September 20, 2016
By Mark Terry, BioSpace.com Breaking News Staff
Now that the U.S. Food and Drug Administration (FDA) has approved Sarepta Therapeutics ’s eteplirsen for Duchenne Muscular Dystrophy (DMD) after a highly controversial process, the internal workings and politics of the decision are coming to light. And that spotlight appears to be shining directly on Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research (CDER).
Despite intense debate inside the FDA, it was Woodcock’s push for approval of eteplirsen that ultimately won out. There were at least three prominent critics of the drug and its approval, including Ronald Farkas, who left the agency recently to join contract research organization (CRO) Parexel International . Farkas has declined to comment when questioned by various news outlets.
Two other strong opponents include the agency’s acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation.
In one memo, Borio wrote, “Granting accelerated approval here on the basis of the data submitted could make matters worse for patients with no existing meaningful therapies—both by discouraging others from developing effective therapies for DMD and by encouraging other developers to seek approval for serious conditions before they have invested the time and research necessary to establish whether a product is likely to confer clinical benefit.”
Borio further argues that the clinical trials did not provide substantial evidence of the drug’s effectiveness, and were based on a “surrogate endpoint with a trivial treatment effect.”
Unger, on his part, argued in a memo that eteplirsen’s safety profile was not fully known, and was significantly harsher in his language, writing, “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.”
Eteplirsen will run about $300,000 for cost of treatment.
Woodcock, for her part, has thirty years at the agency, and is noted for pushing the FDA to partner with the drug industry rather than act as an adversary. She received her medical degree from Northwestern University and held teaching appointments at Pennsylvania State University and the University of California at San Francisco. She joined the FDA in 1986. From 1994 to 2005 she was the director of CDER, and previously served as the FDA’s deputy commissioner and chief medical officer.
Ultimately, Woodcock overruled her staff. The final decision then went to Robert Califf, the FDA’s Commissioner. Despite apparently having some of the same issues as the other critics, Califf sided with Woodcock.
In one rather shocking admission found in the review documents, Woodcock argued that Sarepta “needed to be capitalized,” essentially saying that if the drug wasn’t approved, the company wouldn’t have enough money to continue studying the drug and similar drugs in the pipeline. And that approval would jack up the company’s share price, giving it more money to continue research.
Woodcock, who has repeatedly testified before Congress in her career, has a reputation for being able to deftly thread her way between the politics, public interests, and business interests of the drug approval process. But the behind-the-scenes look at the eteplirsen approval does make one wonder just how much pressure Woodcock was under by the Congress, who sent her a letter signed by 109 Congress members on February 17 urging the agency to approve a DMD drug—any DMD drug.
The review documents also provide more clarity on some of Sarepta and eteplirsen’s deficiencies. Califf, in a memo, noted that “the poor quality of many of the biopsies and the failure of the sponsor to implement a high-quality procedure for assay validation” made much of the data useless in terms of evaluation, as well as the fact that the levels of dystrophin actually produced by the drug were “small compared with expectations at the outset of trials in humans.”
As part of the approval, Sarepta will need to conduct a two-year, randomized controlled trial to verify the drug’s benefits. At its core, more data is needed to prove that the drug actually improves motor functions. If that trial fails, FDA approval could be withdrawn.
Diane Zuckerman, president of the National Center for Health Research, told STAT, “If the drug is effective and the kids do well and the price is affordable [Woodcock] will get the credit. And if not, she’ll get the blame for any problems with this drug and with the precedent it sets resulting in other questionable drug approvals.”
