The FDA’s Rigged Drug Committees
A case study in how the agency gets the advice it wants to hear.
The Food and Drug Administration campus in Silver Spring, Md. PHOTO: ASSOCIATED PRESS
Among the Republican priorities in 2017 should be dismantling a culture of bureaucratic control at the Food and Drug Administration that poisons innovation and costs lives. Here’s an idea: Update part of the approval process that was patient zero for distorting data on a drug for Duchenne muscular dystrophy.
We’ve reported on the drama over eteplirsen, which FDA approved in September and is now marketed as Exondys 51 by Sarepta Therapeutics. Midlevel bureaucrats have since disparaged the therapy in public, and some insurers are denying coverage. Much of the confusion results from an April show trial known as an advisory committee meeting. A process that is supposed to provide independent advice to the FDA instead became a venue to mislead a panel of nonexperts—and the public—about the drug’s efficacy.
Advisory committees exist so FDA can solicit expert counsel, but the agency stacks panels with allies whose career currency is prestige and government funding. Such committees usually vote the way FDA wants—and then the agency tends to follow the recommendation. On eteplirsen, the panel voted 6-7 against accelerated approval after a critical FDA review, which was later overruled by agency management in a rare exception amid unusual public scrutiny.
The 13-member committee that checked out eteplirsen included: a psychiatrist, a stroke doctor and several others with no experience in Duchenne. The agency seldom invites true experts because anyone who has ever talked to a drug company is deemed financially conflicted. In rare diseases like Duchenne, that problem is more pronounced because the pool of experts can be so limited.
Yet meet Caleb Alexander, chairman of the committee. Dr. Alexander invited speakers at the meeting to state organizations they represent. He read this statement at least a dozen times but neglected to mention his own conflict of interest: Dr. Alexander has received a large FDA grant, information that is available online. The conceit is that folks like Dr. Alexander are less motivated by pecuniary interests than someone who has consulted for a company. Dr. Alexander voted against approval.
Sarepta was barely allowed to defend itself at the meeting, which allowed agency distortions to appear as fact. One example: FDA’s documents for Sarepta claim that patients “commonly maintain ambulation to older ages than is often realized, to 18 years or perhaps even older.” Yet the same materials for a Duchenne drug reviewed fewer than six months earlier say that “by age 10-14, patients become wheel chair bound.” This looks like an attempt to make Sarepta’s clinical results look less significant.
FDA’s review also relied on a chart to convince the panel that boys on the drug over time walked no better than patients who were not treated. But we’ve reviewed compelling evidence that someone manipulated the x-axis in later years to make the results look more damning for Exondys. This contentious visual was treated as gospel.
Supportive experts were relegated to the public hearing portion of the meeting for brief comments. Pediatric neurologists, the geneticist who discovered the gene for Duchenne, clinical researchers and others had to move fast through slides and data. The FDA’s lead reviewer, an eye doctor, talked for about an hour.
The nonprofit Jett Foundation collected data on falls, fatigue and other outcomes that the panel more or less ignored. These patient measures will be invaluable as rare diseases become better understood. FDA has the legal authority to incorporate patient data in decisions, but the bureaucracy never does.
At the end of the day, panelists vote on approval questions, and even here FDA tilts the outcome. The agency’s guidance says questions should have “minimal qualifiers” so as not to confuse the committee. So let’s look at one of the questions FDA asked the panel to ponder:
“Do the clinical results of the single historically-controlled study (Study 201/202) provide substantial evidence (i.e., evidence from adequate and well-controlled studies or evidence from a single highly persuasive adequate and well-controlled study that is accompanied by independent findings that substantiate efficacy) that eteplirsen is effective for the treatment of DMD?”
Are you still reading? The obfuscation led one committee member who voted no, Bruce Ovbiagele, to deliver this insight: “Based on all that I heard, the drug definitely works, but the question was framed differently.” Imagine hearing this if you are the parent of a Duchenne boy.
If FDA is going to run these committees merely to achieve a predetermined outcome, then let’s skip the exercise. Drug sponsors should at least be allowed to object to candidates for the panel and be granted time to refute the agency’s contentions, as Joseph Gulfo, executive director of the Lewis Center for Healthcare Innovation and Technology, has suggested. The panels should also include several members who have treated the disease.
These changes would return advisory committee meetings to their original purpose as an outside check on FDA bias or groupthink. If Donald Trump is serious about making government accountable to the people who pay for it, FDA is a prime candidate for reform.
