The International Council for Harmonization (ICH) Good Clinical Practice (GCP) E8 amendments were introduced to align with modern clinical trial practices and improve clinical trial quality, safety, and efficiency globally [1]. The key amendments to ICH E8, effective in April of 2022, emphasized patient-centricity and risk-based approaches with a focus on safety and well-being throughout the clinical trial process [1]. There was also an emphasis placed on informed consent that includes patient needs, preferences, and cultural contexts to ensure patients understand the clinical trial and its risks. In the revised regulatory guidance minimizing patient burden was also prioritized by request to make the trial designs and study protocols more adaptable and patient friendly [2]. Also, a shift toward a risk-based approach to quality management was introduced. This means identifying and mitigating risks in clinical trials proactively and upfront at the study protocol design stage, rather than relying on extensive monitoring in the execution phase. Sponsors and investigators are encouraged to proactively assess risks to trial integrity, patient safety, and data quality and apply appropriate resources to mitigate these risks.

The amended ICH E8 guidance highlighted data quality throughout the trial process and underscored the importance of ensuring data are both reliable and accurate, regardless of the methods used for data collection (e.g., digital tools, remote monitoring). The guidelines also outlined monitoring and data management strategies to ensure consistent and reliable data, including flexible monitoring strategies, as opposed to traditional, on-site visits. In addition, the amendments stressed the importance of establishing a robust quality management system for trials to ensure compliance with GCP and good documentation practices. Risk-based monitoring should be incorporated into the trial’s overall quality management system, ensuring resources are focused on areas with the highest risk [1].

There is a stronger focus on ensuring diverse populations in clinical trials, to better reflect the populations that will use the medical products once they are marketed [3,4,5]. This is essential for improving the generalizability of trial results. In order to achieve equity in trial design the following factors at minimum should be considered: age, gender, race, primary spoken language, health insurance status to prevent health disparities in the treatment of different groups. Diversity in clinical trial populations and inclusive practices are key to improving trial outcomes and generalizability [3,4,5]. Overall, these amendments aim to enhance the quality and efficiency of clinical trials, prioritize patient-centric approaches, and support the innovative use of technologies in clinical research.

According to Getz K., et at., a recent trend in clinical trials is an increase in the number of amendments to study protocols and the time required for these amendments to be enforced [6]. Because each investigational site has a different time frame for obtaining amendment approval from centralized or local institutional review boards (IRBs), often multiple protocol versions are being implemented simultaneously across different study sites [6]. Also, many protocol amendments trigger informed consent changes, leading to further discrepancies and delays between sites.

In addition to an increase in the number of protocol amendments, studies have shown a rise in protocol complexity, which may impact protocol adherence, data integrity, and the overall quality of clinical trials [7]. As described previously by Malikova M.A., protocol’s complexity score is determined by various factors, including the eligibility criteria, product administration, number of study groups, and length of the treatment phase. This score can give study staff insight into how difficult a protocol is to adhere to and help to develop risk mitigation strategies to improve study protocol adherence during the execution phase [8].

Protocol deviations occur when study staff or participants fail to meet the requirements outlined in the protocol, and they can be used to measure how closely patients and investigational sites are following study guidelines [9]. While high numbers and rates of protocol deviations mainly pose a risk to data validity, protocol deviations can also affect patient confidentiality and safety [9]. Additionally, patients who drop out or are withdrawn from studies before their projected end date have the potential to impact the quality of clinical trial data [10].

As emphasized previously by Kaliaev A.O and Malikova M. A., and Ting J, et al., due to complex nature of combination products, which consist of different mixture of drugs, devices, and biologics, have more complex regulatory, storage, and application guidelines than their constituent parts alone, they also have the potential to affect protocol deviation rates in the studies in which they are used [11, 12].

The purpose of this project was to investigate how various study risk factors, such as the number of protocol amendments, amendments triggering informed consent changes, and protocol complexity scores, correlate with protocol deviations in clinical trials with combination products. We also evaluated whether the number and experience levels of study staff, clinical trial phase, the primary mode of action (PMOA), and social determinants of health (SDOH), affect the protocol deviations and data quality and integrity.