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Fewer Bitter Pills?

For the first time in recent memory, there is actually some good news about drug safety. The Food and Drug Administration Revitalization Act, signed into law in September, significantly expands the FDA’s power to protect us from dangerous medications. It also lifts the veil of secrecy from the process of testing new therapies.

Among its highlights, the act authorizes the FDA to require postmarketing studies of drugs whose safety is in question. It limits the conflict-of-interest waivers granted to advisory committee members with financial ties to the pharmaceutical industry. Of particular interest to anyone concerned with research ethics, the legislation requires therapeutic clinical trials to be registered in a public database with their objectives and findings available for all to read. Thus, drug and device companies will have a harder time cherry-picking positive data to publish and hiding adverse effects by pleading “proprietary rights.”

To appreciate the hope raised by this legislation, it helps to revisit the news headlines of drug-safety lapses in the last three years.

In 2004, Vioxx, a blockbuster painkiller, was taken off the market because of evidence that it doubled the risk of heart attack and stroke. The following year, an FDA advisory panel refused to prevent Vioxx from re-entering the market or to force the withdrawal of similar drugs, Celebrex and Bextra, despite their heart risks. But at least 10 of the 32 panel members had financial ties to Merck, Pfizer, and Novartis, the makers of these drugs, according to a 2005 study by the Center for Science in the Public Interest, an advocacy group.

Then, also in 2005, GlaxoSmithKline paid $2.5 million to settle a lawsuit by the New York attorney general alleging that it withheld research showing that Paxil, its antidepressant, might increase suicidal thoughts in children and teenagers.

Last May, the public learned that Avandia, GlaxoSmithKline’s popular type 2 diabetes drug, increased the risk of heart attacks and other cardiovascular problems by 43 percent. FDA officials knew about the cardiac risks for two years before taking action.

In September came a report by the inspector general of the Department of Health and Human Services finding that the FDA does a poor job of overseeing clinical trials and safeguarding the volunteers who participate in them. “In many ways, rats and mice get greater protection as research subjects in the United States than do humans,” said Arthur Caplan, a bioethicist at the University of Pennsylvania, as quoted in The New York Times.

The mandatory public registry should strengthen the FDA’s oversight of clinical trials simply by virtue of the fact that the agency will know what and where those trials are. The power to require postmarketing safety studies should result in swifter action against future Vioxxes and Avandias. Fewer conflict-of-interest waivers for FDA panelists may mean fewer rulings biased in favor of drug companies.

But these hopeful prospects are tempered by some negative factors. Especially controversial is the act’s reauthorization of the user fees that pharmaceutical companies pay the FDA. With $400 million in user fees, reducing conflict-of-interest waivers may do about as much good as a splint on a crushed leg.

“One FDA scientist who was often criticized for being too concerned about drug-risk data was told by his supervisor to remember that the agency’s client was the pharmaceutical industry,” wrote Jerry Avorn, professor of medicine at Harvard Medical School, last April in the New England Journal of Medicine.

Another drawback is that the act exempts from public registration Phase 1 toxicity trials and clinical trials on therapies that do not make it to market. This loophole is ethically troubling because it means that the thousands of people who participate in these studies can be kept in the dark about the findings.

A bit of activism by trial participants may help narrow that loophole. In an editorial on October 25, the New England Journal of Medicine issued a call to arms: “People interested in participating in trials should consider only studies whose sponsors have fully registered them in an appropriate public database and agreed to publish their results.”

But for human volunteers to become activists, they must first become better informed. “The truth is that most prospective subjects probably have no clue what this is all about,” said Thomas Murray, president of The Hastings Center. One way to clue them in is for institutional review boards (IRBs), which protect research subjects, to require consent forms to say whether a trial is publicly registered. If it isn’t, prospective volunteers can exercise their power of the pen and sign on with a trial that is.

Despite its flaws, the revitalization act appears to be good news for the safety of drugs and the process of bringing them to market. How well the FDA and the other players – the clinical trial sponsors, the researchers, IRBs, and the volunteers themselves – to do their parts will determine just how good the news really is.

Published on: November 5, 2007
Published in: Clinical Trials and Human Subjects Research, Conflicts of Interest in Research, Pharmaceutics

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