RTRN Good Clinical Practice Series Coordinated by Mayer B. Davidson, M.D., Charles Drew University Federal Regulations

1. RTRN Good Clinical Practice SeriesCoordinated byMayer B. Davidson, M.D., Charles Drew UniversityFederal Regulations & Good Clinical Practices (GCPs) Susan Partridge, BSN, MBA, CCRC LA Biomedical Research Institute at Harbor-UCLA Medical Center

2. Speaker Disclosure Statement The speaker does not have any financial or personal interest that would conflict with any of the material presented in this lecture.

3. Why do we need to knowabout Federal Regulations and GCPs? Rules of the road for conducting research A national and international standard Adopted/endorsed by Sponsors of drug, biologics and device studies Federal agencies that fund research (NIH, CDC, NSF) Universities and research sites Professional research organizations

4. What is Good Clinical Practice? A standard for the design conduct performance monitoring auditing recording analysis, and reporting of clinical trials The definition above is the stated ICH definition for Good Clinical Practices.The definition above is the stated ICH definition for Good Clinical Practices.

5. What are GCPs? Based on a set of regulatory and ethical requirements, standards and recommendations that apply to thousands of tasks, processes and roles in the conduct of clinical research The current standard for the conduct of clinical trials

6. Why do we need to know about GCPs? Demonstrates high standards for the conduct of clinical research Required for studies (US or foreign) where data will be submitted to FDA for licensure Sponsors and study sites require evidence of training Essential for any research with human subjects � sponsored or unsponsored

7. The pillars of GCPs Good Clinical Practices are supported by 2 major pillars: Protection of Subject�s Rights and Promotion of Data Integrity. These 2 pillars form the basis for ethically and scientifically sound research, and both are necessary for a successful clinical trial. Data from a trial that was not obtained with adequate human subjects protections will not be published. Similarly, a trial that is conducted properly with human subjects protections will be worthless if the study design or data collection methods were flawed. Good Clinical Practices are supported by 2 major pillars: Protection of Subject�s Rights and Promotion of Data Integrity. These 2 pillars form the basis for ethically and scientifically sound research, and both are necessary for a successful clinical trial. Data from a trial that was not obtained with adequate human subjects protections will not be published. Similarly, a trial that is conducted properly with human subjects protections will be worthless if the study design or data collection methods were flawed.

8. Where did GCPs come from? The International Conference on Harmonization (ICH) � founded 1990 Develop a consensus among countries regarding the requirements for the conduct of clinical trials Harmonize efforts to help reduce drug development expense and duplication

9. Composition of ICH The International Conference on Harmonization is made up of ICH Co-Sponsors, International Federation of Pharmaceutical Manufacturers, and ICH Observers. The Co-Sponsors are the United States, Japan and the European Union. The U.S. Component is represented by the Food and Drug Administration and PhRMA. The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country�s leading pharmaceutical research and biotechnology companies.The International Conference on Harmonization is made up of ICH Co-Sponsors, International Federation of Pharmaceutical Manufacturers, and ICH Observers. The Co-Sponsors are the United States, Japan and the European Union. The U.S. Component is represented by the Food and Drug Administration and PhRMA. The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country�s leading pharmaceutical research and biotechnology companies.

10. Advantages of ICH for the pharmaceutical industry Mutual acceptance of data in many countries Ensures the credibility of investigators and the validity of the data New Drug Application (NDA) data to be presented in a standardized format Review time for drug applications shortened Reduction in drug development time Reduction in cost and use of resources

13. What are GCPs based on? Code of Federal Regulations Title 21 (FDA) Part 11 Electronic Records; Electronic Signature Part 50 Protection of Human Subjects Part 54 Financial Disclosure by Clinical Investigators Part 56 Institutional Review Boards Part 312 Investigational New Drug Application Title 45 (HHS) Part 46 Protection of Human Subjects (DHHS) Good Clinical Practices can be found in the Federal Regulations listed above, FDA Information Sheets, FDA Guidelines, the ICH E6 Guideline for GCP and the NIH Guidelines on the Inclusion of Women and Minorities in Clinical Research. The Code of Federal Regulations (CFR) is the codification of the general and permanent rules and regulations (sometimes called administrative law) published in the Federal Register by the executive departments and agencies of the Federal Government of the United States. The CFR is published by the Office of the Federal Register, an agency of the National Archives and Records Administration (NARA). The CFR is divided into 50 titles that represent broad areas subject to Federal regulation. Administrative law exists because the United States Congress often grants broad authority to executive branch agencies to interpret the statutes in the United States Code (and in uncodified statutes) which the agencies are entrusted with enforcing. Under the Administrative Procedure Act, the agencies are permitted to promulgate detailed rules and regulations through a public "rulemaking" process where the public is allowed to comment, known as public information. After a period of time, the rules and regulations are usually published in the Federal Register. Good Clinical Practices can be found in the Federal Regulations listed above, FDA Information Sheets, FDA Guidelines, the ICH E6 Guideline for GCP and the NIH Guidelines on the Inclusion of Women and Minorities in Clinical Research. The Code of Federal Regulations (CFR) is the codification of the general and permanent rules and regulations (sometimes called administrative law) published in the Federal Register by the executive departments and agencies of the Federal Government of the United States. The CFR is published by the Office of the Federal Register, an agency of the National Archives and Records Administration (NARA). The CFR is divided into 50 titles that represent broad areas subject to Federal regulation. Administrative law exists because the United States Congress often grants broad authority to executive branch agencies to interpret the statutes in the United States Code (and in uncodified statutes) which the agencies are entrusted with enforcing. Under the Administrative Procedure Act, the agencies are permitted to promulgate detailed rules and regulations through a public "rulemaking" process where the public is allowed to comment, known as public information. After a period of time, the rules and regulations are usually published in the Federal Register.

14. ICH Guidelines:Where do GCPs fit in? Q Quality Topics E Efficacy Topics S Safety Topics M Multidisciplinary Topics Chemical & pharmaceutical quality assurance Clinical research in human subjects E6: Good Clinical Practices E7: Special populations E8: General considerations E9: Statistical principles for clinical trials E10: Choice of control group In vivo and in vitro pre-clinical studies M1 Medical terminology M2 Electronic standards for submission of data M3 Timing of pre-clinical studies in relation to clinical trials M4 The common technical document ICH Guidelines are organized into 4 major categories, with multiple guidelines included for each category. Quality topics are those related to chemical and pharmaceutical quality assurance. Example: Q1-Stability Testing, Q3 Impurity Testing Safety topics are thse related to in vitro and in vivo pre-clinical studies. Example: S1-Carcinogenicity Testing, S2-Genotoxicity Testing. Efficacy topics are those relating to clinical research studies in human subjects. Example: E2-Clinical Safety Data Management, E4-Dose Response Studies, E6-Good Clinical Practices. Multidisciplinary topics are cross-cutting topics that do not fit uniquely into one of the other categories. Example-M1-Medical Terminology, M2-Electronic Standards for Tramsmission of Regulatory Information. You can download copies of all of the ICH guidelines by visiting their website: www.ich.org. ICH Guidelines are organized into 4 major categories, with multiple guidelines included for each category. Quality topics are those related to chemical and pharmaceutical quality assurance. Example: Q1-Stability Testing, Q3 Impurity Testing Safety topics are thse related to in vitro and in vivo pre-clinical studies. Example: S1-Carcinogenicity Testing, S2-Genotoxicity Testing. Efficacy topics are those relating to clinical research studies in human subjects. Example: E2-Clinical Safety Data Management, E4-Dose Response Studies, E6-Good Clinical Practices. Multidisciplinary topics are cross-cutting topics that do not fit uniquely into one of the other categories. Example-M1-Medical Terminology, M2-Electronic Standards for Tramsmission of Regulatory Information. You can download copies of all of the ICH guidelines by visiting their website: www.ich.org.

15. Where Can IFind TheseDocuments?

16. GCPs at the research site Know the GCPs so you can be ready to discuss the basic requirement and any expectations above that requirement Document GCP training at your site Recognize that sponsors require that you follow their interpretation of GCPs (each funding agency has SOPs) If faced with different interpretations of GCPs, usually the more stringent criteria applies

17. GCP Contents Glossary Principles IRB/IEC Investigator Sponsor Protocol Investigator�s Brochure Essential Documents for the Conduct of a Trial

18. GCP Contents - Today Glossary Principles IRB/IEC Investigator Sponsor Protocol Investigator�s Brochure Essential Documents for the Conduct of a Trial

19. Future sessions May 11, 2011 Essential documents for clinical trials May 25, 2011 Data collection standards for clinical trials Other presenters Institutional Review Boards (IRB) and informed consent � Dr. Junko Nishitani Data and Safety Monitoring � Dr. Roger Lewis

20. Key Concepts: Principles 2.3 The rights, safety and well-being of trial subjects are the most important considerations and should prevail over interests of science and society 2.5 Clinical trials should be scientifically sound and described in a clear, detailed protocol 2.9 Each individual involved in conducting a clinical trial should be qualified by education, training, and experience to perform his or her respective task

22. Key Concepts: Protocol ICH Guidelines provide required content for a protocol Note: These guidelines can also be found in FDA regulations: 21 CFR 312.23 IND Content and Format

23. Key Concepts: Protocol 6.3 The protocol should contain a detailed description of the objectives & purpose of the trial The scientific integrity of the trial and the credibility of the data depend on trial design Primary and secondary endpoints Type of trial design (double-blind, placebo-controlled) Measures to minimize/avoid bias (randomization, blinding) Investigators who are preparing a protocol will find the GCP list helpful.Investigators who are preparing a protocol will find the GCP list helpful.

24. Protocol elements Dosing regimen of investigational product(s) Expected duration of subject participation Stopping rules for individual subjects, parts of the trial, entire trial Maintenance of randomization codes and procedures for breaking codes Subject inclusion, exclusion criteria Subject withdrawal criteria Procedures for eliciting reports of adverse events

25. Protocol elements Methods and timing for assessing, recording and analyzing safety parameters Description of statistical methods to be used, including planned interim analyses Sample size with description of the calculations used and justifications Description of selection of subjects to be included in the analyses Criteria for termination of the trial Ethical considerations

26. Application All versions of the study protocol: are submitted to the FDA (as part of the IND file) must be retained in the site study file must be submitted to the IRB for approval must be given to all members of the study team

27. There is a signature line in the protocol for the PI to sign. What is the PI affirming? A. The protocol was received B. The protocol was reviewed C. The terms of the protocol have been accepted by the investigator D. The protocol has been submitted to the IRB and other institutional departments Application

28. Answer

29. Resources NIH www.NIDCR.nih.gov www.NIAID.nih.gov University/research institute sites UTHSC � www.uth.tmc.edu

31. Investigator�s Brochure (IB) A compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects Purpose: To provide investigators and study personnel with information about the test product pre clinical and clinical data to date dose, frequency precautions metabolism, excretion potential adverse events

32. Application All versions of the IB: are submitted to the FDA (as part of the IND file) must be retained in the site study file must be submitted to the IRB (acknowledgement) must be given to all members of the study team IND safety reports are added to the IB Typically, the PI signs an IB receipt form

34. Key Concepts: Investigators GCPs have helped to define the role of study investigator as distinct from that of primary care physician Investigators are accountable to: Study subjects IRB Institution OHRP (Office of Human Research Protections) Sponsor For IND studies, FDA (Form 1572)

35. Investigators ICH Guidelines address: 4.1 Investigator qualifications 4.2 Adequacy of resources 4.3 Medical Care of trial subjects 4.4 Communication with IRB/IEC 4.5 Compliance with protocol 4.6 Investigational Product(s) 4.7 Randomization procedures and unblinding

36. Investigators ICH Guidelines address (con�t): 4.8 Informed consent of trial subjects 4.9 Records and reports 4.10 Progress reports 4.11 Safety reporting 4.12 Premature termination or suspension of a trial 4.13 Final report by investigator/institution

37. Investigators Investigator GCPs can also be found in: 21 CFR 50 Protection of Human Subjects 45 CFR 46 Protection of Human Subjects 21 CFR 56 Institutional Review Board 21 CFR 312.60-312.70 Responsibilities of investigators

38. Investigator responsibilities FDA Form 1572 Statement of Investigator (an agreement with the federal government)

39. FAQs About the 1572 Form

40. Key Concepts: Investigators 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties

41. Key Concepts: Investigators 4.2.1 The investigator should be able to demonstrate (based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period 4.2.3 The investigator should have an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely

42. Key Concepts: Investigators 4.3.2 During and following a subject�s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es)�.

43. Key Concepts: Investigators 4.5.1 The investigator should conduct the trial in compliance with the protocol� which was given favorable opinion by the IRB. The investigator should sign the protocol, or an alternative contract to confirm their agreement 4.5.3 The investigator, or person designated�, should document and explain any deviation from the approved protocol

44. Key Concepts: Investigators 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution 4.6.2 The investigator/ institution may assign some or all of the investigator�s/institution�s duties for investigational product(s) accountability � to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution

45. Who is responsible for the conduct of a study?

46. The Principal Investigator (PI) The PI is responsible for the integrity of the data at their site(s) and for the safety of the subjects By completing an FDA form 1572, the PI signs an legally binding agreement with the federal government Tasks can be delegated to others. Responsibility for the study cannot be delegated The PI is responsible for ensuring that no harm is done by failure to adhere to the protocol, failure to conformed to standards of care, or unnecessarily putting a patient at risk. The PI is responsible for ensuring that all persons working on the trial are qualified and have received adequate training. If something goes wrong during a trial, the PI cannot offer excuses of �I didn�t know� or �It was the nurse�s fault.� The ultimate responsibility rests with the PI. There are a tremendous number of tasks that must be completed to adequately meet Good Clinical Practice standards. Fortunately, clinical research coordinators, monitors and support personnel provide help with completing the various tasks. The PI is responsible for ensuring that no harm is done by failure to adhere to the protocol, failure to conformed to standards of care, or unnecessarily putting a patient at risk. The PI is responsible for ensuring that all persons working on the trial are qualified and have received adequate training. If something goes wrong during a trial, the PI cannot offer excuses of �I didn�t know� or �It was the nurse�s fault.� The ultimate responsibility rests with the PI. There are a tremendous number of tasks that must be completed to adequately meet Good Clinical Practice standards. Fortunately, clinical research coordinators, monitors and support personnel provide help with completing the various tasks.

47. Who is responsible for ensuring that individuals assisting with the study are adequately informed of the protocol, investigational product and the duties of the staff? A. Sponsor B. Monitor C. Site institution D. Investigator

49. Added FDA Guidance: Supervisory Responsibilities of Investigators Draft Guidance issued May 10, 2007 Federal Register Final version released October 30, 2009 Key to FDA approach in their oversight/audit of clinical trials

50. 4 Major Areas of Concern Are study personnel qualified to perform protocol activities? What is adequate training for study staff? What is adequate supervision of a clinical trial? What are investigator responsibilities for oversight of other parties involved in the conduct of a clinical trial?

51. Application: Demonstrateinvestigator involvement Develop SOPs that include the role of the PI Document communication with PI Copy on study related email and retain in regulatory binder Retain records of meetings/telephone discussions with PI (particularly related to subject eligibility or safety)

52. PI sign off on key documents Consent forms Case report form (study subject data) Serious adverse event reports Progress notes Protocol deviations Regulatory documents (1572, IRB correspondence, protocol signature page, IB signature page) Correspondence from sponsor Application

53. Hold regular project meetings; draft a quick list of topics and keep an attendance sheet. Document ongoing oversight during the trial (PI sign off on QA/QC reports, progress reports) Make sure the PI attends monitor debriefings (in person or by phone) Application

54. Application: Documentation of staff qualifications, PI delegation SOPs should document staff roles for various study procedures, including communications. On the Signature and Responsibility list, leave room for the PI to sign off In the Study Regulatory Binder, include evidence of personnel training and experience including CV, license, human subjects training, certificates, evidence of courses taken

55. Document individuals who attended training sessions. If they did not attend, document how they were trained and by whom. Training sessions for study procedures should include return demonstration. Extra effort should be made to document the roles and qualifications of collaborating site personnel who are not under the direct supervision of the PI. Application

56. Proposed FDA Rule for Disqualification of a Clinical Investigator Issued 4/13/2011 Amend the regulations to expand the scope of clinical investigator disqualification. When the FDA Commissioner determines that an investigator is ineligible to receive certain test articles (drugs, devices, or new animal drugs), the investigator also will be ineligible to conduct any clinical investigation� Comments are due July 12, 2011

58. Key Concepts: Sponsors A sponsor is an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial A sponsor-investigator is an individual who initiates and conducts a clinical trial. The obligations include both those of a sponsor and those of an investigator

59. Key Concepts: Sponsors 5.1.1 The sponsor is responsible for implementing and retaining quality assurance and quality control systems with written SOPs, to ensure that trials are conducted and data are generated� in compliance with the protocol, GCP�. A sponsor�s SOPs for the conduct of a clinical trial may be more stringent than GCP Guidelines. Upon signing the protocol and accepting a new study, the investigator is stating that they will comply with the sponsor SOPs.

60. Key Concepts: Sponsors & CROs 5.1.2 A sponsor may transfer any or all of the sponsor�s trial-related duties and functions to a Contract Research Organization (CRO). The CRO may be an individual or a company The ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor 5.2.2 Any transfer of activity to a CRO should be in writing. The CRO can only take on the sponsor tasks that are agreed to in a contract A CRO must abide by the same regulations as the sponsor

61. Key Concepts: Sponsors 5.5.2 The sponsor may consider establishing an independent data monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all of its meetings.

62. Key Concepts: Sponsors 5.6.1 The sponsor is responsible for selecting qualified investigators. 5.6.3 The sponsor should obtain the investigator�s/institution�s agreement: To conduct the trial in compliance with GCP and with the protocol To comply with procedures for data recording/reporting To permit monitoring, auditing and inspection To retain essential documents The sponsor and the investigator should sign the protocol to confirm this agreement

63. Key Concepts: Sponsors 5.14.2 The sponsor should not supply an investigator/institution with the investigational product until the sponsor obtains all of the required documentation. 5.14.4 The sponsor should Ensure timely delivery of investigational product(s) Maintain records that document shipment, receipt, disposition, return and destruction of the investigational product(s) Take steps to ensure that the investigational product is stable over the period of time

64. Key Concepts: Sponsors 5.14.5 (continued) Maintain sufficient quantities of the investigational product(s) to reconfirm specifications� and maintain records of batch sample analyses and characteristics 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s) 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s), to the IRB, and to the regulatory authorities all adverse drug reactions that are both serious and unexpected

65. Key Concepts: Sponsor Monitoring 5.18.1 The purposes of trial monitoring - to verify that: The rights and well-being of human subjects are protected The reported trial data are accurate, complete and verifiable from source documents The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with regulatory requirements

66. Key Concepts: Sponsor Monitoring 5.18.2 Monitors should be appointed by the sponsor 5.18.3 The sponsor should ensure that trials are adequately monitored (the sponsor determines the frequency and duration of monitoring) The monitor acts as the main line of communication between the sponsor and the investigator

67. Key Concepts: Monitor Responsibilities (GCP ICH 5.18.4) Verify that the investigator has adequate qualifications and resources Ensure that the investigator receives the current Investigator Brochure, all documents and all trial supplies needed Ensure that the investigator (and staff) are adequately informed about the trial

68. Key Concepts: Monitor Responsibilities Verify that informed consent was obtained for each subject Verify re: investigational product: Storage times and conditions are acceptable The investigational product is given only to subjects eligible to receive it The receipt, use and return of the investigational product at the trial sites are controlled and documented

69. Key Concepts: Monitor Responsibilities Data required by the protocol are reported accurately on the CRFs and are consistent with the source documents Adverse events, concomitant medications, and intercurrent illnesses are reported Visits that the subjects fail to attend, tests that are not conducted and examinations that are not performed are clearly documented Subject withdrawals and dropouts are reported and explained

70. Key Concepts: Monitor Responsibilities Informing the investigator of CRF entry errors, and ensuring that changes are made correctly and by an individual who is authorized to initial CRF changes for the investigator Determining whether all adverse events are appropriately reported within the time periods required by GCP, ICH Standards, IRB, sponsor Determining whether a site is maintaining essential documents (regulatory file)

71. Key Concepts: Sponsors Audits The purpose of an audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements

72. Sponsors Sponsor monitoring GCPs can also be found: Guideline for Monitoring of Clinical Investigations 21 CFR 312.55 Informing investigators 21 CFR 312.56 Review of ongoing investigations 21 CFR 312.62 Investigator record keeping and record retention 21 CFR 312.64 Investigator reports ICH GCP Guideline 5.18 Monitoring

73. Conclusions ICH Adopted GCP Guidelines have been in place for 14 years Provided more explicit instructions about the role of the sponsor and investigator Created a benchmark for conducting clinical research Used as an industry standard by FDA Universally accepted in the field of clinical research � now globally

74. Impact of ICH Guidelines Challenges Increased documentation & regulatory burden Need for increased training Growth of outsourced services (CROs, SMOs) Greater cost Positives Higher standards; greater consistency Basis for best practices Ability to accept foreign data and reduce redundancy in clinical trials

75. Wrap up Do you have GCP questions??? Email to spartridge@labiomed.org. Answers will be given during the next class.