Califf on accelerated approvals: Companies need to do more work before FDA says OK
As he awaits a tight Senate vote, Rob Califf, President Joe Biden’s nominee to be the next FDA commissioner, is signaling where the agency may move on accelerated approvals if he takes over at FDA.
Building off comments from his Senate confirmation hearing, in which Califf said that he’s “a fan of accelerated approval” but the US needs a better system to evaluate these drugs once they’re on the market, the nominee raised questions about how well the current structure serves patients.
There’s been “failure to produce confirmatory evidence quickly and in a way that really gives us the information we need as patients and clinicians to decide which treatments are most effective and in which order,” he said at the CERSI Summit last week.
Comparing the accelerated approval pathway to a relay race — potentially poking at the controversial situation where the FDA granted an accelerated approval to Biogen’s Alzheimer’s drug but CMS is requiring an additional randomized clinical trial — Califf argued the “FDA runs the first lap, gets to the end, drops the baton down on the ground, and someone else like CMS has to figure out where the baton is, pick it up and start all over.”
“I think one of the most important things I learned from my time [as FDA commissioner under the Obama administration] is the power of federal agencies working together with common purpose,” Califf said. “In a relay race, you have a number of yards where the second runner is running alongside the first, and we just don’t have that.”
He also lamented the fact that the US is “losing life expectancy in the US and relatively faster than the rest of the world. We’re innovating in the US in a way that’s helping the entire world, but there’s something we’re not doing right in implementing those innovations. That’s the way I see it.”
Julia BeaverJulia Beaver, chief of medical oncology at the FDA’s Oncology Center of Excellence, also spoke on the CERSI panel with Califf, noting that overall, OCE’s work in accelerated approvals has been “a success” by providing years of early access to “transformative, life-prolonging therapies.”
She noted that half of all accelerated approval indications have confirmed benefit in a median of 3 years, and the remainder of those that have not yet confirmed benefit have been those granted AA in the last few years. Less than 10% of these indications have been withdrawn either due to failed trials or because the trials weren’t conducted, she said.
“The situation and framework we’re in now is that although we can’t require this, we are stressing the need for the confirmatory trial to be well underway, if not fully enrolled, at the time of the accelerated approval action to avoid these delays and get the evidence,” Beaver said. “But in terms of our confidence in getting that confirmatory evidence, that does now play into our overall risk/benefit decision. So if we have confidence or early agreement on evidence needed for confirmatory trial, that’s the ideal.”
Such earlier agreements between FDA and companies seeking accelerated approvals, “potentially even on confirmatory metrics,” Beaver noted, would allow for greater confidence in the approval pathway.
Hal Barron, who recently made the leap from CSO at GlaxoSmithKline to CEO of startup Altos Labs, also noted on the panel that there a number of surrogates where the benefit of an accelerated approval is a “smart risk to take.” But “in terms of where it’s failed,” he stressed that there needs to be more rigor in designing the confirmatory trials, “so you believe” the results when they’re positive or negative.
Hal BarronSome of these trials are taking an “enormously long time to convert” to full approval, Barron noted, and he said there’s been a lot of talk about using RWE to satisfy confirmatory trial results. “But I’m not as convinced that that will help as much as randomized trials,” he said.
Califf, a longtime fan of using RWE when randomized, stressed, “Nothing about RWE excludes randomization, which is one of the most powerful tools we have.” He pointed to the UK-based Recovery trial, which quickly tested a number of different Covid-19 therapeutics, and which “beat the socks off” the US trials.
“If the trials are mostly enrolled before the [accelerated] approval comes, you’re going to get the answer,” Califf said.
Barron, meanwhile, noted the push toward doing more observational studies and using those to conclude a drug works when compared to untreated patients: “You can use all these sophisticated techniques, but I’m just not confident. Given that these drugs are going to be used for a long, long time, we’ve got to get it right and not skimping on the randomization, and understanding efficacy and effectiveness is critical.”
Barron also stressed that for a smaller company, it can be a big risk to initiate a confirmatory trial before an approval is granted or before the survey trials are unblinded. He also called for more companies to work in a pre-competitive way to define the utility around the surrogates on which the accelerated approvals are based.
“Whatever legislative framework is inserted, think hard about how every group has skin in the game. Incentivize approvals to get to patients faster but incentivize to quickly figure out if you made a smart decision that was wrong or a smart decision that was right,” he added when asked how Congress could improve the accelerated pathway.
