FDA Documents Reveal Depths of Internal Rancor Over Drug’s Approval Process

In some ways, it reads less like the product of a dusty bureaucracy and more like a Game of Thrones novel. Compelled by a lawsuit, the Food and Drug Administration is releasing thousands of never-before-seen documents regarding the most controversial drug approval in many years. And these documents are beginning to reveal the inner workings of a government agency that’s being torn apart by conflicting loyalties.

In an ongoing series of investigations performed for Undark by the Science, Health, and Environmental Reporting Program at New York University, we examine some recent FDA drug approvals to highlight the messy interface between scientific reasoning, and political and commercial expedience.

Late last year, the FDA approved eteplirsen, a potentially lifesaving drug for young boys (and in rare cases, girls) doomed to die from Duchenne muscular dystrophy, an incurable degenerative disease. That the approval was controversial is an understatement: In approving the drug, the agency overruled its own scientific advisers, rejected the recommendations of its review panel, triggered a formal internal dispute process, and apparently sparked the resignation of one senior official and the retirement of another.

The approval also failed to quash doubts about whether the drug, in fact, works — and it raised questions about how well the agency fulfilled its legal and scientific obligations to ensure that the drugs Americans use are both safe and effective.

Evidence of deep disagreement within the FDA over the decision to approve eteplirsen began to surface almost immediately after the FDA issued its go-ahead last September. Central to the tension was the decision by Janet Woodcock, the director of the agency’s Center for Drug Evaluation and Research, to issue the approval despite the contrary opinions of experts empaneled by the agency to review the drug.

But the new documents being released by the FDA — a response to a Freedom of Information Act lawsuit filed by this reporter to get additional information about eteplirsen’s approval — are now shining added light on the level of internal discord that accompanied the drug’s review. Chief among the new revelations: charges by one high-ranking official that Woodcock, an FDA employee for three decades, skirted established norms, bypassed multiple layers of FDA expertise and authority, and even ignored calls for more thorough studies in greenlighting the controversial drug.

In an email dated September 14, 2016 and addressed to Robert Califf, then head of the FDA, John Jenkins, then the head of the Office of New Drugs and one of the officials who left in the wake of the eteplirsen approval, makes a number of blistering allegations regarding Woodcock’s decision to ignore the advice of the eteplirsen review team. Such review teams, typically comprised of dozens of physicians, pharmacologists, statisticians, and various other experts, weigh clinical evidence for a drug’s safety and effectiveness and decide whether or not the drug should be allowed on the U.S. market.

The team’s decisions can be contentious, and sometimes higher-ups have to settle disputes. However, for a center director to overrule a review team is “rather exceptional,” said Michael Carome, director of the health research group at the nonprofit group Public Citizen. “I’ve never seen circumstances like this, especially with such unanimity by the review team that prepared such a detailed analysis.”

In his email, Jenkins alleges that Woodcock short-circuited normal agency procedures, including the review team’s desire to require better-quality data in a new trial of eteplirsen. “[I]t was Janet that pressed that a new randomized trial not be required,” Jenkins wrote. “So, if Janet had followed the normal CDER process in this case the review team would have required placebo-controlled trials … and we would have better data on which to make a decision.”

Jenkins also insisted that Woodcock’s involvement in the eteplirsen decision — normally the domain of lower-ranking officials than the head of CDER — was abnormally intense, presumably putting pressure on the team to approve the drug. “I have worked with Janet for over 20 years and I can say without a doubt that her involvement in this case far exceeds her usual ‘hands on’ approach,” Jenkins wrote. “You note that there were 14 Center director briefings related to this case, that is clearly not the ‘norm’ for how CDER operates.”

Further, writes Jenkins, the manner in which Woodcock overruled the review team effectively sidestepped several waypoints in what is normally a regimented series of interactions between various FDA subdivisions and managers and a new drug applicant — processes rarely, if ever, abrogated by the director of the Center for Drug Evaluation and Research. “In this case, that process was bypassed,” Jenkins wrote.

Neither Woodcock nor Jenkins would agree to speak on the record to Undark about the newly released correspondence, but according to Carome, the whole exchange casts a shadow over the FDA.

“[Woodcock] has the authority, and the chain of command is hers, but the story of how this unfolded really was extraordinary,” he said. “Her actions eviscerated longstanding procedures within the agency” that ensure that FDA makes consistent decisions in the interest of public health.

Diana Zuckerman, the president of the nonprofit National Center for Health Research, expressed similar concerns. “I’ve seen high-level FDA officials undercut their scientists at meetings, or where they clearly try to take a side,” she said, “but I’ve never seen anything like this from a center director.”

Even more surprising than the alleged breaches of bureaucratic norms were Woodcock’s alleged breaches of scientific ones. The FDA is required by law to allow a drug to market only based upon scientific evidence that the drug is safe and effective; nothing other than science should be the basis of a decision. Jenkins’ memo backs up earlier allegations made by other FDA officials that Woodcock had decided to approve the drug not just before the review team had prepared its final report, but also well before a last round of crucial data were in.

“It’s not supposed to be the mission of the FDA to give treatments to desperate patients because the desperate patients want the treatments,” says Zuckerman, who worries that Woodcock is allowing patient desires to trump scientific evidence. “The role of the FDA is to ensure that the benefits outweigh the risks.”

Jenkins’ memo also supports claims that Woodcock’s decision to approve the drug was motivated, in part, by her worries about the financial solvency of Sarepta Therapeutics, the company trying to get eteplirsen approved. And the most serious allegation of all from Jenkins’ memo is that Woodcock failed to follow FDA’s set-in-stone procedures to log discussions with a drug company that has an application underway: “Janet has had frequent private conversations with the sponsor and the stakeholder community,” he wrote. “To my knowledge, she has not documented the substance of those conversations to the record, as is required under FDA regulations.”

Carome called this “a disturbing statement. “If she’s not following FDA’s required procedures,” he said, “the question is why not?”

Even with the understanding that Jenkins’ perceptions are clearly colored by his antipathy for Woodcock, the newly released documents would seem to illuminate a bureaucracy whose procedural and scientific rules were broken, one after the other, by an administrator determined to get a drug approved.

The reaction by Califf, the recipient of the emailed memo, was one word: “Ouch.”

Charles Seife is a professor of journalism at New York University, and the author of numerous book, including “Proofiness: The Dark Arts of Mathematical Deception.” His work has appeared in The New York Times, The Washington Post, Science, New Scientist, Scientific American, Wired, Slate, ProPublica, The Economist, and many other publications.