Pharmacists Can Use Surrogate Endpoints to Discuss Patient Care

Surrogate endpoints can help pharmacists lead discussions in patient care by incorporating past and existing surrogate endpoints and their limitations and strengths, according to a presentation at the Hematology/Oncology Pharmacy Association Annual Conference 2022.

Surrogate endpoints are a substitute for clinical outcomes that are usually used to help predict clinical benefits.

Overall survival (OS), which is the time from randomization until death from any cause and is a direct measure of clinical benefit, is often described as the gold standard in clinical outcomes.

However, surrogate endpoints can also be used in place of OS as other time-to-even endpoints.

These surrogate endpoints include progression-free survival (PFS), which is the time from randomization until objective tumor progression or death, whichever occurs first; time to treatment failure, which is the time from randomization to discontinuation of treatment for any reason; and time to tumor progression, which is the time from randomization until objective tumor progression and.

The surrogate endpoints can help decrease the needed sample size, which can in turn reduce the occurrence of adverse events (AEs). Therefore, the linkage might not necessarily be accurate, and rare AEs might not be seen in clinical trials.

Additionally, surrogate endpoints can provide earlier efficacy assessment, but the surrogate markers must have a scientifically plausible link to the hard endpoint. Surrogacy also does not necessarily equal correlation alone.

“A surrogate marker is not a correlative marker, in and of itself,” R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA, III, a professor at Emory University School of Medicine, said during the presentation. “It can be, but there has to be more to it than just a correlation, because correlation without causation is meaningless.”

Finally, surrogate validation helps to confirm that the surrogate marker is linked to the outcomes of a trial for a specific population.

Additionally, establishing surrogacy has 4 main requirements. It must significantly impact the surrogate marker, significantly impact the hard endpoint, the surrogate and hard endpoints should be correlated, and the full effect of the treatment on the hard endpoint must be captured by the surrogate marker.

A mathematical model is also essential to help predict the validity of a surrogate by the strength of the association between the surrogate and the hard endpoint across multiple observations.

“Your hard endpoint is easy when it is OS,” Harvey said.

“There are other hard endpoints; you can choose those endpoints. You can feel confident about those endpoints, but they have to be validated,” Harvey said.

“Area under the curve can be a hard endpoint, if that is what you are targeting,” he said.

In the model, PFS is commonly used as a surrogate endpoint for OS, but other hard endpoints can include biomarkers, biosimilars, clinical pharmacology, and quality of life.

However, there are some challenges that should be considered when using surrogate endpoints.

Investigators must establish the surrogacy across many patients and treatment-level variables, because early results are not always confirmed in subsequent larger trials. There are rapid changes being made to the treatment landscape that could affect it.

There is also the potential for influence by observers or other biases.

Additionally, many agents with modest clinical benefits might have lower confidence in linking surrogate endpoints with hard outcomes. There must be large numbers of observations and/or a very tight correlation of the surrogate to hard endpoints.

Increasing the efficacy of agents in many diseases could have a time gap between PFS following the initial treatment while OS is growing.

Finally, surrogates are evolving, and there are many opportunities, specifically with circulating tumor DNA, expansion and primary approvals using patient-reported outcomes, real-world evidence and surrogate endpoint, and PFS-2, which is for use in second-line therapies.

Reference

Arora S, Harvey RD. Surrogate endpoints in oncology clinical trials: measuring outcomes that matter. Hematology/Oncology Pharmacy Association Annual Conference 2022. March 31, 2022; Boston, MA.