Clinical trials often rely on surrogate endpoints to determine whether treatments work. In medicine, surrogates are biomarkers (i.e. blood pressure, cholesterol, proteins) that are thought to lie in the causal pathway of harder health outcomes like heart attacks, strokes, deaths, and dementias. A surrogate endpoint measures that biomarker instead of a more objective measure of a condition’s presence, absence, or progression. Researchers use surrogate or intermediate endpoints because it’s usually faster and less expensive to see effects on these stand-ins than to wait for actual events. However, surrogate endpoints can be misleading and should prompt more skepticism than traditional endpoints.
Deeper dive
A 2008 study in the Journal of the American Medical Association found that surrogate endpoints were the rule more than the exception in 436 clinical trials of diabetes treatments. In that study, patient-important outcomes — including cardiovascular events, death, pain, function, and quality of life — were chosen as primary outcomes just 18 percent of the time. They were primary or secondary outcomes in less than half of the studies.
Sometimes when drugs affect a surrogate endpoint, they also affect the risk of a health outcome. That’s true in the case of statins, which lower LDL or “bad” cholesterol and also reduce the risk of heart attacks. But it’s proving not to be true in many other instances:
Two Alzheimer’s drugs — bapineuzumab and solanezumab — reduce the buildup of beta amyloid protein in the brain. But both ultimately failed to improve thinking or memory better than placebos in patients with mild to moderate Alzheimer’s disease.
The drug Tredaptive increases HDL or “good” cholesterol and lowers LDL, but a large trial found it didn’t prevent heart attacks, strokes, or heart procedures.
Tight control of blood sugar was long thought to be the best way to keep diabetic patients healthy. But more and more studies are describing a paradox — patients with the tightest control of blood sugar sometimes have worse health outcomes than those who don’t lower their blood sugar as aggressively.
The cancer drug Avastin extends progression-free survival in patients with advanced breast cancer, but not overall survival, leading the FDA to revoke its approval for that indication.
For this reason, reporters should always be clear about the limits of studies that use surrogate endpoints.
Here’s how Andrew Pollack handled it in a story for The New York Times on experimental injections that lower cholesterol:
And there are still some caveats. One is that while the drugs lower cholesterol, it has not yet been shown that they actually reduce the risk of heart attacks, strokes or other cardiovascular problems.