Transcript Knowledge Update Clinical documentation: from preclinical

Knowledge Update
Clinical documentation:
from preclinical studies to drug registration
Split, 12 September 2008
Overview of drug development
Drug
discovery
Preclinical
development
Clinical
programme
Regulatory Agency
FDA (US) EMEA (EU)
Registration
Company
Phases of clinical development
• Phase I
– Initial evaluation of safety (max, 50 subjects),
initial PK evaluation
• Phase 2
– Preliminary evidence of activity (max 100
patients, important for planning phase 3)
• Phase 3
– Establish efficacy (100+ patients)
Clinical documentation is hierarchical
Clinical study report
Synthesis
+
Generalization
Synopsis
[Report]
Summary tables
Individual data
Patient listings
Clinical documentation follows
extensive and detailed guidelines
ICH (International Conference on Harmonization)
www.ich.org
Aim: To “harmonise” interpretation and application of technical
guidelines in the three main ICH regions (US, EU and Japan) for
product registration. This should reduce or obviate the need to
repeat trials/experiments during development of new medicines.
Thus, more economical use of human, animal and material
resources can be made while safeguarding quality, safety and
efficacy.
ICH guidelines
Main page menu: Guidelines >>
Note, “safety” does not refer to clinical
safety; that comes under “efficacy”
“Efficacy” guidelines
Actual documents in clinical trials…
• Investigator’s brochure
– A manual distributed to each investigator with
information on the drug in development, including
detailed treatment of safety issues.
• Protocol (later)
• Clinical study report (later)
Clinical trial protocol
A document that describes the objective(s), design,
methodology, statistical considerations, and organization
of a clinical trial.
A clinical trial should not only comply with documentation
requirements of ICH as regards content, but also with
Good Clinical Practice (GCP).
Ensure safety and rights of
participants, define roles and
responsibilities of those involved
More detailed look at
contents of a protocol
1. BACKGROUND AND RATIONALE
2. STUDY OBJECTIVES
3. INVESTIGATIONAL PLAN
Includes overall study design, the study population (inclusion and
exclusion criteria), the study medication, treatment assignment,
efficacy evaluation, safety evaluation.
4. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
Definitions of adverse events
5. STATISTICAL METHODOLOGY AND ANALYSES
Should be predefined (Statistical Analysis Plan [SAP])
6. REFERENCES
7. PROCEDURES AND GOOD CLINICAL PRACTICE
Data management, ethics, Institutional Review Boards/Independent
Ethics Committee, informed consent
Reporting adverse events (AEs)
MedDRA (Medical Dictionary for Regulatory Activities)
Hierarchy
-
System organ class (SOC) [e.g. ‘Cardiac disorders’]
High-Level Group Terms (HLGT)
High-Level Terms (HLT)
Preferred Terms (PT) [e.g. ‘Supraventricular extrasystoles ’]
Lower-Level Terms (LLT)
Ensures Unification
e.g. “blocked nose”/”congested nose”  “nasal congestion”
Severity (severe, moderate, mild)/serious
Causality (definitely, possibly, probably, unlikely, unrelated)
Clinical study reports
Guidelines 
Actual TOC 
The base of a clinical study report
Summary tables
Administrative
documentation
Individual patient data
The body of a report
Synopsis
“Front end”
(administrative
+ rationale
+ methods)
Results
Discussion
Refs/tables/
appendices
Submission – the Common Technical Document (CTD)
Discussion of the data
(e.g. risk-benefit)
Summary of those reports
Individual study reports
The regulatory agencies
EMEA – Secretariat
(mainly administrative tasks)
Several
committees,
including…
Committee for
Human Medicinal
Products (CHMP)
Working parties (WPs)
Efficacy, safety,
pharmacovigilance, etc
EU institutions
Commission / Parliament
Pediatric Committee
Committee for Orphan Medicinal Products
Scientific advisory groups
Oncology, diabetes and
endocrinology, HIV/viral disease
Useful info on the EMEA website
(www.emea.europa.eu)
EPARs (European Public Assessment Report)
Human medicines (top menu) >> EPARs (side menu) << A-Z Listing of EPAR