Applying FDA’s Clinical Trial Imaging Endpoint Guidance to Immuno-oncology Drug Development

Joe Pierro, MD |

Recently, the Food and Drug Administration (FDA) released its final “Clinical Trial Imaging Endpoint Process Standard Guidance for Industry” to assist sponsors in optimizing the quality of imaging endpoint data obtained in clinical trials intended to support drug and biological approvals.  It provides the agency’s recommendations on standardizing imaging endpoint data processing and minimizing data variability in Phase 3 trials.

The Guidance provides suggested processes for standard-of-care imaging and for trials where novel or non-standardized imaging serves as a primary endpoint. The latter provides additional details for trial-specific imaging process “standards that extend beyond those typically performed in medical care.”

Patient / Drug ‘Matching’

Imaging plays an important role in the regulatory assessment of a tumor’s response to therapy utilizing various standardized methods of assessment, such as the Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria, both of which have been acknowledged as the “gold standard” of tumor evaluation tools for several decades. With the advancement of precision medicine, imaging serves an even greater role in clinical trial design, along with the use of advanced technologies to help investigators match patients with the right targeted drug(s).

This patient/drug “match” is based on an understanding of the therapy’s mechanism of action and the tumor’s genomic profile.  Criteria like RECIST and WHO were based on standard cytotoxic chemotherapeutic drugs, where a linear treatment response was expected. In contrast, clinical data in genomic-designed immunotherapy trials have shown that tumors may demonstrate a heterogeneous response due to their genomic profiles.

Over time, new treatment response patterns were observed. One response pattern of note is pseudo-progression as observed in non-small cell lung cancer (NSCLC) patients treated with nivulomab, 2 which resulted in academic groups proposing several modifications to the standard response criteria. These criteria modifications have prompted several variants of immuno oncology response criteria (e.g., immune-related Response Criteria [irRC], immune-related RECIST [irRECIST], immune-based RECIST [iRECIST]) being deployed in clinical trials beginning in 2009 and used to guide treatment decisions.

Advancing Imaging Analysis 

Imaging analysis has shown various tumors can display differential growth and treatment response rates. Imaging techniques such as CT- or MR-based volumetric measurements and tumor density analysis are often included in clinical trials as study-specific imaging processes together with standard-of-care imaging requirements. For example, the initial post-treatment response may show a decrease in the tumor’s CT-based density, as reported in gastrointestinal stromal tumors, solid tumors, renal cell and hepatic carcinomas. Progression in these lesions may not actually reflect an overall increase in size, but may show new areas of contrast enhancement or new intratumoral nodules.

Many pharmaceutical companies modify the standardized response criteria such as RECIST 1.1 to create a more robust or reliable measure of treatment response that incorporates a thorough understanding of the advanced imaging data derived from earlier phase trials or non-clinical data. As defined in the FDA’s guidance document, the sponsor’s imaging charter should include a thorough explanation for the selection of and any modifications to the response assessment criteria.

Over the last decade, there has been extensive developmental work to identify and validate imaging biomarkers (e.g., targeted imaging agents, vessel tortuosity, region-of-interest (ROI), and area-under-the-curve (AUC) quantitative analysis of the tumor’s internal and surrounding radiographic textural features) that more accurately define or predict treatment outcome and extend beyond the tumor density changes described above. Trials that include exploratory endpoints to supplement traditional imaging endpoints should follow the FDA’s suggestions for describing the imaging interpretation methods for imaging-specific processes and how these analyses may be performed by the principal investigators or by centralized imaging reviewers.

Response evaluations in oncology trials are employing more advanced imaging methods and more precise criteria incorporating new response patterns based on the agent’s mechanism of action for new immunotherapies. As new criteria are born, and as current criteria evolve, it is critical that sponsors and centralized imaging providers carefully interpret and implement their processes relative to the FDA’s Guidance to ensure the collection of compliant, high-quality imaging data that meets both the scientific AND business needs of the study protocol. Accomplishing this necessitates a deep understanding of imaging, science, clinical research, and the FDA Guidance, so as to avoid misinterpretation and poor implementation of complex tumor assessment criteria with respect to clinical trial end points.

Learn how technology-driven imaging solutions overcome the limitations of traditional approaches and minimize risk while generating higher quality clinical trial endpoint data.

Dr. Joe Pierro is with ERT’s Scientific Affairs group.


  1. Clinical Trial Imaging Endpoint Process Standards Guidance for Industry,
  1. J. Clin Oncol 2015; 33: 2004-2012