On Sept. 19, 2016, the Food and Drug Administration (FDA) approved eteplirsen (brand name Exondys 51) -- the first drug approved for treating Duchenne muscular dystrophy (DMD) -- despite a disturbing lack of evidence that the drug is actually effective. The approval decision ultimately was made by Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER) -- the center that reviews and approves drugs -- over the strong objections of scientific experts at the agency who had reviewed the new drug application for eteplirsen.
In 1962, Congress dramatically strengthened the process for approval of new drugs by passing a law requiring not only proof of safety but also "substantial evidence" of effectiveness for a drug's intended use. The law stipulates that such evidence must come from "adequate and well-controlled" studies. This approval standard revolutionized prescription drug regulation in the U.S. and has remained unchanged for more than a half-century.
Sarepta Therapeutics, the maker of eteplirsen, submitted data to the FDA from three very small clinical trials involving a total of 25 subjects with DMD. The drug is intended to boost the production of a key muscle protein called dystrophin, which is almost completely absent from the muscles of DMD patients.
FDA staff, including Woodcock, agreed that there were "[m]ajor flaws in both the design and conduct" of the three trials. Moreover, the trials found no meaningful improvement in subjects' physical performance and only minuscule increases in muscle dystrophin levels. FDA scientists also identified serious problems with the integrity of key tests used to measure changes in dystrophin levels in patients enrolled in the clinical trials.
As a result, a team of FDA scientific experts, including physicians and pharmacologists, concluded that the trials failed to provide substantial evidence from adequate and well controlled trials that eteplirsen is effective or that the changes seen in muscle dystrophin levels were likely to predict effectiveness. They therefore recommended against approval.
Dr. Ellis Unger, the senior FDA official who supervised the team of scientists reviewing the data on eteplirsen, agreed with the team's assessment, as did his supervisor, Dr. John Jenkins, director of the Office of New Drugs; the agency's acting chief scientist, Dr. Luciana Borio; and the majority of the members of an FDA advisory committee that evaluated the clinical trial data on April 25, 2016.
Despite this overwhelming opposition to the approval of eteplirsen, Woodcock overruled the FDA's scientific experts and decided to approve the drug.
In a highly unusual move, Unger formally appealed Woodcock's decision to FDA Commissioner Robert Califf. But in a display of cowardice, Califf rejected the appeal and deferred to Woodcock, allowing the approval to go forward.
In his written appeal to Califf, Unger made a number of remarkably blunt statements highlighting the adverse impact on public health that would result from Woodcock's decision to approve eteplirsen. They include:
- "By allowing the marketing of an ineffective drug, essentially a scientifically elegant placebo, thousands of patients and their families would be given false hope in exchange for hardship and risk. I argue that this would be unethical and counterproductive. There could also be significant and unjustified financial costs -- if not to patients, to society." (Sarepta has announced that the average price for one year of treatment will be $300,000.)
Unger characterized Woodcock's involvement in the review of eteplirsen as "unprecedented," including her extensive involvement in the planning of, and her participation in, the April 25 advisory committee meeting. Unger also raised concerns about Woodcock's issuance of her decision memo before he had finished his own decision memo on behalf of the team of FDA scientists who had conducted the review of the drug.
Echoing Unger's concerns, Borio wrote:
"Rather than ensuring that the scientific reviews started at the bottom of the chain of command, Dr. Woodcock made clear from her position at the top that she was pushing for a particular outcome from the very early stages. As a consequence, the regulatory reviews did not start at the staff level with scientific reviews and then proceed through the chain of command for concurrence or non-concurrence at all appropriate levels within the management structure, as would be the typical course of decision-making for a regulatory decision grounded in science. Indeed, before the reviewers had even completed their draft scientific reviews, Dr. Woodcock had told them -- on May 4, 2016 -- that she intended to grant accelerated approval."
Finally, alluding to intense pressure on the FDA from Congress and patient advocates to approve eteplirsen, Unger noted, "Approval of [eteplirsen] would send the signal that political pressure and even intimidation -- not science -- guides FDA decisions, with extremely negative consequences." He continued:
"The ramifications here are profound. The public will perceive that it was their unprecedented lobbying efforts that made the difference and earned eteplirsen its accelerated approval. For the future, this will have the effect of strongly encouraging public activism and intimidation as a substitute for data, which is one of the wors[t] possible consequences for communities with rare diseases. This type of activism is not what was envisioned for patient-focused drug development."
Woodcock's decision to overrule so many agency experts represents a dangerous, unparalled capitulation to pressure from politicians and patients and a stunning disregard of the scientific evidence. Her action eviscerates the FDA's long-standing (but, under Woodcock, already declining) approval standards for new drugs, threatens public health and demonstrates that she is unfit to serve as CDER director.