FDA's Robert Califf on accelerated approval: 'In God, we trust, everyone else must bring good evidence'

When FDA Commissioner Robert Califf, M.D., says the agency’s accelerated approval program is personal, he’s not being cliche. Califf’s mother was able to access multiple myeloma treatment because of it, extending her life. 

But now, seven weeks into the job, Califf is not naive about the debate surrounding the program, which has become his first big test. In an exclusive interview with Fierce Biotech, Califf said the first order of business for reviving trust in the program is improving the necessary confirmatory trials. 

“[W]e've got to do a better job of getting the post-market data,” he said. “And it ought to be easier to do the right thing for companies, easier to get the follow-up data than to not get it." 

The accelerated approval program allows drugs that fill an unmet need to enter the market early based on surrogate, or biomarker data. In the case of cancer, that’s a reduction in tumor size or disease progression. For Alzheimer’s disease, that could mean a reduction in amyloid beta plaques, which is considered to be correlated with disease progression. The potential benefit to starting confirmatory trials earlier would be boosting enrollment before a drug hits the market, which tends to de-incentivize patients from joining a trial for fear of receiving a placebo.  

Califf’s comments came hours before the Centers for Medicare & Medicaid Services (CMS) finalized its coverage determination for  controversial Biogen Alzheimer's med Aduhelm Thursday evening, only allowing coverage when it’s dosed in eligible clinical trials.

Headshot of Robert Califf
Robert Califf, M.D. (FDA)

The therapy was approved by the FDA under the accelerated pathway last summer under Califf's predecessor, acting Commissioner Janet Woodcock, M.D., on the basis of biomarker data that showed it reduced beta-amyloid in the brain, which is believed to be an underlying cause of the neurodegenerative disorder. But Biogen has yet to put up efficacy data and has been given nine years to perform a phase 4 confirmatory trial. 

Some critics have said the CMS did what the FDA wouldn't: ask for more data on the therapy. 

In a dual statement released Friday afternoon, Califf and CMS Administrator Chiquita Brooks-LaSure defended the contradictory nature of the two agencies’ decisions noting they are independent. 

I keep saying one of the mottos for me is ‘in God, we trust, everyone else must bring good evidence.’” —FDA Commissioner Robert Califf

“We recognize the impact these decisions have on people with serious and life-threatening conditions and their loved ones. We share a common goal of wanting to advance the development and availability of innovative medical products,” they wrote. 

Since approval, Aduhelm has been swallowed up by a cloud of controversy. Biogen has struggled to launch the first new Alzheimer's treatment in decades due to a high price tag, physicians who have refused to prescribe it and more challenges, despite a dogged advocacy campaign from patient groups. The agency's advisory committee had recommended against use of the drug, but officials disagreed, prompting two advisory members to resign. 

Califf, who previously led the FDA from February 2016 to January 2017, recognizes the dilemma for patients who do not have any treatment options, but noted quality data were paramount. 

“People with diseases with no effective treatment, or bad outcomes, American people want access earlier,” he said. “But the fair bargain is, I keep saying one of the mottos for me is ‘in God, we trust, everyone else must bring good evidence.’” 

In the same breath, Califf highlighted a proposal by the FDA’s oncology chief, Richard Pazdur, M.D., to start the phase 4 trials before approval. In an earlier interview with Fierce Biotech, Pazdur unveiled “Project FrontRunner,” an effort launching later this year to expand accelerated approval into earlier cancer treatments. 

During his confirmation hearings in February, Califf pledged to reform the accelerated review process, although he did not provide many specifics besides targeting the post-approval studies and holding companies accountable. He said at the time that changes to the program would be a high priority. 

Another alternative, according to Nancy Dreyer, Ph.D., chief scientific officer of clinical research servicer IQVIA—which runs hundreds of trials a year—is to add weight to real-world data after approval. In a statement, she said it could be more beneficial if review committees took those data into account after the fact. 

“Even imperfectly matched external comparators—such as real world data—can provide the context needed for thoughtful evaluation of many benefits and risks,” she said.