CRP 112 Lecture 6 Flashcards
ICH E17
General guidance on general principles on
planning/designing a Multi-Regional
Clinical Trial (MRCT)
Important with increasing globalisation of
drug development
Want data accepted by regulatory authorities
across regions and countries
ICH E17 Objective
General principles for planning and design
of MRCTs
Aim to increase acceptability of MRTs in global
regulatory submissions
Strategic programme issues
To be used with other ICH guidelines
E5, E6, E8, E9, E10 and E18
E5 (R1)
Ethnic Factors in Acceptability of
Foreign Clinical Data – first to introduce
concept of bridging & intrinsic/extrinsic
ethnic factors
E9
Statistical Principles for Clinical Trials –
written after E6 to set statistical principles regional clinical trials
E9 (R1) & MRCTs
E9 has critical protocol design & planning
components
Statistical trial design –randomization, sample sizes,
power
Control of false positive conclusion rate, multiplicity
Intent to treat philosophy, follow-up of participants to
study completion and outcome ascertainment, bias
from conduct
Controlling for, and interpreting, variability (strata)
The ‘estimand’ issue and missing data –what are you
estimating –the role of bias in study results
E10
Choice of Control Group & Related
Issues in Clinical Trials
E8
General Considerations for Clinical Trials
-includes designing quality into clinical studies
E18
Genomic Sampling & Management of
Genomic Data
E17 Planning & Design
Relies upon study conduct that follows
recent revised GCPs, including Quality by
Design concepts
Investigator & site team training critical to
controlling sources of variability & unwanted
heterogeneity (extrinsic factors)
Relies upon study design principles outlined
in ICH E9 Statistical Principles
Multi-centre trials discussed but not in the detail needed for MRCTs
Relevance of ICH E6(R2) to MRCT
GCP is international ethical & quality
standard for trials with human participants
for:
Designing
Conducting & monitoring
Recording
Reporting
GCPs should be viewed in context of E5 (ethnic), E17 (MRCT) and E9 (stats)
Tasks in MRCT Analysis
Review protocols & provide feedback to sponsors:
Ethics
Protection of participants &
Appropriate exposure strategies
Implications of choice of study design and hypotheses, importance of pre-specification, sample sizing rationale
Review and evaluate completed studies submitted
in dossiers to regulatory bodies
Assess gaps in evidence and what to do next
Quality assurance:
inspection
auditing
compliance with guidance,
regulations & policies
It is a team sport
To Assure Quality Study Data
Planning
Appropriate choice & training of
investigators and site team
Understand planned protocol,
how to implement it, and consequences in
study quality resulting from study conduct
Review & evaluate study results, understand systematic & chance variation in treatment responses and impact of biases on: strength of conclusions and evidentiary support
Audit & inspect study data for
compliance, validity, quality &
sources of uncontrolled variability
Clinical Investigator Site Selection Tool
(CISST)
- Risk ranking of sites to
provide framework for site
selection - Standard data exploration
methodology - Assembles many site
characteristics in one tool &
gives user ability to choose
sites based on site views
Easy navigation and functionalities
Improves data analysis time
Automated documentation and form
generation
JReview
Used by FDA scientists to evaluate patient profiles & a variety of user specified analyses of patient level data by various factors (e.g., disease type, AEs, etc.)
dynamically pool multiple studies, even across projects
Any of the reports, graphs, etc. will run against the pooled set of study data
No data moving or copying needed as it happens automatically
CluePoints
Cloud based central statistical monitoring software to drive improved data quality & integrity as part of RBM process
FDA research collaborative project to evaluate clinical trial quality, outliers, protocol compliance
Complies with ICH E6(R2)
Uses statistical algorithms to look for potential issues in
both clinical & operational data
Aids pre-study risk assessment & solution implementation
E17 on GCP Training
GCP training not a substitute for protocol training (conduct, analysis & interpretation)
Types of MRCTs: Large trials
Large trials with objective & semi-objective outcomes
Cardiovascular, diabetes trials with thousands of participants, hundreds of sites, many countries & regions, & multiple categories of subgroups of participants classified in multiple ways
Types of MRCTs – mid-size
To treat symptomatic outcomes using
scoring & rating scales
Major depressive disorders, schizophrenia
May be more difficult to interpret
Types of MRCTs
Acute exposure, short term (2 week) trials
Anti-infectives
Prevention vs. treatment trials
Superiority trials (show a difference)
Non-inferiority trials (no placebo)
Variations in MRCTs - issues
sometimes results are due to A statistical chance occurrence, not
explained by any observed factors
Usually involves analysis of interactions, multiplicity control, differences in sample sizes and variability and outliers (where
GCPs plays a role)
ICH E6(R2) Definition
“A standard for the design, conduct, performance, monitoring,
auditing, recording, analyses, and reporting of clinical trials that
provides assurance that:
Data & reported results are credible & accurate
and
Rights, integrity, and confidentiality of trial participants is protected.”
Informed Consent
MUST be performed BEFORE any study procedures
Informed consent is a process
Participant must read and understand ICF
Must be given opportunity to ask questions
Both participant & person conducting consent must sign and date the ICF at the time of consent
Informed Consent Versioning
If a new informed consent is issued
All participants must be re-consented with new ICF at their NEXT
visit
Explain the changes – DOCUMENT!!
KEEP ALL ORIGINALS
ICFs must be retained as a legal record of participants consent to participate in study
Provide participant with a copy of the new ICF
FDA Most Significant Deviations
Enrollment of ineligible participants
Violations of protocol affecting safety
Extensive data corrections & questionable changes
Inadequate oversight of study personnel
Inappropriate delegation of authority
Poor oversight of satellite sites
No informed consent
Failure to communicate with IRB
