By Shankar Vedantam
Washington Post Staff Writer
Wednesday, April 12, 2006
Pharmaceutical giant Eli Lilly and Co. recently funded five studies that compared its antipsychotic drug Zyprexa with Risperdal, a competing drug made by Janssen. All five showed Zyprexa was superior in treating schizophrenia.
But when Janssen sponsored its own studies comparing the two drugs, Risperdal came out ahead in three out of four.
In fact, when psychiatrist John Davis analyzed every publicly available trial funded by the pharmaceutical industry pitting five new antipsychotic drugs against one another, nine in 10 showed that the best drug was the one made by the company funding the study.
"On the basis of these contrasting findings in head-to-head trials, it appears that whichever company sponsors the trial produces the better antipsychotic drug," Davis and others wrote in the American Journal of Psychiatry.
Such studies make up the bulk of the evidence that American doctors rely on to prescribe $10 billion worth of antipsychotic medications each year. Davis pointed out the potential biases in design and interpretation that produced such contradictory results. Other experts note that industry studies invariably seek to boost the image of expensive drugs that are still under patent. Moreover, they say, the trials are relatively brief and test drugs on patients with simpler problems than doctors typically encounter in daily practice.
By contrast, when the federal government recently compared a broader range of drugs in typical schizophrenia patients in a lengthy trial, two medications that stood out were cheaper drugs not under patent. The medication that worked best for patients with severe, intractable schizophrenia was clozapine, whose sales lag well behind every other drug in its class. And an earlier leg of the study found that the largely unused drug perphenazine had about the same risks and benefits as far more expensive competitors that are widely assumed to be safer.
Reliance on industry-sponsored studies is not limited to psychiatry, but experts say the problem is exacerbated in areas of medicine where the goal of trials is not to demonstrate cures but to measure symptomatic relief, which allows more latitude in how the results are interpreted and marketed. Now a growing chorus of experts is asking whether the research establishment needs to be reoriented toward publicly funded studies that might better guide clinical decisions and the billions of tax dollars the government itself spends on treatment.
"A perfectly independent agency has to be set up that says, 'Here are the areas where trials must be done,' " said Drummond Rennie, deputy editor of the Journal of the American Medical Association. "There will be two classes of trials -- the believable ones and the non-believable ones."
The problem is not that companies fabricate results, experts say. Researchers, in fact, want drugmakers to sponsor more studies, not fewer. But ostensibly valid industry studies can be misleading in multiple ways, Davis said. Some use too low a dose of a competitor's drug, while others choose statistical techniques that show their drug in the best light. Virtually all test drugs on patients with relatively straightforward problems.
Davis warned that the circular results he found could undermine the confidence of clinicians and patients, and even cast doubt on medications that are genuinely superior. He and Rennie also questioned academic researchers' role in these studies.
Davis, who joked in an interview that he no longer gets to fly first class to Tokyo and Monte Carlo since he stopped accepting money from pharmaceutical companies, guessed that 90 percent of industry-sponsored studies that boast a prominent academic as the lead author are conducted by a company that later enlists a university researcher as the "author."
"We know that happens all the time," Rennie said. "The only reason that the company wants a non-company person as an author is to give credence to an advertisement. . . . The whole entire paper from start to finish is an advertisement. It is a much more subtle and telling ad than anything they can publish as an ad."
Drugmakers defend their studies, and Davis emphasized that the drugs do help patients. But doctors, he said, cannot afford to take the results at face value.
Sara Corya, medical director for neuroscience at Eli Lilly, a company Davis singled out for praise for the quality of its studies, said that conflicting results do not cancel each other out, and that they help clinicians understand the strengths of different drugs. Corya and Davis noted that Lilly has strict rules to prevent author-shopping.
"The reality is that even in head-to-head comparisons, study results will differ for a variety of reasons, some transparent, some opaque," added Mariann Caprino, a spokeswoman for Pfizer, whose antipsychotic drug Geodon did not perform as well as Zyprexa in two trials funded by Eli Lilly. Pfizer's own studies found that Geodon was superior to Zyprexa in one trial and inferior in another.
"What this all means," Caprino said, "is there is no substitute for the judgment and experience of the clinician in selecting among a fortunately broad palette of medicines."
But several experts say industry-sponsored trials are failing to answer the questions doctors really need answered: Which drug works best for which patient? Are differences in drugs worth the differences in cost? How many patients are likely to recover entirely, rather than just show progress in the right direction? Head-to-head trials of similar medications may show statistical differences in how they perform, but those differences may not mean very much for doctors and patients, said Robert Rosenheck, a Yale psychiatrist.
What a clinician wants to know is whether the patient she is treating will get better on a drug, said Thomas R. Insel, director of the National Institute of Mental Health. "If they are not going to get well, what is the better approach? The public is less interested in statistical significance and more interested in clinical significance."
The difference between the two was highlighted by the recent study of antipsychotic drugs funded by the National Institute of Mental Health. Rather than focus on how some symptom or side effect waxes and wanes, the government trial focused on the big picture: How do typical schizophrenia patients fare on the drugs over the long term?
The results were sobering: Regardless of the drug, three-quarters of all patients stopped taking it, either because it did not make them better or had intolerable side effects. The discontinuation rates remained high when they were switched to a new drug, but patients stayed on clozapine about 11 months, compared with only three months for Seroquel, Risperdal or Zyprexa, which are far more heavily marketed -- and dominate sales.
"Clozapine is better by far than the other antipsychotics," said Carol Tamminga, a psychiatry professor at the University of Texas Southwestern Medical Center at Dallas, who wrote an editorial in the American Journal of Psychiatry about the trial. "The question is: Why do doctors not use it?"
The drug requires more careful monitoring to prevent potentially fatal bone-marrow toxicity, she said, but a national monitoring program ensures it is used properly. Tamminga agreed that marketing may play a role in why the drug is not used more often.
"Clozapine is less marketed," she said. "It is off patent. Even when it was on patent, it has never been as actively marketed as the other drugs."
The government study also provided the big picture missing from company-sponsored trials, said Jeffrey Lieberman, a Columbia University psychiatrist who led the first phase of the study: "The drugs work, but only so well. They are not meeting expectations."
By focusing on the horse race -- which drug is marginally better -- industry studies obscure the reality that better drugs are needed overall, agreed Rennie, who is a professor of medicine at the University of California at San Francisco.
"Finding the 100th similar antipsychotic drug is not where the research should be," he said. "It should be to develop new drugs, not 'me, too' drugs."
Rennie said that government agencies such as the Centers for Medicaid and Medicare Services and the Department of Veterans Affairs that disburse billions of dollars for treatment should rely on publicly funded studies.
"There are lots of questions that drug companies are not going to be primarily interested in," agreed Robert Temple, a senior official at the Food and Drug Administration. He has long been a personal advocate of what he calls a "national problems laboratory."
But Uwe Reinhardt, a political economist at Princeton, said drug companies, device manufacturers and even physicians are reluctant to delve into questions of cost-effectiveness because such inquiries may find that the latest, most expensive treatment is not worth the cost.
"I have come to believe a lot of inefficiency is quite deliberate and supported by Congress," he said. "One person's inefficiency is another person's income."