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By Ben Locwin

linkedinpicRecently, the Food and Drug Administration (FDA) approved Sarepta’s drug eteplirsen on an accelerated timeline for the treatment of Duchenne muscular dystrophy, which has a potential market of 1 in every 7,250 males aged 5–24 years in the United States alone.

However, the drug approval was not reached without significant internal disagreement and calls for clarification on what their policies really stand for.

Ultimately, Robert Califf, M.D., the Commissioner of FDA, approved the drug based on Janet Woodcock’s opinion (the head of the drug review division). This led to a 13-page position paper by Califf, stating in part, “It is clear that Dr. Woodcock’s decision utilized the flexibility afforded under the relevant statutory provisions, including consideration of the life-threatening decisions of the disease and the lack of alternative treatments.” The need for a position paper was due to a formal dispute filed by Ellis Unger, M.D., (who reports to Woodcock), who disagreed with her decision to approve Sarepta’s drug as well as the means in which Woodcock went about pushing for approval.

In Unger’s , he listed four deviations from the typical drug approval process in this particular case:

  1. That Woodcock was involved in the early stages of the review process
  2. That Woodcock had “extensive involvement” in planning and participating in an expert panel meeting in the spring
  3. That Woodcock made an initial decision last May to approve the drug before the FDA review team completed a draft review memo
  4. That Woodcock issued a final decision memo prior to Unger finalizing his own memo, which is intended to be part of the approval mechanism.

Unger’s appeal also included the following, “I do not agree with your conclusions that all applicable processes and procedures were followed; the appealing parties had ample opportunity to present their views; and the decision to grant accelerated approval was made following consideration of all relevant scientific evidence.”

An additional memo was sent to Califf by Luciana Borio, M.D., the FDA Acting Deputy Chief Scientist who convened the dispute review board. Borio wrote that “we fear that those actions could have chilled scientific debate within [the FDA Center for Drug Evaluation and Review] and reduced the level of participation by the review team during the final stages of the decision-making process.”

These actions, should they be determined to be accurate, are opposed to the chain of causality that is supposed to be in place within FDA for the approval of a new drug, where analysis and opinions at the bottom of the chain are to coalesce and inform higher and higher levels of the approval process so that the balance of evidence is appropriately weighed with as few individual biases as possible.

In principle, there may have not been enough clinical trial data that was relevant or meaningful to make the necessary determinations as to whether enough of the protein, dystrophin (which prevents the degradation of muscle tissue), would be produced in the patients for clinically-meaningful physiological changes. FDA’s expectation on the drug and its effects are listed here.

Surrogate Endpoints in the Future of Medicine

The expectation is that FDA’s stance is based on a proper balance of safety and efficacy data, which should be gleaned from properly-designed and appropriately-conducted clinical trials. Individual decision-makers’ personal opinions are to be isolated out of the process as much as is possible in a review committee. What particularly doesn’t help is that there is also a specter of external pressure that’s at least coincidental with the approval, if not causative: There were no previously-approved drugs to treat Duchenne muscular dystrophy, and families who are dealing with the disease as well as certain lawmakers have pressed hard for accelerated approval of Sarepta’s drug. The accelerated approval process uses surrogate endpoints instead of other clinical physiological endpoints demonstrating functional benefits bestowed onto the patients due to the drug. In fact, an FDA rejection of Sarepta’s drug in April was called a win for ”science over popularity.” This is an early example of what we may indeed see more and more of as part of the Cures Act, which received bipartisan support for accelerating biomedical research and drug approvals. Indeed, President-Elect Donald Trump has also hinted at (among other things) speeding approvals for new drug products that impact serious diseases.

Certainly there is more to follow (just as there have been other issues like this in the past), especially as far as future decisions for high unmet needs. There is also the consideration of rejecting certain treatments–which may work to some degree (a small effect)–when there are no other alternatives. The choices become difficult in this case, where a decision to commit a “false negative” (that is, saying there is no benefit) must be weighed against the existing treatment landscape.

Ben Locwin, Ph.D., M.B.A., M.S., is president at Healthcare Science Advisors and an author of a wide variety of scientific articles for books and magazines. He is an expert contact for AAPS, a committee member for the American Statistical Association (ASA), and also a consultant for many industries including biological sciences, pharmaceuticals, psychology, and academia. Follow him at @BENLOCWIN.