1. Korea Food & Drug Administration Deputy director Kwang-Soo Joo Korea FDA Sep. 29, 2000 : Korean Good Clinical Practice & Relative Guidelines How to Manage Clinical Trials

2. Agenda  History of Regulatory Affairs in Clinical Trials  Publication of Clinical Evaluation Guidelines  Approval Process of Clinical Trials  Guidelines for Clinical Trials  Accredited Institution for Clinical Trials  Amendment of KGCP  Inspection Korea Food & Drug Administration

3. History of Regulatory Affairs in Clinical Trials 1983Start of the study on KGCP introduction Feb. 28, 1987Establishment of KGCP as a guideline Dec. 31, 1991Establishment of regulations for the approval of Investigational Product Jun. 30, 1992Preparation of Principle Act to manage clinical trials Jul. 18, 1994Establishment of approval process for Clinical Study Protocol Jul. 27, 1995Amendment of KGCP Oct. 1, 1995Enforcement of KGCP Jan. 4, 2000KGCP amended to be harmonized with ICH Guideline E6 : effective in Jan 2001

4. Guideline for Anticancer drugs Aug. 1993 Guideline for New drug Feb. 1994 Guideline for Antimicrobials Apr. 1994 Guideline for Antiarrhythmatic agents Dec. 1994 Guideline for Antihypertensives Dec. 1994 Guideline for Antiinflammatory agents Dec. 1995 Guideline for Lipid-lowering agents Dec. 1995 Guideline for Studies in support of Special Population : Geriatrics Dec. 1996 Guideline for Structure and Content of Clinical Study Reports Dec. 1997 Korea Food & Drug Administration Publication of Clinical Evaluation Guidelines

5. Investigational Product’s safety and Clinical Study Protocol should be validated before clinical trial. Korea Food & Drug Administration Approval Process for Clinical trials Approval for Manufacturing / Importing : Validation of Investigational Products (KFDA) ↓ Approval for Clinical Study Protocol (KFDA)

6. -001991 49144193Total 12- 2000 118191999 922311998 324271997 319221996 823311995 334371994 -12 1993 -111992 -111990 No. of ProcessingNo. of ReportedNo. of ApprovedYear (As of Aug. 31, 2000) Status of New Drug Clinical Study Approved in KFDA Korea Food & Drug Administration Approval of Clinical Study

7. Clinical Trials should : Be carried out in the approved Protocol Be studied at accredited sites Be studied by qualified and well-trained Principal Investigator Require Informed Consent before enroll patients Protect the rights and safety of clinical subjects Use only Investigational Products labeled Keep all documents for 10 years Follow other guidelines requested from KFDA (The Practice of Pharmaceutical Law, Article 28) Korea Food & Drug Administration Guidelines for Clinical Trials

8. Purpose - To supply accurate information about investigational sites where can conduct clinical study with KGCP What are essentials to accredit? –Total no. of beds and doctors –Appropriate facilities and equipments –Pool of person to support clinical study –Activities of IRB(Institutional Review Board) –Regular education program for GCP –Structures and activities to manage study related documents, investigational product and laboratory Korea Food & Drug Administration Accredited Institution System

9. 441 Dental Medicines 654415 General Medicines Phase IIIPhase IIPhase IClass (As of Aug. 31, 2000) Korea Food & Drug Administration No. of Accredited Institutions Sites

10. Korea Food & Drug Administration Purpose – To harmonize with ICH Guideline & Global Standard – To intensify rights and safety for clinical subjects – To ensure quality and validation When it is performed? – This year is a grace period – Enforcement will be effective in Jan. 2001 Amendment of KGCP (revised in Jan. 2000)

11. (5 chapters, 47 articles) General provisions - purpose - glossary - principle of KGCP Contracts - duties of head of Institution IRB - responsibility - composition, function & operation Investigator Sponsor -including essential documents (9 chapters, 22 articles) General provisions Contracts IRB Responsibility of investigators Sponsor Protection of trial subjects Final report Investigational drug managements Supplementary - inspection & consultation - maintenance of documents & data Current KGCP(effective in Jan. 2001)Till Dec. 2000 Regulatory Changes in Clinical trials / KGCP Korea Food & Drug Administration Amendment of KGCP (revised in Jan. 2000)

12. Amended major points  Define glossary of clinical trials  Clarify responsibility of Investigator  Protect the rights of Trial Subjects  Reinforce the function of IRB  Secure quality assurance of trials  The others amended Korea Food & Drug Administration Amendment of KGCP

13. – Head of Institution : should be establish operating procedures – IRB : protect the right, safety and well-being of trial subjects – Principal Investigator : medical care of trial subjects & compliance with protocol – Sponsor : Q/A & Q/C for clinical trial Define glossary of clinical trial – For the efficiency of clinical trial, the meaning of glossary is defined more clearly – Definition of glossary is identical with ICH-GCP Clarify responsibility of clinical trial-related Korea Food & Drug Administration Amendment of KGCP

14. Reinforce the function of IRB – Authoritative management of clinical trial – IRB members should be included legal and religious people for the ethical review Protect the rights of Trial Subjects – Strengthen the process of informed consent – Setup the compensation to the subjects Korea Food & Drug Administration Amendment of KGCP

15. The others amended – Control of Investigational Drugs – Serious Adverse Event & Safety information reporting system – Documentation & Maintenance of clinical data Secure Quality Assurance of trials – Maintenance of SOP for the consistency – Introduction of QA/QC system – Introduction of Monitoring & Auditing system Korea Food & Drug Administration Amendment of KGCP

16. Inspection by KFDA Korea Food & Drug Administration Target All clinical trial approved by KFDA and conducted in Korea Definition The act by regulatory authorities(KFDA) of conducting an official review of documents, facilities, records and other resources that are deemed by the KGCP and guidelines to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and contract research organization’s(CRO’s) facilities

17. Korea Food & Drug Administration Target in Foreign Countries – Application for NDA after clinical trial – Principal investigator is involved in several trials – Investigator with some troubles previously – Investigator or clinical sites at issue. – Investigator with too many patients enrolled – Sponsor’s or patients’ complaint to Government – Under lawsuit in related investigator Inspection is executed selectively in the following cases : Inspection by KFDA

18. Clinical Study Site Compliance with KGCP and Study Protocol IRB proceedings Management and record of Investigational Product Source Documents and CRF Informed Consent Clinical Study Report Sponsor or CRO Manufacturing documents & records of Investigational Product(I. P.) Full documents related in quality control Labeling of I.P. Managing Documents of I.P. Stock of I.P. Monitoring Report What are inspected? Korea Food & Drug Administration Inspection by KFDA

19. Korea Food & Drug Administration Frequently Indicated Problem Subject Enrollment before Protocol Approval Not qualified IRB members Violation of Inclusion/Exclusion Criteria Violation of dose and administration Administration of inhibited Concomitant Drug Violation of wash-out period Change of Subject’s Visit Schedule Start to study before signing Informed Consent Conduction of amended protocol before regulatory approval Insufficient action against Serious Adverse Events Violation of random allocation in comparative study Illegal opening of Blind Code in Blind Study Inspection by KFDA - Major Violation

20. Missing of lab.data Using old data of subjects in screening Illegibility of CRF entries and correction Insufficient follow-up against Adverse Events and abnormal clinical records Insufficient management of IRB and Investigator Insufficient management of Investigational Products Investigator’s insufficient acknowledgement of KGCP regulation Investigator’s insufficient acknowledgement of protocol Insufficient management of subjects Korea Food & Drug Administration Inspection by KFDA Frequently Indicated Problem - Minor Violation - Others

21. Korea Food & Drug Administration : Korean Good Clinical Practice & Relative Guidelines How to Manage Clinical Trials Thank you very much for your attention!