UCL Protocol Development
Involvement of UCL MRC CTU
Presenter: Shiva Taheri, PhD Student, UCL MRC CTU
Contact: s.taheri@ucl.ac.uk
Understand the Importance of Clinical Trial Protocols
Need for a clinical trial protocol
Different uses of a protocol
Formulate a Construction Plan
Plan for creating a clinical trial protocol
Identify Stakeholders
Involvement of various personnel in protocol development
Content Importance
Key elements to include in protocols and reasons why
Quality of Protocol Comparison
Differences between "good" and "bad" protocols
Consequences of Protocol Quality
Benefits of a well-written protocol
Risks associated with poorly written protocols
What is a Trial Protocol?
An essential document; often referred to as the "Holy Book" of the trial
Can greatly influence trial success or failure
Elements of Essential Documents
Aid in evaluating trial conduct, participant safety, and data quality
Provides full description of trial, outline rules including eligibility, safety reporting, rationale, and roles
Helps with clinical decision-making
ICH GCP Guidelines
First produced June 1996
International standard ensuring ethical and scientific quality
Must be scientifically sound and backed by evidence
Collaboration is Key
Chief Investigator's role
Importance of clinical input
Consideration for Roles and Infrastructure
Roles involved in trial execution
Locations and infrastructure availability
Active Groups to Include
Functional (Data Science, Clin Ops, etc.)
Oversight groups (IDMC, TSC, TMG)
Patient and Public Involvement (PPI)
Review Committees
Protocol Review Committees (PRC) and Peer Review
Required Components
Introduction: Justification of the trial (facts, stats, clinical benefits)
Trial Design: E.g., double-blind, randomized
Aims and Objectives: Primary and secondary outcomes
Eligibility Criteria: Justification of criteria
Specifics on Intervention: Risk/benefit, side effects (IB and SmPC)
Comparator Justification: Placebo or sham, associated risks
Safety Section
Definitions, timelines, and pharmacovigilance requirements
Health Economics
Data Management
Collection, storage, sharing, analysis methods
Questionnaires and outcome coverage, licenses
Participant Timeline
Assessments, checks, and follow-ups
Statistics
Sample size, power, attrition factors, randomization
Teams List
Identify sponsors, oversight, PPI involvement
Protocols Not Used in Isolation
Importance of SOPs and working practice instructions
Investigators Brochure (IB), Statistical Analysis Plans, and Patient Information Sheets
Uniformity Requirement
Necessity for consistency across all trial documents
Template Usage
No mandatory template, organizations develop their own
Examples: CCTU template, Health Research Authority (HRA) template, SEPTRE template
Grant Application Reference
Use grant information for consistency and reduced workload
Key Features
Clear, well-structured, and operationally feasible
Compliance with ethical/regulatory guidelines
Tailored to specific trial needs, incorporating expert opinions
Avoid vagueness and ensure easy navigation
Importance of Detail
Define eligibility, aims, and justifications with precision
Benefits to Trial Operations
Facilitates appraisal of scientific, ethical, legal considerations
Supports high-quality data collection and management
Reduces workload due to clarity and conciseness
Enhances implementation and minimizes amendments/deviations
Consequences of Poor Design
Need for protocol rewrites post-ethics/regulatory review
Increased risk to patient safety and trial integrity
Higher withdrawal rates, impacting study power
Additional Workload
Complications in the trial due to misinterpretation of information
Users of the Protocol
Regulatory bodies (REC/HRA/MHRA), funders, intervention suppliers
Trial oversight groups, public interest entities, and medical journals
Trial teams at sponsors' offices and site teams conducting research
Role in Clinical Decision Making
Guidance on eligibility, tests, randomization, treatment delivery
Aids in understanding treatment modifications and follow-up scheduling
Necessary Approvals
Protocol requires ethical approval from a REC
HRA approval combines governance and ethical compliance processes
Unified application process in the UK for trials in England and Wales
Regulatory Oversight
MHRA controls trials on investigational medicinal products (CTIMPs)
Overview of the application process via the Integrated Research Application System (IRAS)
Local site R&D approvals required prior to starting trials
Types of Amendments
Substantial: Significant changes impacting scientific value or safety
Non-substantial: Minor changes that do not affect core trial integrity
Importance of documenting and justifying changes
Considerations for Protocol Changes
Rationale for changes must be explicitly described
Rarely should changes alter the direction of the original trial
Must undergo oversight group review and resubmission
Definition and Impact
Any change or departure from approved study design/procedures
Important deviations can adversely affect participant safety or trial results
Importance of Reporting
Essential for trial management and to maintain protocol adherence
Transparency across sites is crucial for trial integrity
Need for Transparency
Protocols should be made publicly available on trial websites and registries
Publication must comply with funder and supplier agreements
Core Takeaways
Protocol is essential for clinical trials, supported by SOPs
The complexity of trials warrants clarity and thoroughness
Importance of involving all relevant parties from the outset
Adherence to ethical, legal, and funding guidelines
A well-written protocol lays the foundation for reliable trials
Standards and Tools for Protocols
SPIRIT statement and SEPTRE resources for trial protocol guidance
MRC CTU clinical trials monitoring toolkit
Final Page: Q&A Section