Drug Problems: Dangerous Decision-Making at the FDA

On July 14, 2011, a retired social worker named Sidney Denham was taken to an emergency room in Savannah, Georgia. Weeks after undergoing prostate surgery, and days after resuming use of a relatively new blood thinner called Pradaxa, the 81-year-old widower was bleeding profusely from his urinary tract. He had lost so much blood that his pressure had plunged to about half the normal level and his body was in shock. In the intensive care unit, a medical team deployed treatment after treatment in a struggle to save him.

One of Denham’s daughters, Kay Denham, recalled the scene: “More blood than I think I've ever seen in my life … Millions of people in the room … They could not control the bleeding.”

A hospital record shows that Denham was given 12 units of red blood cells and another 12 of fresh-frozen plasma—almost two gallons. He was pumped with platelets and other blood products. He was put on dialysis to purge the Pradaxa from his system. Nothing worked.

Even as they replaced his blood, it was draining out of him.

“It was horrible,” said daughter Mary Denham, “that feeling of helplessness, for the people in the ER and for us. There was nothing they could do to stop the bleeding. My sister and I watched him bleed to death.”

Denham had been taking the anticoagulant Pradaxa to treat a condition called atrial fibrillation, in which irregular functioning of the heart can cause blood clots and strokes; the medicine is supposed to prevent the clots from forming. But, according to Denham’s “DEATH SUMMARY” from Memorial University Medical Center in Savannah, the FDA-approved drug contributed to his demise.

The patient, the document says, suffered an “uncontrollable hemorrhage from Pradaxa.”

The Food and Drug Administration is responsible for making sure medicines sold to the public are safe and effective. But how much comfort should medical consumers take from the words “FDA approved”?

In judgment call after judgment call involving the prescription blood thinner Pradaxa, which has been named as a suspect in thousands of patient deaths, the FDA took a lax or permissive approach, a Project On Government Oversight investigation has found.

The result 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. The issues ranged from what standards to demand from the manufacturer-sponsored clinical trial used to secure the drug’s approval to what warnings to give patients about potential hazards and what claims to allow in ads for the product.

POGO’s findings, based on interviews with key participants and researchers and upon thousands of pages of public records, many obtained through the Freedom of Information Act, call into question the reliability of a crucial regulatory system.

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Overview

The public depends on regulators for sound scientific judgments and for protection from the potentially distorting effects of drug makers’ profit motive. But, time and again, far from resolving questions about a drug’s safety or effectiveness, FDA approval has become a prelude to pharmaceutical scandal or controversy.

The history stretches from Vioxx and Avandia to Yaz and Yasmin, from Fen-Phen to Baycol, Darvon, Ketek, and Paxil. In some cases, drugs approved by the FDA after undergoing supposedly rigorous clinical trials have gone on to cause serious harm. In other cases, after drugs have been allowed on the market, questions set in.

Doctors, patients, and FDA regulators alike have been left struggling to determine whether serious or deadly mishaps are actually side effects—whether drugs meant to help people are actually hurting them. Were significant risks foreseen before the drugs were approved, or were they foreseeable? Were they properly weighed and disclosed? Did the clinical trials used to test the drugs provide a sound basis for FDA approval? Once the drugs were released to the market, how did the FDA track and respond to whatever happened next? Fundamentally, how well did the agency do its job?

To shed light on the FDA’s oversight of prescription drugs, POGO took a close look at one drug’s journey from clinical trial to regulatory approval and beyond. From the drug’s origins in a pharmaceutical company’s research laboratories, the steps in the process included a clinical trial in which the company and doctors working on its behalf tested the drug in thousands of human guinea pigs around the world; inspections in which the FDA scrutinized the performance of a sample of those doctors; analysis of the clinical trial’s results by FDA staff; a hearing and vote by an advisory committee of outside experts convened by the FDA (though advisory committee recommendations are non-binding, the FDA generally follows them); the FDA’s decision to approve the drug; and, once the drug was cleared for use in the United States, ongoing FDA oversight of such issues as the drug maker’s marketing activities and the occurrence of side effects in people taking the drug.

POGO chose to focus on Pradaxa—also known by the generic name dabigatran—because, after it was approved by the FDA in 2010, it became one of the drugs most frequently named in so-called “adverse event” reports submitted to the agency about suspected side effects. In 2011 and 2012, Pradaxa was the drug most frequently named in adverse event reports submitted directly to the FDA by doctors, patients, family members and the like, according to reports by the Institute for Safe Medication Practices (ISMP), which tracks data on adverse events. By September 2012, it had been identified as the primary suspect in almost 2,000 reports about patient deaths, according to data from another source, adverseevents.com.

Such reports do not prove that a drug caused a medical mishap like Sidney Denham’s fatal hemorrhage, but they identify it as a potential factor. Pradaxa was associated with hemorrhages.

The adverse event reports were not the only causes for concern. In 2012, the drug’s manufacturer, Boehringer Ingelheim, prematurely stopped a follow-on clinical trial of Pradaxa use in patients with mechanical heart valves because subjects taking the drug were suffering from excessive blood clots and bleeding.

The FDA approved Pradaxa in 2010 for prevention of strokes and blood clots in patients with atrial fibrillation, a condition estimated to affect 2.7 to 6.1 million people in the United States.  It was the first of a new type of anticoagulant and, the manufacturer says, the first oral anticoagulant approved by the FDA for non-valvular atrial fibrillation in more than 50 years. It has been sold to the public as offering a distinct advantage over warfarin, the decades-old drug it was meant to replace: patients taking it wouldn’t need to undergo regular blood tests.

Other new anticoagulants in Pradaxa’s class include Eliquis (generic name apixaban), Savaysa (edoxaban), and Xarelto (rivaroxaban), which is promoted in television ads featuring golfer Arnold Palmer, NASCAR driver Brian Vickers, and comedian Kevin Nealon.

Pradaxa “posted mammoth results in 2012, reaching blockbuster status in its second full year, with $1.4 billion in sales,” an industry publication reported. As of November 3, 2014, it had been prescribed for more than 935,000 patients in the United States, according to the manufacturer.

Meanwhile, Boehringer Ingelheim became the target of thousands of lawsuits filed by Pradaxa patients and their families, including the Denhams.

While the litigation was playing out, the federal judge presiding over it, Chief Judge David R. Herndon of the U.S. District Court for the Southern District of Illinois, found that the companyhad been withholding or failing to preserve records sought by plaintiffs. He fined Boehringer Ingelheim $931,500 and accused the company of acting in “bad faith.”

Some of the documents cited in the judge’s December 2013 order—internal company emails—appear to raise questions about one of the drug’s principal claimed advantages, the notion that there is no need to monitor patients’ blood and adjust their doses in response. According to the judge’s order, a high-level scientist at Boehringer Ingelheim named Thorsten Lehr drafted a paper concluding that, as the judge paraphrased it, “both safety and efficacy of dabigatran are related to plasma concentrations and … there is a therapeutic range for Pradaxa.” (The term “therapeutic range” means a range within which a drug is typically expected to yield the desired results.)

The judge recounted that others inside the company resisted publishing that conclusion.

“I have been facing heavy resistance internally on this paper about the concept of a therapeutic range, at least stating it outright,” Paul Reilly of Boehringer Ingelheim, who was tasked with revising the paper, said in an internal email quoted by the judge.

Publishing the information “will make any defense of no monitoring … extremely difficult … and undermine our efforts to compete” with other new anticoagulants, Boehringer Ingelheim’s Jutta Heinrich-Nols said in a February 2013 email that was posted online by The New York Times.

In May 2014, against the backdrop of those disclosures, Boehringer Ingelheim agreed to settle Pradaxa litigation for $650 million. The company said it was trying to put about 4,000 claims involving the drug behind it, and it conceded no liability. “We continue to stand resolutely behind Pradaxa® and believed from the outset that the plaintiffs’ claims lacked any merit,” Andreas Neumann, the company’s general counsel, said in a news release at the time.

To be sure, there might have been legitimate arguments on both sides of health and safety issues confronted by regulators. However, taken together, the FDA’s decisions about Pradaxa add up to a troubling pattern. For example:

• The FDA approved Pradaxa despite the absence of an antidote to thicken the blood and stop patients from bleeding uncontrollably if they start to hemorrhage. Unlike warfarin—the longtime standard for blood-thinning—Pradaxa has no reversal agent.
• As reports of fatal hemorrhages in patients taking Pradaxa fueled concern about the safety of the blood thinner, the FDA issuedstatements defending the new drug. But outside experts said the scientific analysis behind those statements was deeply flawed and that the FDA should not have reassured the public on the basis of it. Jerry Avorn, a professor at Harvard Medical School, wrote that the FDA’s analysis ignored key variables and was “unsuitable for informing the care of patients.” David Madigan, professor of statistics and dean of the Faculty of Arts and Sciences at Columbia University, called the FDA’s Pradaxa study “junk.”
• Though Pradaxa can cause fatal bleeding, and though there is no antidote—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, the decades-old warfarin carries a warning framed in a black box about “major or fatal bleeding.”)
• The FDA approved the drug on the basis of 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. As a result, adverse events such as hemorrhagic strokes that might have occurred had they continued taking Pradaxa would have been averted, cardiologist Steven Nissen, who served on an FDA advisory committee, explained. That would make Pradaxa look safer than it was. Addressing the committee, Nissen said the possibility the trial was biased was “the elephant in the room.” 
  
  At the same meeting, Aliza Thompson, a medical officer in the FDA’s Division of Cardiovascular and Renal Products, voiced concern that the unblinded approach “sort of inflates the findings relative to warfarin.” 
  
  FDA records show that the agency expressed a preference for a double-blind study (in which the people on the clinical trial’s front lines would not know which patients were taking which drug)—but did not insist upon it.
• The FDA approved the drug on the basis of a single clinical trial. The absence of another trial confirming the results of the first “adds a measure of uncertainty,” Thompson told the advisory committee.
• The scoring system for the clinical trial was not finalized until the trial was over. A key document called the Trial Statistical Analysis Plan specified, among other things, criteria for determining whether adverse events such as strokes and heart attacks were to be counted as part of the study’s results or left out. But the Statistical Analysis Plan was not finalized until May 8, 2009, about two months after the data had been gathered and the study had ended, according to FDA documents. 
  
  An FDA review found that the way the lines were drawn helped Pradaxa in comparison to warfarin with respect to mortality rates.
• In its publicly posted memo announcing and explaining its decision to approve Pradaxa, the FDA redacted its assessment of the drug in a way that protected the product’s image at the expense of informing the public. The deleted section, which POGO obtainedthrough the Freedom of Information Act (FOIA), said that patients who were well-treated using warfarin had no reason to switch to Pradaxa.
• Initially, the FDA refused to allow Boehringer Ingelheim to claim Pradaxa was superior to warfarin. The agency concluded that the experimental data did not warrant such a claim. But, without much of an explanation for its change of heart, the FDA later acceded to the manufacturer’s request and allowed the company to make a superiority claim.
• The FDA allowed Boehringer Ingelheim to make another promotional claim that the agency itself eventually declared “misleading.” The manufacturer originally advertised that, in a clinical trial, Pradaxa “reduced stroke risk 35% more than warfarin.” After the drug had been on the market for more than two and a half years, the FDA explained that it had changed its opinion about the 35 percent claim and it directed the company to add a clarification: “That means that in a large clinical study, 3.4% of patients taking warfarin had a stroke compared to 2.2% of patients taking Pradaxa.” In other words, in absolute terms, the difference between the drugs was only 1.2 percent.
• The FDA tolerated sloppiness and arguably loose controls on the part of the drug maker in its management of the clinical trial. The agency’s own inspection documented regulatory violations by Boehringer Ingelheim, according to an FDA memo. The inspection found such violations as “failure to ensure proper monitoring of the study and ensure the study is conducted in accordance with the protocol and/or investigational plan.” 
  
  When the company originally submitted its application for approval of Pradaxa, the agency refused to even consider it because it was riddled with errors and numbers the FDA described as “highly implausible.”
• When doctors helping to run the trial were found by FDA inspections to have mismanaged their part of it, the FDA did not restrict their participation in future clinical trials. As far as POGO could determine from public records, at most, the FDA gave them a warning or reprimand and asked them to explain how they would avoid repeating their mistakes. According to FDA documents, those mistakes included enrolling patients with liver disease and severe kidney impairment even though such patients were supposed to be excluded from the study, failing to promptly inform the drug maker about possible adverse effects of the experimental drug, failing to obtain the fully informed consent of human research subjects, and failing to oversee the study closely enough “to protect the rights, safety, and welfare of subjects enrolled in the study.”
• The FDA’s handling of offenders in the Pradaxa trial appeared to be par for the course. Based on a review of FDA records and other documents related to the clinical trial, dozens of researchers the FDA had cited in the past for violating the standards for clinical trials, including repeat or even three-peat offenders, were allowed to enroll and monitor patients in the Pradaxa trial.
• Looking beyond the Pradaxa trial, a POGO analysis of 10 years of FDA inspection data shows how infrequently the FDA has inspected “clinical investigators”—medical professionals treating and tracking human subjects in clinical studies—and how rarely the FDA has imposed sanctions on doctors whose performance the agency faults. From 2005 through 2014, in trials of new experimental drugs, the FDA found deficiencies in the work of about 50 percent of the clinical investigators it inspected—1,573 of 3,120. More than 170 of those investigators received an inspection code at the severe end of the scale, indicating that their violations were “significant/serious and/or numerous.” Over that same period, in the realm of drug evaluation, the FDA disqualified only 26 clinical investigators from participating in clinical trials. 
  
  (To put those numbers in some perspective, there were more than 1,500 clinical investigators in the Pradaxa trial alone, and, from 2005 through 2014, there were more than 170,000 clinical trials of various kinds registered with ClinicalTrials.gov, a website of the National Institutes of Health.)
• Members of the FDA advisory committee that reviewed Pradaxa and endorsed it 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. According to his curriculum vitae, in 2013, one of them became “Study Co-Chair” of a clinical trial that is identified elsewhere as sponsored by Boehringer Ingelheim. A public database that goes back to 2012 shows that, over a recent three-year period, he received payments from the maker of Pradaxa totaling between $75,000 and $134,994. The other former committee member went on to receive payments totaling $95,764 from Boehringer Ingelheim, according to a different database that covers only 2013 and 2014.
• Further blurring the lines between the regulatory system and the interests it regulates, when Boehringer Ingelheim held a practice session to prepare for its questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal. Members of the advisory committee that reviewed Pradaxa later took on roles at a consulting firm that specializes in helping drug companies win the support of FDA advisory committees.
• In addition to approving the drug in the absence of an antidote, the FDA approved the drug in the absence of a system to monitor patients’ coagulation levels and adjust dosing—burdensome requirements associated with taking warfarin. 
  
  On this issue, as on others, the FDA and its advisors took an eyes wide shut approach—spotting the issue but looking past it nonetheless. As one advisory committee member who voted to approve Pradaxa recently told POGO, “I didn’t understand how anybody could take a drug that thins the blood and not check it.“ 
  
  The chance to do without regular blood tests was touted as a key Pradaxa advantage when the manufacturer made its pitch to the FDA and, later, when the company advertised the drug to consumers. But the information that came to light in litigation against Boehringer Ingelheim—about research that company insiders resisted publishing—suggests that at least some testing might have had value for some Pradaxa patients. In hindsight, it makes the FDA’s handling of Pradaxa appear even more questionable. 
  
  In a May 2012 email quoted by the judge, Boehringer Ingelheim Corporate Senior Vice President of Medicine Klaus Dugi hypothesized that monitoring could lead to “a reduction of major bleeding events compared to well-controlled warfarin of perhaps up to 30-40%.” 
  
  A senior FDA official has argued more recently that “optimizing dose or blood level seems like a very good idea.”Years after Pradaxa won FDA approval, Boehringer Ingelheim submitted for FDA approval a drug to reverse Pradaxa’s blood-thinning effect—acknowledging, in effect, that having an antidote available would be a good idea.
• Years after Pradaxa won FDA approval, Boehringer Ingelheim submitted for FDA approval a drug to reverse Pradaxa’s blood-thinning effect—acknowledging, in effect, that having an antidote available would be a good idea. The FDA thought the experimental antidote was so important that it decided to review it on an expedited basis. That review is pending.

How Pradaxa measures up in terms of safety and efficacy have been subjects of scientific debate, and this report does not take sides in that debate. What POGO’s investigation shows is, 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. It is unclear why the agency was so willing to accommodate the drug maker. The FDA’s own record appears to contain good reasons for the agency to have taken a different approach.

“The FDA actions since dabigatran was approved in 2010 have been almost entirely supportive of dabigatran and apparently intended to discount safety concerns,” the Institute for Safe Medication Practices said in an October 2013 report, referring to the drug by its generic name.

BMJ, formerly known as the British Medical Journal, put it this way: “[R]ecent insights into the development and approval of dabigatran—the first new oral anticoagulant brought to market—have raised serious questions about its risks. … In effect, the current situation leaves clinicians and patients the choice between the devil they know and the one they don’t.”

In a 2014 news release responding to coverage in BMJ, Boehringer Ingelheim defended its product and the study that served as the basis for FDA approval, the clinical trial conducted by Boehringer Ingelheim and known as “RE-LY.”

“RE-LY® showed Pradaxa® to be a breakthrough for improving stroke prevention versus standard of care,” the company said.

“The design of the RE-LY® trial, which studied two different doses of Pradaxa® in one trial, was intensively discussed and agreed with regulatory authorities as it was found to be robust and valid,” the company added.

Asked about flaws in the RE-LY trial, the FDA’s Gerald J. Dal Pan said:

“There are many things found to be wrong—our job is to poke holes in trials. We go looking under every rock. If you look at our reviews on any drug trial, you’ll find that when we looked under all the rocks we find all kinds of gremlins and goblins and sites where they didn’t do things quite right, and people who didn’t take the drug quite right. That happens. But we have to apply judgment and look at all that in the context of what’d ya got?”

The agency’s Ellis Unger struck a similar note.

“I’m inherently skeptical of every company,” he said. “[T]hey tell you that they care about patients, but we know what companies are here for. So we look at everything as carefully as we can.”

In a presentation to the FDA advisory committee, a leader of the Pradaxa clinical trial highlighted the heart of the case for Pradaxa. Salim Yusuf said that higher risks of gastrointestinal hemorrhage and heart attack for patients taking Pradaxa came with a benefit: reduced risk of bleeding in the brain. Yusuf called intracranial hemorrhages “the most dreaded fear” associated with warfarin and “a devastating complication.”

Boehringer Ingelheim provided some information to POGO and answered some questions early in POGO’s work on this report. Then, in the fall of 2013, the company declined to respond further.

“Consistent with our prior communications, we will not provide further response beyond what we previously provided and beyond the wide range of information we have released to the public regarding the favorable benefit-risk profile of Pradaxa,” company spokeswoman Lauren Murphy said in an August 2015 email.

Asked to highlight any information released to the public that Boehringer Ingelheim regarded as responsive to POGO’s questions, Murphy replied, “I would direct you to our website: http://us.boehringer-ingelheim.com/news_events/press_releases.html.”

Questions about FDA oversight aren’t limited to Pradaxa, even within the realm of blood thinners. In its handling of two of the other new anticoagulants, the FDA acted over strong objections from within the agency, taking a similarly permissive or forgiving posture toward the drugs, the manufacturers, and the clinical trials.

In the case of Xarelto, also known as rivaroxaban, the primary clinical reviewers evaluating the drug recommended that the FDA not approve it, according to a memo laying out the agency’s decision to approve it nonetheless.

“[I]f rivaroxaban is approved, patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully,” the reviewers had written. They argued that warfarin use was not controlled well enough in the clinical trial of Xarelto, and that as a result the trial might have been biased in favor of Xarelto. They also believed that Xarelto should be administered twice a day—not once, as tested by the manufacturer. Even some FDA advisory committee members who voted in favor of Xarelto’s approval were concerned about the one-a-day dosing “being used as a marketing ploy,” the advisory board minutes said.

In a memo explaining why the FDA dismissed those objections, Deputy Division Director Stephen M. Grant said Xarelto was tested in “a ‘real world’ trial,” and he seemed to embrace a less-than-assertive interpretation of the FDA’s authority.

He said there was no evidence that the maker of Xarelto deliberately chose investigators who were unskilled at managing warfarin doses.

Grant sympathized with the reviewers’ concern about Xarelto’s dosing, saying that, given the drug’s half-life of less than 12 hours, taking only one pill per day could lead to a sharp drop between doses in the level of Xarelto in the patient’s system. He wrote that, in designing the clinical trial, the manufacturer had rejected the FDA’s advice to test two doses per day. But the FDA didn’t let that stand in the way of the drug’s approval. “Absent significant toxicity,” Grant wrote, “inadequate dose exploration is rarely an impediment to approval.”

A spokeswoman for Janssen, the maker of Xarelto, said in an email that the Xarelto clinical trial “demonstrated the safety and efficacy of once-daily” dosing.  The FDA approved the drug “based on the positive benefit-risk profile” observed in the study, she added.

In the case of Eliquis, an FDA official argued against the agency’s conclusion that, compared to warfarin, the drug reduces deaths, according to a recent news report. The Milwaukee Journal Sentinel and MedPage Today jointly reported that the official, Thomas Marciniak, argued that missing data on hundreds of patients rendered the Eliquis clinical trial inconclusive on that point.

In a 2012 memo the two publications posted online, Marciniak said the problem was part of a broader pattern.

“I consider it to be very unfortunate that [the Eliquis trial], like many other recent outcome trials, has substantial problems with data quality,” Marciniak wrote. “Some of the responsibility for the data quality problems rests with us, the FDA: We have approved drugs ignoring similar data quality issues, granting superiority claims and not discussing in the labels the data quality issues. We must stop doing this.”

Other FDA reviewers wrote that the volume of missing data in the Eliquis trial was “not especially large,” adding that it was unclear which way, if at all, the missing data tilted. A spokesman for Pfizer, one of the marketers of the drug, said: “As the FDA ultimately decided, the small fraction of patients lost to follow-up did not adversely alter the interpretation of superior results vs. warfarin.”

Like Pradaxa, the other new blood thinners were approved by the FDA without antidotes.

POGO’s glimpse inside the FDA serves as a cautionary tale as Congress advances a bill called the 21^st Century Cures Act. Passed by the House in July with strong support from both parties, the bill has been touted as a way to speed needed cures to patients. In fact, it could open the door to a dramatic lowering of standards for FDA approval, allowing drug companies and other manufacturers to market unproven products. Diana M. Zuckerman, president of the National Center for Health Research, has written that it would turn patients “into unwitting guinea pigs while making them pay for the privilege.”

The process that led to Pradaxa’s approval and the record of FDA oversight since then do not inspire confidence in the regulation of prescription drugs. They do, however, suggest ways that the system could be improved. Those include a greater emphasis on safety and an insistence on higher standards in the clinical trials on which the system depends.

Download the full report as a PDF with hundreds of notes on sources and other extra information.

This article was written by David Hilzenrath. It was based on reporting by John Crewdson, Hilzenrath, and Michael Smallberg; it was reported principally by Crewdson. Lydia Dennett provided fact-checking and other editorial support. Editing by Danni Downing. Web design, graphics, and production by Leslie Garvey. Additional credits appear in the PDF version of the report.