As President Obama’s nominee for FDA Commissioner, former Duke University researcher Robert Califf has faced questions about the independence of clinical trials he conducted for drug companies.
At a confirmation hearing in November and in a written response to later questions from Senator Elizabeth Warren (D-MA), Califf offered comforting answers. He said that plans for clinical trials are subject to FDA review.
But those answers omitted some history that might be less reassuring: a clinical trial Califf had co-chaired was conducted in defiance of FDA guidance.
At least one member of an FDA advisory committee looked back on that history at a 2011 committee meeting and worried that the clinical trial put commercial considerations ahead of health and safety. Minutes of the meeting say that, within the committee, “There was concern about . . . a marketing ploy.”
The issue Warren asked Califf to address as part of his confirmation review essentially boiled down to this: How much confidence can the public and the FDA have in clinical trials that are sponsored by the very companies whose drugs are being tested? At Duke, Califf led an institute that tests drugs for pharmaceutical companies. The companies use the test results when petitioning the FDA to approve their products, and the FDA bases decisions on that data.
The financial support Califf and his research have received from drug companies “naturally raises questions about your relationship with the drug industry,” Warren told Califf during his confirmation hearing. “And one particular concern with industry funding of academic work is that drug companies may be able to exert influence over the conduct of those studies,” Warren said.
Warren asked Califf to detail, among other things, what input the sponsors of the clinical trials had in the design of trials he conducted or oversaw at Duke.
Califf said that, though the drug companies participate in the design process, the academic leaders of the trial have the final say. He also highlighted the FDA’s involvement.
“When industry funds a clinical trial, whether it’s devices or drugs, done through our institute, the design of the trial is something that’s done jointly and done very publicly, because typically it’s done to try to get an indication from the FDA,” Califf said.
The plan or “protocol” for the trial “has to be submitted” to the FDA “before the trial starts,” Califf said.
Warren followed up with written questions, and, in his answers, Califf offered similar reassurance.
“All aspects of the design are included in the protocol, which is subject to review and approval by the FDA,” Califf wrote.
Califf’s comments might leave the impression that, because the FDA gets to review the protocols, there’s no reason to worry.
But the people running manufacturer-sponsored clinical trials don’t necessarily have to do what the FDA says, and a clinical trial that Califf helped lead illustrated that fact by disregarding the FDA’s wishes.
That history is reflected in FDA records, including a review of the clinical trial by FDA staff, an FDA memo explaining the agency’s decision to approve the drug, the minutes of the 2011 FDA advisory committee meeting, and the transcript of that meeting.
The clinical trial, known as ROCKET AF, studied the safety and effectiveness of the blood thinner Xarelto. In 2011, based on that trial, the FDA approved the drug to prevent blood clots and strokes in patients with a heart condition called atrial fibrillation. Califf co-chaired the ROCKET AF executive committee, which “designed the trial and was responsible for oversight of study conduct.”
The FDA was consulted before the trial began, but that wasn’t the whole story, FDA records show.
Because Xarelto has a half-life in the body of about half a day, FDA staff wanted the trial to use a regimen in which patients took the drug twice a day. Instead, in ROCKET AF, patients were given only one dose per day.
Taking one dose per day is more convenient than taking two, so once-a-day dosing had potential marketing advantages. However, given Xarelto’s half life, FDA reviewers worried that, if patients were taking only one dose per day, the concentration of the drug in their bodies would plunge between doses and fluctuate sharply over each 24-hour period.
For patients who need blood thinners, there are dangers if their blood gets either too thick or too thin. If the blood is too thin, they are at heightened risk of bleeding, including strokes caused by bleeding the brain. If the blood is too thick, they are at heightened risk of developing clots, which can travel through the body and block blood circulation, potentially causing a different type of stroke.
In an FDA memo, the agency’s Stephen M. Grant recounted that, before the Xarelto trial began, drug company Janssen Pharmaceuticals asked the FDA if it agreed with the planned once-a-day dosing regimen.
“[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.
A report by FDA reviewers literally underlined the difference of opinion between the people behind the clinical trial and the regulators at the FDA. As that review put it:
“Agreement was not prospectively achieved on the dose(s) to be tested prior to the execution of the ROCKET trial.” [Emphasis in original]
For a more detailed account of that history, see the Project On Government Oversight’s report, Drug Problems: Nominee to Head FDA Led Clinical Trial FDA Faulted.
Califf’s responses to Warren are not his only dubious statements on the subject.
After the Xarelto trial was completed, he co-authored an article that presented the results in the New England Journal of Medicine. The article included this statement:
“Pertinent national regulatory authorities . . . approved the protocol” for the ROCKET AF trial.
POGO asked FDA spokeswoman Sandy Walsh if it would be accurate to say the FDA approved the protocol for ROCKET AF.
“No, we say that we allowed it to proceed,” she answered.
Apparently, the FDA refrained from blocking the trial, which is not the same as explicitly approving the protocol. The agency allowed the trial to proceed because, based solely on “inadequate dose selection,” it lacked the authority to do otherwise, the FDA’s Grant wrote in his memo.
The statement in Califf’s New England Journal of Medicine article glossed over the FDA’s objections to the dosing regimen and made it appear that the FDA blessed the protocol when it merely capitulated.
Califf did not respond to questions sent by email for this article. His nomination, which is awaiting a vote by the full Senate, won the endorsement last month of the Senate Committee on Health, Education, Labor and Pensions.
In the committee, Warren voted for Califf. “I am satisfied that he has conducted himself with integrity as an academic researcher,” she said in a statement.
She did express broader concerns.
“My examination of the Califf nomination has raised serious questions about our current clinical trials system,” Warren said. “I am particularly concerned with a lack of overall transparency, numerous opportunities for conflicts of interest, and a marked shortage of trials that are designed to determine which products to treat a given condition are the most effective—as well as cost-effective—for various patient populations.”
“My examination has also raised concerns about the FDA’s willingness to stand up to industry preferences in the design and conduct of clinical trials,” Warren said.
Califf has committed to address those issues, Warren added.
It is unclear if or when Califf’s nomination will be voted on by the full Senate. Citing a variety of concerns, including his ties to the pharmaceutical industry, several Senators have placed holds on the nomination or said they will try to block it by other means.
Read our report, “Drug Problems: Dangerous Decision-Making at the FDA”
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