CRP 112 Lecture 6

Question 1

ICH E17

Answer 1

 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

Question 2

ICH E17 Objective

Answer 2

 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

Question 3

E5 (R1)

Answer 3

Ethnic Factors in Acceptability of
Foreign Clinical Data – first to introduce
concept of bridging & intrinsic/extrinsic
ethnic factors

Question 4

E9

Answer 4

Statistical Principles for Clinical Trials –
written after E6 to set statistical principles regional clinical trials

Question 5

E9 (R1) & MRCTs

Answer 5

 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

Question 6

E10

Answer 6

Choice of Control Group & Related
Issues in Clinical Trials

Question 7

E8

Answer 7

General Considerations for Clinical Trials
-includes designing quality into clinical studies

Question 8

E18

Answer 8

Genomic Sampling & Management of
Genomic Data

Question 9

E17 Planning & Design

Answer 9

 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

Question 10

Relevance of ICH E6(R2) to MRCT

Answer 10

 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)

Question 11

Tasks in MRCT Analysis

Answer 11

 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

Question 12

To Assure Quality Study Data

Answer 12

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

Question 13

Clinical Investigator Site Selection Tool
(CISST)

Answer 13

• 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

Question 14

JReview

Answer 14

 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

Question 15

CluePoints

Answer 15

 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

Question 16

E17 on GCP Training

Answer 16

 GCP training not a substitute for protocol training (conduct, analysis & interpretation)

Question 17

Types of MRCTs: Large trials

Answer 17

 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

Question 18

Types of MRCTs – mid-size

Answer 18

 To treat symptomatic outcomes using
scoring & rating scales
 Major depressive disorders, schizophrenia
 May be more difficult to interpret

Question 19

Types of MRCTs

Answer 19

 Acute exposure, short term (2 week) trials
 Anti-infectives
 Prevention vs. treatment trials
 Superiority trials (show a difference)
 Non-inferiority trials (no placebo)

Question 20

Variations in MRCTs - issues

Answer 20

 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)

Question 21

ICH E6(R2) Definition

Answer 21

“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.”

Question 22

Informed Consent

Answer 22

 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

Question 23

Informed Consent Versioning

Answer 23

 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

Question 24

FDA Most Significant Deviations

Answer 24

 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