President Obama’s nominee to head the Food and Drug Administration, Robert Califf, has been hailed as an expert on the clinical testing of prescription drugs, but he helped lead a clinical trial that was sharply criticized by FDA reviewers and some outside advisors to the agency.
The clinical trial of the blood thinner Xarelto was biased in favor of the experimental drug, an FDA staff review found.
A “lack of care” in the trial’s design and execution might have led to avoidable strokes among test subjects, a senior FDA official wrote.
The FDA approved Xarelto in 2011 over the objections of the primary FDA scientists assigned to study its safety and effectiveness. The report by the reviewers argued that patients could be “at greater risk of harm from stroke and/or bleeding” if they took Xarelto than if they were treated skillfully with warfarin, a blood thinner that has been on the market since the 1950s.
The official who issued the FDA’s decision to approve the drug expressed a series of misgivings about it.
“The decision was made difficult by the limitations in the design and conduct” of the clinical trial, FDA Deputy Division Director Stephen M. Grant said in a November 2011 memo explaining the agency’s reasoning.
“Although ultimately coming to a different conclusion than some of the reviewers, both the Division Director and the Deputy shared the team’s concerns,” Grant wrote.
The story of Xarelto adds to the picture of Califf, who as FDA commissioner could affect the interests of the drug industry and the health and safety of the public. It also opens a window on the testing of experimental drugs and the FDA’s vetting of those products.
Like the story of a competing drug, Pradaxa, which was the subject of a recent Project On Government Oversight report, the FDA’s handling of Xarelto illustrates how low the government has set the bar for drug approval, how manufacturer-sponsored clinical trials that serve as the basis for FDA decisions can be of questionable value, and why the words “FDA approved” should not necessarily inspire confidence in prescription drugs.
The Xarelto story also shows how much of the testing of prescription drugs is conducted in parts of the world where medical standards may be lower than in the United States and results may be less applicable to patients here.
Complaints raised during the FDA’s review of Xarelto included the following:
- In the trial, Xarelto was tested against warfarin, which has been in use for decades and served as the control or standard of comparison. But warfarin was allegedly managed relatively poorly in the clinical trial, putting patients in the control group at increased risk and making Xarelto look better than it otherwise might have.
- Though Xarelto has a half-life in the body of about half a day, the clinical trial tested it based on once-a-day dosing. FDA staff wanted Xarelto tested based on two doses per day to maintain a steadier concentration of the drug in patients’ systems—a concern the agency raised before the Xarelto trial began. The minutes of an FDA advisory committee meeting said members were concerned about once-per-day dosing “being used as a marketing ploy.”
- Toward the end of the trial, when patients were taken off the experimental drug, inadequate provisions were made to transition them to another anticoagulant, allowing their blood to thicken dangerously and possibly contributing to an observed spike in strokes.
The concerns were spelled out during a 2011 FDA advisory committee hearing held as part of the agency’s drug approval process and in related documents.
One of the advisory committee members, cardiologist Steven Nissen of the Cleveland Clinic, said at the hearing that the trial’s approach to warfarin treatment “was a fatal flaw in the study design.”
“And so, if you were cynical, you’d say that warfarin was designed to not be given particularly well in the trial,” Nissen said. According to the hearing transcript, Nissen said he thought the problem “was an oversight, not necessarily an intent,” but he added that other clinical trials of anticoagulants had managed warfarin more effectively.
The “poor warfarin control” in the trial of Xarelto, also known by the generic name rivaroxaban, “biased the study in favor of rivaroxaban,” the FDA staff review said.
“[L]ack of care in designing and conducting” the clinical trial “could have resulted in some XARELTO subjects suffering unnecessary strokes,” Grant wrote in his 2011 “Decisional Memo.”
Califf co-chaired the executive committee of the Xarelto clinical trial. That committee “designed the trial and was responsible for oversight of study conduct,” according to a disclosure accompanying an article in a European medical journal Califf had co-authored. The committee “retained independent ability to analyse and present the data, and take[s] responsibility for the accuracy and completeness of data analyses,” the disclosure added.
Since early this year, Califf has been deputy commissioner of the FDA for medical products and tobacco. In a news release announcing his appointment, the FDA said he has been recognized “as one of the top 10 most cited medical authors, with more than 1,200 peer-reviewed publications.”
Before joining the FDA, Califf was vice chancellor of clinical research at Duke University. He founded and led the Duke Institute for Clinical Research, which has become a major contractor to the pharmaceutical industry.
When the FDA convened the panel of outside experts for the hearing on Xarelto in 2011, Califf said his institution was paid by Johnson & Johnson, the maker of the drug, to conduct the Xarelto study. He was introduced as “co-principal investigator” of the clinical trial, helped deliver the drug maker’s presentation, and made a case for Xarelto’s approval.
Addressing the FDA advisory committee, Califf said the Xarelto trial was exceptional for testing an experimental drug on a relatively sick population. Distinguishing the Xarelto trial from studies that took a less challenging approach, he described one way clinical trials can provide a less-than-representative view of new drugs.
“[W]e routinely do trials in namby-pamby populations of low-risk patients for a lot of reasons. It's easier to do the studies. And then we extrapolate to the 80-year-old person on 15 other medications,” Califf said.
“We think it's time to begin to think about doing trials in the more sick people and having enough overlap that you can talk about the general population. We're somewhat responding to what practitioners are saying, which is, you're doing these trials. They're not relevant to the patients that are of biggest concern to us,” Califf said.
Summarizing the trial results, Califf said Xarelto “has a favorable safety profile” and is “a proven alternative to warfarin.”
Califf did not respond to inquiries for this story.
The Senate health committee is scheduled to hold a hearing on his nomination Tuesday. In a recent statement, the chairman of the committee, Senator Lamar Alexander (R-TN), said Califf has “impressive credentials.” Alexander added that he wanted to hear Califf’s views “on how we can move medical discoveries more rapidly through the FDA.”
The nomination comes as Congress is advancing legislation to speed drug approvals.
Supporters of Califf’s confirmation say he is a leading authority on clinical research.
“He is a world expert in the design of clinical trials that are driven by sound science and patient need,” an organization called FasterCures, which is led by former junk-bond king Michael Milken, said in an endorsement. The New England Journal of Medicine praised “his experience in the testing of new and established drugs.”
Opponents say Califf is too close to the drug industry. A group called AIDS Healthcare Foundation accused him of “pimping for the pharmaceutical industry’s efforts to avoid regulation.” The consumer advocacy group Public Citizen called on the Senate to reject Califf’s nomination, saying his appointment “would accelerate a decades-long trend in which agency leadership too often makes decisions that are aligned more with the interests of industry, rather than those of public health and patients.”
Xarelto is one of a new generation of anticoagulants prescribed for atrial fibrillation, a condition in which irregular beating of the heart can create blood clots. The clots can cause strokes and other potentially fatally blockages. The condition is estimated to affect millions of Americans. The blood thinners are meant to prevent clots from forming.
However, thinning the blood entails risks of its own: it can cause hemorrhages. One of the key challenges in anticoagulation is making sure the blood is neither too thick nor too thin—neither too fast nor too slow to clot. Otherwise, patients could avoid one calamity only to suffer another. For example, instead of being crippled by a blood clot in the brain, they could develop a no less devastating stroke from bleeding in the brain.
Since it won FDA approval, Xarelto has been cited relatively often in reports submitted to the agency about adverse medical events in patients, according to the Institute for Safe Medication Practices (ISMP), which tracks those reports. In 2014, Xarelto was named in more than 3,331 “serious” adverse event reports, including 379 cases in which patients died, ISMP said. The reports included hemorrhages and embolisms.
The reports indicate that the drug was suspected of playing a role in the adverse events; they do not prove causality.
Among reports about serious injuries submitted to the FDA directly by health professionals and consumers—as distinct from those filed by drug makers—Xarelto “led all other therapeutic drugs with 525 reports,” ISMP said.
Meanwhile, Xarelto has become the subject of lawsuits by more than 3,000 plaintiffs alleging the drug has caused harm, according to a securities filing by drug-maker Johnson & Johnson.
As recently as last month, the FDA stood behind its decision to approve Xarelto. In a commentary posted on the agency’s website, Ellis Unger, an official involved in the FDA’s evaluation of new drugs, said Xarelto and three other blood thinners approved in recent years caused fewer intra-cranial hemorrhages than warfarin.
“[I]t was clear that the drugs were worthy of approval and continue to provide valuable options for patients who require anticoagulant therapy,” Unger wrote.
Xarelto has been getting another boost from television ads featuring comedian Kevin Nealon, NASCAR driver Brian Vickers, golfer Arnold Palmer, and basketball’s Chris Bosh.
In an email to the Project On Government Oversight, a spokeswoman for Janssen, a subsidiary of Johnson & Johnson, said, “As you may be aware, FDA Advisory Committee meetings provide a forum for the FDA to obtain input from a diverse panel of experts regarding the medicine that they are evaluating for approval, and it is not uncommon for there to be varying views amongst panel members.”
The spokeswoman, Kristina Chang, added that the FDA “considered all input received from the independent reviewers” and approved Xarelto “based on the positive benefit-risk profile observed” in the clinical trial.
That profile remains favorable now, after Xarelto has been prescribed for more than 3 million patients in the United States, Chang said in a later email.
The corporate team behind Xarelto, which included Janssen and its partner, Bayer, had a lot riding on FDA approval.
In 2014, Xarelto generated U.S. sales of $1.5 billion, according to a Johnson & Johnson financial report.
For those who pay for the drug—patients, insurance companies, and government programs such as Medicare—switching from an old generic to a new brand-name medicine can carry a steep price.
With discounts, a 30-tablet supply of warfarin retails from $4 to just under $14 at major pharmacy chains and supermarkets, according to the price-checking site goodrx.com. In contrast, with coupons and other discounts, the site says, a 30-tablet supply of Xarelto sells in the range of $341 to $372.
Setting the Bar
To win FDA approval, a new drug need not be proven superior to an established treatment such as warfarin. The manufacturer need only prove that it is “non-inferior.”
You might think “non-inferior” means “at least as good as.” But the FDA applies the term loosely.
In the case of Xarelto, it meant at least half as effective.
“We agreed, in advance, that the study would need to show that it [Xarelto] preserved not just any of the effect of warfarin, but 50 percent of it,” Robert Temple, a senior FDA official, told the advisory committee.
It can be surprising, Temple acknowledged, that FDA standards “allow the loss of as much as 50 percent of the enormously-valued effect of the control agent.” But setting the bar higher could be impractical, he said. For statistical reasons, proving something close to actual equivalency would require testing drugs in many more people.
Based on the clinical trial results, Xarelto cleared the FDA’s non-inferiority hurdle with room to spare.
But how much stock to put in the trial results was another question.
The Xarelto trial Califf helped lead, dubbed “ROCKET AF,” involved more than 14,000 test subjects who were enrolled and monitored at almost 1,200 sites in 45 countries. Some were given Xarelto, and others were given warfarin.
Warfarin—which is also sold under the brand name Coumadin—requires regular blood tests and potential dose adjustments to keep patients’ clotting rates in the not-too-fast, not-too-slow zone known as the therapeutic range.
However, in the ROCKET trial, on average, subjects on warfarin were in the therapeutic range just 55 percent of the time, the FDA staff review said. That was markedly worse than the 63 percent to 73 percent achieved in recent warfarin-controlled studies of other drugs.
In the ROCKET trial, the percentage of time subjects on warfarin were in the therapeutic range varied widely from country to country—from a high of 75 in Sweden to a low of 36 in India. The U.S. average was 63 percent.
ROCKET’s sites in Eastern Europe enrolled more than twice as many patients as any other region, but on average patients in Eastern Europe were in the therapeutic range less than half the time, FDA reviewer Martin Rose told the advisory committee.
At ROCKET sites where “where warfarin was used skillfully”—those with an average time in therapeutic range of at least 68 percent or so—Xarelto seemed to perform worse than warfarin by a key measure. At those sites, patients on Xarelto seemed to suffer a higher rate of strokes and systemic embolisms, the FDA staff review said. The review added that, given the small number of subjects at sites where warfarin was used “skillfully,” there was a substantial measure of statistical uncertainty around that particular comparison, and it called for additional testing.
In 2010, when the FDA approved Pradaxa, the first of the new generation of anticoagulants, FDA officials expressed similar concerns that uneven warfarin control was making the experimental drug look better. But, in their review of Xarelto, FDA scientists cited the Pradaxa trial as a comparatively shining example—as evidence that ROCKET could have delivered more meaningful results.
“The study results do not convincingly demonstrate the non-inferiority, much less the superiority, of rivaroxaban to warfarin when the latter is used skillfully,” the FDA staff review said.
Some advisory committee members faulted the ROCKET trial for not giving test sites better instructions about what to do if patients’ clotting rates strayed outside the desired range.
“I find it a little disturbing that the protocol allowed the investigators to wait up to four weeks to bring the patients back, to check the patients with subtherapeutic [clotting rates]. That's too long, and it allows for a suboptimal treatment to go forward too long,” Vasilios Papademetriou, a cardiologist at the Veterans Affairs Medical Center in Washington, DC, said at the hearing. In the United States, he said, patients with inadequate anticoagulation returned for medical attention on average “in a week or 10 days.”
Nissen, the Cleveland Clinic cardiologist, made a similar point.
“I’m just puzzled as to why you didn’t make an effort to give sites, particularly third world sites, some guidance about what to do,” he told Califf.
“We did instruct them to make every effort to get the patient back,” Califf said, “but there are limitations on what a site can do in practice in many places.”
“Now, one could argue that one should spend a fortune sending a limousine out to pick up patients in countries that need anticoagulation and artificially make the TTR [time in therapeutic range] come out better,” Califf said.
The FDA staff’s assessment was framed “in a very provocative way,” Califf said, “and this compels us to stand up for our investigators and tell you that we gave warfarin not only in an acceptable way, we gave it in a commendable way during this trial.”
Some members of the advisory committee applauded ROCKET for showing warfarin as it is used in the real world—even if that meant parts of the world where conditions differ from those in the United States
Though the FDA works for the American public, Califf appealed to the agency to take a more global perspective and consider the interests of patients in other countries.
—Cardiologist Stephen Nissen
Before the Xarelto trial began, Janssen Pharmaceuticals asked the FDA if it agreed with the planned once-a-day dosing regimen, the FDA’s Grant recounted in his decisional memo.
“[W]e said that we did not concur,” Grant wrote. “[W]e suggested that administering XARELTO twice a day might result in better outcomes.”
ROCKET used the once-a-day regimen anyway.
The FDA allowed the trial to proceed “because we lack authority to put trials on clinical hold for inadequate dose selection,” Grant wrote.
FDA officials worried that, given the drug’s half-life of less than 12 hours, once-a-day dosing could lead to sharp fluctuations in the amount of the drug in patients’ blood, sacrificing safety or efficacy. Grant wrote that, at the low point of a 24-hour cycle, the serum concentration could sink to less than a quarter of its peak level.
As FDA reviewers saw it, there was “no rational basis for the applicant’s choice of the dose tested in ROCKET,” Grant wrote.
But a drug taken once a day had potentially greater appeal than one that had to be taken twice, and patients were arguably less likely to miss doses.
Xarelto was studied as both a once-daily and twice-daily medication in its early clinical development, and in that setting neither regimen was found to be safer or more effective than the other, the Janssen spokeswoman told POGO.
At the FDA advisory committee meeting, panel member Papademetriou said the once-a-day regimen used in the ROCKET trial “probably increased the risk of bleeding.”
Nissen questioned motive.
“Maybe this is a little bit out of line, but my concern was that the dose was selected more for a marketing advantage rather than for the scientific data that was available,” Nissen said.
Califf defended the choice with a dig at politicians.
“Now, anyone who says they know exactly” the right parameters for optimal anticoagulation “I think would have insight that only some of our politicians today actually seem to have,” he sarcastically noted.
Califf said twice-daily dosing would have been a viable choice but once-daily dosing was picked because “it was felt that the convenience factor and the likely improvement in adherence should dominate.” At the 24-hour mark, Califf said, “we’re in a range where there still is anticoagulation present.”
After the trial had been conducted with disregard for the FDA’s dosing concern, Califf said the FDA should accept Xarelto based on the trial as conducted.
“And, after all, we’re here today, presenting results of a trial with the dose that was chosen, and we think that should be the determinant of a decision about whether the patient should have access to this treatment,” Califf said.
The FDA staff review took a firm position. It concluded that a twice-daily dosing regimen “must” be studied “before this product is approved.”
That didn’t happen. The FDA approved the drug with dosing as tested.
Now, the website for Xarelto touts the fact that “you take XARELTO® just once a day.”
During the last month or so of the ROCKET trial, after subjects received their final dose of Xarelto, there was a spike in strokes among those who had been on Xarelto.
They experienced 22 strokes, compared with 6 in subjects who had been on warfarin.
The trial had left a three-day gap before patients who had been on Xarelto were put back on a conventional anticoagulant, Califf explained. And, once that happened, there would be a lag before the conventional anticoagulant—generally, warfarin—was working as intended, according to the FDA staff review. As a result, for several days, subjects coming off of Xarelto “would not be adequately anticoagulated,” the staff review said.
The spike in strokes might have been “a result of this study design feature,” the review said. Other clinical trials had avoided that pitfall by overlapping treatment with warfarin as patients were coming off the experimental drug.
Jonathan Fox, a vice president at drug-maker AstraZeneca and the non-voting industry representative on the advisory committee, said the ROCKET transition plan “could have been a whole lot better in retrospect.”
Califf told the advisory committee that, when ROCKET was designed, there was little data about giving Xarelto and warfarin together. “It was felt it would be better to err on the side of not causing bleeding by over-anticoagulating.”
The ROCKET executive committee “believes excess events at the end of the trial are a result of the transition strategy that we take accountability for, but we believe it was done in good faith and with a lot of discussion and thought,” Califf said.
In the end, the advisory committee voted 9 to 2 with 1 abstention that the FDA should approve Xarelto. One member who voted in favor of approval nonetheless said he did not consider Xarelto an effective alternative to warfarin and thought of it as a “thirdline option” after other anticoagulants.
The FDA considered restricting Xarelto to use as a “second line therapy,” Grant, the deputy division director, wrote.
The FDA rejected the idea, Grant explained, because officials could not think of any scenario in which a patient should be switched from warfarin or Pradaxa to Xarelto.
Read our report, “Drug Problems: Dangerous Decision-Making at the FDA”
Read more articles in the “Drug Problems” series:
- FDA to Tighten Standards for Blood-Test Devices
- Drug Problems: Did Bad Blood Tests Turn a Clinical Trial into a Mistrial?
- New Cloud over Clinical Trial Led by FDA Nominee
- After Problems Revealed, FDA Seeks Solutions for Blood Testing Devices
- Leaders of Xarelto Clinical Trial Reaffirm Conclusions
- European Regulator Investigating Trial Led by FDA Nominee
- Duke Reassessing Data From Trial Led By FDA Nominee
- FDA Approves Antidote for Pradaxa, Calls It “Necessary”
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