Clinical Trials in T/CM Towards GCP Compliance

1. Clinical Trials in T/CM Towards GCP Compliance Nor Shahidah Khairullah1, Visweswaran Navaratnam2 and Ismail Merican3 1.Institute For Medical Research,2 Science University of Malaysia 3Selayang Hospital

2. Topics • Introduction • Historical perspectives • A brief look at GCP- investigator’s perspectives • National Committee for Clinical Research • Conducting Clinical Trials in Malaysia • Conclusion

3. Biomedical Ethics

4. Evolution of Practice of Medicine • Before 18th Century : • Traditional Medicine is the only form of Medicine in the East.Survival and Quality of Life dependent on Traditional Medicine Traditional Medicine Integrated Modern Medicine Increasing popularity of T/CM Medicine • 19th Century • Influx of Modern Medicine • -noted for its ease and effectiveness • 21st Century • Efforts towards • Integration of • Modern and T/CM Modern Medicine 20th century

5. What should be the objective of R&D in Traditional Medicine? 1. Integration of proven safe and efficacious Traditional medicine practice and products into the healthcare system of the country, as envisaged by WHO in 1978 Alma-Ata Declaration 2. Practitioners of traditional medicine should be qualified and adhere to professional ethics in their practice 3. The practice and the products used should be proven safe and effective

6. R&D CHAIN FROM BIORESOURCES TO PRODUCT TRADITIONAL TEXTS FOLKLORE ETHNOBOTANICAL CHOICE OF PLANT RELATED SPECIES IDENTIFICATION & AUTHENTICATION COLLECTION EXPERIMENTAL CLINICAL TRADITONAL FORMULATION (with GMP) EXTRACTION BIOLOGICAL SCREENING EFFECTIVE ACTIVE ANALYTICAL STANDARDISATION SAFETY MODERN TECHNOLOGY NEW DOSAGE FORMULATION BIOASSAY LINKED FRAC & CHARAC ACTIVE COMPOUND PURE COMP. / STD. EXTRACT PHARMACOKINETICS CLINICAL TRIALS BIOAVAILABILITY PILOT PLANT PRODUCTION REGISTRATION COMMERCIAL PRODUCTION MARKETING

7. Team of Researchers PHARMACOLOGIST BOTANIST • Activity profile • Detailed Pharmacology • Pharmacokinetics • Toxicology • Survey & collection • Taxonomy • Strain improvement • Cultivation packet CLINICIAN CHEMIST • Clinical trial of • Traditional remedies • Phase I - III • Post-marketing • surveillance • Isolation & characterisation • of active principle • Standardisation & shelf life • GMP Norms • Semisynthetic derivatives

8. The drug development process from the preclinical testing stage to approval takes an average of 15 years

9. What is Good Clinical Practice (GCP)

10. Good Clinical Practice • High ethical and scientific standard • Integrity of data • Safety • Protect rights of study subjects

11. Why bother with GCP?…some standard responses • What is that? • I’m far too busy to be bothered with that! • What’s wrong with the way things are now? • After all, Traditional medicines have been used extensively over generations by our forefathers without complications • How do you do it? • How much will it cost?

12. Why GCP?

13. Why GCP • As physicians and healthcare practitioners, we want only safe and effective treatments for our patients • Adhering to GCP is the best way to ensure this in a clinical trial • Adhering to GCP is in our patients best interest

14. Topics • Introduction • Historical perspectives • A brief look at GCP- investigator’s perspectives • National Committee for Clinical Research • Conducting Clinical Trials in Malaysia • Conclusion

15. Nuremberg Code

16. International Military Tribunal Nov. 1945- Oct. 1946

17. 1946 Dr. Leo Alexander points to scars on victim’s legs

18. International Military Tribunal-Indictments • Conspiracy to commit crimes against peace • Planning, initiating & raging wars of aggression • War crimes • Crimes against humanity

19. The Nuremberg Code • A judicial codification of 10 prerequisites for the moral and legal use of human beings in experiments

20. The Nuremberg Code • 10 principles to guide physicians/inveatigators in experiments involving human subjects • Principles based on legal concepts of “voluntary consent” as medical codes of ethics at time of Nazi atrocities did not address consent and other safeguards for human subjects

21. Belmont Report

22. Tuskegee Study • Ethical misconduct in human research • Symbolises racism in medicine • Paternalism by Physicians • Government abuse of vulnerable people

23. BELMONT Report A. Boundaries between practice & research B. Basic Ethical Principles 1. Respect for persons 2. Beneficience 3. Justice • C. Applications • Informed consent • Assessments of Risks & Benefits • Selection of Subjects

24. WMA Declaration of Helsinki • Set of recommendations guiding medical doctors in biomedical research involving human subjects • Adopted by the 18th World Medical Assembly (WMA), Helsinki 1962 • Amended by the 29th WMA in Tokyo, Japan 1975 • Amended by the 35th WMA in Venice , Italy 1983 • Amended by the 41st WMA in Hong Kong, 1989 • Amended by the 48th WMA in Somerset West, South Africa in 1996 • Amended in 2000 • It is the mission of the physician to safeguard the health of the people • His or her knowledge and conscience are dedicated to the fulfillment of this mission

25. Declaration Of Helsinki • 3 divisions • I. Basic Principles • 12 Items • II. Medical Research combined with clinical care (Clinical research) • 6 Items • III. Non therapeutic biomedical research involving human subjects (non clinical biomedical research) • 4 Items

28. Topics • Introduction • Historical perspectives • A brief look at GCP- investigator’s perspectives • National Committee for Clinical Research • Conducting Clinical Trials in Malaysia • Conclusion

29. ICH GCP Guideline • Table of Contents • Glossary of Terms • Principles of GCP • Role of IRB/IEC • Investigator’s Role • Sponsor’s Role • Clinical Protocol • Investigator Brochure • Essential Documents

30. If you want to be an investigator…… • You must make time to do the study • You must be interested in the scientific aspects of the trial and not the finance aspects • You must be sure that you can meet the recruitment targets • You should not have competing trials • You must be aware of and adhere strictly to the investigator’s GCP responsibilities

31. Time • Time to identify subjects • Time with the sponsor and trial monitor • Attending investigator meetings • Time with the subject • Time for audits and inspection

32. Does the centre have adequate facilities • Clinical trials team effort • Principle investigator (Physician) • Co investigator (TM practitioner) • Study coordinator (Nurse) • Pharmacist

33. Investigator’s ResponsibilitiesPre-Study • Ensure adequate time, facilities, staff • Obtain IRB/Ethics Committee approval of the protocol, amendments, informed consent document and any advertisements • Investigational drug brochure

34. Investigator’s ResponsibilitiesDuring Study • Ensure that the study is conducted according to the protocol and ICH/regulatory agency standards, randomization procedures • Obtain written informed consent of each subject to whom the drug is administered prior to entering the study

35. Investigator’s ResponsibilitiesDuring Study (cont’d) • Prepare and maintain accurate and complete records • Case records • Progress, final reports • Safety reporting • Maintain Drug Accountability

36. Investigator’s ResponsibilitiesDuring Study (cont’d) • Implement a system of drug disposition, including: • Dates • Quantity • Use by Subjects

37. Helpful Hints Proven methods to improve GCP compliance and save your time

38. Follow the Protocol • make sure all site staff understand completely • adhere to Inclusion / Exclusion Criteria • be aware of "interfering medications" • may confound data interpretation, invalidate results

39. Documentation Review To establish that: • Research was conducted under proper authority • Patients' rights and safety were protected • Study can be reconstructed • Data supports conclusions

40. Data supports conclusions... Source documents • exist • are readily available • accurately support data reported • tell the whole story

41. Demonstrate Involvement in the Study • Documentation of: • Physical Exams • Patient Histories • Adverse Events • Abnormal Lab Results • Be Able to Describe Unusual Events • Early Discontinuations • Serious Adverse Events • Protocol Violations

42. Documentation • “If it is not written, • IT DID NOT HAPPEN !” • Document what happened as well as what did not happen

43. Informed Consent • To address all 21 elements as itemised by Malaysian Guidelines for GCP pgs 41-42 • Voluntary from each volunteer • Volunteer have legal capacity to give consent • Sufficient understanding of implications of participation • Informed decision to participate (PIS) • Volunteers have no physical or mental conditions that might be aggravated by proposed research • Volunteer has the right to revoke consent at any time without prejudice

44. Informed consent • Verify • Contact physician responsible if medical attention required • Treatment available for trial related injuries • Existing insurance covers trial related injuries

45. Patient Information Sheet (PIS) • Nature,duration and purpose of study • Method and means it is to be conducted • Convenience & hazards expected • Effects on health as result from trial • Include contact info of secretariat for subject complaints pertaining to participation or • Conduct of study

46. Topics • Introduction • Historical perspectives • A brief look at GCP- investigator’s perspectives • National Committee for Clinical Research • Conducting Clinical Trials in Malaysia • Conclusion

47. National Committee for Clinical Research(NCCR) Objectives of NCCR • Infrastructure development • Training • Regulation / Legislation • Promotion of Clinical Research

48. NCCR: Activities • Dialogue with Industries, Clinical Researchers from MOH/Universities/ Private hospitals • Survey on infrastructure 1998/1999 • Implement GCP guidelines for Malaysia

49. NCCR: Activities-II • Bioequivalence (BE) studies • Training on GCP / GLP/ Biostatistics • Site-inspection on current infrastructure for clinical trials • Review processes for application of clinical trials • Develop curriculum for GCP training

50. NCCR: Guidelines • Guidelines for Application to Conduct Drug-Related Clinical Trials in Malaysia • Malaysian Guidelines for Good Clinical Practice (Revision in 2002/3) • Guidelines for Application For Clinical Trial Import Licence and Permit in Malaysia (updated version, Dec. 2000) • Malaysian Guidelines to conduct BE studies ( September 2000)