How to Ensure Compliance with Good Clinical Practices (GCP) in Clinical Trial Imaging

GCP in Clinical Trial Research Overview

For nearly three decades those involved in clinical trial research have likely been familiar with the concept of Good Clinical Practice (GCP). GCP is an internationally recognized quality standard for the conduct of clinical trial research. The International Council for the Harmonisation (ICH) first introduced GCP in 1996 with the aim to establish responsibilities and expectations for those conducting clinical trials¹. The principles of GCP extended from primary investigators to study monitors, sponsors, and ethical review boards². While originally focused on outlining appropriate conduct of pharmaceutical trials, GCP now commonly covers a wide range of clinical trial research, including observational studies as well as medical device trials. Various countries may have additional clinical trial governance policies and regulations, such as the EU Clinical Trials Directive (2001/20/EC) in the European Union, The Medicines for Human Use (Clinical Trials) Regulations 2004 in the United Kingdom, or Food and Drug Administration (FDA) regulations supported by the Code of Federal Regulations (CFR) in the United States; however, these regulations all draw from the core principles of GCP.

Principles of GCP

There is no central GCP training platform, rather, regions provide training through various third-party providers. Training courses may vary slightly depending on the region and focus (i.e. US GCP references FDA and CRF, whereas European GCP may not), but all incorporate similar principles. These can include, but are not limited to:

• Ethical Review/Institutional Review Boards: This section introduces the concept of external ethical review using local ethical review boards or institutional review boards in the US. This external review is crucial in providing an unbiased assessment of a proposed clinical trial prior to commencement.
• Informed Consent: This section describes the process of informed consent of clinical trial participants. This section describes when informed consent is necessary and how to perform consent in various trial scenarios.
• Patient Confidentiality: This section is concerned with highlighting the importance of patient confidentiality in the conduct of clinical trials. This may extend further from routine clinical patient confidentiality as access to data, including who acts as data controllers and processors for the purposes of the clinical trial, must be detailed. This section may have variations depending on region (i.e. additional General Data Protection Regulation (GDPR) considerations in the EU).
• Participant Safety and Adverse Event Reporting: This section details how to effectively monitor patient safety during a clinical trial and how to report untoward adverse events to appropriate clinical and regulatory bodies.
• Quality Assurance: This section details recommendations for quality checking and monitoring during the course of a clinical trial.
• Research Protocol and Documentation: This section describes all aspects of clinical trial design and documentation. This includes the development of trial protocols, information sheets, consent forms, and monitoring plans, to name a few. This section also details data handling and archiving considerations.
• Roles and Responsibilities: This section highlights the various roles that may be involved in clinical trial research. Specialty roles and responsibilities may be identified for particular trials but will always take guidance from GCP.
• Investigational Medicinal Products or Medical Devices: This section details definitions of investigational medicinal products and/or medical devices. Depending on the country providing GCP training, this section may also detail approval pathways for drug/device market authorization.

Typically, completing modules of these courses requires a set pass mark on end-module quizzes. Clinical Trial sponsors will often require these GCP certificates from all clinical trial staff prior to their participation in any aspect of a clinical trial. GCP training is often refreshed every 2-3 years, but local policies may differ.

GCP Considerations in Clinical Trial Imaging

In clinical trials that incorporate imaging in their protocols, there are additional considerations that borrow guidance from the core GCP principles. Such trials may include X-Rays to monitor investigational implants, CT scans to detect cancer, echocardiograms to assess cardiac function during chemotherapy, or angiography to visualize peripheral vascular disease to name a few. Regardless, the totality of clinical trial imaging must adhere to the principles of GCP.

Protocol Development

GCP considerations in clinical trial imaging begin as soon as the trial is conceived. During protocol drafting, detailed descriptions of imaging modalities to be used must be carefully considered and included. If drug or medical device trials are concerned with imaging-based endpoints, such as reduction of tumor size in chemotherapy trials or improvement of blood flow in aortic stent trials, it is crucial to build clinical trial imaging protocols that detail all aspects of imaging within the trial. Such documents and procedures are created via discussions with multidisciplinary expert teams. Further considerations may be highlighted during external ethical review and subsequently incorporated into the trial prior to commencement. Not only is the appropriateness of imaging modality considered, but also the patient safety and experience. This is especially important in modalities that distribute radiation during image acquisition such as CT and X-Ray imaging. Again, expert teams, potentially with ethical support, carefully consider the patient experience and describe how to mitigate potential adverse effects, often through the process of risk assessment.

Patient Informed Consent

The patient informed consent process will also incorporate additional information in trials that include imaging. The process routinely involves detailing trial participation, risks and benefits, and data privacy considerations, but is expanded upon when imaging is included. Details of the imaging modality and acquisition, including the expected patient experience of being scanned, details of radiation exposure if applicable, and ownership of acquired imaging must be transparent during the informed consent process as part of GCP. Increasingly, participants are concerned with data privacy and access, and it is crucial to detail who will have access to acquired clinical trial imaging, how this data will be analyzed, and where this data will be stored. Onward sharing of acquired data is often detailed in the informed consent process, whether further analyses are planned or not. Highlighting that any data transferred to external collaborators will be in a de-identified form is paramount in adhering to data privacy regulations and maintaining patient confidentiality.

Image Acquisition

Acquiring images for a clinical trial will be guided mostly by local clinical practice, but there are still additional GCP considerations to be made. Participating trial sites must be thoroughly vetted, ensuring those actively participating comply with all GCP regulations, and are appropriately trained in image acquisition as per the clinical trial protocol. Clinical trial sponsors may opt to provide on-site training conducted by experts in the chosen image modality. This helps to harmonize image acquisition across the trial sites and provides additional quality assurance. For clinical trial imaging modalities with radiation exposure, thorough documentation of total exposure time (including the consideration of any additional exposure through the participant’s routine clinical care pathway) must be recorded to ensure patient safety. In the US, the FDA provides guidance for clinical trials with imaging endpoints focused on optimizing the quality of imaging acquired as part of a clinical trial³.

Image Transfer

Technology has mostly moved away from the days of physical imaging films, and even physical storage media has become uncommon. The majority of clinical trial image transfer is conducted over the internet. This adds additional data privacy concerns which must be addressed when conducting a clinical trial. It is generally accepted that simple email of patient data, including images is not a secure method of transfer, and as such, many image transfer platforms have been developed specifically designed for clinical trials. These image transfer systems provide a central platform through which all images acquired for a study can pass through. Such platforms demonstrate compliance with data protection regulations and appropriate data management per GCP and reduce the risk of data breaches or mishandling of patient data. Built-in image anonymization and quality control measures provide further assurance that patient imaging data is appropriately transferred from participating clinical trial sites to imaging core laboratories responsible for image analysis in clinical trials.

Image Quality Assurance

Clinical trials are often conducted over many investigational sites either within a single country or across numerous countries in global clinical trials. Even if standardized training is provided prior to site activation, there can still be variations in image acquisition which may significantly impact the results of a clinical trial. It is thus crucial, and a principle of GCP, to have in place appropriate quality assurance measures throughout the lifespan of a clinical trial to continuously monitor image quality for consistency and reliability. Ensuring a detailed clinical trial imaging manual is developed during the trial design process is a key step to limit variations in image acquisition by providing clinical trial imaging requirements. A clinical trial imaging manual may also outline the process by which the sponsor representative, usually an imaging core laboratory, can communicate with clinical trial sites if deviations from the clinical trial imaging manual are observed. A streamlined method of reviewing image quality is at the point of image transfer. Many image transfer platforms include a workflow step where manual review of images against established clinical trial imaging requirements is performed. Should any issue be identified, such as missing images, improper scan region, or overall poor-quality imaging, imaging analysts can generate queries within the image transfer platform and assign them to local clinical trial staff. As part of good documentation practices detailed in GCP, if any severe deviations from the protocol or clinical trial imaging manual remain unresolved, a protocol deviation will be documented and retraining with a clinical trial site may be conducted if deemed necessary.

Image Analysis

Once images have been acquired, assessed for quality, and transferred to a central platform, analysis can be conducted. In clinical trial research, sponsors will routinely employ a clinical trial imaging core laboratory to perform data analysis. While imaging core laboratories will routinely aid in image quality assurance, they are primarily responsible for performing harmonized image analysis as directed by the clinical trial sponsor. During trial development, imaging core laboratory project managers will liaise with the trial sponsor to develop a standardized list of measurements to be performed to support the endpoints of the trial. The development of these measurement definitions allows for a harmonized method of core laboratory imaging analysis, limiting variability in results. By utilizing an external core laboratory, clinical trial sponsors can avoid conflicts of interest within data analysis as recommended by GCP, increasing the robustness of trial results. The clinical trial imaging core laboratory also works closely with clinical trial safety monitoring teams, alerting appropriate parties if any cause for concern is identified during image analysis. This may involve measurements detected outside of expected ranges, or physical device defects in the case of medical device trials. The manner of handling such safety concerns should be in accordance with GCP safety event reporting and ensure patient safety is at the forefront of any clinical trial.

References

1. International Council for Harmonisation. E6 Good Clinical Practice. Efficacy Guidelines. https://www.ich.org/page/efficacy-guidelines
2. U.S. Department of Health and Human Services. Good clinical practice training. National Institutes of Health. https://grants.nih.gov/policy-and-compliance/policy-topics/clinical-trials/good-clinical-training
3. Food and Drug Administration. (2018, April). Clinical Trial Imaging Endpoint Process Standards. Food and Drug Administration. https://www.fda.gov/files/drugs/published/Clinical-Trial-Imaging-Endpoint-Process-Standards-Guidance-for-Industry.pdf
4. National Drug Abuse Treatment Clinical Trials Network. Good clinical practice. Good Clinical Practice. https://gcp.nidatraining.org/
5. CITI Program. Good clinical practice (GCP). Good Clinical Practice (GCP). https://about.citiprogram.org/series/good-clinical-practice-gcp/
6. National Institute for Health and Care Research (NIHR). Good clinical practice (GCP). https://www.nihr.ac.uk/career-development/clinical-research-courses-and-support/good-clinical-practice
7. Ecraid. Ecraid GCP Course. https://ecraid.eu/education/gcp