Planning, Development of Clinical Trials
Planning of Clinical Trials
Development of a Clinical Trial
Idea
Reviews from the experts(Sponsor or CRO)
First planning meeting (basic design features)
Second planning meeting (draft protocol)
Final protocol (ethical and scientific, signed by a statistician)
Evaluation (scientific review, IRB, funding)
Implementation
Final analysis and publication
Evolution of Trial Structure
* Large cooperative trials (multicenter trials)
* High scientific level protocol
* Well-defined administrative structure
* Control of performance at all levels (SOPs)
* Competent biometric advice (ICH E9)
* Careful ethical considerations
Why Multicenter Trials?
* Small but important effect
* Enhance generalizability of the results
* Bring new treatment to the community
Clinical Trial Protocol
* A detailed plan giving instructions to the study investigators(doctors) about the way
to conduct the study.
o Contributors to the protocol development
+ investigators,
+ medical personnel from the Sponsor or delegated CRO
+ representatives from the study monitoring team
+ project statistician
Crucial Roles of Statisticians
* Design (very important!!!)
* Monitoring
* Analysis
* Reporting
* New statistical methodology
Sophisticated Statistical Techniques
* O’Brien and Fleming Boundaries
* Lan & DeMets “Spending function”
* Equivalence testing
* Repeated measures
* Bayesian methods
* Nonlinear random effect modeling
Functions of Clinical Trial Protocol
* Guideline for the conduct of the trial
* Quality control for all aspects of a clinical trial
* To provide guidelines to the monitoring groups such as: IEC / IDMC.
* Written agreement between:
o the investigator
o the participant,
o and the scientific community
* Legal documents for
o FDA and other regulatory bodies
* To procure funding
Duration of Protocol Development
7days-6months!!!
4-50 pages long!!!
Three Fundamental Aspects
* Which patients are eligible
* Which treatment are to be evaluate
* How each patient’s response is to be assessed
Background
* Rationale
* Unpublished work of the investigators
* Pharmacological and toxicity
* Any new and non standard methods
Specific Objectives
* New treatment
* New indication
* Determine the best of a number of standard treatments
* To provide additional data on safety or efficacy
Methods
o Hypothesis
o Patient population (operational definition)
+ Inclusion Criteria
+ Exclusion Criteria
More homogeneous less generalizable!!
Treatment Regimens
Required procedures for treatment administration, including precise rules for does
determinations
Trial Design
Control groups
+ Define and justify the control group
+ Safety consideration of the placebo group
+ Randomization (verifiable method)
# Method used to generate the allocation schedule
# Method of allocation concealment
* Packing number
* Telephone
* Remote data entry
# Timing of assignment
+ Balance on Prognostic Factors
# Stratification
# Minimization
Blinding
+ Mechanism of treatment blinding
+ Single, double, triple, quadruple blinding
+ Assessment of the effectiveness of blinding
Experimental design
+ Parallel designs
+ Cross-over designs
+ Factorial designs
+ Sequential designs
* Patient management guidelines, including specifications for does reductions, treatment
delays and treatment terminations
* Schedules of required clinical tests and assessments
Follow-up phase
* Schedule of submission of required materials and data, including long-term follow-up
* Data and materials submission procedures
Termination
* Procedures for ending patients’ participation in the trial
Study Flow Diagram
* A flowchart describe how patients progress through the trial
o Initial screening
o Randomization
o Planned schedule
o Follow-up visits
o Early termination
Outcome Measures
* Primary end points
Secondary end points
Statistical Issues
* Power analysis justifying sample size requirements
* Interim monitoring and analysis plans
* Planned time and methodology of final analyses e.g. ITT, PP, NNT, CI
* Methods on secondary aims, compare toxicities
Ethics and Safety
* Protection of the trial patient’s right and safety
o How the patient is approached for entry into the trial
o Regulatory obligations, including informed consent and reporting of adverse
events
o Plan and action if a SAE be detacted
Other Topics in a Study Protocol
* Laboratories
* Compliance
o How compliance is monitored
o Methods used to improve compliance
* Organization
o Roles
o Responsibilities
* Budget
* Study Forms (CRFs) and data handling
* Administrative responsibilities
CRF Design
* Identification data
* Research data
* Administrative data
* Regulatory data
Basic Information in CRF
* Consent dates
* Eligibility checklist
* Baseline assessments
* Dosing of study medications ( incl. compliance)
* Concomitant illness
* Safety
* Effectiveness
* Premature termination of study
Administrative Structure of Multicentre Trials
* Steering Committee
o Leadership body of the investigative group
* Data and Safety Monitoring Committee
o Assess the progress, safety and efficacy
o Recommendations about continue, modify or terminate.
Study Chairman
* Chair steering committee
* Responsible for the overall project
* Overseeing the design and conduct of the trial
* Implementation of SOPs and good clinical practices
* Compliance with international and local regulations.
Coordinating Centre
o Training
o Registration
o Randomization
o Supplying
o Collecting and processing CRFs
o Coordination of accrual sites
o Auditing study sites
o Regulatory reporting
Statistical Centre
o Data entry and processing
o Ongoing monitoring of toxicity data
o Periodical interim analysis of study endpoints
o Final data analyses
o Preparation abstract and manuscripts
Central Laboratory
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