Published: July 14, 2013 3:00 a.m.
Claims of sloppiness draw FDA’s interest
Drew Armstrong | Bloomberg News
NEW YORK – Drugmakers have increasingly been turning to China for large clinical trials because they’re cheaper and there’s a bigger population of subjects to draw on.
Now U.S. regulators have stepped in, questioning sloppy data and irregularities from the world’s most populous country.
Bristol-Myers Squibb Co. and Pfizer Inc.’s blood thinner Eliquis, approved in December, was stalled for nine months because of misconduct, errors and an alleged cover-up attempt at a Chinese trial site overseen by Bristol-Myers, according to documents posted by the Food and Drug Administration. The delay came after the company told the FDA that patients got the wrong medicine, records were secretly changed and “serious adverse events” went unreported, the documents show.
The errors led to a lengthy reanalysis of the data and spurred a debate within the agency on what the drug’s label should say about its effectiveness. An agency official also questioned whether large trials in countries like China with similar data shortfalls were a viable basis for approving treatments, according to the documents.
The mistakes showed a “pattern of inadequate trial conduct and oversight,” according to minutes of a Feb. 9 agency meeting involving the two New York companies and the FDA, posted on the agency’s website.
Sales for Eliquis may one day reach $10 billion a year, according to analysts. The delay, though, may cut the time Eliquis is protected by patent, reducing revenue by billions of dollars.
The Eliquis case is an example of the increasing scrutiny the pharmaceutical industry is facing on its research in China, which offers a huge base of test subjects and costs that the Tufts Center for the Study of Drug Development says can be half those in the United States.
Drugmakers will keep having problems with sloppy data and misconduct as long as they keep doing trials in places like China without providing better oversight, said Thomas Marciniak, an FDA medical team leader who wasn’t directly involved in the Eliquis application but reviewed the trial independently.
“What we need is high-quality trials. If we’re not getting them in the low-cost areas, either fix the low-cost areas, or stop doing them,” Marciniak said in an interview, emphasizing that he was speaking for himself and not the agency.
Last month, London-based GlaxoSmithKline said it fired its head of Chinese research after the scientist allegedly misrepresented data that was published in a medical journal.
Bristol-Myers, which ran the Eliquis trial known as Aristotle, responded appropriately once the mistakes became known, said Elliott Levy, the company’s executive who oversaw the research. A reanalysis done by the company and the FDA deleted the questionable data and found it didn’t substantially affect the final, positive result, he said.
The mistakes “were not exceptional,” Levy said in a telephone interview. “The issues they raised required recourse to the primary source data and some months to fully evaluate, but they’re not exceptional issues.”
Asked whether the issues in China created concerns that other misconduct or bad data may have occurred in the trial, Levy said Bristol-Myers was confident they hadn’t. “I don’t think there’s anything unique about China in this regard,” Levy said. “We’ve looked closely at the quality of the data and reliability and it’s not distinguishable from the United States and Europe.”
Pfizer is confident in the trial results, said Mackay Jimeson, a spokesman for the company.
Christopher Granger, a professor of medicine at Duke University in Durham, N.C., who was the lead outside researcher on the trial, disagreed with Levy.
“There is a greater likelihood of some of this impropriety in certain regions,” Granger said in a telephone interview. “We’ve had experiences in India and China where we’ve had more than we would have expected.”
Eliquis was developed as a safer and easier-to-take replacement for warfarin, a half-century-old blood thinner widely used to combat blood clotting and strokes.
Pfizer, the world’s biggest drugmaker, and Bristol-Myers share sales on Eliquis, which competes with Boehringer Ingelheim’s Pradaxa, and Bayer and Johnson & Johnson’s Xarelto.
The final-stage trial of Eliquis began in 2006, and eventually grew to more than 1,000 sites in 40 countries, according to the FDA. About 16 percent of the 18,000 patients were in Asia, with three dozen sites located in China.
Doctors and hospitals who sign on as investigators are typically paid for getting patients to enroll in the trial. They’re overseen by the drug companies, which monitor the patients in coordination with the physicians. Much of that work is done by contract research organizations.
In the Eliquis trial, Bristol-Myers hired Pharmaceutical Product Development Inc., a closely held Wilmington, N.C., company known as PPD, to help oversee it.
The Eliquis trial was questioned on two issues, according to the FDA documents first cited by the journal Pharmaceutical Approvals Monthly.
One was the improper manipulation of records at a study site for 35 patients at the Shanghai 9th Peoples Hospital in China. The second involved the high percentage of the 9,000 patients who were supposed to be getting Eliquis, and instead were either given the wrong drug, or the wrong dose.
There was a broad list of issues at the Shanghai hospital, according to FDA documents.
They included failure to report four potential adverse medical events, late reports on three others and three medical outcomes that weren’t included in the data. The FDA also reported that some patient records disappeared just ahead of a site visit by agency inspectors.
“The records were altered in order to cover-up GCP violations which had occurred at the site,” the FDA said in its report. GCP stands for “good clinical practice.”
Levy disputed some aspects of the report. The company “examined the trial data at that site and found that all the primary endpoints and the key secondary endpoints were appropriately documented and reported,” he said.