Experts Say Surrogate Endpoints Should Only be Used as a Last Resort in Drug Trials

A growing number of drugs are being approved on the basis of indirect (surrogate) measures that do not always reliably predict outcomes that matter most to patients, such as living longer or feeling better.

In a recent issue of The BMJ, experts argue that surrogate endpoints provide no guarantee of clinical benefit and should be used only as a last resort in drug trials. In a linked feature, journalists say the routine use of surrogate endpoints for drug approvals is not benefiting patients or the economy.

Using surrogate endpoints to measure whether a new drug works can reduce the duration, cost, and complexity of clinical trials before regulatory assessment and facilitate faster patient access to new therapies, especially for chronic diseases, explain Dalia Dawoud at the National Institute for Health and Care Excellence (NICE) and colleagues. However, the use of such endpoints can also have negative implications, such as making decisions more challenging for health technology assessment bodies and complicating treatment decisions for patients and clinicians.

The experts point out that over the past three decades, the proportion of clinical studies measuring the efficacy of new drugs using surrogate endpoints alone has increased from less than 50% in the mid-1990s to roughly 60% in the 2015 to 2017 period. In some therapeutic areas such as cancer, surrogate endpoints account for almost 80% of all clinical studies supporting regulatory approvals.

Calling for more selective use of surrogate endpoints when evaluating new drugs, the experts also recommend restricting their use to chronic diseases, especially when collecting data on patient-relevant clinical outcomes requires trials with unattainably long follow-up periods. They also say greater involvement of patients (and organizations representing patients) in regulatory and health technology assessment processes is essential to ensure that the conditions for accepting surrogate endpoints for decision making are adequately met.

When journalists Jeanne Lenzer and Shannon Brownlee examined the U.S. Food and Drug Administration (FDA) expedited approval process, which allows drugs onto the market before their effectiveness has been proven, they found that in 2018, 73% of FDA-licensed drugs (43/59) received expedited approval based on surrogate endpoints. As part of the accelerated approval process, the manufacturer must conduct postapproval trials to confirm clinical benefit. If these trials show no benefit, the drug’s approval can be withdrawn.

However, Lenzer and Brownlee say postapproval trials can be delayed for many years and the FDA has not held companies accountable when they fail to prove such benefit. They argue that by allowing drugs onto the market based on surrogates only, “the pharmaceutical industry and FDA have effectively offloaded the burden of proof onto the shoulders of the public, along with the physical harms and financial costs of clinical testing (if done at all).”

Meanwhile, industry supports the use of surrogate endpoints, claiming it is too expensive to go back to approvals based on clinically important endpoints. To this point, Jerome Hoffman, professor emeritus at the UCLA Medical Center, says: “The final economic cost of approving and using harmful drugs is actually far greater than the cost of demanding better studies at the outset.”

Edited by Gary Cramer