1. Knowledge Update Clinical documentation: from preclinical studies to drug registration Split, 12 September 2008

2. Overview of drug development Company Drug discovery Preclinical development Clinical programme Registration Regulatory Agency FDA (US) EMEA (EU)

3. 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)

4. Clinical documentation is hierarchical Synthesis + Generalization Individual data Clinical study report Patient listings Summary tables [Report] Synopsis

5. 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.

6. ICH guidelines Main page menu: Guidelines >> Note, “safety” does not refer to clinical safety; that comes under “efficacy”

7. “Efficacy” guidelines

8. 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)

9. 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

10. 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

11. 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)

12. Clinical study reports Guidelines  Actual TOC 

13. The base of a clinical study report Summary tables Administrative documentation Individual patient data

14. The body of a report Synopsis “Front end” (administrative + rationale + methods) Results Discussion Refs/tables/ appendices

15. Submission – the Common Technical Document (CTD) Individual study reports Summary of those reports Discussion of the data (e.g. risk-benefit)

16. 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 institutions Commission / Parliament Working parties (WPs) Efficacy, safety, pharmacovigilance, etc Scientific advisory groups Oncology, diabetes and endocrinology, HIV/viral disease

17. 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