Depending on the DSMB charter scope, DSMBs may review all or some of the clinical trial data obtained in the specified time interval, with a focus on patient safety or resolving ambiguous data. Chief among the potentially ambiguous data in clinical trials is imaging data, due to the variability in processes and practices of acquiring, displaying, and interpreting images in medical establishments. According to the FDA’s non-binding Clinical Trial Imaging Endpoint Process Standards Guidance for Industry from 2018,

This variability may have little or no impact on the ability to provide a diagnosis in medical practice, yet in a clinical trial, imaging process variability may result in increased variability in endpoint measurements and may compromise the ability of the trial to achieve its objectives. Therefore, depending on the impact of imaging data on trial outcomes, in certain cases it is recommended that Sponsors develop trial-specific imaging process standards on elements including, but not limited to, choice of imaging modality, choice of centralized versus local image evaluation, choice of blinding image interpretation to clinical data, and frequency and process of the evaluations.

Trials with “light” imaging needs, with low possibility for variability in acquisition and interpretation or low impact of imaging data over the endpoints can integrate imaging protocol into the main study protocol. In some cases, however, a separate imaging charter might be required, clearly outlining “the imaging methodology with references to multiple other imaging-specific documents that form a component of the charter, such as imaging acquisition protocols, data transfer plans, or image submission guidelines.” Imaging charters are, therefore, fairly technical in nature, and deal with all the aspects of the imaging process that might cause ambiguity of the obtained data, such as used equipment and processes, protocol and methods of image interpretation, qualifications of the interpreters, timing, recording and archiving of the images, etc.

In cases when, despite following the Imaging charter or relevant guidelines in the protocol, ambiguity arises, independent adjudication committees, blinded to clinical data, are set up, in order to obtain the most objective reading of images possible. Similarly to DSMBs, Core Lab committee members are selected on the basis of their expertise in the relevant therapeutic area and their reputation in the scientific community. Core Lab committee meetings can take place face-to-face or online, via an electronic platform, and, again, all patient data need to be pseudonymized/anonymized prior to the meetings in order to comply with Good Clinical Practice.

The dynamic recent changes of technological and regulatory requirements for clinical trials conduct do not exclude the areas of DMC/DSMB & Core Lab management, which have evolved into electronically managed, GDPR-compliant processes. Based on ClinSearch’s experience with multiple trials involving DMCs and Core Labs, we have developed both the electronic tools and regulatory expertise for their effective management. Our team has practical know-how on recruiting experts for the committees, writing the DSMB charters and manuals, organizing and chairing the meetings, including the preparation of patient files and safety narratives, and reconciliation of adverse events.

As a result of this experience, we have developed and integrated SOPs for all parts of the process: from charter writing to anonymizing patient document packages for the expert meetings, through reporting and archiving. Below, our experts discuss several key questions in their respective areas: the development of DSMB and Core Lab electronic modules, regulatory compliance issues, and organization challenges.

Data Monitoring Committees (DMCs), also known as Data Safety Monitoring Boards (DSMBs) or, in Europe, Clinical Event Committees (CECs) have been part and parcel of clinical trials since the 1960s. Continuously, their chief function has been to ensure the validity and objectivity of collected data, continued compliance with ethical standards, and respect of novel discoveries or safety concerns throughout the duration of the trial. Initially, DMCs were primarily used in large, randomized, multi-center trials or trials targeting improved survival or reduced risk of major morbidity, and managed by governmental bodies or national public health organizations.

However, they have recently become much more commonplace due to industry trends such as an increased focus on solutions at improving survival or morbidity, public concerns for patient safety, improved collaboration with governments, and “a heightened awareness within the scientific community of problems in clinical trial conduct and analysis that might lead to inaccurate and/or biased results.”

Due to the significant financial and logistical burden to Sponsors and their Agents for the organization and management of DMCs, the latter are currently required by the FDA only for trials “under 21 CFR 50.24(a)(7)(iv) for research studies in emergency settings in which the informed consent requirement is excepted.”

In addition, whereas DMCs are recommended for any trial with a pharmaceutical compound or medical device that compares mortality or morbidity, they are commonly not needed at early stages of product development, or trials addressing less serious outcomes such as symptoms relief.

The structure, composition, and format of the required or recommended DMC varies widely, depending on the level of risk posed to patients, the type of patients (e.g. vulnerable groups like children, the elderly, or patients at an elevated risk of death), the invasiveness or potential toxicity of the treatment, and the duration of the trial. According to the Operational Guidelines for the Establishment and Functioning of Data and Safety Monitoring Boards/TDR/GEN/Guidelines/05.1 by UNICEF, UNDP, the World Bank, and WHO, a DSMB “should provide independent, competent, and timely review of the data from an ongoing study…free from political, social, institutional, professional, and market influences.”

It is, therefore, imperative that the Sponsor ensures that the DSMB is composed by experts and independent observers who are respected by the study team and scientific community alike. In order to ensure its smooth functioning, the Sponsor should provide adequate financing and management for the DSMB, most commonly by the establishment of a DSMB charter at the beginning of the study, specifying the precise safety monitoring needs of the study (per protocol, scientific and ethical standards) and the duty and responsibility of each involved party.

In addition, the charter should specify “the authority under which the DSMB is constituted together with its responsibility, operational procedures, means of communications, and decision-making procedures - when and as applicable - vis-à-vis the sponsor, the investigator(s), study statistician, data manager, ethics committee(s), and regulatory authority(ies).” The data and endpoints to be evaluated at DSMB meetings, the scientific criteria for evaluation, as well as their interval and reporting paradigms, are other essential elements. Finally, the charter needs to cover the documentation of meetings and the resulting evaluations and their archiving and specify the conditions under which a trial might be stopped.