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Ivelina Georgieva
2020 September, 2

Upgrading Management for DMC/DSMB and Core Labs in Clinical Trials

Recent Changes & ClinSearch’s Experience

DMC/DSMB Overview
Data Monitoring Committees (DMCs), also known as Data Safety Monitoring Boards (DSMBs) or, in Europe, Clinical Event Committees (CECs)
1 This article uses DMC and DSMB interchangeably and does not use CEC, due to its use in Europe only.
, have been part and parcel of clinical trials since the 1960s
2 In 1967, an NIH external advisory group first introduced the concept of a formal committee charged with reviewing the accumulating data as the trial progressed to monitor safety, effectiveness, and trial conduct issues in a set of recommendations to the then-National Heart Institute in the USA.
. Since their introduction, their chief function has been to ensure the validity and objectivity of collected data, compliance with ethical standards of research, and respect of novel discoveries and safety concerns throughout the duration of the trial.

Initially, DMCs were primarily used in large, randomized, multi-center trials and trials targeting improved survival or reduced risk of major morbidity, and were managed by governmental bodies or national public health organizations
3 Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees, p. 2.
. However, they have recently become much more commonplace, due to industry trends such as an increased focus on solutions for 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.
4 Ibid, p. 2.

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”
5 Ibid, p. 3.
. In addition, whereas DMCs are recommended for any trial with a pharmaceutical compound or medical device that compares mortality or morbidity, they are commonly considered redundant at early stages of product development, or in trials addressing less serious outcomes such as symptoms relief
6 Ibid, p. 4.

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
7 Ibid.
. 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
8 Operational Guidelines for the Establishment and Functioning of Data and Safety Monitoring Boards/TDR/GEN/Guidelines/05.1, p.6.

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 of 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 and 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)
9 Ibid, p. 8.
”. The data and endpoints to be evaluated at DSMB meetings, the scientific criteria for evaluation, as well as their interval and reporting schedule, 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
10 Ibid.

Imaging/Core Lab Overview
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 sources of potentially ambiguous data 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 the Sponsor develops trial-specific imaging processing 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
11 Ibid, p. 3-8.

Trials with “light” imaging needs, with low possibility for variability in acquisition and interpretation or low impact of imaging data over their endpoints, can integrate the 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
12 Ibid, p. 9.
”. 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.
13 Ibid, p. 13-26.

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.

Recent changes
& ClinSearch’s experience
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 and Core LAb charters and manuals, organizing and chairing the meetings, and reconciliation of adverse events. As a result of this experience, we have developed SOPs for all parts of the process: from charter writing, through anonymizing patient document packages for expert meetings, to 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.

Electronic module development

Giuseppe Carissimo, Data Manager

What are the specificities of setting up image collection during clinical trials from a technological perspective?

The most important thing is to know in advance what type of files the operating sites will provide, as well as a rough estimate of how many files per patient they will upload. We use this information to set up sufficient storage on our EDC, EdClin, and provide a precise budget estimate to the client. We also need to know in advance if the files will be used as they are, or they will need to undergo any type of treatment (pseudonymization, anonymization, editing, conversion, compression, etc.), again for reasons of resource allocation and budgeting.

What type of images can be uploaded? In what format are they processed?

Our platform currently allows the upload of .DICOM 14 Standing for the Digital Imaging and Communications in Medicine standard commonly used by clinicians globally. , .PDF, .PNG, .JPEG, and .DOCX files, with the possibility to ultimately convert them all into .PDF format. Working with EdClin, there is no limitation in terms of file size: we tend to allocate a limited space on a server for the upload but have the possibility to upgrade the storage size at any moment. In fact, the main limiting factor during upload is usually the internet speed on the side of the operator uploading the file(s).

Is video upload possible?

Although the function has never been fully exploited, it is technically possible to upload video files, provided that no image treatment is required after the upload, since pseudonymization, anonymization, etc. for video are much more complex for evident technical reasons.

What differentiates the technological environment at ClinSearch in relation to Core Lab management?

The upload is performed directly on the EDC, which provides two main advantages. First, the whole process of upload, pseudonymization, and storage is fully centralized and makes the images virtually accessible from any computer connected to the Internet. Second, it is possible—if required, to link all the uploads to a variable/item/field/event of the CRF (for example, the final user will always know which of two scans was provided from baseline and which from a follow-up evaluation, thanks to the referencing of the images operated via the database). Lastly, it is crucial to point out that the technology we use depends on the outcomes of the risk analysis made by the ClinSearch DPO with the assistance of the operational and IS teams. I believe that makes the difference. It often happens that, after launching their studies, Clients ask us to amend the remote data system of their Core Lab to comply with data privacy regulations.

Regulatory compliance

Petra Ulm, Global Regulatory Affairs Director & DPO

What are the specificities of setting up image collection during clinical trials from a regulatory perspective? Do you mean regarding clinical trial application to Authorities or in general?

There are no specific requirements pertaining to images in the GDPR. In other words, they are treated as any other personal data. Therefore, the highest security measures have to be applied and, as other patient data, images have to be pseudonymized by the hospitals before their upload to the eCRF. Our eCRF has the function to do the pseudonymization, which is a major advantage because not all EDCs do. We can also allocate resources to perform anonymization on site if required, which is an increasingly requested service by our clients.

What are the current regulations about DSMB/Core Lab member selection?

As a minimal requirement, the Member has to be an expert in the field and independent of the study team. That is to say, the Member cannot be an investigator or a co- investigator, to ensure no conflict of interest can arise. Aside from that, the Members’ number and required specialization is defined according to the complexity of the study design and analysis and the level of risk to human health posed by the product being studied 15 Data and Safety Monitoring Board (DSMB) Guidelines, NIDCR.
Click to consult.


Cecile Train, Sr Director Pharmaceutical & Medical Device Development

What is a common scenario of DSMB/Core Lab use by ClinSearch clients?

So far, our team has supported use of Core Lab primarily in neurovascular trials. Specifically, we have done a lot of work with ECG imaging with Zoll, one of our long-term clients. The total number of studies we have supported is around a dozen, with a similar number of ongoing requests from clients. Over the years, we have definitely observed an increase in DSMB/Core Lab use in both pharmaceutical and medical device trials.

What experience does the ClinSearch team have in DSMB/Core Lab set up and management? What dedicated processes & resources?

We have been involved in the initial stages of studies: in preparing recommendations for DSMB/Core Lab use and supporting sponsors in choosing committee members. In addition, our CRAs and Deputy Project Leaders have worked on anonymizing all patient materials, translating and proofreading source documents, and preparing the narrative of patients’ history of participating in the study, their images and SAEs. We have integrated SOPs governing the processes internally, continuously updated according to changing standards & practices.

To learn more about our capabilities in DMC/DSMB and Core Lab management or devise a specific strategy for your study, contact us today.