Column: To appease a patient lobby, did the FDA approve a $300,000 drug that doesn’t work?


A couple of weeks ago, the big insurance company Anthem decided that it wouldn’t pay for Exondys 51, a drug that already had been approved by the Food and Drug Administration to treat Duchenne muscular dystrophy.

Anthem’s decision was controversial, because two other insurers had said they’d cover the treatment for their patients. But it was less controversial than it could have been for two reasons: The drug costs $300,000 a year, and the evidence that it works is almost laughably thin. To put it another way, Anthem’s decision undoubtedly infuriated advocates for DMD patients, but it may well have been the right call.

The Exondys 51 case is a sterling example of the emerging tug of war between patient advocates and drug regulators. Bowing to appeals from the patient lobby, the FDA launched a program to allow accelerated approvals of experimental drugs for certain diseases for which no treatments existed.


The risk of lowering the bar for new drug approval is a serious concern ... [that] could expose unsuspecting patients to the harmful effects of these drugs.

— FDA Commissioner Robert Califf

The program is designed to apply very narrowly; the question is whether FDA officials were too lenient in this case. It wouldn’t be accurate even to say that there was much difference of opinion within the FDA about the drug, because the agency’s scientific staff overwhelmingly opposed its approval.

They were overruled by Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, and she was upheld — albeit reluctantly — by FDA Commissioner Robert Califf. “The risk of lowering the bar for new drug approval is a serious concern,” Califf wrote in a 13-page review that essentially deferred to Woodcock’s judgment. “Lowering the regulatory hurdle could expose unsuspecting patients to the harmful effects of these drugs.”

But Califf also had harsh words for the research touted by the drug’s manufacturer, Sarepta Therapeutics, to support its claims for the drug’s efficacy. Questioning Sarepta’s reporting on a key research study, Califf observed that “experts assembled by the FDA fundamentally debunked this study, which has yet to be retracted,” which he plainly considered the proper course.

There’s no question that Duchenne muscular dystrophy is a horrific disease warranting special attention from the FDA. With a strong hereditary component, the disease strikes mainly males at the rate of one in every 3,600 to 6,000 births, implying that 325 to 550 children born in a year will eventually face it. The disease, which progressively saps muscle strength, typically appears before the age of 5, puts its victims in a wheelchair in their teens, and takes their lives by their 20s or 30s.

The development of Exondys 51 was greeted by the muscular dystrophy patient community as a potentially lifesaving advance, and its approval by the FDA on Sept. 19 as a landmark moment. Declared Steven M. Derks, head of the Muscular Dystrophy Assn.: “This is the outcome MDA dreamed of 25 years ago when it was the first to invest in the breakthrough research that led to development of eteplirsen [the scientific name for Exondys 51].”


Yet there were strong reasons to question the drug’s effectiveness and safety. The main evidence submitted by Sarepta was a single study of 12 patients, of whom four got a placebo. The study did not focus on any clinical improvement in the patients, but rather on whether the drug increased their levels of a certain protein the lack of which is thought — albeit inconclusively — to be related to the disease. The results suggested that the drug could increase the protein, but not whether the increase was enough to affect the disease. In fact, the FDA staff concluded it was not.

The staff tried to head off Woodcock’s approval of Exondys 51 by appealing to Califf, who endorsed the pending approval on Sept. 16. Three days later, Woodcock made it official. She tried to accommodate both the expectations of disease sufferers and the cavils of her staff in issuing the approval, which came with unusual conditions. “In rare diseases,” she said, “new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders.” She cautioned that the approval of the drug was based only on “initial data,” and she required Sarepta to conduct a “confirmatory clinical trial” to show that its drug actually works.

There will be lots of ground for Sarepta to cover. Califf agreed with scientific staff that there were “major flaws” in the study design. He acknowledged the conclusion of acting chief scientist Borio, that Sarepta had shown “serious irresponsibility” by promoting an article that overstated the results of a clinical trial. “Sarepta’s misleading communications led to unrealistic expectations and hope for DMD patients and their families,” Borio complained, adding that “the findings did not hold up to careful review.”

Nevertheless, Califf ruled that Woodcock had all these objections at hand when she approved Exondys 51. Observing that his own technical expertise wasn’t better suited than that of his staff or Woodcock to judge the results of the clinical trial, he waved her decision through.

The effect on Sarepta’s fortunes was immediate. The day the decision was announced, the company’s share price soared from $28.15 to $48.94, a gain of 74%, and continued to rise until closing at a peak of $62.35 on Oct. 5. The next day Anthem weighed in, declaring that “the clinical benefit of treatment for DMD with eteplirsen, including improved motor function, has not been demonstrated,” and terming the drug “not medically necessary.” Since then, Sarepta stock has slid to below $42.


But the FDA’s action puts insurers, as well as government programs that are bound to pay for FDA-approved treatments, in a bind. If Exondys 51 turns out to be a dry hole, they will have spent millions of dollars with no hope of a rebate. The disease sufferers will have been offered a mirage, and one with potentially harmful side effects to boot. The FDA’s standards, which customarily required that a drug be shown to work before it could be administered to patients, will have suffered a blow from which they may not easily recover.

The desire of victims of a horrific disease for a solution — any solution — is understandable. The worse the disease, and the more remote the prospects of a cure, the more fevered this desire gets. But the approval of a drug with such sketchy evidence of efficacy doesn’t profit anyone (except perhaps for the manufacturer’s shareholders) and carries immense costs that work against the interests of patients and society as a whole. Whether the FDA properly weighed these costs in the case of Exondys 51 is doubtful.

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