Breaking the Seal on Drug Research

Dr. Doshi’s renown comes not from solving the puzzles of cancer or discovering the next blockbuster drug, but from pushing the world’s biggest pharmaceutical companies to open their records to outsiders in an effort to better understand the benefits and potential harms of the drugs that billions of people take every day. Together with a band of far-flung researchers and activists, he is trying to unearth data from clinical trials — complex studies that last for years and often involve thousands of patients across many countries — and make it public.

The current system, the activists say, is one in which the meager details of clinical trials published in medical journals, often by authors with financial ties to the companies whose drugs they are writing about, is insufficient to the point of being misleading.

There is an underdog feel to this fight, with postdocs and academics flinging stones at well-fortified corporations. But they are making headway. Last fall, after prodding by Dr. Doshi and others, the drug giant GlaxoSmithKline announced that it would share detailed data from all global clinical trials conducted since 2007, a pledge it later expanded to all products dating to 2000. Though that data has not yet been produced, it would amount to more than 1,000 clinical trials involving more than 90 drugs, a remarkable first for a major drug maker.

The European Medicines Agency, which oversees drug approvals for the European Union, is considering a policy to make trial data public whenever a drug is approved. And on June 17, the medical world saw how valuable such transparency could be, as outside researchers published a review of a spinal treatment from the device maker Medtronic. The review, which concluded that the treatment was no better than an older one, relied on detailed data the company provided to the researchers.

For years, researchers have talked about the problem of publication bias, or selectively publishing results of trials. Concern about such bias gathered force in the 1990s and early 2000s, when researchers documented how, time and again, positive results were published while negative ones were not. Taken together, studies have shown that results of only about half of clinical trials make their way into medical journals.

Problems with data about high-profile drugs have led to scandals over the past decade, like one involving contentions that the number of heart attacks was underreported in research about the painkiller Vioxx. Another involved accusations of misleading data about links between the antidepressant Paxil and the risk of suicide among teenagers.

To those who have followed this issue for years, the moves toward openness are unfolding with surprising speed.

“This problem has been very well documented for at least three decades now in medicine, with no substantive fix,” said Dr. Ben Goldacre, a British author and an ally of Dr. Doshi. “Things have changed almost unimaginably fast over the past six months.”

Much of that change is happening because of what Dr. Goldacre calls an “accident of history.” In 2009, Dr. Doshi and his colleagues set out to answer a simple question about the anti-flu drug Tamiflu: Does it work? Resolving that question has been far harder than they ever envisioned, and, four years later, there is still no definitive answer. But the quest to determine Tamiflu’s efficacy transformed Dr. Doshi and others into activists for transparency — and turned the tables on drug makers. Until recently, the idea that companies should routinely hand over detailed data about their clinical trials might have sounded far-fetched. Now, the onus is on the industry to explain why it shouldn’t.

IN summer 2009, Dr. Doshi received a call from Dr. Tom Jefferson, a British epidemiologist based in Rome. That year, the swine flu pandemic was spreading worldwide, and Dr. Jefferson had been hired by the British and Australian governments to update an earlier review of Tamiflu, a drug produced by the Swiss company Roche, aimed at reducing the flu’s severity and preventing more serious complications. He asked if Dr. Doshi wanted to help.

Determining Tamiflu’s efficacy had significant economic as well as health consequences. Around the world, private companies and governments — including that of the United States — were stockpiling Tamiflu in case of influenza outbreaks, and their spending accounted for almost 60 percent of the drug’s $3 billion in sales in 2009.

The review of Tamiflu was being conducted under the auspices of the Cochrane Collaboration, a well-regarded network of independent researchers, including Dr. Jefferson, who evaluate medical treatments’ effectiveness by analyzing all available research.

At the time, Dr. Doshi knew little about clinical trials or even much about the drug industry. But he knew Dr. Jefferson. Dr. Doshi, after receiving undergraduate and master’s degrees in anthropology and East Asian studies from Brown and Harvard, had shifted focus and was pursuing a doctorate at M.I.T., studying the intersection of medicine and politics. He met Dr. Jefferson, a prominent skeptic of the flu vaccine, after researching whether the Centers for Disease Control was exaggerating the deadliness of the disease.

“We were both lone wolves in the field of influenza,” Dr. Doshi recalled.

Dr. Jefferson had conducted a Cochrane review of Tamiflu’s effectiveness a few years earlier, concluding that the drug reduced the risk of complications from the flu. He assured Dr. Doshi and other researchers on his team that the update would be fairly simple.

But just as their work was getting under way, a simple comment arrived on the Cochrane Web site that changed the course of the research and would ultimately fuel a worldwide effort to force drug companies to be more transparent.

The author of that comment, Dr. Keiji Hayashi, had no connection to the Cochrane group; he was a pediatrician in Japan who had prescribed Tamiflu to children in his practice, but had come to question its efficacy. He was curious about one of the main studies on which Dr. Jefferson had relied in his previous analysis. Called the Kaiser study, it pooled the results of 10 clinical trials. But Dr. Hayashi noticed that the results of only two of those trials had been fully published in medical journals. Given that details of eight trials were unknown, how could the researchers be certain of their conclusion that Tamiflu reduced risk of complications from flu?

“We should appraise the eight trials rigidly,” Dr. Hayashi wrote.

Article source: http://www.nytimes.com/2013/06/30/business/breaking-the-seal-on-drug-research.html?partner=rss&emc=rss