The Food and Drug Administration was “lax” and “permissive” in its review of a blood-thinning drug designed to prevent strokes and clots in patients with a heart condition affecting millions of Americans, a watchdog group said Thursday.
The federal regulator made questionable calls to “accommodate” the manufacturer of the anticoagulant Pradaxa, the Project on Government Oversight says in a new investigation, from setting loose standards for the drug’s company-sponsored clinical trial to a lack of proper warnings to patients about its potential health hazards.
“… In the FDA’s oversight of Pradaxa and in the factors it was willing to overlook when reviewing the manufacturer’s clinical trial, the agency has appeared permissive,” POGO wrote in an 81-page report. “The FDA’s own record appears to contain good reasons for the agency to have taken a different approach.”
POGO, which based its conclusions on interviews with patients, researchers and thousands of pages of public records, says the regulatory process that led to Pradaxa’s approval and the government’s oversight since “do not inspire confidence in the regulation of prescription drugs.” The watchdog calls on the FDA for a stronger emphasis on drug safety in its approval process and “higher standards” in clinical trials.
Pradaxa, made by the German drugmaker Boehringer Ingelheim, won FDA approval in 2010 as the first in a new line of blood thinners designed to replace an older treatment, warfarin, which requires patients to monitor themselves with frequent blood tests and follow a strict diet. The drug is intended to prevent strokes and blood clots in patients with a heart-rhythm disorder known as atrial fibrillation.
But the drug, also known by the generic name dabigatran, has had a checkered history. Boehringer Ingelheim agreed last year to pay $650 million to settle about 4,000 lawsuits in state and federal courts filed by patients and their families who claimed the drugmaker failed to properly warn them that Pradaxa caused life-threatening and sometimes fatal bleeding.
Company documents made public last year by the judge overseeing the lawsuits showed that Boehringer employees called for revising and even suppressing internal research on the drug. The employees feared the research would lead some patients to conclude that they should take blood tests after all. They were concerned that the testing could undercut a major selling point of the drug.
FDA spokeswoman Sandy Walsh said in an e-mail that the agency does not comment on specific studies about its review process “but evaluates them as part the of body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
She said the FDA stands by Pradaxa for the vast majority of patients, providing “an important health benefit when used as directed.”
“Health-care professionals who prescribe Pradaxa are asked to carefully follow the dosing recommendations in the drug label, especially for patients with severe renal impairment to reduce the risk of bleeding,” she said.
She noted that in May 2014, the FDA compared Pradaxa to warfarin (Coumadin, Jantoven, and generics) used by Medicare patients and found that the risks were lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa compared to warfarin.
But POGO, which began research into the FDA’s review in 2013, found that on the tightrope drug regulators walk, moving as fast as possible to get promising drugs to patients while being careful not to let dangerous drugs reach the market, FDA did not do its job.
Here are some of the watchdog group’s findings as it investigated Pradaxa’s path from clinical trial to regulatory approval and beyond in “Dangerous decision-making at the FDA”:
- The government approved the drug knowing that there was no antidote to stop patients from hemorrhaging by thickening their blood when treatment went awry. (Boehringer Ingelheim is now developing an antidote).
- As reports of fatal hemorrhages in patients taking Pradaxa fueled concern about the drug’s safety, the FDA issued statements defending it. But outside experts said the scientific analysis behind those statements was deeply flawed and that regulators should not have relied on it to reassure the public.
- Although Pradaxa can cause fatal bleeding — dangers acknowledged in the fine print of the product’s package insert — the FDA has not required the drug to carry a more conspicuous “black box” warning about those hazards. (In contrast, warfarin, which has been around for decades, carries a warning framed in a black box about “major or fatal bleeding.”)
- The FDA approved Pradaxa on the basis of a single clinical trial. The absence of another trial confirming the results of the first “adds a measure of uncertainty,”according to a medical officer in the FDA’s Division of Cardiovascular and Renal Products.
- The FDA also approved the drug on the basis of what is called an unblinded trial. Researchers knew which subjects were taking the experimental drug, and, according to a key FDA reviewer, handled them differently. When patients in the study showed signs of trouble, those on Pradaxa were more likely to have their treatment discontinued, an FDA review found. That would make Pradaxa look safer than it was.
- When doctors helping to run the trial were found by FDA inspections to have mismanaged their part of it, the agency did not restrict their participation in future clinical trials but at most gave them a warning or reprimand and asked them to explain how they would avoid repeating their mistakes, some of them serious.
- Members of the FDA advisory committee that reviewed and endorsed the drug by a vote of nine to zero had ties to the pharmaceutical industry. Financial disclosures for later years show that two of those committee members developed substantial financial relationships with Boehringer Ingelheim.