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A recent paper provides guidance for clinicians to determine the validity of surrogate endpoints in clinical trials related to hematologic malignancies.
Surrogates are often used as prognostic markers in hematology and oncology clinical trials because they can be measured earlier than other markers and yield insight into a treatment’s effect.
However, statisticians determine surrogate validity, and the process they use is not always accessible to clinicians. A recent paper in Blood intends to change that by providing a clinically useful view of the statistics behind validating surrogate endpoints.
“While innovative therapies are designed every year in almost all indications in hematology, it takes long years for a randomized trial to assess the difference of long-term overall survival between two groups of patients. For that very reason, investigators love using surrogate endpoints to replace overall survival as the primary endpoint,” lead author Côme Bommier, MD, PhD, explains in an interview with Physician’s Weekly.
“As surrogates are often erroneously assimilated to prognostic markers, we intended to provide clinicians with an understandable paper on the statistical aspects related to the use of surrogate endpoints in hematology.”
Defining Clinically Meaningful Endpoints
Clinically meaningful endpoints can be defined as patient-centered endpoints that reliably assess a drug’s efficacy and safety. When sufficient time and resources are not available, surrogates can be used as endpoints. (Figure)
However, the authors of the paper pointed out two important concepts: surrogacy analyses do not answer the same questions, and surrogacy endpoints are valid only for a specific disease setting and type of treatment or intervention.
Validating Surrogate Endpoints
In the article, the researchers write that “an ideal surrogate lies on the causal pathway of the disease process, can be measured easily and in a timely manner, is significantly changed under the experimental treatment, and captures the magnitude of treatment effect that will be observed when the true clinical outcome will be measurable.”
This causality is determined via a statistical demonstration that involves the surrogate, assigned treatment, and outcome. Statisticians have four main approaches to validate surrogates:
- Proportion of treatment effect: used in single trials to identify a causal effect
- Trial-level coefficient determination: used in multiple trials to establish causal association
- Principal stratification: used in a single trial or multiple trials to determine causal association
- Mediation analysis: used in a single trial to demonstrate a causal effect
No matter the method, the authors noted that the surrogate is only validated for the specific class of intervention and disease setting.
Validated Surrogates in Hematology
The researchers defined several levels of validation for surrogates in trials for hematologic malignancies, including levels 2, 3, and 4.
Level 2 consists of surrogates validated in academic research and currently used by the FDA. “When validated surrogates (level 2) are used in registration trials, this represents a precious time saving for sponsors, clinicians, and patients,” the authors said.
Level 3 includes unvalidated surrogates with a likely ability to predict a clinical benefit. Like level 2, they are currently used by the FDA. Dr. Bommier and colleagues advised, “When non-validated surrogates (level 3) are used in registration trials, this time saving must be weighed against the downside of increased uncertainty of clinical benefit arising from using non-validated surrogates.”
Level 4 consists of correlates, including the time to next treatment and the POD24 marker. These are not academically validated or used by the FDA.
The researchers provided a flowchart that can help clinicians determine which level a surrogate falls into and if it can be used as a primary endpoint, co-primary endpoint, or neither.
“Surrogate endpoints may only be used in randomized clinical trials—thus replacing overall survival as the primary endpoint. When they are validated for the studied indication, they are a very reliable early endpoint that may inform clinical decisions,” Dr. Bommier says.
