1. © 2004 Aeras Global TB Vaccine Foundation Introduction to Clinical Research Clinical Research Practice 1

2. © 2004 Aeras Global TB Vaccine Foundation 2 2 The basics of clinical research, types of clinical trials and why clinical research is necessary. The basics of clinical research, types of clinical trials and why clinical research is necessary. Good Clinical Practice and Good Laboratory Practice that guide the conduct of clinical research. Good Clinical Practice and Good Laboratory Practice that guide the conduct of clinical research. The importance of protecting participants and the informed consent procedures. The importance of protecting participants and the informed consent procedures. The overall goals of the current trials. The overall goals of the current trials. This Course Will Introduce You To:

3. © 2004 Aeras Global TB Vaccine Foundation 3 3 Objectives: Define clinical research and explain why we perform clinical research. Define clinical research and explain why we perform clinical research. Define Standard Operating Procedure. Define Standard Operating Procedure. Identify the types of clinical research trials. Identify the types of clinical research trials. Define protocol. Define protocol. State the protections given to human participants in clinical research. State the protections given to human participants in clinical research. Define Good Clinical Practice and Good Laboratory Practice. Define Good Clinical Practice and Good Laboratory Practice.

4. © 2004 Aeras Global TB Vaccine Foundation 4 4 Objectives: Explain why GCP and training given by the PDP are important to you. Explain why GCP and training given by the PDP are important to you. Identify staff that must comply to research ethics and standards. Identify staff that must comply to research ethics and standards. Explain the importance of “amendments” to a protocol. Explain the importance of “amendments” to a protocol. Define Case Report Forms and Source documents and their importance in a trial. Define Case Report Forms and Source documents and their importance in a trial. Define informed consent and list some of the rules of the process. Define informed consent and list some of the rules of the process. State the overall goals of the clinical trial you are working on. State the overall goals of the clinical trial you are working on.

5. © 2004 Aeras Global TB Vaccine Foundation 5 5 What Is Clinical Research? A scientific research study. A scientific research study. A clinical trial looking for answers to specific questions. A clinical trial looking for answers to specific questions. Method for finding safe, new and improved vaccines, drugs, and other treatments to improve health. Method for finding safe, new and improved vaccines, drugs, and other treatments to improve health. Research that relies on human volunteers. Research that relies on human volunteers.

6. © 2004 Aeras Global TB Vaccine Foundation 6 6 So…… Clinical Research Is… Research performed on humans. Research performed on humans. Designed to answer specific questions related to human disease, diagnosis, prevention, outcomes and treatments. Designed to answer specific questions related to human disease, diagnosis, prevention, outcomes and treatments.

7. © 2004 Aeras Global TB Vaccine Foundation 7 7 Why Do We Perform Clinical Research? Test new therapies and drugs. Test new therapies and drugs. Gather data from participants who have had a known intervention and monitor results. Gather data from participants who have had a known intervention and monitor results. Determine the safety and effectiveness of drugs, therapies, and other treatments. Determine the safety and effectiveness of drugs, therapies, and other treatments. Develop new drugs and treatments that are safer, more effective and faster working than any before. Develop new drugs and treatments that are safer, more effective and faster working than any before. Ultimately – to improve health status. Ultimately – to improve health status.

8. © 2004 Aeras Global TB Vaccine Foundation 8 8 What Happens In a Clinical Trial? Human participants are recruited for a particular study based on stated criteria as described in the protocol of the study. Human participants are recruited for a particular study based on stated criteria as described in the protocol of the study.

9. © 2004 Aeras Global TB Vaccine Foundation 9 9 Then……. Participants are fully informed about the trial and give informed consent to participate in the clinical trial. Participants are fully informed about the trial and give informed consent to participate in the clinical trial.

10. © 2004 Aeras Global TB Vaccine Foundation 10 And Only Then…. A team of doctors, nurses and other research professionals: A team of doctors, nurses and other research professionals: check the health of the participant at the beginning of the trial. check the health of the participant at the beginning of the trial. give specific instructions for participating in the trial. give specific instructions for participating in the trial. monitor the participant carefully during the trial. monitor the participant carefully during the trial. collect the relevant data collect the relevant data analyze the data and draw conclusions analyze the data and draw conclusions report results and share conclusions report results and share conclusions

11. © 2004 Aeras Global TB Vaccine Foundation 11 How Does The Team Ensure Uniformity In Research? Standard Operating Procedures Detailed, written instructions to achieve uniformity of the performance of a specific function. Detailed, written instructions to achieve uniformity of the performance of a specific function.

12. © 2004 Aeras Global TB Vaccine Foundation 12 Types of Clinical Research Trials Treatment trials Treatment trials Prevention trials Prevention trials Diagnostic trials Diagnostic trials Screening trials Screening trials Quality of life trials Quality of life trials

13. © 2004 Aeras Global TB Vaccine Foundation 13 Types of Clinical Research Trials Treatment trials: Test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

14. © 2004 Aeras Global TB Vaccine Foundation 14 Prevention trials: Look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. May include medicines, vitamins, vaccines, minerals, or lifestyle changes.

15. © 2004 Aeras Global TB Vaccine Foundation 15 Diagnostic trials: Are conducted to find better tests or procedures for diagnosing a particular disease or condition.

16. © 2004 Aeras Global TB Vaccine Foundation 16 Screening trials: Test better ways to detect a disease or particular health condition.

17. © 2004 Aeras Global TB Vaccine Foundation 17 Quality of life trials: Explore ways to improve comfort and the quality of life for individuals with a chronic illness.

18. © 2004 Aeras Global TB Vaccine Foundation 18 Define Research Question (What do you want to know?) The Life Cycle Of A Clinical Research Project Write a Research Proposal Find Funding & Select Research Team Write Protocol Conduct Research Analyse Results Report Results Get Regulatory Approval

19. © 2004 Aeras Global TB Vaccine Foundation 19 Key Parts of the Process Find Funding: A sponsor, pharmaceutical company, research institution, or other organization funds the project. Find Funding: A sponsor, pharmaceutical company, research institution, or other organization funds the project. Protocol: The study plan. Written procedures detailing the steps to conduct a study, keep participants safe and ensure valid data. Protocol: The study plan. Written procedures detailing the steps to conduct a study, keep participants safe and ensure valid data. Get Regulatory Approval: Regulatory bodies monitor and approve research. Get Regulatory Approval: Regulatory bodies monitor and approve research. Institutional Review Board or Ethics Committee (IRB/IEC) Institutional Review Board or Ethics Committee (IRB/IEC) Medicines Control Council (MCC) Medicines Control Council (MCC) South African National Accreditation System (SANAS) South African National Accreditation System (SANAS)

20. © 2004 Aeras Global TB Vaccine Foundation 20 Performing Research in South Africa Offers an Unique Environment South Africa High technological medical expertise and infrastructure. Significant burden of disease. Racial- Cultural Diversity Money, resources and other support for research.

21. © 2004 Aeras Global TB Vaccine Foundation 21 Rapid Increase in Research South Africa has seen a 40% growth in research since 1997. South Africa has seen a 40% growth in research since 1997. Could lead to the potential for unscrupulous, unethical and unnecessary conduct of clinical research. Could lead to the potential for unscrupulous, unethical and unnecessary conduct of clinical research.

22. © 2004 Aeras Global TB Vaccine Foundation 22 Risk of Research Misconduct Greatest When Dealing With… Poor populations. Poor populations. Low levels of literacy. Low levels of literacy. Unquestioning acceptance of authority. Unquestioning acceptance of authority. Great need for health services. Great need for health services. No knowledge of research. No knowledge of research.

23. © 2004 Aeras Global TB Vaccine Foundation 23 Research Is So “New” …Can You See Why We Need Guidelines? In the light of this growth and unique environments, the need to carefully regulate and guide the conduct of clinical trials becomes urgent and necessary.

24. © 2004 Aeras Global TB Vaccine Foundation 24 How Do We Protect Our Research Participants Against Research Misconduct? Research principles and guidelines Research principles and guidelines Research regulations Research regulations Informed Consent Informed Consent

25. © 2004 Aeras Global TB Vaccine Foundation 25 Principles to Protect Participants Good Clinical PracticeGood Laboratory Practice

26. © 2004 Aeras Global TB Vaccine Foundation 26 Good Clinical Practice Good Clinical Practice An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human volunteers. An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human volunteers. Simply put …. GCP is the rules by which we conduct our research. Simply put …. GCP is the rules by which we conduct our research.

27. © 2004 Aeras Global TB Vaccine Foundation 27 Good Laboratory Practice Good Laboratory Practice Represents a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. Represents a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. Simply put …. GLP is the rules of research in the lab. Simply put …. GLP is the rules of research in the lab.

28. © 2004 Aeras Global TB Vaccine Foundation 28 GCP GCP

29. © 2004 Aeras Global TB Vaccine Foundation 29 History of GCP Nazi Medical War Crimes Nazi Medical War Crimes Nuremberg Code - 1947

30. © 2004 Aeras Global TB Vaccine Foundation 30 Declaration of Helsinki (DOH) 1964 Developed by the World Medical Association First significant effort of the medical community to regulate itself.

31. © 2004 Aeras Global TB Vaccine Foundation 31 Tuskegee Syphilis Study 1932-1972 Belmont Report 1979 Cornerstone for ethical principles underlying the acceptable conduct of research using human volunteers.

32. © 2004 Aeras Global TB Vaccine Foundation 32 Many regulations……needed one standard Many regulations……needed one standard International Conference on Harmonization April 1990 Principles of ICH GCP

33. © 2004 Aeras Global TB Vaccine Foundation 33 13 Principles of ICH GCP Two important principles are: The rights, safety, and well-being of the trial participants are the most important considerations and should prevail over the interest of science and society. The rights, safety, and well-being of the trial participants are the most important considerations and should prevail over the interest of science and society. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

34. © 2004 Aeras Global TB Vaccine Foundation 34 GLP GLP

35. © 2004 Aeras Global TB Vaccine Foundation 35 History of GLP  Malpractice – 1970’s  Organization for Economic Co-operation and Development (OECD) 30 Countries-1981 OECD GLP Principles

36. © 2004 Aeras Global TB Vaccine Foundation 36 OECD GLP Principles  Regulates the practices of scientists working on the safety testing of prospective drugs.  Imposed by regulatory authorities.  South African National Accreditation System (SANAS)

37. © 2004 Aeras Global TB Vaccine Foundation 37 GLP: Fundamental Points  Resources  Rules  Characterization  Documentation  Quality Assurance Photo courtesy of Aeras Global TB Vaccine Foundation.

38. © 2004 Aeras Global TB Vaccine Foundation 38 Why Is Following GCP and GLP Important ? Compliance with these standards assures: participant rights are protected. participant rights are protected. the safety of human volunteers. the safety of human volunteers. participant well-being is a priority. participant well-being is a priority. results are used for improvement of health and well-being of all. results are used for improvement of health and well-being of all.

39. © 2004 Aeras Global TB Vaccine Foundation 39 Why Is Following GCP and GLP Important to You? As part of the research team, each and every one of us is responsible for following ethical guidelines and ensuring valid and credible results. As part of the research team, each and every one of us is responsible for following ethical guidelines and ensuring valid and credible results.

40. © 2004 Aeras Global TB Vaccine Foundation 40 How Do We Protect Our Research Participants Against Research Misconduct? Research principles and guidelines Research principles and guidelines Research regulations Research regulations Informed Consent Informed Consent

41. © 2004 Aeras Global TB Vaccine Foundation 41 How Is Research Regulated? How Is Research Regulated? Research Participant Institutional Review Board or Ethics Committee Medicines Control Council Data Safety Monitoring Board SANAS

42. © 2004 Aeras Global TB Vaccine Foundation 42 ……What If We Need To Change Something ? Remember the Protocol?...... Ask for a protocol amendment…… “A written description of a change(s) to or formal clarification of a protocol.” ( Definition from the ICH Guideline for Good Clinical Practice 1.45)

43. © 2004 Aeras Global TB Vaccine Foundation 43 Data Collection Source Data All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. (ICH 1.51) All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. (ICH 1.51) Source Documents Original documents, data and records. (ICH 1.52) Original documents, data and records. (ICH 1.52) 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. (ICH 1.11) 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. (ICH 1.11)

44. © 2004 Aeras Global TB Vaccine Foundation 44 A Few Rules for Completing Study Documentation: Make sure that you are designated to complete the documents. Make sure that you are designated to complete the documents. Write legibly. Write legibly. Do not leave any blank fields on documents. Do not leave any blank fields on documents. Do not use correctional fluid. Do not use correctional fluid. Double check that information is accurate and consistent with the source document. Double check that information is accurate and consistent with the source document. Make corrections and edits according to GCP guidelines. Make corrections and edits according to GCP guidelines. (ICH 4.9) (ICH 4.9)

45. © 2004 Aeras Global TB Vaccine Foundation 45 How Do We Protect Our Research Participants Against Research Misconduct? Research regulations Research regulations Research principles and guidelines Research principles and guidelines Informed Consent Informed Consent

46. © 2004 Aeras Global TB Vaccine Foundation 46 Informed Consent A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial,  …after having been informed of all aspects of the trial  …that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. (ICH 1.28) Informed consent is documented by means of a written, signed and dated informed consent form. (ICH 1.28)

47. © 2004 Aeras Global TB Vaccine Foundation 47 According to the ICH GCP Guidelines 4.8.5.. “The investigator, or a person designated by the investigator, should fully inform the participant/legal representative, of all pertinent aspects of the trial……” Who Is Responsible For Performing The Informed Consent Procedure?

48. © 2004 Aeras Global TB Vaccine Foundation 48 The Rules Of The Informed Consent Process ICH GCP GUIDELINES 4.8 (see attached handout)

49. © 2004 Aeras Global TB Vaccine Foundation 49 No study procedures are allowed before the informed consent process is complete and the informed consent document is signed.

50. © 2004 Aeras Global TB Vaccine Foundation 50 ? Projects/Trials ? ? OBJECTIVES ? CCS Adoll. BCG HIV BCG RCT PHASE I TB HIV Neo- natal

51. © 2004 Aeras Global TB Vaccine Foundation 51 Other Relevant Definitions To Make The Protocol a Little Clearer:  Study Population: Entire group of individuals that has common characteristics designated by the researcher.  Inclusion/Exclusion criteria: The medical or social standards determining whether a person may or may not be allowed to enter a clinical trial.

52. © 2004 Aeras Global TB Vaccine Foundation 52 Using Your Current Study Protocol: Find the Following and Explain…….  Study title  Primary objectives  Secondary objectives  Study population  Inclusion criteria  Exclusion criteria

53. © 2004 Aeras Global TB Vaccine Foundation 53 Review Clinical research is performed on human volunteers and is used to answer specific questions with the ultimate goal of improving human health. Clinical research is performed on human volunteers and is used to answer specific questions with the ultimate goal of improving human health. The research team follows SOP’s to ensure uniformity within a research study. The research team follows SOP’s to ensure uniformity within a research study. There are 5 types of clinical research trials. There are 5 types of clinical research trials.

54. © 2004 Aeras Global TB Vaccine Foundation 54 Review The protocol is the study plan. If we would want to change anything in this plan we need to amend it by using the correct process. The protocol is the study plan. If we would want to change anything in this plan we need to amend it by using the correct process. Compliance with GCP and GLP ensures valid research data and protects the participants against research misconduct. Compliance with GCP and GLP ensures valid research data and protects the participants against research misconduct. Research is regulated by various committees and regulatory bodies to ensure compliance with ethics and standards. Research is regulated by various committees and regulatory bodies to ensure compliance with ethics and standards. Data collection is an important part of the research process. Data is captured on specified CRF’s. Data collection is an important part of the research process. Data is captured on specified CRF’s.

55. © 2004 Aeras Global TB Vaccine Foundation 55 Review Proper completion of study documentation is critical to compliance with GCP and GLP. It also helps ensures valid study results. Proper completion of study documentation is critical to compliance with GCP and GLP. It also helps ensures valid study results. The informed consent process, where participants are fully informed about details of the study, is key to protecting the rights of research participants. The informed consent process, where participants are fully informed about details of the study, is key to protecting the rights of research participants. No study procedures are allowed to happen before the informed consent documents have been signed. No study procedures are allowed to happen before the informed consent documents have been signed. Each clinical research trial has a unique goal. It is important for you to understand the goal of the trial you are working on, so you can best support the trial goals in your routine work. Each clinical research trial has a unique goal. It is important for you to understand the goal of the trial you are working on, so you can best support the trial goals in your routine work.

56. © 2004 Aeras Global TB Vaccine Foundation 56 Clinical Research Practice 1 This presentation is produced by Aeras Global TB Vaccine Foundation SM in collaboration with the University of Cape Town and the South African Tuberculosis Vaccine Initiative. A special thanks to Professor Greg Hussey, Dr. Tony Hawkridge, MBChB, Deon Minnies, Lucrecia Michaels, Marie Buchanan, Marijke Geldenhuys, MSHS CRA, Dr. Sylvia Silver, D.A., and Jen Page, M.Ed. for their contributions and support for this presentation.