The difference between what drug companies tell the government and doctors suggests that they're cooking the books, which could mislead doctors making prescriptions.

Of 33 new drugs approved by the Food and Drug Administration in 2001 and 2002, one-fifth of supporting clinical trials were not published in medical journals, according to a new study. And those results that were published were often more positive than what companies presented to the FDA in their applications. As a result, potentially unreliable data is being used to promote drugs on which billions of dollars and thousands of lives may ride.

"Some studies aren't published at all. Then, when they are, there are little changes that make the papers look more favorable towards the product," said review co-author Lisa Bero, a University of California, San Francisco health policy expert.

If new — and typically more expensive — drugs are only slightly better than existing drugs, but otherwise are comparable, this is largely an ethical and financial problem. But if the drugs later prove harmful, the damage can be profound.

In 2004, Merck's blockbuster anti-inflammatory drug Vioxx was pulled from the market after killing an FDA-estimated 27,000 people. The drug doubled heart attack risk — a side effect that critics say was glossed over in the company's studies, which in retrospect were partly marketing propaganda. Another Merck blockbuster, the cholesterol-lowering drug Vytorin, has proven ineffective. GlaxoSmithKline's best-selling diabetes drug Avandia was allowed to remain on the market, but only with a label stating its apparent cardiovascular risks.

None of those drugs were among the applications reviewed in by Bero, and her team reviewed only efficacy rather than safety data. But the underlying problem was similar: Doctors and researchers who trusted in prestigious, peer-reviewed journals were given a false impression of the medicines.

"It's more of the same," said Arthur Levin, director of the nonprofit Center for Medical Consumers. "It confirms that this is not an open, transparent process. There is still the opportunity for sponsors of new products to try and tip the scales in their favor."

Among the differences between results submitted to medical journals and to the FDA were trials that didn't favor a company's product, Bero found. Only half of 43 such outcomes were reported in the literature.

More subtly, but just as importantly, key pieces of trial data vanished.

"The main thing that jumped out at me was the addition and deletion of primary outcomes. Those are the most important outcomes of a trial. To find that one disappeared from a paper, or just appeared in a paper, is pretty amazing to me," said Bero.

FDA spokeswoman Rita Chappelle stressed that the agency bases its decisions on application data, not medical literature. Once a drug is approved, she said, the agency's scientific review is made available to the public. "This allows anyone to see what studies were done and what the results were," she said.

But in a commentary accompanying Bero's review, published yesterday in Public Library of Science Medicine, Mayo Clinic researcher

An-Wen Chan wrote that the content and availability of FDA releases "is variable, and sections are often redacted." Such information, agreed both Chappelle and Levin, is also harder for doctors to read than traditional journal articles.

However, even if the FDA makes application data available, and no changes are made to journal publications, the troublesome fact remains that commercially funded studies systematically favor their sponsors.

Bero calls for the FDA to be overhauled to run clinical studies itself, as is done by comparable agencies in Italy and Spain.

"The Italian FDA collects money from every drug company that sells drugs in Italy, pools that, and funds drug trials. They fund the sort of head-to-head drug comparisons that companies don't like to fund. And they have independent people peer-reviewing the trials. It's a great model," she said.

The Pharmaceutical Research and Manufacturers Association of America, the drug industry's trade group, defended the current system in a prepared statement.

“The critical information that health care providers need to make appropriate prescribing decisions are found in the Food and Drug

Administration-approved drug label, which synthesizes key details, including important drug safety information that may not be included in a published paper," said senior vice president Ken Johnson.

Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation [PLoS Medicine]

Bias, Spin, and Misreporting: Time for Full Access to Trial Protocols and Results [PLoS Medicine]

Image: Chelsea Oakes

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