1. 11 “So You Think You Know GCP...” Professional Development Session S049 Sunday, 15 April 2012

2. 22 Presenters Jill Matzat, RN, BSN, CCRA – President, Medical Research Management, Inc. and CRA Solutions, Inc. Paul Below, MS, CCRA – Contract Clinical Project Leader, American Medical Systems, Inc. – Principal, P. Below Consulting, Inc. and GCP Training Specialists, CCRT, CCRT

3. 33 Disclosure Neither Jill nor Paul have a relevant financial relationship in relation to this educational activity

4. 4 Background This presentation was developed to correct numerous errors and myths about Good Clinical Practice overheard by the presenters throughout their clinical research careers

5. 55 Are you sure this is right? I’ve never been asked to document it this way before. Yes, you have to do it this way. It’s an FDA requirement. 5

6. 66 I never heard of this FDA requirement before but it must be true. He is the monitor and he should know … I wouldn’t count on it 6

7. 77 Learning Objectives Define Good Clinical Practice (GCP) Differentiate between GCP requirements (stated in regulation) and recommendations (stated in guidance documents) in several key areas Identify several circumstances where “industry best practices” exist that go above and beyond what the FDA requires or even recommends

8. 8 What is Good Clinical Practice (GCP)? Good Clinical Practice (GCP) is a unified standard for designing, conducting, recording, and reporting trials that involve human subjects GCP is composed of many parts that cannot be found in any one book or place

9. 99 Sample Title Sample Text 9 GCP Other Federal Regulations FDA Regulations (21 CFR) State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices

10. 10 Sample Title Sample Text 10 GCP Other Federal Regulations State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices Informed Consent (21 CFR 50) Institutional review boards (21 CFR 56) Financial disclosure (21 CFR 54) Electronics records and signatures (21 CFR 11) Investigational new drugs (21 CFR 312) and application to market a new drug (21 CFR 314) Investigational device exemptions (21 CFR 812) & premarket approval of medical devices (21 CFR 814) Informed Consent (21 CFR 50) Institutional review boards (21 CFR 56) Financial disclosure (21 CFR 54) Electronics records and signatures (21 CFR 11) Investigational new drugs (21 CFR 312) and application to market a new drug (21 CFR 314) Investigational device exemptions (21 CFR 812) & premarket approval of medical devices (21 CFR 814) FDA Regulations (21 CFR)

11. 11 Sample Title Sample Text 11 GCP State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices FDA Regulations (21 CFR) Nuclear Regulatory Commission regulations for the medical use of radioactive substances (10 CFR 35 and 21 CFR 361) Department of Transportation regulations for the shipment of hazardous materials (49 CFR) HIPAA Privacy Rule (45 CFR 160-164) for the use and disclosure of protected health information “Common Rule” (45 CFR 46) - Human subjects protection rules for federally funded research Nuclear Regulatory Commission regulations for the medical use of radioactive substances (10 CFR 35 and 21 CFR 361) Department of Transportation regulations for the shipment of hazardous materials (49 CFR) HIPAA Privacy Rule (45 CFR 160-164) for the use and disclosure of protected health information “Common Rule” (45 CFR 46) - Human subjects protection rules for federally funded research Other Federal Regulations

12. 12 Sample Title Sample Text 12 GCP Other Federal Regulations State Law Local Law (Institutional and IRB Policies) International Standards Sponsor SOPs Industry Best Practices FDA Regulations (21 CFR) FDA Information Sheets ICH Guidelines for Good Clinical Practice (1997) Investigator Responsibilities (2009) Adverse Event Reporting to IRBs (2009) FAQs on the Form FDA 1572 (2010) Risk-Based Approach to Monitoring (Draft, 2011) FDA Information Sheets ICH Guidelines for Good Clinical Practice (1997) Investigator Responsibilities (2009) Adverse Event Reporting to IRBs (2009) FAQs on the Form FDA 1572 (2010) Risk-Based Approach to Monitoring (Draft, 2011) FDA Guidance Documents

13. 13 Sample Title Sample Text 13 GCP Other Federal Regulations State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents Sponsor SOPs Industry Best Practices FDA Regulations (21 CFR) Ethical Doctrines: Declaration of Helsinki Nuremberg Code Clinical Research Guidelines: ICH Guidelines for GCP (E6) ICH Guidelines for Safety Reporting (E2A) ISO 14155 – Medical Devices EU Directives Country-Specific Requirements Ethical Doctrines: Declaration of Helsinki Nuremberg Code Clinical Research Guidelines: ICH Guidelines for GCP (E6) ICH Guidelines for Safety Reporting (E2A) ISO 14155 – Medical Devices EU Directives Country-Specific Requirements International Standards

14. 14 Sample Title Sample Text 14 GCP Other Federal Regulations Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices FDA Regulations (21 CFR) Age of consent Legally authorized representatives Clinical research registration Medical records privacy Gene research STD/HIV reporting Gifts to practitioners Age of consent Legally authorized representatives Clinical research registration Medical records privacy Gene research STD/HIV reporting Gifts to practitioners State Laws

15. 15 GCP Other Federal Regulations State Law FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices FDA Regulations (21 CFR) Institutional Policies: Internal Protocol Review Committee Approval Investigational Product Storage / Dispensing Personnel Training Requirements IRB Policies: Protocol Deviation Reporting Requirements SAE Reporting Requirements Frequency of Continuing Review and Reporting Format Informed Consent Requirements Institutional Policies: Internal Protocol Review Committee Approval Investigational Product Storage / Dispensing Personnel Training Requirements IRB Policies: Protocol Deviation Reporting Requirements SAE Reporting Requirements Frequency of Continuing Review and Reporting Format Informed Consent Requirements Local Law (Institutional and IRB Policies)

16. 16 Sample Title Sample Text 16 GCP Other Federal Regulations State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Industry Best Practices FDA Regulations (21 CFR) CRF Completion Guidelines SAE Reporting Requirements Regulatory Document Organization Sponsor-Specific Form Completion Source Documentation Practices Investigator Signature Requirements Investigational Product Storage and Accountability Requirements CRF Completion Guidelines SAE Reporting Requirements Regulatory Document Organization Sponsor-Specific Form Completion Source Documentation Practices Investigator Signature Requirements Investigational Product Storage and Accountability Requirements Sponsor SOPs

17. 17 Sample Text 17 GCP Other Federal Regulations State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs FDA Regulations (21 CFR) Good Documentation Practices GCP Training Requirements Site SAE Reporting Requirements Investigational Product Storage Handling Lost to Follow-Up Subjects Curriculum Vitae Requirements Form 1572 and Clinical Investigator Agreement Requirements Good Documentation Practices GCP Training Requirements Site SAE Reporting Requirements Investigational Product Storage Handling Lost to Follow-Up Subjects Curriculum Vitae Requirements Form 1572 and Clinical Investigator Agreement Requirements Industry Best Practices

18. 18 Sample Title Sample Text 18 GCP Other Federal Regulations FDA Regulations (21 CFR) State Law Local Law (Institutional and IRB Policies) FDA Guidance Documents International Standards Sponsor SOPs Industry Best Practices

19. 19 Learning all of the parts of GCP can take some time and may seem daunting to those new to the clinical research industry

20. 20 Time to Test Your GCP Knowledge

21. 21 The following slides are a series of questions to test your knowledge of GCP You will be able to submit your answers by text messaging or through the web All answers are anonymous (no one is identified by name or phone number) 21

22. 22 How to Vote by Text Message Example Question: What is your favorite color? Red(72612) Blue(72613) Green(72614) Orange(72615) To vote, text the corresponding keyword to 22333 NOTE: Standard carrier text messaging rates apply but there are no additional fees to participate in the quiz

23. 23 How to Vote Through the Web Example Question: What is your favorite color? Red Blue Green Orange To vote, go to: PollEv.com/ACRP2012 NOTE: Standard carrier data usage charges apply but there are no additional fees to participate in the quiz

24. 24 Informed Consent Questions

25. 25 FDA Regulations (21 CFR 50) specify the following: QuestionKeyword The ICF must be signed and dated by the subject 118968 The ICF must be signed and dated by the person obtaining consent 118969 The ICF must be signed and dated by the Principal Investigator 118970 The ICF must be signed by a child subject if the IRB determines that assent is required 118972 All of the above 118973 Question 25

26. 26 FDA Regulations (21 CFR 50) specify the following: QuestionKeyword The ICF must be signed and dated by the subject 118968 The ICF must be signed and dated by the person obtaining consent 118969 The ICF must be signed and dated by the Principal Investigator 118970 The ICF must be signed by a child subject if the IRB determines that assent is required 118972 All of the above 118973 Text your answer (keyword) to 22333 or go to PollEv.com/ACRP2012 to vote Question 26

27. 27 Poll Results

28. 28 FDA Regulations (21 CFR 50) specify the following: QuestionKeyword The ICF must be signed and dated by the subject 118968 The ICF must be signed and dated by the person obtaining consent 118969 The ICF must be signed and dated by the Principal Investigator 118970 The ICF must be signed by a child subject if the IRB determines that assent is required 118972 All of the above 118973 Specified in 21 CFR 50.27a Answer 28

29. 29 The ICF must be signed and dated by the person obtaining consent – Specified by ICH GCP (4.8.8). The ICF must be signed and dated by the Principal Investigator – Not specified by FDA Regulation or Guidance but sometimes required by IRBs. The ICF must be signed by a child subject if the IRB determines that assent is required – The method of documenting assent is determined by the IRB (21 CFR 50.55) and does not necessarily have to be by child signature. Explanation

30. 30 FDA Guidance (Guide to Informed Consent Info Sheet & ICH GCP) specifies the following: QuestionKeyword The ICF should be written at a 6 th grade reading level41600 When it is anticipated that consent interviews will be conducted in a foreign language, a translated ICF should be prepared 41604 A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial 41704 All study personnel involved in the informed consent process should be trained in Human Subjects Protection 41740 All of the above 41871 Question

31. 31 Poll Results

32. 32 FDA Guidance (Guide to Informed Consent Info Sheet & ICH GCP) specifies the following: QuestionKeyword The ICF should be written at a 6 th grade reading level41600 When it is anticipated that consent interviews will be conducted in a foreign language, a translated ICF should be prepared 41604 A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial 41704 All study personnel involved in the informed consent process should be trained in Human Subjects Protection 41740 All of the above 41871 Answer 32 However, the Guide to Informed Consent indicates that if a non-English speaking subject is unexpectedly encountered, investigators will not have a written translation of the ICF and must rely on oral translation.

33. 33 The ICF should be written at a 6th grade reading level – No specific grade level requirement is defined. Instead, the FDA Information Sheets say: “The IRB should ensure that technical and scientific terms are adequately explained or that common terms are substituted. The IRB should ensure that the informed consent document properly translates complex scientific concepts into simple concepts that the typical subject can read and comprehend.” Similarly, ICH (4.8.6) specifies that the consent language should be “as non-technical as practical and should be understandable to the subject.” Explanation 33

34. 34 A subject who can understand and comprehend spoken English, but is physically unable to talk or write, should not be enrolled in a clinical trial – They can be enrolled if an impartial witness is present during the entire informed consent discussion. All study personnel involved in the informed consent process should be trained in Human Subjects Protection – Required for NIH studies but not currently specified by FDA. Explanation 34

35. 35 Financial Disclosure Question

36. 36 FDA Regulations (21 CFR 54) specify the following: QuestionKeyword Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials 47817 Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial 47914 Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria) 47915 In general, financial disclosure is not required for large open safety studies conducted at multiple sites 48364 None of the above 48393 Question 36

37. 37 Poll Results

38. 38 FDA Regulations (21 CFR 54) specify the following: Question Keyword Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials 47817 Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial 47914 Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria) 47915 In general, financial disclosure is not required for large open safety studies conducted at multiple sites 48364 None of the above 48393 Answer Specified in 21 CFR 54.2e. Financial disclosure applies to any study of a drug or device in humans submitted in a marketing application that the applicant or FDA relies on to establish efficacy or any study in which a single investigator makes a significant contribution to the demonstration of safety. 38

39. 39 Part- or full-time employees of the sponsor may not participate as Clinical Investigators in that sponsor’s trials – This is allowed but financial disclosure is required. Clinical Investigators may not have a proprietary interest (i.e., patents, royalties) in the tested product in a trial – Same as above. Clinical Investigators may not receive more than $25,000 a year in “payments of other sorts” (i.e., grants, consulting fees, speaker honoraria) – Same as above. Explanation 39

40. 40 Sponsors may include individuals as Investigators who have these financial interests but they have to explain any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments (21 CFR 54.4a) FDA then decides if the steps are adequate to ensure the reliability of the study (21 CFR 54.5a) Interestingly, there is no requirement for financial disclosure by monitors or other sponsor personnel who have the capacity to bias the data Explanation 40

41. 41 IRB Question

42. 42 FDA Regulations (21 CFR 56) specify the following: QuestionKeyword An IRB must be composed of five (5) members 9820 An IRB must have at least one female member 9855 If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board 9858 An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings 10017 None of the above 10265 Question 42

43. 43 Poll Results

44. 44 FDA Regulations (21 CFR 56) specify the following: QuestionKeyword An IRB must be composed of five (5) members 9820 An IRB must have at least one female member 9855 If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board 9858 An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings 10017 None of the above 10265 Answer 44

45. 45 An IRB must be composed of five (5) members – Must have at least 5 members (21 CFR 56.107a). An IRB must have at least one female member – The FDA Regulations (21 CFR 56.107b) specify: “Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender.” Explanation 45

46. 46 If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board – Consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects (21 CFR 56.107a). An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings – These individuals can participate in order to provide information requested by the IRB (21 CFR 56.107e). Explanation 46

47. 47 Monitoring Question

48. 48 FDA Guidance (ICH GCP) specifies the following: QuestionKeyword A monitoring report should be submitted to the sponsor after each site visit or trial-related communication 92521 Monitors should not make any notations or corrections on the CRF pages 93121 Monitors should ensure that all corrections to the CRF are completed with a single line through the incorrect entry and initiated and dated by the completer 93342 Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial 93345 All of the above 93348 Question 48

49. 49 Poll Results

50. 50 FDA Guidance (ICH GCP) specifies the following: QuestionKeyword A monitoring report should be submitted to the sponsor after each site visit or trial-related communication 92521 Monitors should not make any notations or corrections on the CRF pages 93121 Monitors should ensure that all corrections to the CRF are completed with a single line through the entry and are initiated and dated by the completer 93342 Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial 93345 All of the above 93348 Answer Specified in ICH 5.18.6a 50

51. 51 Monitors should not make any notations or corrections on the CRF pages – Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator (ICH 4.9.3). Monitors should ensure that all corrections to the CRF are completed with a single line through the entry and are initiated and dated by the completer – Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (ICH 4.9.3). Explanation 51

52. 52 Monitors should attempt to meet in person with the Investigator at every visit to discuss the progress of the trial – There are several sections of ICH that address the monitors responsibility to communicate with the Investigator but the frequency of these communications is not specified (ICH 5.18.4). This is often specified in sponsor SOPs. Explanation 52

53. 53 Source Documentation Question

54. 54 FDA Regulations (21 CFR 312/812) specify the following: QuestionKeyword It is prohibited to use CRFs (other than questionnaires) directly as source documents 186220 Each subject’s case history should document that informed consent was obtained prior to participation in the study 186239 All source documents must be signed by the completer 186240 If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11 186241 All of the above 186242 Question 54

55. 55 Poll Results

56. 56 FDA Regulations (21 CFR 312/812) specify the following: QuestionKeyword It is prohibited to use CRFs (other than questionnaires) directly as source documents 186220 Each subject’s case history should document that informed consent was obtained prior to participation in the study 186239 All source documents must be signed by the completer 186240 If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11 186241 All of the above 186242 Answer 56 Specified in both 21 CFR 312.62b and 812.140a. “Case histories” include CRFs, signed and dated consent forms, and medical records (physician progress notes, individual's hospital chart and the nursing notes)

57. 57 It is prohibited to use CRFs (other than questionnaires) directly as source documents – There is no regulation preventing this practice or from using copies of CRFs as source documents. All source documents must be signed by the completer – There is no requirement for this but several FDA Guidances do specify that data should be “attributable.” Explanation 57

58. 58 If a site uses electronic medical records as source documents, the EMR system must be compliant with 21 CFR part 11 – There is currently no FDA Regulation or Guidance specifying this. However, a recent FDA Draft Guidance does indicate: “For those who use electronic signatures based upon the use of identification codes in combination with passwords, the clinical site must employ controls to ensure the security and integrity of the authorized user names and passwords (21 CFR 11.300a).” Draft Guidance on Electronic Source Documentation in Clinical Investigations (December 2010) Explanation 58

59. 59 Investigator Responsibilities Question

60. 60 FDA Guidance specifies the following: QuestionKeyword A Trial Delegation List should identify the training that individuals have received that qualifies them to perform delegated tasks 187191 In device studies, the field clinical engineer’s activities should be described in the protocol and informed consent (if face-to-face contact with subjects) 187193 Investigators should develop a plan for the oversight of the clinical trial that might include the creation of specific SOPs 187214 Investigators conducting studies of drugs with potentially fatal toxicity should be readily available 24 hours/day and in reasonably close proximity to study subjects 187219 All of the above 187241 Question 60

61. 61 Poll Results

62. 62 FDA Guidance specifies the following: QuestionKeyword A Trial Delegation List should identify the training that individuals have received that qualifies them to perform delegated tasks 187191 In device studies, the field clinical engineer’s activities should be described in the protocol and informed consent (if face-to-face contact with subjects) 187193 Investigators should develop a plan for the oversight of the clinical trial that might include the creation of specific SOPs 187214 Investigators conducting studies of drugs with potentially fatal toxicity should be readily available 24 hours/day and in reasonably close proximity to study subjects 187219 All of the above 187241 Answer 62

63. 63 Study Records Storage Question

64. 64 FDA Regulations (21 CFR 312/812) and Guidance (ICH GCP) specify the following: QuestionKeyword It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained 187650 In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor 187653 Sponsors should pay for the costs of records storage by Investigators 187671 For device studies, an Investigator may transfer custody of study records to anyone who will accept responsibility for them 187672 None of the above 187677 Question 64

65. 65 Poll Results

66. 66 FDA Regulations (21 CFR 312/812) and Guidance (ICH GCP) specify the following: QuestionKeyword It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained 187650 In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor 187653 Sponsors should pay for the costs of records storage by Investigators 187671 For device studies, an Investigator may transfer custody of study records to anyone who will accept responsibility for them 187672 None of the above 187677 Answer 66 Specified in 21 CFR 812.140e (however, there is no comparable language in Part 312)

67. 67 It is the Investigator’s responsibility to inquire with the sponsor when study records no longer need to be retained – Per ICH 4.9.5, it is sponsor’s responsibility to do so. In addition, ICH 5.5.12, indicates: “The sponsor should inform the investigators/ institutions in writing of the need for record retention and should notify the investigators/institutions in writing when the trial related records are no longer needed.” Explanation 67

68. 68 In general, study records should be obtained indefinitely because it is never certain when product development will be permanently discontinued by the sponsor – The FDA Regulations and ICH GCP both have criteria for retention that are well defined. The current reality is that sites and sponsors usually plan to hold onto records for many decades. Explanation 68

69. 69 Sponsors should pay for the costs of records storage by Investigators – There is no FDA Regulation or Guidance that address this but many experienced sites now demand this as a line item in their Clinical Trial Agreements. Explanation 69

70. 70 In Conclusion That doesn’t sound right to me. Where exactly is that listed in the CFR? Yes, you have to do it this way. It’s an FDA requirement.

71. 71 In Conclusion Well, uh … OK, maybe it’s not a regulation but it’s what the FDA expects. Well, uh … OK, maybe it’s not a regulation but it’s what the FDA expects. That still doesn’t sound right. What guidance document is that from?

72. 72 In Conclusion I’m not sure but it doesn’t matter. It’s a requirement of my sponsor company.

73. 73 In Conclusion OK, that’s fine. Why didn’t you just say so in the first place? I’m happy to do it to satisfy your company policy. You didn’t have to use those FDA excuses to justify your request.

74. 74 Learning Objectives Define Good Clinical Practice (GCP) Differentiate between GCP requirements (stated in regulation) and recommendations (stated in guidance documents) in several key areas Identify several circumstances where “industry best practices” exist that go above and beyond what the FDA requires or even recommends

75. 75 Closing Thoughts Much of what we do in clinical research is driven by our own industry best practices and not by FDA requirements or even recommendations It takes a serious effort to understand all of the component parts of GCP and to stay up-to-date with changes As sponsor representatives, we often act as trainers for new site staff and they rely on us to provide accurate information

76. 76 Closing Thoughts Be careful when telling an investigator site, “You have to do this because the FDA requires it” unless you are certain that it is specified by regulation – it can seem like a very heavy handed play if you are wrong The FDA requires it” “The FDA requires it” Compliance Toolbox

77. 77 Your Chance to Ask Us Questions

78. 78 Jill Matzat, RN, BSN, CCRA jmatzat@cra-training.com Paul Below, CCRA paul@gcp-training.net Complete poll results are available at: www.pbelow-consulting.com/gcp.html 78 You are welcome to use these slides for your own internal training purposes but they remain the copyrighted property of the presenters. Please contact Paul or Jill for permission to reuse.

79. 79 Thank You!