treatments, was quoted last year in the online medical publication TheHeart.org criticizing the publication of Dr. Nissen's study and of editorials that supported it in two other journals.
"The three major medical journals are becoming more like British tabloid newspapers. All they lack is a bare-chested woman on Page 3," Dr. Haffner was quoted as saying.