FDA Guidance Document Focuses on Cancer Trial Endpoints

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."

The following article explores the impact this guidance is having on the clinical research industry and the increasingly important role that imaging has in the assessment of cancer tumors.

An evolving view on endpoints

As part of its Critical Path Initiative (www.fda.gov/oc/initiatives/criticalpath/), FDA has joined the U.S. National Cancer Institute (NCI), the pharmaceutical industry, and academia in a number of activities that will facilitate the use of medical imaging during product development and the development of new imaging agents. These efforts are focused on finding new surrogate markers and validating new endpoints for clinical trials.

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."

In order to clearly understand the imaging components of the study, the FDA recommends that an independent review charter be submitted before the study begins, outlining the IRC design and detailing key points such as image handling, endpoint interpretation, and review discrepancy resolution. The charter must be aligned with the study protocol and the statistical plan, all of which may be required to support a Special Protocol Assessment (SPA).

Images are data—Integration is key

Recent approvals of oncology drugs such as Sutent, Erbitux, Gleevec, and others have highlighted the use of imaging to support accelerated approval. The FDA guidance document is evidence of an increasingly rigorous approach to documentation in oncology trials. For sponsors, this approach presents increased complexity given the need to integrate imaging into the mainstream clinical trial functions. Key to the success of the imaging-based endpoints are the participating radiology departments. Inclusion of the radiology department in the development of the investigational site is essential in optimizing performance. Radiology will need to acquire data consistent with a protocol and submit the image data for central analysis. Adding the radiology department to the sponsors' budgets and including them in activities such as investigator meetings, monitoring visits, and study communication will go a long way toward improving the chances of success.

Further integration with data management and biostatistics activities can improve the speed and accuracy of the blinded reads. The use of electronic case report forms during the blinded reads affords the reader the use of logic tools and auto calculations in their interpretation of the criteria. Integration of the imaging and clinical databases can streamline the statistical analysis and ensure high-quality data supporting the endpoint.

The FDA guidance also strongly advises that the images be available for submission to the agency for review if and when necessary. Often this is accomplished through interactive databases that combine the clinical information, results of the blinded reads, and the images themselves. This allows the reviewer and the sponsor to search for specific cases, to look for specific outcomes such as all complete responders, and to consider what the readers saw and how they made their decisions. Additional tools and methods are currently available to execute the use and management of this data in an efficient and auditable manner.

The FDA and the pharmaceutical industry have adopted medical imaging to support the latest endpoints in cancer oriented clinical trials. The arrival of the April 2005 guidance not only reinforces the FDA's full adoption of medical imaging to support cancer endpoints, it also clearly points to the importance of skillful management of the imaging aspect of cancer oriented trials in responding to more rigorous expectations of documentation and methodology.

Ted Gastineau, PhD, is the CEO and co-founder of Beacon Bioscience, 4259 W. Swamp Road, Suite 410, Doylestown, PA 18901-1033.

References

1. Food and Drug Administration, Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, www.fda.gov/cder/guidance/6592dft.htm (FDA, Rockville, MD, April 2004).