Knowledge Update Clinical documentation: from preclinical studies to drug registration

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Knowledge UpdateClinical documentationfrom
preclinical studies to drug registration

• Split, 12 September 2008

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Overview of drug development
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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)

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Clinical documentation is hierarchical
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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.

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ICH guidelines
Main page menu Guidelines gtgt
Note, safety does not refer to clinical safety
that comes under efficacy
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Efficacy guidelines
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Actual documents in clinical trials

• Investigators 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)

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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
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More detailed look at contents of a protocol

1. BACKGROUND AND RATIONALE
2. STUDY OBJECTIVES
3. INVESTIGATIONAL PLANIncludes 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. REFERENCES
7. PROCEDURES AND GOOD CLINICAL PRACTICEData
   management, ethics, Institutional Review
   Boards/Independent Ethics Committee, informed
   consent

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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)

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Clinical study reports
Guidelines ?
Actual TOC ?
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The base of a clinical study report
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The body of a report
Synopsis
Front end(administrative rationale methods)
Results
Discussion
Refs/tables/ appendices
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Submission the Common Technical Document (CTD)
Discussion of the data (e.g. risk-benefit)
Summary of those reports
Individual study reports
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The regulatory agencies
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Useful info on the EMEA website
(www.emea.europa.eu)
EPARs (European Public Assessment Report) Human
medicines (top menu) gtgt EPARs (side menu) ltlt A-Z
Listing of EPAR