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Leveraging Imaging Biomarkers to Improve Drug Development

Imaging biomarkers, molecular imaging in oncology clinical trials

Molecular Imaging – Valuable Drug Development Tools

Clinicians need ways to better predict patient responses

The estimated cost for developing a drug is approaching upwards of $5 Billion dollars with a process spanning well over a decade. Coupled with high failure rates in late phase clinical trials and increased complexities in acquiring and analyzing clinical trial data, traditional approaches based on the premise of "one size fits all" are becoming less cost effective and suboptimal.

Clinicians are relying more and more on biomarkers to better understand and monitor disease progression and responses to treatment. Different classes of biomarkers include somatic mutations, polymorphisms, and gene/protein expression profiles that are associated with a particular disease state. Throughout the clinical trial process, the ability to detect and visualize patient biomarkers can be used to help optimize trial eligibility and enrollment, to monitor and improve treatment responses and patient outcomes, and to inform the off-target effects of a therapeutic. In particular, utilizing biomarkers early in the clinical trial process to guide go/no-go decisions can have a major impact on resource allocation and development costs.

In oncology studies, imaging provides a reliable methodology to assess the presence, location and extent of disease using anatomic imaging (e.g. CT, MRI). The Response Evaluation Criteria In Solid Tumors (RECIST 1.0) were introduced in the year 2000, as part of collaborative efforts between the European Organization for Research and Treatment of Cancer (EORTC), the National Cancer Institutes (NCI) of the United States, and the National Cancer Institute of Canada (NCIC) Clinical Trials Group.1 RECIST refined an objective set of criteria that defined when tumor lesions in cancer patients improve (partial or complete response), remain unchanged (stable disease), or worsen (progressive disease) during treatment.

However, the RECIST method has not been demonstrated to be a good predictor of response to treatment in early phase oncology trials, showing a high failure rate in phase II and contributing to diminishing ROI for pharmaceutical companies. Advances in molecular imaging including the use of Positron Emission Tomography (PET) enable earlier assessment of treatment response by evaluating the functional activity of tumors using radiotracers (e.g. 18F-fluoro-deoxy-glucose). Typically changes in tumor metabolic activity precede reduction in tumor size. PET can be used as imaging biomarker to identify patients most likely to benefit from treatment and in conjunction with other diagnostics as a decision making tool for measuring treatment efficacy and advancing drug candidates in a clinical pipeline.

Implementing PET approaches for clinical trials

The widespread application of PET in clinical trials presents several challenges to drug sponsors including site selection, training, and image analysis. Clinical trial sites must have the capability to perform high quality FDG-PET scans. Key organizations including the American College of Radiology (ACR), The Society for Nuclear Medicine and Molecular Imaging-Clinical Trials Network (SNMMI-CTN), and the European Association of Nuclear Medicine (EARL) are providing important tools and resources (e.g. PET scanning protocols) for standardization of PET imaging in the clinic. Furthermore, imaging core labs are supplementing these efforts with harmonized training materials, read criteria protocols, and other resources for drug sponsors relying on PET imaging endpoints.  Proper analysis of PET images also requires specialized scientific expertise. It is important that, sponsors utilize site investigators and site readers that are proficient in PET and have a knowledge base of applicable criteria.

In addition to identifying the presence, location, and distribution of specific tumor biomarkers, radiopharmaceuticals can be used to objectively obtain quantitative measurements including region of interest (ROI) assessments of single or multiple areas. A common measurement used in molecular imaging for assessing treatment responses is the standardized uptake value (SUV), which represents the ratio of the concentration of radioactivity in a selected region to the total injected dose. Quantitative measures like SUV values provides more reliable trial data that can be used to support patient care and guide trial decisions.

Closing Thought

Taken together, Molecular Imaging approaches are valuable drug development tools that serve as predictive biomarkers and contribute to the likelihood of successful clinical outcome. Today’s drug sponsors rely on them to stratify patients (personalized medicine approach), monitor disease progression, selectively target sites of disease, and help reduce the tremendous cost burden associated with the clinical trial process.

Reference

Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines). J Natl Cancer Inst. 2000;92:205–16.

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