Last week, a number of news outlets that Robert Califf, MD, may again be nominated to serve as FDA commissioner. Califf's prior term as FDA commissioner was brief; he was nominated during the final year of the Obama administration, serving from February 2016 to January 2017. During that time, he made one decision of monumental importance -- a decision that can be seen as the intellectual predecessor to recent drug approvals. As we consider Califf's potential nomination, let's revisit his previous tenure.
The Exondys 51 Controversy
In what feels like a lifetime ago -- 2016 -- we were in the midst of a different FDA debate. Eteplirsen (Exondys 51, Sarepta) was facing a regulatory decision by the FDA. The drug was intended to treat Duchenne muscular dystrophy, a grave and progressive condition for which there were limited and unsatisfactory treatment options.
The evidence supporting the drug was of very poor quality. We did not have a randomized controlled trial showing kids who get this drug lived longer or lived better. In fact, at the time of approval, the specifically, "There was no significant difference in change in 6MWD [six minute walking distance] between patients treated with EXONDYS 51 and those treated with placebo." Instead, the drug was approved based on a change in dystrophin protein level, a surrogate endpoint of dubious value and uncertain correlation with living longer or better. Documents from within the FDA revealed considerable disagreement and turmoil about the approval.
Specifically, the drug advisory committee voted against approval, and FDA reviewers the drug's application. Janet Woodcock, MD, director of the Center for Drug Evaluation and Research at the time, suggested the company perform additional biopsies to evaluate changes in the dystrophin protein, and authored an internal memorandum supporting the case for accelerated approval. This led agency director Ellis Unger, MD, to file a formal complaint of interference, and FDA's chief scientist Luciana Borio, MD, asked FDA Commissioner Califf to conduct a new scientific review of the product.
Califf wrote a memo deferring to Woodcock, an action that essentially granted the accelerated approval of this controversial treatment. With eteplirsen, Califf had a choice: he could trigger a re-evaluation of this product or he could accept the recommendation of Woodcock, ensuring approval. The former choice meant standing up for FDA reviewers, advisors, and scientific standards, and the latter would provide a financial boon to a drug company.
In deferring to Woodcock, Califf chose the latter, and the Los Angeles Times , "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." In November 2016, Nature Biotechnology , "doubts now surround standards for accelerated approval."
Accelerated approval of eteplirsen was not just a bad decision. It was the intellectual precedent needed for further erosion of FDA standards. We can even draw a line from the eteplirsen decision to recent controversies. In the last year, we witnessed the aducanumab (Aduhelm) decision for Alzheimer's disease. Here again, the FDA granted accelerated approval for a drug with no evidence people live longer or better, but on the basis of improving a disputed, uncertain biomarker. As I wrote in "The FDA is Failing the American People," the aducanumab decision was, once again, against the advice of an advisory panel vote.
Like a criminal empowered to push the envelope by getting away with past crimes, we likely would not have had aducanumab without eteplirsen. It set the precedent that these types of decisions are permissible and acceptable. The major difference is aducanumab will cost society many times more because of the larger patient population. And worse, with each approval of a new drug with limited evidence, we open the door for several more unjustifiable approvals down the road.
Where Does This Leave Us Today?
I wish to make two points about the potential re-appointment of Califf as FDA commissioner. First, I believe it is not only reasonable but necessary to judge a candidate for commissioner by past decisions on drug products or other regulatory matters. The eteplirsen decision was the first domino in a series that has led us to the present state of the agency when approving drugs that may cost society more than $100 billion without any idea if people are better off (aducanumab). This practice is unsustainable.
Second, in order to foster diverse and evolving thinking in leadership, choosing different people is a virtue. It is difficult to believe that there are so few scholars of regulatory science suitable for the position that we have to return to past holders. The challenge with repeat service as FDA commissioner is that former commissioners often , and their reappointment via a revolving door.
For more than a century, the FDA has set the standard globally. It defines what safe and effective therapies are, not only at home but across the world, and its imprimatur means something. Yet, the FDA has continued to lower its own standards, and approved products it would have quickly dismissed 25 years ago. The FDA stamp of approval now increasingly guarantees lofty pharmaceutical profits, but the U.S. public -- and the globe -- is getting increasingly suspicious. In this moment, the FDA has only one choice left: enforce a true efficacy standard or prepare for irrelevance. Only time will tell which choice we make.
is a hematologist-oncologist and associate professor of medicine at the University of California San Francisco, and author of .