April 1 is usually a day to expect the unexpected. However, on April 1, 2005, the U.S. Food and Drug Administration (FDA) released the "Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics."¹ The document describes the agency's "current thinking" while providing "recommendations to sponsors on endpoints for cancer clinical trials submitted to the FDA."

An evolving view on endpoints

Endpoints based on tumor assessment include disease-free survival, objective response rate, time to progression, and progression-free survival. In the FDA's recent guidance document, two tumor assessment endpoints emerge as clear favorites: objective response rate (ORR) and progression-free survival (PFS). These are both based on radiological endpoints.

ORR, as the name suggests, is determined by an observable and measurable response to treatment (i.e., tumor shrinkage) over a predefined period of time. Its biggest advantage as an endpoint, in the FDA's view, is that it is directly attributable to drug effect and can be assessed in single-arm studies.

PFS is also cited as a desirable endpoint because "it reflects tumor growth (a phenomenon likely to be on the causal pathway for cancer-associated morbidity and death), can be assessed prior to demonstration of a survival benefit, and is not subject to the potential confounding impact of subsequent therapy." Today, ORR is the endpoint most often used to support cancer drug approvals, but the FDA is clear that PFS is also a "preferred endpoint."

Imaging in tumor assessment

Endpoints based on tumor assessment (ORR, PFS) are typically based on medical imaging evaluations of the size of the tumor. In practice, this means Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and more recently Positron Emission Tomography (PET) imaging are used over the course of a clinical trial to view and measure changes in tumor size or function.

Although a variety of assessment tools and measurement criteria exist, the FDA itself does not have standard regulatory criteria for defining tumor progression. Instead, the agency relies on sponsors to "carefully define tumor progression in the protocol" using established criteria such as the World Health Organization criteria, the newer RECIST (Response Evaluation Criteria in Solid Tumors) guidelines for solid tumors, the International Workshop Criteria for Lymphoma, and emerging standards for PET.

Toward more consistency and accuracy

The adoption and use of imaging to support efficacy endpoints is well established. However, acceptance of medical imaging-based trial endpoints requires data to be rigorously acquired, collected, analyzed, and delivered. Medical images must be treated as source documents, and their interpretation must be standardized and objective. Because tumor assessment is so critical, the FDA has expressed its concern for reliability, especially given "the potential for uncertainty or bias in tumor assessments." To reduce bias, the FDA has made some specific recommendations:

"When the primary study endpoint for drug approval is based on tumor measurements (e.g., progression-free survival or ORR) it is recommended that tumor endpoint assessments generally be verified by central reviewers blinded to study treatment."

This is accomplished through the use of an Independent Endpoints Review Committee (IRC), which provides "a mechanism to minimize bias in interpretation of the radiologic findings and independent adjudication of endpoints."