Imaging Endpoints: Designing, Operationalizing, and Defending the Signals that Matter

Introduction

Clinical trial endpoints are the outcome measures used to determine whether an investigational drug or therapy is working safely and effectively. Endpoints are pre-specified and documented within the clinical trial protocol, defined in accordance with the disease context and study objectives. Endpoints can be primary, secondary, or exploratory, and are typically assessed through blood-based biomarkers, clinical assessment, or imaging measures.

Imaging endpoints enable visual objective evidence of disease progression and treatment effect, providing valuable early evidence to enhance clinical research findings. Sponsors must integrate imaging endpoints into protocol design early to enhance success, aligned with well-defined and validated imaging modalities and robust data-integrity measures. Here, Rohit Sood, Vice President of Scientific and Medical Services at Perceptive Imaging, highlights the importance of early imaging endpoint integration, providing advice for sponsors on de-risking trial execution through use of an imaging core lab.

Defining Endpoints

“The role of an endpoint, a measurable outcome, is to provide a method or metric that regulatory agencies use to objectively assess the effect of an investigational drug or intervention, essentially determining whether it works, and to what extent,” defines Dr. Sood.

A therapeutic intervention can influence a wide range of biomarkers, including clinical, laboratory, and imaging biomarkers. The biomarker a sponsor selects should be the one which best represents the specific aim they hope to demonstrate using statistical methods, typically safety or efficacy. When sponsors compile a list of all potential endpoints or biomarkers, the endpoint that most directly measures the key clinical outcome of interest is designated as the primary endpoint.

Secondary or exploratory endpoints provide supportive data on a treatment’s effect beyond the main goal (the primary endpoint), providing additional evidence of clinically important effects and treatment considerations. The use of secondary endpoints must be balanced against operational considerations, cost implications, population factors, and risk of diluting focus from the primary endpoint, but can provide regulatory agencies with valuable context of the therapy’s overall benefit.

The Importance of Early Endpoint Integration

Several factors should be considered when determining the best imaging endpoint to assign, including existing clinical evidence, scientific literature, past trials and approvals, and the phase at which they are conducting the study. If there is specific evidence that an imaging endpoint should be considered, sponsors should incorporate imaging into protocol design early. Introducing imaging late results in additional cost and operational burden and can limit the integrity of imaging data if not properly considered from the beginning.

“Perceptive works closely with sponsors to determine whether a clinical or imaging-based endpoint is most appropriate for their study,” explains Dr. Sood. “This includes helping sponsors to understand the strengths and limitations of imaging endpoints, what types of measures are likely to be viewed favorably by regulatory agencies, and how to select endpoints that are reproducible, clinically meaningful, and aligned with the trial’s objectives.”

“Our role is to guide sponsors toward smart, evidence-based decisions that ensure the chosen endpoint can reliably demonstrate the intended therapeutic effect.”

Protecting the Endpoint

Protecting the integrity of imaging data relies on various factors, including a well-aligned imaging modality, robust imaging acquisition standards, appropriate image interpretation, and use of well-thought-out central reads. Defining the read strategy early, selecting imaging experts based on appropriate experience and qualifications, providing standardized training, and implementing ongoing quality monitoring are essential to ensure imaging data tracks with regulatory expectation. Blinded independent review, investigator reads, expected discordance, and clinical adjudication should be well-defined and integrated early into the imaging protocol design.

“Careful imaging data acquisition and read design are critical to selecting reliable endpoints. Whether using single, double, or consensus reads, the approach must be tailored to the study’s objectives and verified with regulatory agencies to ensure objective, reproducible, and high-quality imaging data that can support decision-making,” highlights Dr. Sood. “Poor read design can directly negatively impact the primary and/or secondary endpoint and result in an investigational drug not being approved.”

Site-to-site variation can impact data collection; sites may use different scanners or staff with varying levels of experience. The key role of an imaging core lab is to protect trials from these layers of complexity, harmonizing image acquisition through calibration, training, and the use of standardized protocols across all imaging sites.

De-risking Imaging Endpoints

As an imaging expert, Dr. Sood has provided his top five tips for de-risking imaging endpoints:

1. Use scientifically validated endpoints – Select imaging biomarkers backed by robust scientific evidence from peer-reviewed medical journals, those widely accepted throughout the scientific and research community.
2. Regulatory alignment – Ensure your chosen imaging endpoints are acceptable to regulatory agencies and aligned with your specific investigation. Ensure you follow regulatory guidance regarding image acquisition throughout.
3. High sensitivity and specificity – Do your chosen endpoints reliably detect the true effect of the intervention, while minimizing false positives and false negatives?
4. Feasibility across sites – Confirm that the imaging data can be consistently collected across large, multi-center, or global trial sites, considering the availability of scanners and any differences in hardware or site capabilities.
5. Staff training and expertise – Evaluate and account for the expertise of site staff, consider additional training early, and implement standardized procedures to ensure consistent data acquisition and interpretation.

Perceptive Imaging

Sponsors who do their due diligence, working alongside an experienced imaging CRO, are more likely to succeed. Perceptive has supported thousands of imaging trials, observing both the successes and failures of imaging integration, and can provide valuable insight and practical wisdom to clinical trial sponsors.

“Imaging has come a long way since I joined the company 17 years ago,” concludes Dr. Sood. “Today, imaging endpoints are carefully curated, and engaging early with an imaging core lab is considered vital. While KOLs provide valuable scientific insights, they often do not have a global trial perspective. Perceptive is happy to join the conversation from a practical standpoint, providing guidance on what is feasible, as well as the limitations and challenges of implementing imaging endpoints across multicenter trials.”

At Perceptive Imaging, we put a lot of time and effort into guiding sponsors on how to make the best possible decisions around the use of imaging endpoints. With strong imaging expertise and robust processes in place to protect the integrity of imaging data, complemented by a strong track record of success, we help sponsors to design, implement, and execute imaging strategies effectively.