Breaking the Seal on Drug Research
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.
Reviews by the Cochrane group are known for being among the most thoroughly researched medical analyses available. But in trying to answer the pediatrician’s question, Dr. Jefferson realized that there was a flaw: they relied too heavily on the assumption that the articles published in journals accurately represented the results of all clinical trials that had been conducted.
As he tried to track down the authors of the Kaiser study and the two published trials, Dr. Jefferson said he hit dead ends:
One author said he had moved offices and no longer had the files; another said he had never seen the primary trial data, instead relying on a summary analysis provided by Roche. All the authors suggested that he contact the company.
“We took it on faith — on trust,” Dr. Jefferson, 59, said recently in a phone interview. Dr. Hayashi’s question had tested that faith. Dr. Jefferson began typing each new discovery in a private journal he called Hayashi’s Problem, which, he said, “charted my transformation from Dr. Jekyll to Mr. Hyde.”
Dr. Doshi said that medicine “relies on hierarchies of trust.” He added: “A patient is not going to be in a position to review the entire evidence base themselves. But they trust that there is a watchdog out there.”
As they dug into the Tamiflu research, Dr. Doshi said,
he realized that such a watchdog didn’t exist. Instead, he said, “we have partial watchdogs who see part of the full picture.” It became his mission to see the full picture.
Having struck out with the authors of the disputed Kaiser paper and the two other published trials, Dr. Jefferson approached Roche itself, asking for the underlying data from the missing trials. But when he declined to sign a confidentiality agreement, Roche decided not to cooperate with the researchers.
Without more complete data about the clinical trials, the Cochrane group decided that it could not include the disputed study that summarized those results.
In December 2009, the team reported that Tamiflu could not be shown to reduce complications like pneumonia or hospitalizations.
The British Medical Journal, which printed the team’s conclusions, also published its own investigation, showing that Roche had hired ghost writers to author some of the articles involving Tamiflu, and that those writers had said they were under pressure to highlight positive messages about the drug. Roche responded that hiring such writers was common industry practice at the time of the articles, and it rejected the idea that they had been pressured to write positively about the drug.
The articles in the British journal created a sensation, and the Cochrane Collaboration’s efforts became a cause célèbre. “Everyone knows about publication bias,” said Dr. Steven Woloshin, a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice and an advocate of more widespread sharing of clinical trial data. “But they just had so much energy and they brought so much attention to it.”
The group’s efforts seemed to make a difference: After the articles in the British journal, Roche turned over partial copies of study reports, amounting to a little more than 3,000 pages. Then, in 2011, the European Medicines Agency turned over more than 22,000 pages of documents for 19 trial reports to Dr. Jefferson and his team.
The door had been opened. As they read through the records, the researchers discovered the importance of documents called clinical study reports, which are thousands of pages long and contain details as varied as descriptions of trial protocol and design and the ingredients of the placebo pills.
“We used to know that there was a published paper and there were data behind it,” said Dr. Fiona Godlee, the editor of the British Medical Journal. “But people haven’t talked about these things, like clinical study reports, that are now being talked about a great deal.” Last fall, the journal said it would publish the results of clinical trials only if drug companies and researchers agreed to provide data upon request.
In April, Roche said it would make available to the Cochrane researchers clinical study reports for all Roche-sponsored trials of Tamiflu. Dr. Jefferson, Dr. Doshi and their colleagues hope to complete another update to their review of the drug by year-end.
Some said it was a shame that it took this long for the company to relent. “All these years later, and we still don’t know if Tamiflu is effective,” said Dr. Harlan Krumholz, the Yale cardiologist who oversaw the review of Medtronic’s bone treatment. “It’s perplexing to have a billion-dollar drug, and you’re still not willing to share everything you’ve got to know whether this thing is effective and safe.”
https://www.nytimes.com/2013/06/30/b...-research.html