Boehringer Ingelheim GmbH didn’t disclose a data analysis to U.S. regulators that indicated the blood-thinner Pradaxa may have caused more fatal bleeding after it was cleared for sale than the drug did in a study used to win approval, unsealed court filings show.
Boehringer gave U.S. regulators one analysis of data gathered after the drug’s October 2010 approval that showed the number of people who died from bleeding was less than expected, according to internal documents made public in lawsuits over the product. The company didn’t share a second analysis showing a higher death rate, the documents show.
The Food and Drug Administration was reviewing the bleeding as part of a safety check spurred by results seen in adverse incident reports sent to the agency. Andreas Clemens, an executive who oversees Pradaxa, acknowledged the Ingelheim, Germany-based company shared only one of the analyses and said he couldn’t say why, according to the unsealed court filings.
“Having run an analysis in several ways, there is no good reason not to disclose all the results,” said Harlan Krumholz, a Yale University cardiologist in New Haven,Connecticut, who is leading an effort to get companies and researchers to share their findings fully.
Boehringer gave the FDA the underlying data and provided an analysis using what the drugmaker considered to be the most appropriate comparison, said Marjorie Moeling, a company spokeswoman, in an e-mailed response to questions. “The company is completely confident that all of the facts will show that Boehringer Ingelheim acted appropriately and responsibly.”
A company filing this month said Boehringer faces more than 2,000 suits involving Pradaxa, a treatment used to prevent strokes in patients who suffer from atrial fibrillation, a heart-rhythm disorder. Regulators cleared the drug, which generated $1.4 billion in 2012 sales, as the first alternative to warfarin, a product sold by Bristol-Myers Squibb Co. under the brand name Coumadin that’s been used for 50 years to avert strokes caused by blood clots.
Patient lawsuits contend Boehringer knew the drug posed a deadly risk when it won FDA approval. While warfarin offers a way to counteract excessive bleeding, there’s no approved antidote available yet for those on Pradaxa. In November, the company released data from the first human study of an antidote in 145 healthy volunteers.
Boehringer’s decision to provide only one analysis on Pradaxa’s use after the drug’s approval may complicate the company’s defense as it prepares to face the first trial of claims that it hid the medication’s health risks.
“It is important to resist selective presentation of results, especially when the finding depends on which analysis is done,” said Krumholz, who isn’t involved in any of the Pradaxa lawsuits, by telephone. “The fact that different analyses of the same data can yield different conclusions makes it imperative that we promote an opportunity for independent analyses through data sharing so that these issues will be out in the open.”
In the Pradaxa case, the regulators asked Boehringer to compare fatal bleeding reports received by the FDA against the number of patients using the drug in order to establish a death rate. The request was made to allow the FDA to “evaluate the need for modifications to the Pradaxa label or future study,” according to a letter made public as part of the court files.
The company reported back that 6.1 of every 10,000 patients who used the drug after approval developed fatal bleeding, the court documents showed. The regulators also asked Boehringer to reanalyze results from an earlier study used to gain approval to see how that rate compared.
That effort produced two separate analyses by the company, according to the unsealed court documents. One, looking only at people whose primary cause of death was bleeding, found 5.8 of 10,000 patients died per year. The other, which included anyone who had a major bleeding event and died for any reason, found a rate of 19.5 fatal events per 10,000 patients per year, the documents show.
The report sent to the FDA, though, contained only the analysis indicating the death rate from the earlier research was much higher than the numbers seen after approval, according to the court filings. Potentially, such a finding could head off any after-market action by the FDA because the data showed the drug was safer after it was approved and widely used.
Boehringer’s Clemens, mentioned in the e-mails including in the court documents as one of the executives who decided what information to give the FDA, said it would have been possible to provide both numbers.
He said that Boehringer’s decision to withhold the analysis showing the lower bleeding rate in the pre-approval research may have been driven by concerns about the “quality of this number,” according to the filings.
Moeling, the Boehringer spokeswoman, said the 5.8 per 10,000 number wasn’t an appropriate comparison because it reflected a limited number of cases where doctors determined the bleed was the primary cause of death. Because reports to the FDA aren’t always complete, the company wasn’t able to identify the same specific subgroup after the drug’s approval, she said.
The FDA, meanwhile, hasn’t identified any unrecognized risk factors for bleeding with Pradaxa, said Sandy Walsh, an agency spokeswoman, in an e-mail. The FDA, though, is continuing to evaluate “multiple sources of data in an ongoing safety review,” according to Walsh, who declined to comment on the pending litigation.
Selective disclosure of Pradaxa information may have camouflaged a serious safety signal, according to an assessment report from European Medicines Agency’s Committee for Medicinal Products for Human Use in August 2012. That agency is the European Union’s drug regulator, equivalent of the U.S. FDA.
“If the reporting rate in the post-marketing phase had been higher than in” Boehringer’s study, “there would clearly have been a safety concern,” agency officials wrote. European drug regulators have Pradaxa under review and American regulators are planning another assessment of the drug’s safety as part of its program to monitor FDA-regulated products.
Boehringer’s conduct regarding Pradaxa may also have a negative impact on future requests for regulatory approvals, said Erik Gordon, a University of Michiganbusiness and law professor who teaches classes about how drugs are developed and regulated in the U.S.
“These are the kinds of drug-company actions that can drive a stake through the heart of an FDA approval process that is based on the idea that companies will be forthright with the data about their products,” Gordon said.
If drugmakers are allowed to continue to select the safety information they share with regulators, consumers can’t be sure the disclosures aren’t being driven by financial concerns, Gordon said in a telephone interview.
This case “should raise some eyebrows,” he said.
Pradaxa suits filed against Boehringer in federal courts across the country have been consolidated for pretrial information exchanges before U.S. District Judge David Herndon in East St. Louis, Illinois. Other cases have been filed in state courts in Delaware, California, Illinois and Connecticut.
Herndon set the first case for trial among the consolidated federal suits for August, according to court dockets. He also ordered Boehringer to pay almost $1 million in fines for withholding or failing to preserve files about the drug’s development and marketing.
The case is In re Pradaxa Products Liability Litigation, 12-MD-02385, U.S. District Court, Southern District of Illinois (East St. Louis).