Good Clinical Practice GCP

1. Good Clinical Practice (GCP) Kelly Robertson, RN, BSN, CCRP Assistant Director, Clinical Research, MHMC

2. Objectives Review research and development process Review trial design measurements IND drugs Early stopping rules Good clinical practice

3. Research & Development Process Includes all of the activities required to move the Investigational Product from discovery to market Discovery Pre-clinical testing Permission to test in humans Phase I, II, III testing Process & interpret the data Obtain approval to market the product Market the product Phase IV testing

4. Key Players in a Clinical Trial Sponsor Investigation Site Team IRB/IEC Regulatory Authority/Competent Authority Subject/Participant Contract Research Organization

5. Trial Design:Measurements Safety Efficacy Primary endpoint/objective Secondary endpoint/objective

6. Trial Design:Blind or Open Blind Single Blind Double Blind Open or open-label All parties know the identity of the subject�s treatment

7. Trial Design:Randomization Treatment assigned by some element of chance. Treatment groups may be stratified (divided) into different sub-groups based on characteristics such as age, gender, and race.

8. Trial Design:Sample Size An adequate sample includes a population large enough to make generalizations from the data. Statisticians will help answer question

9. Clinical Testing:Timeline

10. IND Requirements Must show the drug is safe for clinical trials Required for all clinical trials, except Drugs not subject to pre-market approval Approved drugs

11. Stopping the Clinical Trial Development can be stopped at any time Safety Efficacy Business Reasons/$$$ Clinical trial can be halted at one site or all Clinical trial can be halted by the PI, IRB/IEC, Sponsor, or the CRO

12. International Conference on Harmonization (ICH)

13. Objectives of ICH guidelines Provide a unified standard EU; US; Japan To facilitate mutual acceptance of clinical data Developed in accordance with existing standards in US, EU, Australia, Canada, Nordic Countries, and WHO

14. Good Clinical Practice Definition � a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected.� (ICH GCP)

17. Principles of ICH GCP Conduct trials according to GCP Weigh risks vs. benefits Protect the subjects Have adequate information to justify trial Write a sound protocol Receive IRB/IEC approval Use qualified physicians

18. Form FDA 1572 Contract between FDA and the Investigator Includes logistics such as names and addresses Section 9 Commitments of the Investigator

19. ICH GCP Glossary Principles of ICH GCP Information regarding IRB/IEC Investigator Sponsor Protocol Investigator�s Brochure Essential Document

20. GCP-ICH-Glossary: Definitions related to clinical study issues Investigator Monitoring Monitoring report Multicenter trial Nonclinical study Protocol Randomization Sponsor Sponsor-initiated Subinvestigator Case Report Forms (CRF) Clinical study report Clinical trial Coordinating investigator Identification code (of trial subjects) Interim clinical study report Investigational product Subject Trial Site

21. GCP-ICH-Glossary: Definitions related to safety issues Adverse drug reaction (ADR) Adverse events (AE) Serious adverse events Unexpected adverse drug reaction

22. GCP-ICH-Glossary: Definitions related to regulatory issues Amendments Applicable regulatory requirement Contract Research Organization (CRO) Direct access Documentation Good clinical practice Institution (medical) Investigator Brochure Legally acceptable representative Standard operating procedures

23. GCP-ICH-Glossary: Definitions related to ethical issues Confidentiality Contract Impartial witness Institutional review board (IRB) Independent ethics committee (IEC) Informed consent Minimal risk Opinion Vulnerable subjects Well-being

24. GCP-ICH-Glossary: Definitions related to compliance/auditing issues Audit Audit certificate Audit report Compliance (in relation to trials) Inspection Quality assurance Quality control Source data Source documents

25. How to comply with ICH GCP Use qualified support staff Obtain informed consent Record information appropriately Protect confidentiality Handle investigational products appropriately Implement quality systems

27. Investigator Responsibilities * Ensure the study is conducted according to the investigator statement/agreement, protocol and regulatory requirements Ensure the protection of the participant�s rights, safety and welfare. Ensure the control of investigational drug. Obtain informed consent *(21 CFR 312.60 and 312.61)

28. Investigator Responsibilities Maintenance of records Investigator Qualifications and Agreements Adequate Resources Medical Care of Subjects Communication with IRB Compliance with protocol Investigational product Randomization Informed Consent Disposition of drug; Case histories; including CRF�s, ALL supporting data (research records, progress notes, labs, ECG�s, etc.) and consent Record retention Ensure accuracy, completeness, legibility and timeliness of data Data on CRF derived from source documents Changes made appropriately Allow direct access *(ICH 4.1-4.9) Financial disclosure IRB/IEC Compliance Make records accessible * (21CFR312.62, 312.64,312.66 &312.68 Qualified by education, training and experience Familiar with protocol, IB, IP Aware of and compliant with GCPs and applicable regs Permit monitoring List of qualified personnel who are delegated duties *(ICH 4.1-9) Recruit adequate subjects Sufficient time Qualified staff and adequate facilities Responsible for all trial related medical decisions *(ICH 4.1-4.9) Approvals Ensure compliance Proper delegation of duties *(ICH4.1-4.9) Disposition of drug; Case histories; including CRF�s, ALL supporting data (research records, progress notes, labs, ECG�s, etc.) and consent Record retention Ensure accuracy, completeness, legibility and timeliness of data Data on CRF derived from source documents Changes made appropriately Allow direct access *(ICH 4.1-4.9) Financial disclosure IRB/IEC Compliance Make records accessible * (21CFR312.62, 312.64,312.66 &312.68 Qualified by education, training and experience Familiar with protocol, IB, IP Aware of and compliant with GCPs and applicable regs Permit monitoring List of qualified personnel who are delegated duties *(ICH 4.1-9) Recruit adequate subjects Sufficient time Qualified staff and adequate facilities Responsible for all trial related medical decisions *(ICH 4.1-4.9) Approvals Ensure compliance Proper delegation of duties *(ICH4.1-4.9)

29. Regulatory Authorities will inquire about: Source of study subjects Did they have the disease under study Did the meet the eligibility criteria Was the protocol precisely followed Were AE�s reported appropriately

30. Common Findings via FDA and OHRP Failures to adhere to protocol Eligibility criteria Randomization Required efficacy tests Changes unauthorized by the sponsor

31. Common Findings via FDA and OHRP Failures to maintain adequate/accurate records Data changed to could not be verified Records destroyed or otherwise missing Medical course not documented

32. Common Findings via FDA and OHRP Failures to report concomitant therapy Failures to maintain drug acct. records Failures to obtain proper consent Verbal Obtained after admission

33. Common Findings via FDA and OHRP IRB failed to review the research at a convened meeting Investigators failed to promptly report unanticipated problems involving risks to subjects to IRB, OHRP, and sponsor Continuing review of research was NOT substantive nor meaningful

34. Common Findings via FDA and OHRP IRB did not ensure additional protections for vulnerable subjects IRB members inappropriately participated in new and continuing review of protocols of which they had a conflicting interest

36. Informed Consent An agreement between researchers and participants A mutual commitment Both parties agree to�

37. ICH GCP Principles of the Informed Consent Process The investigator must comply with all applicable regulations The investigator must obtain prior written IRB/IEC approval of the consent form, and any other information given to the participant The informed consent process must be free of any coercion or undue influence

38. Informed Consent Process The investigator must provide �want to know� information to participant, including risks and benefits Clinical trial information must be presented in a way that ensures understanding Subjects must have adequate time to ask questions and get answers

39. Informed Consent Process Subjects must understand that they are able to withdraw consent at any time The informed consent form/process must contain no language that implies the waiver of rights The consenting process must be clearly documented in the subject�s chart

40. Informed Consent Document Templates are provided by the sponsor (MH, or pharmaceutical companies) Templates may be modified by the site to meet the local requirements

41. Informed Consent Document Must contain elements of informed consent relevant to your clinical trial Protocol title Version date of the consent form Page numbers Participant signature line

42. Informed Consent Review/Approval IRB must approve the form prior to use by any subject IRB must approve of all information provided to participants including written material such as handouts or brochures, verbal instruction and videotapes

43. Signatures Participants must sign and date the most current IRB approved form The person administering the consent signs and dates the form The investigator and/or a witness may sign and date Participants are given a copy of the consent form and the originals are filed with the participants� records

44. Special Circumstances Vulnerable participants May have a legal representative Underage participants Must have a parent or legal guardian sign the consent form Depending on the age of the subject, assent may be required Problems with literacy A witness must be present

45. Common Consenting Errors State and local requirements for legally authorized representatives are not adhered to Informed consent form is not properly signed and dated as indicated on the form and according to the regulations Subject signing informed consents that sections of the consent have been crossed out

46. Common Consenting Errors Subject not signing informed consent prior to administration of protocol required procedures. Subjects are provided the informed consent document, but are told to read and sign it without opportunity to ask questions or obtain clarification Document not approved by the IRB or is an outdated version

48. Adverse Events What are Adverse Events? Any untoward medical occurrence in a clinical trial participant who has received test article/intervention that may or may not have a causal relationship with this treatment

49. Adverse Events Why is complete, accurate reporting of AE data important? Allows timely methodical evaluation of clinical safety data for clinical trial participants both individually and as a group Maximizes individual participation safety Develops accurate drug toxicity profiles Compliance with regulatory requirements

50. Intensity of the Event All adverse events will be assessed by a sponsor and/or protocol defined grading system The following guidelines are often used to quantify intensity Mild: events require minimal or no treatment and do not interfere with the patient�s daily activities Grade I

51. Intensity of the Event Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interterence with functioning Grade II Severe: events interrupt a patient�s usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating Grade III

52. Intensity of the Event Life threatening: any adverse drug experience that places the patient or subject in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death Grade IV Death Grade V

53. Relationship to study products All adverse events must have their relationship to study product assessed using the following terms: Definitely Related Probably Related Possibly Related Probably Not Related Not Related Pending (temporary assignment for death)

54. Association with Study Product Determination of association with the study product must be done by a qualified staff member What makes someone qualified to assess association with a study product?

55. SAE Definition ANY adverse event that at any dose: Results in death Is life threatening Requires inpatient hospitalization or prolongs hospitalization

56. SAE Definition Results in persistent or significant disability/incapacity Is a congenital anomaly or birth defect Important medical event Other conditions as specified in the protocol 21 CFR 312.32

57. Reporting Timeframes Per MH IRB Internal AE �unexpected and related-report in 10 days External AE-serious and unexpected and related-report in 10 days Death-Report within 24 hours of discovery Must be reported within 24 hours If patient died within 30 days of participating and is deemed related to study

58. Resolution of Event All AE/SAE should be followed: Until event has stabilized Condition returns to baseline Condition is resolved Condition no longer meets the SAE criteria

59. Trends Adverse events and serious adverse events are reviewed throughout the course of all clinical trials for potential trends Review of these �data snapshots� allows for identification of potential trends which can be related to: Concomitant medications Toxicities Secondary indications

60. Summary/Investigator Responsibilities Report all SAEs per sponsor/protocol defined timelines Notify IRB of AEs/SAEs per IRB policy Comply with all applicable regulatory requirements related to the reporting of unexpected serious adverse events

62. Working Definition of Source Documents All written and printed documents that are pertinent to a research participant�s: Exposure to the investigational agents Exposure to other treatments Progress of the disease course Response to therapy

63. Definitions Source Documents are �original documents, data, and records� and may include: Hospital records, clinic charts, laboratory notes, memoranda, subject diaries, x-rays, subject file

64. Deviations from Protocol Referred to as Protocol Violations and/or Protocol Deviation/Departures Occur when there is non-adherence to Protocol All deviations from Protocol must be addressed in clinical trial subject source document The documentation should include the reasons for the deviation and all attempts to prevent or correct them

65. Electronic Medical Records Monitors are permitted at MH to have direct access into the Epic system if a DRA amendment has been approved by the IRB Copies of electronic medical records DO NOT need to be certified for the sponsors to accept them

66. Verifying Source Documents Ensure that source data are complete, accounted for, follow a logical sequence of events Ensure that source data support entries in CRF

67. Protocol Required Documentation All inclusion/exclusion criteria be addressed Clinical trial required tests and procedures done on time or if not, why not Withdrawals, dropouts, lost to follow up AEs/SAEs properly documented/reported Endpoints of the clinical trial

68. Resources 21 CFR 11 21 CFR 312.62 ICH section 4.9,5.5 FDA form 3500A Medwatch 21 CFR 312.32 ICH section 4.11, 5.16, 5.17 and 7.3 ICH E2A 21 CFR 50 21 CFR 312.60 ICH 4.8 ICH 5.18.4e 45 CFR 46