Regulatory Focus™ > News Articles > Government Watchdog: FDA Took 'Lax or Permissive' Approach to Pradaxa Approval

Government Watchdog: FDA Took 'Lax or Permissive' Approach to Pradaxa Approval

Posted 15 October 2015 | By Zachary Brennan 

Government Watchdog: FDA Took 'Lax or Permissive' Approach to Pradaxa Approval

The US Food and Drug Administration's (FDA) judgments regarding the clinical trial and approval of Boehringer Ingelheim's blood thinner Pradaxa (dabigatran) reveal "a lax or permissive approach," according to a new report from the Project On Government Oversight (POGO).

Approved by FDA in 2010 to prevent blood clots in patients with atrial fibrillation, POGO chose to investigate the approval of Pradaxa because it's been suspected of contributing to thousands of patient deaths since its approval, and it's been cited as having the most frequent number of adverse event reports for nearly any drug in 2011 and 2012.

Unsealed court documents also revealed in 2014 that Boehringer failed to disclose a data analysis to FDA that indicated Pradaxa may have caused more fatal bleeding after it was approved than during the clinical trial.

The result of the approval decisions made by FDA, according to POGO, "was to accommodate a pharmaceutical company by easing a drug’s passage to market and then deflecting questions about its safety once the product had won approval."

As for the unblinded clinical trial (meaning researchers knew which subjects were taking the experimental drug) used to earn Pradaxa approval, POGO notes that "FDA tolerated sloppiness and arguably loose controls on the part of the drugmaker in its management of the clinical trial. The agency’s own inspection documented regulatory violations by Boehringer Ingelheim."

The report follows a House Committee on Energy and Commerce letter from last month to FDA's acting commissioner Stephen Ostroff requesting more information on the standard drug used for blood-thinning – warfarin – to see if there are "any further actions FDA could take to decrease the incidence and severity of adverse events" related to its use. That letter also noted the high number of adverse events linked to Pradaxa.

Reversal Agent

Among the major charges made by POGO is that FDA knowingly approved Pradaxa without a way to stop patients from bleeding if they started to hemorrhage, as, unlike warfarin, Pradaxa has no reversal agent. (Editor's note: One day after the release of this report, FDA approved Boehringer's reversal agent).

POGO asked cardiologist Steven Nissen of the Cleveland Clinic how he would treat Pradaxa patients who arrived with a hemorrhage, and Nissen "gave POGO a succinct answer that was only partly in jest": “Pray,” he said. “Transfuse and pray.”

A few years after Pradaxa won FDA approval, Boehringer submitted for approval a drug to reverse Pradaxa’s blood-thinning effect, which FDA is still reviewing on an expedited basis.

Jerry Avorn, a professor at Harvard Medical School, also wrote that the FDA’s analysis behind its statements defending Pradaxa was “unsuitable for informing the care of patients.”

Superiority Claim

In its publicly posted memo announcing and explaining its decision to approve Pradaxa, FDA redacted its assessment of the drug, POGO says. The deleted section, which POGO obtained through the Freedom of Information Act, noted that patients who were well-treated using warfarin had no reason to switch to Pradaxa.

And although initially FDA refused to allow Boehringer to claim Pradaxa was superior to warfarin, later, without much explanation, FDA allowed the company to make a superiority claim.

In addition, FDA initially allowed Boehringer to make a marketing claim about Pradaxa that FDA eventually concluded was “misleading.”

POGO Report


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