GUIDELINE FOR GOOD CLINICAL PRACTICE

1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE GUIDELINE FOR good CLINICAL PRACTICE E6(R1) Current Step 4 version dated 10 June 1996 (including the Post Step 4 corrections) This GUIDELINE has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. E6(R1) Document History First Codification History Date New Codification November 2005 E6 Approval by the Steering Committee under Step 2 and release for public consultation.

2 27 April 1995 E6 E6 Approval by the Steering Committee under Step 4 and recommended for adoption to the three ICH regulatory bodies. 1 May 1996 E6 Current Step 4 version E6 Approval by the Steering Committee of Post-Step 4 editorial corrections. 10 June 1996 E6(R1) GUIDELINE FOR good CLINICAL PRACTICE ICH Harmonised Tripartite GUIDELINE Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 1 May 1996, this GUIDELINE is recommended for adoption to the three regulatory parties to ICH (This document includes the Post Step 4 corrections agreed by the Steering Committee on 10 June 1996) TABLE OF CONTENTS 1. 2. THE PRINCIPLES OF ICH 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)..9 Composition, Functions and Operations ..11 4. Investigator's Qualifications and Adequate Medical Care of Trial Communication with Compliance with Protocol.

3 13 Investigational Product(s)..14 Randomization Procedures and Unblinding ..15 Informed Consent of Trial Records and Progress Safety Premature Termination or Suspension of a Final Report(s) by 5. Quality Assurance and Quality Contract Research Organization (CRO)..20 Medical Trial Trial Management, Data Handling, and Record i GUIDELINE for good CLINICAL PRACTICE Investigator Selection .. 22 Allocation of 23 Compensation to Subjects and 23 23 Notification/Submission to Regulatory Authority(ies).. 23 Confirmation of Review by 23 Information on Investigational Product(s) .. 24 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s).24 Supplying and Handling Investigational Product(s).. 24 Record 25 Safety 25 Adverse Drug Reaction 26 26 26 Selection and Qualifications of Monitors.

4 26 Extent and Nature of 26 Monitor's 26 Monitoring Procedures .. 28 Monitoring 28 28 29 Selection and Qualification of 29 Auditing 29 Noncompliance .. 29 Premature Termination or Suspension of a 30 CLINICAL Trial/Study 30 Multicentre 30 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S).. 30 General 30 Background 31 Trial Objectives and 31 Trial 31 Selection and Withdrawal of 32 Treatment of 32 Assessment of 32 Assessment of 32 ii GUIDELINE for good CLINICAL PRACTICE Direct Access to Source Quality Control and Quality Data Handling and Record Financing and Publication 7. INVESTIGATOR S General Title Confidentiality Contents of the Investigator s Table of Physical, Chemical, and Pharmaceutical Properties and Nonclinical Effects in Summary of Data and Guidance for the APPENDIX 1.

5 39 APPENDIX 2:..40 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL Before the CLINICAL Phase of the Trial During the CLINICAL Conduct of the After Completion or Termination of the Trial ..52 iii GUIDELINE FOR good CLINICAL PRACTICE INTRODUCTION good CLINICAL PRACTICE (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the CLINICAL trial data are credible. The objective of this ICH GCP GUIDELINE is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of CLINICAL data by the regulatory authorities in these jurisdictions.

6 The GUIDELINE was developed with consideration of the current good CLINICAL practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). This GUIDELINE should be followed when generating CLINICAL trial data that are intended to be submitted to regulatory authorities. The principles established in this GUIDELINE may also be applied to other CLINICAL investigations that may have an impact on the safety and well-being of human subjects. 1 GUIDELINE for good CLINICAL PRACTICE 1. GLOSSARY Adverse Drug Reaction (ADR) In the pre-approval CLINICAL experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.

7 The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH GUIDELINE for CLINICAL Safety Data Management: Definitions and Standards for Expedited Reporting). Adverse Event (AE) Any untoward medical occurrence in a patient or CLINICAL investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

8 An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH GUIDELINE for CLINICAL Safety Data Management: Definitions and Standards for Expedited Reporting). Amendment (to the protocol) See Protocol Amendment. Applicable Regulatory Requirement(s) Any law(s) and regulation(s) addressing the conduct of CLINICAL trials of investigational products. Approval (in relation to Institutional Review Boards) The affirmative decision of the IRB that the CLINICAL trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, good CLINICAL PRACTICE (GCP), and the applicable regulatory requirements.

9 Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), good CLINICAL PRACTICE (GCP), and the applicable regulatory requirement(s). Audit Certificate A declaration of confirmation by the auditor that an audit has taken place. Audit Report A written evaluation by the sponsor's auditor of the results of the audit. 2 GUIDELINE for good CLINICAL PRACTICE Audit Trail Documentation that allows reconstruction of the course of events. Blinding/Masking A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).

10 Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. CLINICAL Trial/Study Any investigation in human subjects intended to discover or verify the CLINICAL , pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.