Protocol development
A detailed plan of the study to be carried out in order to answer a particular research question. It describes in a systematic way the elements that need to be developed, a document that coherently articulates the different elements that comprise it through a solid and convincing argument about the importance of carrying it out. It should include essential elements such as:
- 1) What it is that we want to investigate
- 2) Why we want to investigate it (RELEVANCE)
- 3) How we are going to do it (APPROACH)
Research management
Research management involves the administrative planning and governance steps and processes that are vital for all clinical trials. Clinical trial management involves the finance management, planning, coordination and oversight of the trial which is conducted to evaluate the safety and effectiveness of any intervention under study, be it a medical treatment, drug product or a medical device, behavioural or educational program, health system or policy intervention. Good clinical trial management is essential to deliver a high-quality trial and work closely with the trial team. See the subcategories in this section for detailed stages of the trial management.
Contractor management
Contractors (vendors) play a crucial role providing specialised services and products chosen for their expertise, quality of services and cost-effectiveness. Contractors may include central laboratories, trial supplies, electronic date capture or biostatistics.
Archiving
Archiving includes important considerations such as having a named archivist from the TMG to check the facilities to archive, and to keep a log of the records. The PIs at sites are responsible for archiving the essential documents in accordance to the Sponsor's and local requirements for restricted access and custody. Electronic data must be stored in a generic software platform which can be available later and with appropriate backup.
During the trial
During the trial many tasks are performed in parallel, such as maintaining and updating the TMF with a tracking log of amendments to send to all sites.
Recruitment strategies to reach recruitment targets include how potential participants are screened and identified based on inclusion and exclusion criteria defined in the protocol, methods of consent, staff procedures to follow, responding to site queries promptly, PPI feedback, effective marketing, and any possible barriers such as the number of scheduled follow-up visits. Consider relevant conferences and educational brochures to promote interest, a list of frequently asked questions for sites, close communication to reinforce the importance of the trial. The informed consent process is of utmost importance.
Any updated training evidence of the trial team or site team is documented in the TMF and ISF. Screening and enrolment using logs give an overview of the recruitment activities across sites. Planned versus actual recruitment can be plotted on a graph and updates and reports are provided at the trail management meetings.
Refer to the Communication Plan for site updates, trial team feedback, attending conferences, sending newsletters, provide recruitment awards, videoconferences to share best practices from high recruiting sites or discuss difficulties together. Poor recruitment may be caused by competing trials, staff presenting the trial inconsistently, not in equipoise, or burdensome follow-up visits.
Retention of participants is crucial for good data capture and to avoid possible loss to follow-up. Participants must have a continuous understanding of the trial and its requirements. Refer to the Data Management Plan for the ongoing data collection, accuracy, completeness, data protection, an auditable trail and storage of paper and electronic versions.
Refer to the Monitoring Plan for overseeing the rights and wellbeing of participants and the trial conduct under the current protocol, ICF and PIS, up-to-date SOPs and regulatory requirements. Monitoring sites will confirm compliance with eligibility, CRF completion, missing data, IMP management, ISF review, and site staff training, followed by a report.
Refer to the Quality Management Plan for the role of audits to ensure compliance with the protocol, SOPs, and regulatory requirements (such as GCP). The Quality Assurance Team will work with the study team to support preparatory tasks for the audit.
In trials of medical products, the trial pharmacist at each site is responsible for part of the IMP management in close collaboration with the trial manager and Sponsor.
The Safety Management Plan outlines the Sponsor's responsibility in safety reporting, with participant safety and wellbeing the most important consideration. The protocol outlines the agreed timelines for safety reporting (at the point of intervention or at a follow-up), and notification to the Sponsor and regulatory authorities of any safety events.
End of the trial
End of the trial is defined in the protocol, and is usually the date of the last participant visit or completion of follow-up data collection for analysis and reporting.
A close-out plan will include activities with those responsible. PIs are reminded that the ongoing obligations such as data collection and archiving are required. The trial manager and CI send an end of trial letter to all the site PIs and their teams. The Sponsor, REC, regulatory authority (requesting an end of trial report and declaration). The sites close-out can be done in person or remotely, once the TMF and site files are complete.
Trial reports are led by the CI, and exact requirements are provided by the Sponsor and funder.
Trial participants are informed of the end of trial and results, and PPI can help tailor this.
Trial planning and development
Trial planning and development is essential for good trial conduct and management involving clear objectives in a project plan, effective teamwork, careful planning of scope to determine the work required, realistic timelines with milestones and regular financial review to keep within budget. Risk analysis and mitigation is essential for a high quality and successful trial, as is quality assurance and good communication. These are the essential skills of the project/trial manager, together with monitoring progress and recognising processes that can be improved.
Following the trial research idea and protocol planning, funding applications need to be underway to secure monetary cover. In addition, early community engagement and Patient and Public Involvement (PPI) is good practice and expected of most funders. Many funders have specific guidance on cost breakdown for the main stages of a trial, depending on its size and complexity, and including research versus standard care costs. PI and site selection is vital for a successful trial, based on feasibility studies, previous successful trials at those sites, subject-matter experts, and country-regional specific knowledge on local facilities and resources. Prior to the start of a trial, the site staff must be trained in the trial protocol and documents and demonstration of any software used for that trial. Some Sponsors use a 'green light' document to list all essential tasks necessary before recruitment begins.
Trial design services may be available in some countries to provide support and advice in trial design and methodology. It is recommended that a Clinical Trials Unit (CTU), if available, is approached for local expertise.
Trial oversight is maintained by the Trial Management Group (TMG), the TSC and the DSMB, and should be detailed in the protocol.
Reports will be required by the funder, the Sponsor, REC and the Development Safety Update Report (DSUR) required by country-specific regulatory authorities, who provide guidelines on the milestones, data required to be included and frequency of reporting.
Trial set-up
Trial set-up begins once funding is secured, and there may be some overlapping tasks with the trial planning. The trial sites will have research contracts and agreements in place. The team usually consists of the Principal Investigator, Trial Manager, Statistician, Data Manager, and Pharmacist
Staff need to be trained on SOPs. A training log must be maintained and updated for new version documents, and new trial staff. Trial specific procedures are written into various plans (project plan, risk management plan, safety management plan, data management plan, communication management plan), and charters for the TSC and DSM.
Core trial documents are necessary to manage the trial as templates (protocol, participant/patient information leaflet/sheet (PIS) and informed consent form (ICF)).
Case Report Forms and questionnaires can also come in electronic form to collect accurate and consistent trial data. Other forms may include IMP accountability, dispensing and destruction forms.
Trials will need a reliable platform for managing data. Case Report Forms (CRFs) and questionnaires can also come in electronic form to collect accurate and consistent trial data.
Storage of source data (original documents and certified copies of original findings), is documented in the local Site Investigator File (ISF) with Table of Contents and all the relevant information.
The Trial Master File (TMF) and/or electronic TMF contains all the essential trial documents and site-specific documents, maintained throughout the trial. All amendments are stored in the TMF. Other documents for the ISF may include the Clinical Trial Authorisation (CTA), Investigator's Brochure (IB) or Summary of Product Characteristics (SmPC), pharmacy documentation/file and IMP Management plans and records on procurement/supply/manufacture/shipping, together with the Qualified person (QP) release to trial certificates).
PI and site selection is vital for a successful trial, based on feasibility studies, previous successful trials at those sites, subject-matter experts, and country-regional specific knowledge on local facilities and resources. Prior to the start of a trial, the site staff must be trained in the trial protocol and documents and demonstration of any software used for that trial. Some Sponsors use a 'green light' document to list all essential tasks necessary before recruitment begins.
Budget management continues during the trial set up. Actual spending must be monitored against the forecasted spending in the budget schedule.
Global trials must comply with country and local specific regulations, collaborating with a local CTU at an academic institution or a Contract Research organisation (CRO). Indemnity arrangements must be in place. Check the local ethics and regulatory permissions. Local language consideration must be in place for trial documents.
Check data protection rules per country.
Check IMP release procedures, importation and local taxes, storage and labelling procedures.
Check local laboratory accreditation requirements.
Consider monitoring across regions and how to standardise procedures.
Understanding clinical trials
Navigating around this app will provide useful guidance in the management of clinical trials, providing some hints and references for novice and experienced trial teams. Understanding randomisation and its different types to evaluate the effect of an intervention versus a control, blinding the information regarding the assignment of the intervention, the sample size to ensure the study has adequate power to detect a clinically relevant difference between the treatment arms, different trial designs, statistical power, interpretation of confidence intervals, confounding, and trial end points, all require a basic understanding.
Phases of clinical trials can be found here:- https://www.allclinicaltrials.com/blog/phases-of-clinical-trials
Feasibility studies are vital to evaluate the likelihood of conducting the trial in a particular country/region and patient population, with the overall aim to complete the patient recruitment and follow-ups of the trial to scope, schedule and budget. Note different countries may have different standards of care or age of consent
A pilot study is a small version of the main trial to evaluate feasibility, acceptability, recruitment, randomisation procedures, retention, implementation of the trial intervention and method.
Operations
Operations play a crucial role in the successful execution of a trial with participant safety at the forefront. The core of operations is a chosen trial team who are committed to the trial's success through efficient communication and coordination. A 'study walk-through' approach ensures that every step outlined in the protocol is explicitly considered regarding operations, and trial standard operating procedures (SOPs) must reflect local site processes.
Core operations include site evaluation, selection and feasibility, site set-up and management, clinical monitoring and the lab responsibilities developed in the lab manual which outlines which tests will be collected, how they will be packaged, handled and shipped. There may be some overlap between operations and research management.
In addition, pharmacy staff training is necessary on trial-specific procedures, including the handling of IMPs, documentation requirements, and safety protocols. The pharmacy facilities must meet the necessary standards for storing and handling IMPs.
Risk management
Risk management involves assessing, identifying and monitoring risks. The trial-specific risk management assessment should be part of the funding application. A more detailed risk assessment is undertaken during the protocol development, involving the Sponsor, CI, TMG and the quality team. Risks include to the participant and the trial design and methods, and are categorised by likelihood, impact and occurrence. Risk monitoring is essential throughout the trial, with regular reviews and updates. The risk management plan should be transparent and understood by all stakeholders.
Financial management
Financial management involves the planning and monitoring of trial expenditure and budget maintenance. All expenditures should be monitored regularly against the forecasted budget included in the protocol and actual work completed (key milestones, tasks completion). Costings to be considered include: salaries for trial staff and the Trial Steering Committee members (TSC), Data Safety Monitoring Board members (DSMB) and PPI reimbursement, costings for pre-site visits (PSVs), site initiation visits (SIVs), monitoring visits (MVs), close-out visits, ethics and review board fees. Vendor costs (randomisation, software, electronic data capture (EDC) software, electronic Patient Reported Outcome (ePRO), medical equipment hire for home visits, advertising costs of leaflets, website or social media accounts, publications, archiving, the investigation medical product (IMP) costs for manufacture, labelling, storage, distribution, destruction) must all be taken into account. Costings are trial specific.
Financial management is an essential component following successful grant proposals to funders for conducting a high-quality clinical trial. Financial reporting is required by the funder.
Governance
Governance is a framework of regulations and standards, processes and procedures to achieve high quality, ethical, safe and compliant trials. Regulatory compliance ensures obtaining approvals from the necessary regulatory authorities and ethics committees. Oversight is undertaken by committees which regularly review and monitor the trial conduct, quality and integrity, with participants' safety at the forefront.
Ethics and regulatory compliance
The trial must comply with national and international legislation, guidance and regulations (such as GCP, GDPR, The EU Clinical Trials Directive (2001/20/EC) (27), Medicines for Human Use (Clinical Trials) Amendment (No2) 2006, Medicines and Medical Devices Regulations 2021 (amendment), Human Tissue (2004 Regulations)). Regulatory approvals are sought from the country-specific authorities to approve the interventional new drug (IND), or interventional medicinal product (IMP) and the REC or Institutional Review Board (IRB) (central, local or mixed) reviews and approves the study to ensure it is ethical and protects the rights and safety of participants.
Quality management
Robust quality assurance and quality monitoring must be in place to ensure high-quality trials are conducted in compliance with regulatory and GCP standards and guidelines, as well as recognising where processes can be improved. The quality management plan and SOPs ensure consistency and adherence to trial planning and execution. Monitoring and auditing ensure data integrity and patient safety. Risk-based quality management identifies and mitigates trial risks. Training staff in clinical trials is an important aspect of quality management, which maintains integrity and reliability of the trial data, and ensures compliance with regulatory standards.
Safety management
Safety management and monitoring is crucial to ensure the safety of trial participants. The safety management plan outlines the procedures for identifying adverse events, assessing, managing, analysing and reporting potential trial-specific safety risks, and mitigation management. The trial Sponsor is responsible for safety reporting and to notify the relevant authorities, CI, TSC, DMC of immediate safety concerns. A system for managing safety data must be agreed and in place.
Data Science
Data Science refers to the methods for data collection, data cleaning, data management, data analysis and data sharing in clinical research, in order to generate a high-quality, reliable and statistically sound dataset. A clinical trial will require a statistician, a data management team and eventually a programmer to develop computer software for the emerging use of electronic data capture (EDC), all integral in designing, analysing and interpreting datasets. Mobile data collection tools such as mobile phones or tablets will increase trial accessibility for participants in the community. See the sub-sections on Data Management Plan (DMP) Data Management and Statistics.
Data Management Plan (DMP)
This outlines the processes for maintaining data collection, storage, organisation, maintenance, security, sharing and archiving, that is fit for trial purpose. It identifies the roles and responsibilities for managing accurate and complete data, the format of data, storage, back-up, data-sharing/linkage, access and data protection, budget and archiving.
Data Management
Data management refers to data collection, storage, organisation, maintenance, security, sharing and archiving, all included in the DMP. The Data management plan should be detailed in the protocol to ensure trial-specific data is captured accurately, timely and statistically sound. See https://edctpknowledgehub.tghn.org/Dat-man-por/getting-started/
Statistics
A Statistical analysis plan (SAP) plays a pivotal role in the trial's design, analysis and interpretation, to draw meaningful conclusions about the trial's interventional treatment's efficacy and safety.
Uptake into policy and practice
Uptake and policy in clinical trials involves the integration of findings into clinical practice and policy. Through evidence-based decision making, stakeholder engagement and dissemination, the results of the trial can address the important impact to improved patient health outcomes and health policy.
A dissemination plan will ensure there is a comprehensive process in place for the summary of results, a final study report, participant data, and the best way to translate the results into clinical practice and policy. Policies regarding authorship should be established early on, and are required by the funder and Sponsor. Participants and their caregivers are not clinical experts and will not have access to clinical journals, so alternative dissemination channels must be made available to them, such as newsletters, plain letters, the trial website, patient advocacy groups, social media, etc.
Community engagement
Involving patients and the public has become an essential component of clinical trials. Patients with lived experience of health conditions are often best placed to advise researchers on the acceptability, feasibility, design and implementational aspects of trials. The views of the general public and recipients of public health services can also contribute to the improvement of trials. Seeking input and guidance from community engagement/PPI can enhance the quality of the trial design for target populations by reviewing trial documents such as the Patient Information Sheet, becoming a member of the Trial Steering Committe, and advising on dissemination of the results. Funders are particularly interested in the value of /community engagement/PPI to the clinical trial, and encourage inclusion, and this requires planning, resources and organisation.