Knowledge Update

Clinical documentation:from preclinical studies to drug registration

Split, 12 September 2008

Overview of drug development

CompanyDrug discovery

Preclinicaldevelopment

Clinicalprogramme

Registration

Regulatory AgencyFDA (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

Synthesis+

Generalization

Individual data

Clinical study report

Patient listings

Summary tables

[Report]

Synopsis

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 RATIONALE2. STUDY OBJECTIVES3. 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 REQUIREMENTSDefinitions of adverse events

5. STATISTICAL METHODOLOGY AND ANALYSESShould be predefined (Statistical Analysis Plan [SAP])

6. REFERENCES7. 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

Administrativedocumentation

Individual patient data

The body of a reportSynopsis

“Front end”(administrative + rationale+ methods)

Results

Discussion

Refs/tables/ appendices

Submission – the Common Technical Document (CTD)

Individual study reports

Summary of those reports

Discussion of the data

(e.g. risk-benefit)

The regulatory agencies

EMEA – Secretariat (mainly administrative tasks)

Several committees,including…

Committee for Human Medicinal Products (CHMP)

Pediatric Committee

Committee for Orphan Medicinal Products

EU institutionsCommission / Parliament

Working parties (WPs)Efficacy, safety, pharmacovigilance, etc

Scientific advisory groupsOncology, 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