The use of medical imaging in clinical trials, managed by an imaging core lab (ICL) (or imaging CRO [iCRO]) has now become a standard process. Sponsors tend to rely on the ICL to then develop the so called Imaging Charter (IC) or Imaging Review Charter (IRC), which is specified in the FDA Guidance Document “Clinical Trial Imaging Endpoint Process Standards” released in April 2018. However, this is not the only document that should be carefully evaluated and reviewed in context with the imaging endpoints.
There are 7 important documents (generated in conjunction with an ICL) to help ensure high quality imaging data from your clinical trial. Whether you are a sponsor, CRO, project manager, or data manager, familiarity with these documents will contribute to smoother imaging endpoint handling and full GCP compliance.
Obviously the study protocol is the primary document and is the reference point for all trial methodologies and documents. The protocol should clearly state that the images will be sent to a third party ICL and therefore by default an IC will be needed. The IC is, by definition, subservient to the protocol and must be aligned. To support this, additional documentation is essential for success. Using a best practice approach, we will examine the key 7 documents:
1. Imaging Charter (IC)
The IC serves as a roadmap for standardizing and interpreting the images coming from the trial, including which images are “on protocol” and “off protocol” and available for reading. Charters provide a comprehensive and detailed description of the clinical trial imaging methodology and the key assessments that will be exported from a study. In 2018, as stated the FDA released a guidance entitled Clinical Trial Imaging Endpoint Process Standards, which details the structure and content of an IC. Based on this guidance, Bracken has developed an IC checklist available for download. ICL’s have expertise generating ICs and work with sponsors and regulatory agencies to make sure that they contain the correct elements for compliance. However, the IC probably will not include all the necessary details, and for efficiency, further supporting documents should be referenced and produced, and therefore subservient to the IC.
2. Communications Charter
Some ICLs extract specific information from the IC to create a separate a communication charter or document. This can assist in streamlining processes but can also add more complexity to the writing and approach. Successful delivery of quality data requires coordination between the ICL, sponsor, and the clinical CROs. A communications charter helps ensure responsibilities and interfaces are clearly defined. The relationship of the two documents must be detailed, as in many instances, the communications charter includes information that the FDA expects to be in the IC. However, creating this document can slim down the IC, allowing it to focus more on the independent reads. As stated, this document is ICL dependent, and the sponsor needs to be aware of the importance of the communications charter in the overall scheme.
3. Business Requirements Specification (BRS)
The Business Requirements Specification or similarly titled document formally outlines the business needs identified in the IC and translates the logic to the software specifications. Most ICL’s will have a “standard RECIST 1.1 read platform” so this document may also follow a standard format and might not require review unless modifications to the standard read are necessary (which is often the case. The BRS is a critical part of the overall project documentation and must be distributed, understood, controlled and managed during a trial. It should also include the eCRF that the readers complete, the logic behind the read, and the process by which images are available for evaluation at each stage of the eCRF.
4. User Acceptance Testing (UAT)
A UAT is a formal evaluation to ensure that the read software and system conforms to the BRS. This should include so-called positive and negative testing to ensure the software application for the reads is robust and will generate the results (data export) as expected and aligned with the IC.
5. Reviewer (Reader) Rules
Different clinical trials utilize different reader paradigms, ranging from a relatively straight-forward single reader to more complex paired reads with adjudication; the so-called 2+1 read design. The choice of read paradigm, which should be detailed in the IC, is based on a number of factors including study phase, regulatory compliance, operational efficiency and cost-benefit analysis. The Reviewer Rules document guides independent reviewers by providing necessary details for the accurate interpretation of imaging data. Some studies may also contain an Imaging Atlas which further defines the imaging endpoints and serves as a guide for independent reviewers. The document should also contain the instructions for using the read software (which should align with the BRS). Readers should participate in a formal training session as a collective team where this document provides the foundation of the training and alignment (calibration) among the reviewers. Completion of the training will result in sign-off and documentation of the training content.
6. Image Acquisition Guidelines
Standardized image acquisition is essential to ensure consistency, reliability, and clinical relevance across all imaging sites participating in a trial. Image acquisition guidelines define the technical parameters, timing, anatomical coverage, and patient preparation necessary to capture high-quality, protocol-compliant images. These guidelines also include instructions for scanner calibration (when needed), contrast administration, and positioning, which help minimize variability and enable accurate analysis of imaging endpoints. ICLs play a critical role in training sites on these requirements and conducting qualification scans to confirm adherence prior to subject enrollment. To maintain data integrity, a trial’s acquisition parameters must align with the Imaging Review Charter and imaging manual, and any deviations should be documented and evaluated for impact on trial outcomes.
7. Data Export Specifications
Ultimately, the data associated with a clinical trial will be exported in preparation for sponsor review and regulatory submission. Data export specifications define the exact requirements, format and conditions of the data that are derived from medical images. This includes the export of image files and associated metadata in standardized formats (e.g., DICOM) to ensure compatibility with sponsor and regulatory systems. ICLs have SOPs and policies in place for data export to ensure that all patient information associated with trial data are encrypted, delivered electronically to the sponsor in a secure manner, and aligned with all the other trial data. To ensure the accuracy of imaging data, the Imaging Review Charter, BRS, and data export specifications must be consistent, particularly regarding the primary imaging endpoints, but secondary and sensitivity results should also be considered including inter and intra reader variability results.
Discussion
Careful planning and implementation of key clinical trial documents will prepare sponsors and ICLs for handling complex data derived from medical images in clinical trials. Having all these documents ready prior to the start of the study is often challenging, so breaking the key aspects into manageable checkpoints allows for more time and ultimately should lead to better quality documents and results.
For instance, the IC needs to be signed off before programming the read application and developing the BRS, while the Reader Training document can be delayed until reader training. Additionally, understanding the hierarchy and which document is subservient to the others is important in development content. Fig 1 below displays the hierarchy in a graphic format.
Fig. 1
In conclusion, when planning a trial with a medical imaging endpoint, a holistic view of all key documents, beyond just the IC, is essential.
For more information on these documents or Medical Imaging in Clinical Trials, contact The Bracken Group.
