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Any company that plans to mimic the approach taken by Sarepta Therapeutics to win regulatory approval of a drug should think twice. That was the blunt message delivered on Tuesday by a high-ranking US Food and Drug Administration official in the wake of simmering controversy over a recent decision to approve a Sarepta drug for Duchenne muscular dystrophy, a rare and fatal disease.

The approval last month was seen as a litmus test for agency approval of new medicines, notably for diseases with unmet medical needs, as parents and lawmakers pressed the FDA to greenlight the drug. The episode was marked by unusual bickering inside the agency over clinical trial data and, moreover, is now prompting vociferous debate over whether the FDA lowered its approval standards.

That was the issue that John Jenkins, who heads the Office of New Drugs at the Center for Drug Evaluation and Research (CDER), attempted to address at a conference held by the National Organization for Rare Disorders. He offered a pointed slide show about what he called the “lessons learned” from the Sarepta episode, and essentially outlined regulatory do’s and don’ts for drug makers to follow.


The “path taken by Sarepta NOT a good model for other development programs,” read one of his 28 slides. (The emphasis added was his.) “A poorly planned and executed development program for a rare disease misuses valuable patient resources and serves to delay obtaining the knowledge required to understand the benefits and risks of a drug to support regulatory review and approval.” The slides were first reported by Endpoints and FDA Webview.

But FDA staff confronted several obstacles as it reviewed the Sarepta drug, which is called Exondys 51 and will cost about $300,000 per patient. There was uncertainty about whether a biomarker was a reliable proxy for clinical benefit, and an unusually small trial of just 12 boys who were treated with the drug. Sarepta also failed to conduct a larger trial involving the use of a placebo, as the FDA requested.


So Jenkins flashed several more slides that pointed out what other drug makers should be certain to do, unlike Sarepta. These included that assays for biomarkers, especially those that are invasive and involve children, should be validated before being used in order to avoid obtaining misleading information, while studies should be carefully blinded to minimize bias.

Jenkins also noted that personal attacks on FDA reviewers, which occurred at a meeting last spring to review the drug, are unacceptable. And one slide chastised Sarepta supporters for pushing for accelerated approval. The “use of (the) accelerated approval pathway should be prospectively planned, NOT (used) as a ‘rescue’ for a failed program.”

The internal squabbling at the agency was, ultimately, decided by Dr. Robert Califf, the FDA commissioner, who sided with Janet Woodcock. She oversees drug reviews and pushed hard to approve the Sarepta drug. FDA watchers, however, say that Jenkins is hoping to signal that such situations are extraordinary.

“My sense is that Jenkins and others worry that the decision undermines CDER’s credibility for rigor and procedural consistency,” said Daniel Carpenter, a Harvard University political scientist who studies the FDA. “FDA is facing what political scientists call a ‘credible commitment problem.’ They have created so many exceptions to their usual rules in recent years that drug companies widely doubt that CDER will stick to its rules, much less its guns.”

Indeed, other experts believe there will be more companies that may be tempted to mimic Sarepta.

“In my view, we should be concerned that at least some companies will try Sarepta’s approach, and this is true in two different senses,” said Rachel Sachs, an associate professor at the Washington University School of Law, who specializes in drug regulation. “First, we may see companies asking the FDA for approval based on less robust data sets than have been accepted in the past.

“Second, companies may hope to engage patient advocates in the FDA approval process in a much more direct way than they have in the past. I wouldn’t be surprised at all if companies sought to involve themselves more closely with patient advocacy groups going forward,” Sachs added.

Some other drug makers, though, may already feel emboldened. PTC Therapeutics, whose own marketing application drug for Duchenne muscular dystrophy was bounced earlier this year by the FDA, is now escalating its appeal after being denied yet again this month. And BioMarin Pharmaceutical is considering reactivating an application for another such drug that the FDA rejected.

But whether they will have any luck seems uncertain, at best.

“In case the companies didn’t read Califf’s memo upholding Woodcock’s decision on Sarepta where he basically declared it to be a one-off, Jenkins was making sure there was another document on the record underscoring that point,” said Ira Loss of Washington Analysis, a consulting firm that examines the intersection of Wall Street and FDA regulation.

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