RENEE MONTAGNE, host:
This is MORNING EDITION from NPR News. I'm Renee Montagne.
Opening statements are beginning this morning in Angleton, Texas, in the first trial of a wrongful death case brought by the family of a Vioxx user. Drugmaker Merck faces more than 3,000 such death and injury suits in the United States. The plaintiffs in these cases will try to prove that long before it pulled the drug from the market in 2004, Merck knew Vioxx was risky for the heart and that Merck hid that knowledge from doctors and patients. The drugmaker denies that categorically. One argument juries are likely to hear focuses on a scientific study published in The New England Journal of Medicine in 2000. That paper told doctors that Vioxx was safe on the stomach and safe for the heart. But as NPR's Snigdha Prakash reports, critics argue the paper was deliberately misleading.
SNIGDHA PRAKASH reporting:
It would be difficult to overstate the prestige and influence of a paper published in The New England Journal of Medicine. To be published in NEJM, as it's called, papers have to pass some of the most rigorous reviews in the business by top scientists and by journal editors. For getting papers published in NEJM or its illustrious rival, the Journal of the American Medical Association, or JAMA, is good for scientists, and it's good for sales.
Catherine DeAngelis is editor of JAMA.
Ms. CATHERINE DeANGELIS (Editor, JAMA): If a detail person working for a pharmaceutical company can hand a reprint of a publication from a high-powered journal like JAMA or NEJM to a doctor, that has a very significant effect on the physician. They look at these journals as places where you get good research and you can trust the research.
PRAKASH: When NEJM published the results of what's called the VIGOR trial in November 2000, doctors took notice. The trial compared a large group of patients taking Vioxx to a similar group taking an older painkiller, naproxen. The study showed that Vioxx was safer for the stomach. Most of the New England Journal article was devoted to that scientific development. The paper also noted that there were more heart attacks among Vioxx patients than among those taking naproxen, but the message was reassuring. The paper said there were more heart attacks in the Vioxx group because the older drug, naproxen, protected the heart in the way that aspirin does. Plaintiffs' lawyers are expected to argue that this interpretation was a deliberate attempt to soft-pedal Vioxx's emerging risks.
That's also the view of cardiologist Eric Topol of the Cleveland Clinic. He isn't connected with any of the lawsuits, but he's been a persistent critic of Merck's actions. Topol says the clinical trial compares patients taking an experimental drug to patients taking a sugar pill or an established drug.
Dr. ERIC TOPOL (Cleveland Clinic): And when we see something unexpected, in this case a five-fold increase in heart attacks, the accepted way to interpret that is there's something wrong with the experimental arm, namely Vioxx, here. This was twisted to be interpreted as, `Oh, there's something right, there's something advantageous about naproxen.
PRAKASH: The VIGOR paper eased potential concern about the excess heart attacks in another way. It told doctors that most of the excess heart attacks were in high-risk patients. Topol says, in fact, the trial was designed to exclude high-risk patients. He says accounting for the excess heart attacks by classifying patients as high-risk and low-risk after the results came in is not an acceptable way to interpret the data. But the editor in chief of The New England Journal of Medicine, Jeffrey Drazen, says he stands by the decision to publish the paper, given what was known at the time.
Mr. JEFFREY DRAZEN (Editor in Chief, NEJM): In a 2,700-word article, you can't cover everything. We think that by identifying this as a problem, we planted the seed. We lit the light that let others go forward to work on this area.
PRAKASH: Drazen says it's easy to criticize with the benefit of hindsight. He says back in November 2000 when the article was published, no one wrote the journal to complain about the paper's logic. Topol himself didn't examine the article until a few months later, in February 2001. That's when a panel of the Food and Drug Administration met to consider the COX-2 painkillers and the FDA made the full VIGOR data publicly available for the first time. It turned out that Merck had submitted more data to the FDA than to the New England Journal. Topol says when he looked at the FDA data...
Dr. TOPOL: There were more deaths, there were more heart attacks, there were more strokes and there were more blood clots in other locales, such as the veins in the legs or the veins of the lungs.
PRAKASH: Topol and two colleagues at the Cleveland Clinic used the additional numbers from the FDA and different statistical methods to reanalyze the VIGOR data. They concluded that Vioxx doubled a patient's risk for cardiovascular problems. They published their findings in NEJM's rival, the Journal of the American Medical Association, in August 2001, along with their recommendation that doctors be cautious in prescribing Vioxx and the other COX-2 painkiller, Celebrex.
Dr. TOPOL: Without the data that was available in the FDA documents, we would never have been able to make the diagnosis that there was a problem with Vioxx.
PRAKASH: The editor in chief of the New England Journal, Jeffrey Drazen, says the journal's editors believed they'd been given all the relevant data from the VIGOR trial when they published the paper in November, 2000.
Mr. DRAZEN: So we were taken totally by surprise by the Topol paper that appeared in August 2001, suggesting that there were additional data on cardiovascular events that occurred during the VIGOR trial that weren't in our paper.
PRAKASH: He says when NEJM editors investigated, they learned that because of an unusual quirk in the design of the trial, Merck hadn't given them the data about adverse events that it received in the last weeks of the trial. Drazen says the New England Journal feels it was hoodwinked, because the data concerned serious events.
Mr. DRAZEN: There's a difference between the letter of the law and the spirit of the law, and what they did conformed with the letter of the law. But in my opinion, it kind of broke the spirit of the law because you're using human subjects, participants in this trial, and you're putting them at risk. I believe it's the responsibility of the authors to come forward with that data when they become available.
PRAKASH: Merck didn't make the company scientists who wrote the paper available for an interview with NPR, and the lead authors, who are independent university scientists and Merck consultants, didn't agree to be interviewed. But Ted Mayer, a lawyer representing Merck, defended the paper.
Mr. TED MAYER (Merck Attorney): I believe the paper accurately disclosed the information from the VIGOR trial that was relevant to assessing the risks and benefits of the medicine.
PRAKASH: He says the weight of evidence from previous studies suggested that Vioxx was safe for the heart, and that's why it was logical for scientists working on the paper to conclude that naproxen was protecting patients in the other group.
Mr. MAYER: They applied the best science they could, the best analysis they could, looking at all the data, and that was the most likely conclusion from looking at the entire body of data on the safety of this medicine.
PRAKASH: Mayer says the NEJM paper's authors included distinguished independent scientists, and the paper was rigorously reviewed by other top researchers, and he dismisses the argument that the additional data Merck submitted to the FDA affected the paper's overall results.
Mr. MAYER: The few additional events that were subsequently learned about after the previously specified cutoff date did not materially change any of the conclusions in the article or any of the analysis of those conclusions.
PRAKASH: Moreover, he says, all the data was submitted to the FDA.
As the Vioxx cases go to trial in the months ahead, juries around the country will have to weight the subtleties of these scientific arguments. They will also have to judge in each individual case if a patient's heart problems were directly caused by Vioxx. In Texas today, the jury will hear about a 59-year-old marathon runner who allegedly died of heart problems after taking Vioxx for a few months.
Snigdha Prakash, NPR News.
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