After accelerated approval: keeping confirmatory trials enrolling

Accelerated approval exists to get promising therapies to patients sooner, on the condition that confirmatory evidence follows. That bargain is easy to state and surprisingly hard to execute operationally — and two September actions make a useful illustration.

Two September examples

On September 4, the FDA granted accelerated approval to camizestrant with a CDK4/6 inhibitor for ESR1-mutated, HR-positive, HER2-negative advanced breast cancer, based on progression-free survival from the SERENA-6 trial. The agency's notice states that confirmatory trials are required for full approval.

On September 9, the FDA expanded the accelerated approval of sevabertinib to patients with HER2-mutant non-squamous NSCLC regardless of prior systemic therapy. The basis was the single-arm SOHO-01 trial, with an objective response rate of 75% among 69 eligible patients.

In both cases, the approval answers the question of access. It simultaneously raises a new question for the teams running the confirmatory studies.

The recruitment tension

Once a drug is commercially available, patients and clinicians can reach it without enrolling in a trial. For a confirmatory study that needs to randomize patients — sometimes against a comparator that now looks less appealing — this changes the calculus in several ways:

• Willingness to randomize can drop. Patients and investigators may reasonably prefer direct access to an approved therapy over a chance of assignment to the control arm.
• Eligible patients get siphoned off. The same population the trial needs is now being treated in routine practice.
• Site enthusiasm can fade. If sites see approval as the finish line, the confirmatory study can slide down the priority list even though its completion is a regulatory obligation.

None of these are inevitable, and many programs manage them well. But they're predictable, which means they can be planned for.

What planning for it looks like

• Model post-approval enrollment explicitly during feasibility, instead of assuming pre-approval accrual rates will hold.
• Design with the approved landscape in mind. Comparator choices and eligibility criteria that still make sense after approval are easier to enroll than ones that only made sense before it.
• Keep sites and patients informed about why the confirmatory study matters and how it differs from receiving the drug in routine care.
• Make remaining trials findable. If a patient with the right profile can't discover an open study, they'll simply receive the approved drug elsewhere. Discoverability is part of enrollment strategy.

That last point is where patient-facing search and trial operations meet. A confirmatory trial that is open but invisible to the people who would qualify is, practically speaking, closed.

This post reflects the author's commentary on publicly posted FDA approval notifications. Refer to the sources below for the full approval details.