If the regulatory, policy, and political temper tantrums over the FDA’s approval of Exondys 51 (for Duchenne muscular dystrophy) and Aduhelm (for Alzheimer’s disease) teach us anything—it’s that we’re very lucky to have Rob Califf, MD as the agency’s new commissioner. At a time when politicians and pundits are decrying “unscientific” and “unduly influenced” decisions, he understands the importance and nuance of the Accelerated Approval pathway.
Accelerated Approval is available under federal law when a drug intended for a serious disease is expected to provide a meaningful advantage over available treatments. But what does “meaningful” mean? Is it a specific p value? Certainly, data must always be at the foundation of every FDA decision, but data isn’t always black and white. Claude Debussy said, “Music is between the notes.” And the same is true for data because what often falls between the notes is the patient voice.
During his initial tenure as FDA Commissioner, Califf said that when there is a life-threatening disease with no effective treatment, “patient groups have been very clear that they are willing to take a high degree of risk to have earlier access.”
During a recent interview, Califf weighed in on the debate surrounding the FDA’s approval of Aduhelm: “I actually look at the controversy as an opportunity now, because it’s pointing out these systemic issues that, if we solve them, there’ll be a lot less controversy in the future.”
Understanding What’s Between the Data
Highly intelligent, dedicated, and experienced regulators can look at the same data sets and reach different conclusions. That’s science. And the more advanced the science, the greater the nuance and the more difficult the decision. When it comes to orchestrating “between the notes” Rob Califf is a maestro conductor of Toscanini-esque proportions. He is the right man, in the right place, at the right time.
Per Califf, “Rules of engagement must be transparent and developed through a process that builds consensus across the relevant ecosystem and its stakeholders.” In the post-pandemic “next normal,” the FDA will, increasingly, consider a far broader range of evidence such as real-world evidence, patient-reported outcomes, and quality of life measures. Post-approval studies will become more sophisticated, robust—and required.
Commissioner Califf understands that a more progressive expression of how data evolves over time is particularly relevant for those innovative medicines approved via regulatory review arteries such as Accelerated Approval.
As the FDA considers its decision for AMX0035 (for the treatment of amyotrophic lateral sclerosis, or ALS), the focus will once again be on the agency’s appetite for reevaluating regulatory paradigms. A key lesson is that Commissioner Califf will listen to all sides, ask tough questions, support his team, and accept responsibility for the agency’s ultimate action. That’s what real leaders do.
Don’t let the bow ties and the sugary southern accent fool you. Robert Califf is a change agent of the first order.