If you are a medical device manufacturer/sponsor starting a clinical trial, you have the obligation to adequately monitor the study (MDR Article 72, par. 2); ISO 14155:2020) [1,2]. Monitoring is the act of overseeing the progress of a clinical trial and to ensure that it is conducted, recorded, and reported in accordance with the CIP, written procedures, GCP-ISO14155, and other applicable regulatory requirements. Sponsor as the main responsible for initiating, managing and financing the clinical trial is expected to define how much monitoring is required in particular for this clinical trial. Simply saying, the extent and nature of monitoring required must be based on the study objectives and methodology and how much the intervention deviates from normal clinical practice (MDR Article 72, par. 2). In practice, the monitoring rationale follows a risk-based approach.
High-risk areas related to the safety and quality of clinical trials can be listed as following:
- Ethical considerations
Ethics Committee (EC) approvals and Informed Consent of each subject are essential. Each subject shall be given sufficient time to review the consent and obtaining answers to all their questions. Signatures must be collected for each participant before any study procedures are performed.
- Primary efficacy endpoint assessment
Primary efficacy endpoint collection includes more than simply checking to see that endpoint data are collected. It is important to verify if the primary efficacy endpoint process was aligned with the Clinical Investigation Plan (CIP)
- Safety management
This includes identifying and reporting safety events and subjects- associated risks from ongoing clinical trial. Monitoring of serious or fatal adverse events, adverse events that lead to discontinuation, and other signals that could affect subject safety shall be taken into assessment.
- Investigational product (IP) management and accountability
If the IP is not used as designed, the outcome of the clinical trial is not going to be meaningful. IP management also includes assuring IP is shipped, received, stored, and destroyed as defined in the CIP.
- Study documentation
All the relevant documentation must be complete and correct. This includes regulatory documents, subject source documents, training documents, site management documents. Documents defining the selection process for the vendors, defining the set-up of each technology system, training, and access control are also required.
- Protocol deviations
Protocol deviations are critical to identify how many deviations from the study plan have occurred as well as why and how future deviations can be prevented. Protocol deviations are, by definition, events in which CIP was not followed, and they point out clinical trial quality and integrity issues. Assessment of major deviations should be done systematically from the start of the clinical trial .
Risk based monitoring aims to ensure the quality of clinical trials by identifying, assessing and mitigating the risks related to the safety and quality.
How to design the monitoring activities of the study
Monitoring activities are oversight activities used to validate collected clinical data and its alignment with the CIP by applying relevant guidelines, regulations, Good Clinical Practice (GCP)and ethical aspects.
Monitoring costs have shown to be one of the highest costs in the clinical investigations [4,5]. Therefore, it is important to plan the monitoring methods effectively taking into account the expected possible errors.
The Corona pandemic has partially changed the clinical monitoring approach. Before the pandemic the most common type of monitoring was on-site monitoring. Nowadays 97% of clinical trial sponsors use technology to review a study’s source data and documents remotely, making use of a portal and electronic Investigator Site Files. In 2023, 78% of sponsors plan to use a site-friendly eISF for remote monitoring. Remote monitoring can be considered as one option to reduce the costs of the clinical investigations.
As a general practice, risk-based monitoring strategy shall be designed with the risk-based focus in accordance with the needs of the investigation.
The monitoring plan is part of the clinical trial documentation that defines how and when monitoring activities will be performed as well as expected degree of Source Data Verification (SDV). SDV is defined as the process that confirms that data collected from source records is the same with the data entered on the CRFs. The monitoring plan is either integrated into the Clinical Investigation Plan (CIP) or documented as a separate monitoring plan (with rationale, summary, and reference to the plan in the CIP) before the initiation of the clinical investigation. Essentially, independent Data Monitoring Committees play a critical role in monitoring for safety signals.
The monitoring is done by a monitor / Clinical Research Associate (CRA). CRA’s often have an educational background in life sciences – nowadays often a graduate degree – they are familiar with medical terminology and speak the local language. Before performing the monitoring activities, the monitor (CRA) must be sufficiently trained on the protocol, the device& its use, the sponsor’s relevant standard operating procedures and Good Clinical Practices (preferably ISO 14155 GCP). The monitor should follow the monitoring plan that has been prepared by the sponsor for the clinical investigation.
The investigator at the research site has the obligation to provide the monitor access to the clinical trial related records and to facilitate monitoring visits.
Types of Monitoring Visits of Clinical Investigations
These are the types of monitoring visits that are routinely performed for clinical investigations:
- Site selection visit
This is a pre-study visit performed by the sponsor or monitor and/or a senior member of the project team. In its simplest form, this visit is to have initial discussions with the investigator on possible clinical trial participation (often remotely). In its most advanced form this is an on-site visit of several hours during which the capabilities of the site are assessed in detail with the goal of formally qualifying the site for clinical trial participation. In the latter case, a detailed visit report will address -among many other items- site recruitment procedures, qualifications and availability of site personnel, storage facilities for investigational devices, publication expectations of the investigator, etc.
- Site initiation visit (SIV)
An initiation visit for each participating investigation site shall be conducted and documented by the sponsor at the beginning of the clinical investigation . During this visit the site receives final training by the monitor on the CIP, Investigators Brochure (IB), Informed Consent Form (ICF) and procedures, Case Report Forms (CRF), Instructions For Use (IFU), and any other procedures and agreements. Often a recap of GCP principles or a GCP refresher training is done and documented. The monitor does a final check on the availability and completeness of all study documentation, investigational devices, and the paper Investigator Site File (ISF) on site or checks access to the portal and electronic Investigator Site File. After the initiation visit, the site should be ready to start enrolment.
- Interim monitoring visits (IMV)
These are remote or on-site visits during which the monitor primarily performs Source Data Verification (SDV). The goal of SDV is to verify that data entered by the site on the CRFs corresponds to the medical records of the patients in the hospital. Note that the monitor can only access patient files when these patients have provided consent. Therefore, the monitor should first verify that the consent process has been followed and that a signed consent form is available for each study subject. The monitor will further verify whether the regulatory approvals are in place and the investigator site file is up to date. The monitor will review important study logs such as the delegation of authority log; training logs; device accountability log and visit logs with the goal of verifying that the study is conducted in compliance with the protocol and by adequately trained and qualified personnel. The monitor closely collaborates with the site study coordinator (or research nurse) and will usually have a brief meeting with the principal investigator to discuss the results of the visit and any findings. Results of the monitoring activities are documented in detail in visit reports for the sponsor. A follow-up letter summarizing the visit outcomes will be shared with the site.
- Site close-out visit (COV)
After the last visit of the last study subject and when follow-up is completed, the monitor should conduct a close-out visit. During this visit the monitor ensures that all site records are complete, all documents that are needed for the sponsor’s file are retrieved, remaining clinical trial materials are disposed of or returned to sponsor, and any previously identified issues are resolved and all parties notified.
Monitoring is required to comply with GCP-ISO14155, EU MDR and applicable guidelines/regulations during conduct of clinical investigation. Quality of collected data; integrity and safety of the clinical trial is dependent on the design and method of the monitoring. Considering the direct correlation with quality and cost, effective monitoring strategy is required.
How can Qserve help you
Qserve has experienced clinical research associates (CRAs) within their team and abroad worldwide network of monitors. Our CRA team (internal or outsourced) is strategically located geographically to cover a broad range of site locations.
When you delegate your monitoring activities to Qserve, we will create a tailored monitoring plan and allocates dedicated monitors/CRAs to your study and site(s). This will establish a good site relationship and the CRA serve as the site’s primary point of contact. The monitor’s in-depth knowledge of the protocol, ICF, CRFs, and operational and procedural plans results in efficient and compliant monitoring. Qserve supports site selection and initiation, interim monitoring, close-out visits, (re-)training of sites, file reviews, query resolution and support of follow-up actions. Our monitors are comfortable with remote monitoring and risk-based monitoring, as well as 100% on-site source data verification (SDV).
- ISO 14155: 2020- Clinical investigation of medical devices for human subjects — Good clinical practice
- EU MDR 2017/745 Regulation
- Monasco P, Bhatt D. I, Evaluating the evaluators – Developing evidence of quality oversight effectiveness for clinical trial monitoring: Source data verification, source data review, statistical monitoring, key risk indicators, and direct measure of high risk errors, Contemporary Clinical Trials Volume 117, June 2022
- Moore J, Heyward J, Anderson G, et al., Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015–2017: a cross-sectional study, BMJ Open 10 (2020)
- Sertkaya A, et al., Examination of Clinical Trial Costs and Barriers for Drug Development, US Department of Health and Human Services, 2022