'Premature Approvals': Why is FDA Granting Full Approval for Surrogate Data?

Bishal Gyawali, MD, PhD


November 18, 2022

Over the past several years, several drugs approved for advanced breast cancer on the basis of progression-free survival (PFS) have failed to show improvements in overall survival.

Alpelisib in combination with fulvestrant failed to significantly improve overall survival in patients with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer with a PIK3CA mutation, despite impressive median PFS gains of 5.3 months in the SOLAR-1 trial.

Everolimus had a similar fate, demonstrating a median PFS gain of 4.6 months in combination with exemestane but a nonsignificant effect on overall survival in the BOLERO-2 trial. Likewise, bevacizumab showed significant PFS gains but no improvement in overall survival in several trials.

Margetuximab in HER2-positive breast cancer also failed to improve overall survival in the SOPHIA trial; however, in this case, the PFS gains were marginal, with a median PFS difference of less than a month.

Despite these underwhelming overall survival results, none of these drugs have been withdrawn from the market, except for bevacizumab. In 2011, the US Food and Drug Administration (FDA) revoked its approval in advanced breast cancer because the PFS gains did not translate to overall survival.

What can explain the difference in the regulatory fate of bevacizumab?

The short answer: Bevacizumab received an FDA nod under the accelerated approval pathway whereas the other three received regular approvals.

When a Regular Approval Is Premature

The accelerated approval pathway allows the FDA to approve cancer drugs early on the basis of surrogate endpoints, whereas regular approval is typically granted when clinical benefit has been verified. For cancer drugs, this means improved overall survival or quality of life.

However, in recent years, several studies have shown that even regular approvals are being granted on the basis of surrogate markers. This is problematic because, unlike regular approval, accelerated approval comes with a safety net — a mandatory trial confirming the benefit.

In other words, a regular approval will continue to stay on the market even if overall survival results are not upheld in confirmatory trials, whereas an accelerated approval can be withdrawn or revoked.

So bevacizumab's approval could be subsequently revoked or withdrawn after the drug failed to improve clinical outcomes, but drugs like everolimus or margetuximab have not been withdrawn because of their regular approval status.

In fact, I don't know of any cancer drug with regular approval that has been withdrawn.

There may be valid reasons to grant a drug accelerated approval based on surrogate endpoints. But I can think of no regulatory or clinical reason to remove the safety net of a confirmatory trial and grant upfront regular approval based solely on surrogate endpoints. They're what I call premature regular approvals.

In a recent analysis, my colleagues and I found that the proportion of cancer drugs receiving regular approval based on surrogate endpoints was increasing while the proportion of cancer drugs that received accelerated approval was decreasing. This is surprising because the accelerated approval pathway is reserved for approvals based on surrogate endpoints.

To continue with examples in advanced breast cancer, everolimus, alpelisib, margetuximab, and olaparib all received initial regular approval based on surrogate endpoints alone and failed to improve overall survival subsequently.

So, why might the FDA be granting premature regular approvals rather than accelerated approvals?

A cynical explanation for this phenomenon could be that regulators want to avoid complications related to potentially withdrawing drugs, such as the FDA Oncologic Drugs Advisory Committee meetings called last year to reconsider the status of a number of "dangling accelerated approvals" — drugs granted accelerated approval and left on the market even though their manufacturers never provided the mandatory follow-up survival data.

Another concern with premature regular approvals is the possibility that the FDA considers PFS as a clinical endpoint rather than a surrogate marker. Allowing premature regular approval based on surrogate markers reflects a confidence that these markers will translate into overall survival gains without waiting for those data. However, studies have clearly shown that PFS does not correlate with overall survival in advanced breast cancer, nor does it correlate with quality of life. Patients and physicians care about PFS because we assume it to correlate with either overall survival or quality of life, not because we care whether the tumor size has grown beyond an arbitrary threshold.

The accelerated approval pathway is available to the FDA to strike a balance between the uncertainty of evidence and early access to therapy. There are problems with this pathway, to be sure, but the answer is not fast-tracking these drugs to full regular approval using surrogate endpoints alone. In doing so, the FDA is relinquishing its regulatory power and failing the patients it is meant to protect.

Bishal Gyawali, MD, PhD, is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen's University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women's Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.

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