Knowledge Update

Clinical documentation: from preclinical studies to drug registration Split, 12 September 2008

Overview of drug development

Drug discovery Preclinical development Clinical programme Registration Company Regulatory Agency FDA (US) EMEA (EU)

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 Individual data Synopsis [Report] Summary tables 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)

Guidelines 

Clinical study reports

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) EU institutions Commission / Parliament Pediatric Committee Committee for Orphan Medicinal Products

Working parties (WPs)

Efficacy, safety, pharmacovigilance, etc

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