Clinical trial monitoring: What you need to know
Clinical trial monitoring is a crucial process that ensures every aspect of a trial is conducted with the utmost integrity. The process ensures that protocols are adhered to, data is accurately recorded, and prioritises participant safety.
This not only ensures compliance with regulatory standards but also enhances the reliability of the trial’s outcomes. Read on to learn more about who is responsible for trial monitoring, how to create a monitoring plan, and what is involved in clinical trial monitoring.
What is the purpose of clinical trial monitoring?
The primary purpose of clinical trial monitoring is to ensure that trials comply with the clinical trial protocol, standard operating procedures (SOPs), and regulatory requirements, such as Good Clinical Practice (GCP) guidelines and ethical standards.
Monitoring activities aim to identify and address potential issues proactively to enhance data integrity, participant safety, and trial quality. Monitoring helps establish robust quality management systems and quality control measures and prepares for audits and inspections.
Who is responsible for clinical trial monitoring?
In Australia, clinical trial monitoring is a collaborative effort involving sponsors, contract research organisations (CROs), clinical research associates or monitors (CRAs), Principal Investigators (PIs), Human Research Ethics Committees (HRECs), and the Therapeutic Goods Administration (TGA).
Each party plays a crucial role in ensuring that trials are conducted ethically, safely, and in compliance with regulatory standards to safeguard participant well-being and trial data integrity.
Sponsor
- Primary responsibility: The sponsor is ultimately responsible for initiating, managing, and financing the clinical trial. They ensure the trial is conducted according to the approved protocol, GCP guidelines, and regulatory requirements.
- Monitoring plan: The sponsor develops and oversees the execution of the monitoring plan, which includes on-site, remote, and centralised monitoring activities.
- Selection of monitors: Sponsors are responsible for hiring and training CRAs or monitors who conduct monitoring activities.
- Ensuring compliance: Sponsors ensure compliance with national regulations and international guidelines.
Clinical Research Associates (CRAs) or Monitors
- Day-to-day monitoring: CRAs are employed by the sponsor or a Contract Research Organisation (CRO) acting on behalf of the sponsor. CRAs conduct the actual monitoring visits. They are responsible for verifying data, ensuring protocol adherence, and checking the proper documentation of informed consent.
- Site visits: CRAs perform site initiation, interim, and close-out visits to ensure ongoing compliance and data integrity.
Contract Research Organisations (CROs)
- Delegated monitoring: Sponsors often delegate monitoring tasks to CROs. CROs assume the responsibilities of conducting monitoring activities, including developing monitoring plans, performing site visits, and ensuring regulatory compliance.
- Reporting: CROs provide detailed reports to the sponsor on the status and findings from monitoring activities.
Principal Investigator (PI) and site staff
- Conducting the trial: The PI is responsible for the day-to-day management of the trial at the site and for ensuring that the trial is conducted according to the protocol, GCP guidelines, and regulatory requirements.
- Compliance: The PI ensures that the site complies with monitoring activities and addresses any issues identified during monitoring visits.
Human Research Ethics Committees (HRECs)
- Ethical oversight: In Australia, HRECs are responsible for the ethical review and oversight of clinical trials. They ensure that the rights, safety, and well-being of participants are protected.
- Review and approval: HRECs review and approve the trial protocol and any amendments. They also may be involved in reviewing monitoring reports, particularly those related to participant safety and ethical conduct.
Regulatory Framework
The Therapeutic Goods Administration (TGA) is the regulatory authority overseeing clinical trials in Australia. The TGA ensures that trials comply with national standards and guidelines, including the National Statement on Ethical Conduct in Human Research and GCP guidelines.
The TGA may conduct compliance audits and inspections to ensure that trials meet regulatory requirements.
Clinical trial monitoring oversight
Data Safety and Monitoring Board (DSMB)
The DSMB periodically reviews and evaluates the accumulated study data. It makes recommendations to the Trial Steering Committee (TSC) with regard to the continuation, modification or termination of the trial.
Trial Steering Committee (TSC)
The TSC provides trial oversight, including overall responsibility for the scientific integrity of the protocol and assessment of study quality and conduct. The TSC receives documentation from monitoring visits and data analyses to monitor the trial towards its interim and overall objectives. It considers the recommendations of the DSMB and resolves problems brought by the trial coordinating team.
What is a trial monitoring plan?
A comprehensive and detailed monitoring plan should be developed before the trial begins, outlining the scope, frequency, methods, and responsibilities for monitoring activities.
The monitoring plan should be developed collaboratively with the sponsor and PI, and tailored to human participant protection and data integrity risks. The monitoring plan often follows a risk-based approach, focusing on high-risk sites (for multi-centre trials) and critical data points to optimise resources and enhance efficiency.
The extent and nature of monitoring should be determined by:
- a risk assessment of the trial’s intervention(s) relative to standard care or practice
- for investigational medicines or devices, the extent of knowledge about the product
- complexity of the trial design and methodology
- trial team experience.
A trial monitoring plan should:
- describe the monitoring strategy and the responsibilities of all parties
- document the rationale for the chosen monitoring strategy and methods and the rationale for their use
- outline a systematic, prioritised, risk-based approach with an emphasis on the monitoring of critical data and processes
- identify any aspects that are not routine clinical practice and that require additional training
- identify the visit schedule and describe the types of visits to be conducted (i.e. interim monitoring visits, for-cause visits, and close-out visits)
- in cases where the scope of monitoring permits, use varied approaches that improve the effectiveness and efficiency of monitoring (i.e. on-site monitoring only, a combination of on-site and centralised monitoring, or, where justified, centralised monitoring only)
- reference the applicable organisational policies and procedures or project-specific Standard Operating Procedures (SOPs).
The monitoring plan should be documented, continually reviewed and updated accordingly.
What’s involved in clinical trial monitoring?
Clinical trial monitoring involves a series of activities designed to ensure that clinical trials are conducted according to the approved protocol, GCP guidelines, and applicable regulatory requirements.
The key components of clinical trial monitoring are:
Pre-trial activities
- Site selection and qualification: Evaluating and selecting sites capable of conducting the trial according to the protocol and regulatory requirements.
- Training and initiation: Conducting site initiation visits (SIVs) to train site staff on the protocol, GCP guidelines, and trial-specific procedures.
Ongoing monitoring activities
Interim Monitoring Visits (IMVs) involve regular visits to trial sites to verify data accuracy, protocol adherence, and regulatory compliance. Activities during these visits include:
- Source data verification (SDV): Ensuring that data recorded in case report forms (CRFs) match source documents.
- Regulatory compliance: Checking that informed consent procedures are followed and that all required documentation is maintained.
- Safety monitoring: Verifying that adverse events (AEs) and serious adverse events (SAEs) are reported and managed appropriately.
- Data monitoring: Analysis of the accumulating clinical trial data for participant safety, study conduct and progress, and, where appropriate, efficacy. They are generally performed in trials that have a Data Safety Monitoring Board (DSMB), have a long recruitment period and have potential serious outcomes. The study protocol should include descriptions of interim analyses and when they will be conducted.
Close-out activities
- Close-out visits (COVs): Conducted at the end of the trial to ensure all data is complete, final regulatory documentation is in order, and trial materials are accounted for.
- Archiving: Ensuring that all trial documentation is properly archived according to regulatory requirements for future reference and audits.
Documentation and reporting
- Monitoring reports: Documenting each monitoring visit in detailed reports, including findings, deviations, and required corrective actions.
- Action plans: Developing and implementing action plans to address any issues identified during monitoring.
Types of monitoring
- In-person: In-person monitoring is a traditional method of monitoring sites involved in a clinical trial. It involves the CRA being provided with hard copy and/or electronic records for review.
- Remote monitoring: Remote monitoring is the process of virtually monitoring and reviewing clinical trial data and documentation electronically. A significant benefit of this type of monitoring is the ability to monitor data in real-time, allowing for early detection of issues. Remote monitoring can occur as a stand-alone task or as a supplement to on-site visits.
- Centralised monitoring: Centralised monitoring involves the collation of data from all trial sites in a central location, where it is evaluated remotely using statistical and analytical methods to monitor data trends and identify anomalies or potential issues.
FAQs about clinical trial monitoring
Clinical trial monitoring involves overseeing the conduct of a clinical trial to ensure it complies with the approved protocol, GCP guidelines, and regulatory requirements. The primary goals are to protect participant safety, ensure data integrity, and maintain compliance with ethical and legal standards.
Several parties share responsibility for monitoring clinical trials in Australia, including:
- Sponsors: They are ultimately responsible for ensuring proper trial conduct.
- Clinical Research Associates (CRAs) or Monitors: Employed by the sponsor or a Contract Research Organisation (CRO) to conduct on-site and remote monitoring.
- Contract Research Organisations (CROs): Often delegated by sponsors to perform monitoring activities.
- Principal Investigators (PIs) and site staff: Responsible for the day-to-day management of the trial at their site and ensuring compliance.
- Human Research Ethics Committees (HRECs): Provide ethical oversight and review of the trial.
Clinical trial monitoring in Australia is governed by several guidelines and regulations, including:
- Therapeutic Goods Administration regulations: National regulatory authority overseeing clinical trials.
- ICH GCP guidelines: International standards for designing, conducting, recording, and reporting clinical trials.
- National Statement on Ethical Conduct in Human Research: Provides guidance on ethical considerations for human research in Australia.
- Site selection and qualification: Evaluating potential sites for their capability to conduct the trial.
- Site initiation visits (SIVs): Training site staff on the protocol and GCP guidelines.
- Interim monitoring visits (IMVs): Regular visits to verify data accuracy, protocol adherence, and regulatory compliance.
- Source data verification (SDV): Ensuring that data in case report forms (CRFs) matches source documents.
- Close-out visits (COVs): Ensuring all data is complete and regulatory documentation is in order at the trial's end.
- In-person, remote and centralised monitoring: Supplementing on-site visits with electronic data review and centralised data monitoring.
The frequency of monitoring visits varies depending on the complexity of the trial, the risk assessment, and the monitoring plan. Typically, visits may be scheduled monthly, quarterly, or at specific milestones in the trial.
Risk-based monitoring focuses resources on high-risk areas and critical data points in a clinical trial. This approach enhances efficiency by concentrating monitoring efforts where they are most needed, based on a risk assessment of the trial.
During a monitoring visit, a CRA will:
- review informed consent forms and verify they are properly completed
- compare data recorded in CRFs with source documents (source data verification
- check that the trial is conducted according to the protocol
- ensure that adverse events (AEs) and serious adverse events (SAEs) are reported correctly
- review regulatory documents and ensure they are up-to-date
- provide feedback and training to site staff as needed.
Findings from monitoring visits are documented in detailed monitoring reports, which include observations, deviations, and any corrective actions required. These reports are submitted to the sponsor and may also be reviewed by HRECs and regulatory authorities.
Common issues include:
- incomplete or inaccurate data in CRFs
- deviations from the approved protocol
- inadequate documentation of informed consent
- delays in reporting adverse events
- missing or outdated regulatory documents.
Issues identified during monitoring visits are addressed through corrective and preventive action plans (CAPAs). The CRA works with the site staff to implement these plans and ensure that similar issues do not recur.
HRECs provide ethical oversight of clinical trials. They review the trial protocol and any amendments and monitor ongoing compliance with ethical standards. They may also review monitoring reports related to participant safety and ethical conduct.
Yes, remote monitoring is increasingly common, especially with the use of electronic data capture (EDC) systems. Remote monitoring involves reviewing data and documentation electronically, which can supplement on-site visits and enhance efficiency.
Centralised monitoring involves using statistical and analytical methods to monitor data trends and identify anomalies from a central location. This approach allows for the detection of issues.
