1. GCP ICH Dr. Ghiath Alahmad

2. Goals and Objectives To understand: The affect of Good Clinical Practices on institutions conducting Clinical Research To discuss: What is GCP Guidelines for GCP The history of GCP Basic principles of GCP 3. ICH definition - GCP Monitoring Standard Design ReportingAuditing Recording AnalysesConduct Performance Clinical Trials Data and Reported Results are credible and accurate Rights, Integrity, & Confidentiality of Trial Subjects are protected 4. ICH-GCP ICH is the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH-GCP is Good Clinical Practice guidelines agreed at the conference ICH GCP 5. Derived from the International Conference on Harmonization (ICH) Based on the Declaration of Helsinki Assures protection of human subjects Assures unified, high standards for designing, conducting, recording and reporting trials Good Clinical Practices 6. Good Clinical Practices Applies to Clinical Data intended to be submitted to regulatory authorities Also applies to: Clinical Interventions Observational Studies 7. History of Good Clinical Practice The Nuremburg Code of 1947 Experiments performed in Germany during WWII opened the eyes of the world for guidance for clinical testing on humans. The code did set ethical guidelines, but it lacked legislation to back it up. Declaration of Helsinki In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. These guidelines influenced national legislation, but there was no set standard between nations Prior to an actual set of guidelines to follow for GCP Clinical Studies were Dangerous Serous Disease Possibly Death 8. Declaration of Helsinki Adapted from the Nuremberg Code by The World Medical Association to address the needs of the biomedical community First published in 1964, revised five time most recently in 2001 Lists 31 principles It is the international standard for the conduct of clinical research 9. Key Points: Declaration of Helsinki Concern for the interests of the subjects must always overcome over the interests of science and society The experimental protocol must be reviewed by a specially-appointed committee independent of the investigator and the sponsor. 10. Key Points: Declaration of Helsinki Distinguishes between research in which the aim is essentially diagnostic or therapeutic for a patient and research which is purely scientific Diagnostic & Therapeutic Purely Scientific 11. Key Points: Declaration of Helsinki In research which does not offer the hope of direct benefit to the participant is restricted to healthy volunteers or volunteers for whom the experimental design is not related to the patient illness. Diagnostic & Therapeutic Purely Scientific 12. History of Good Clinical Practice (Continued) The formation of the International Conference on Harmonization (ICH) led to the creation of the Consolidated Guidance on GCP The ICH consisted of the governments of the United States, EU and Japan coming together to develop common regulations for the pharmaceutical markets among member countries 13. Harmonization Process Japan EU ICH USA ICH 14. Milestones in Good Clinical Practice 1977 Federal Registers published in U.S. by FDA (Food and Drug Administration) 1986 UK published guidelines Good Clinical Research Practice 1987 France and Nordic Countries published laws 1990 European GCP Guidelines published 1996 International Conference on Harmonisation produced ICH GCP E6 document. 15. ICH Structure: founding parties European Commission - European Union (EU) European Federation of Pharmaceutical Industries' Associations (EFPIA) Ministry of Health, Labour and Welfare, Japan (MHW) Japan Pharmaceutical Manufacturers Association (JPMA) US Food and Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America (PhRMA) 16. The Observers The World Health Organization (WHO) The European Free Trade Association (EFTA), represented by Switzerland Canada, represented by Drugs Directorate, Health Canada The International Federation of Pharmaceutical Manufacturers Association (IFPMA) 17. ICH topics Q "Quality" Topics, i.e., those relating to pharmaceutical quality assurance (24 guidelines). S "Safety" Topics, i.e., those relating to in vitro and in vivo pre- clinical studies (15 guidelines). E "Efficacy" Topics, i.e., those relating to clinical studies in human subject (18 guidelines). M Multidisciplinary Topics, i.e., cross-cutting topics which do not fit uniquely into one of the above categories such as: Medical Terminology Electronic Standards for Transmission of Regulatory Information (ESTRI) The Common Technical Document (5 guidelines) 18. ICH topics Q "Quality" Topics, i.e., those relating to pharmaceutical quality assurance (24 guidelines). S "Safety" Topics, i.e., those relating to in vitro and in vivo pre- clinical studies (15 guidelines). E "Efficacy" Topics, i.e., those relating to clinical studies in human subject (18 guidelines). M Multidisciplinary Topics, i.e., cross-cutting topics which do not fit uniquely into one of the above categories such as: Medical Terminology Electronic Standards for Transmission of Regulatory Information (ESTRI) The Common Technical Document (5 guidelines) 19. Efficacy Guidelines E2 - Clinical Safety Data Management E3 - Structure and Content of Clinical Study Reports E6 - Good Clinical Practice E7 - Studies in Support of Special Populations/Geriatrics E8 - General Consideration of Clinical Trials E9 - Statistical Principles for Clinical Trials E11 - Clinical Investigation in the Pediatric Population E12 - Clinical Evaluation of New Antihypertensive Drugs 20. ICH GCP Guidelines documents Guideline for Good Clinical Practices (released 5/96) Essential Documents for the Conduct of a Clinical Trial Investigator's Brochure Clinical Safety Data Management: Definition and Standard for Expedited Reporting (released 10/94) Structure and Content of Clinical Study Reports (released 11/95) 21. Who must comply with GCP? All individuals involved in any aspect of the trial must be suitably qualified to be able to comply with GCP 22. Who must comply with GCP? Sponsors/ Clinical Investigators are responsible for ensuring that all staff are able to comply with GCP All individuals involved in any aspect of the trial must be suitably qualified to be able to comply with GCP Sponsors/CIs 23. Who is responsible for ensuring adherence to GCP? You 24. Principles of ICH GCP 1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements Declaration of Helsinki RegulationsGCP 25. Principles of ICH GCP continued 2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject & society. A trial should be initiated and continued only if the anticipated benefits justify the risks. Risks Benefits 26. Principles of ICH GCP continued 3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science & society. Science & SocietyTrial Subjects 27. 4. The available non-clinical & clinical information on an investigational product should be adequate to support the proposed clinical trial. Principles of ICH GCP continued Clinical Trial 28. 5. Clinical trials should be scientifically sound, and describe in a clear, detailed protocol. Principles of ICH GCP continued Scientifically Sound 29. 5. A trial should be conducted in compliance with the protocol that has received prior IRB (or IEC) approval. Principles of ICH GCP continued IRB 30. 7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. Principles of ICH GCP continued 31. 7. Each individual involved in conducting a trial should be qualified by education, training & experience to perform his or her respective tasks. Principles of ICH GCP continued Education Training Experience 32. 9. Freely given informed consent should be obtained from every subject prior to clinical trial participation. Principles of ICH GCP continued 33. 9. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate: 1. Reporting 2. Interpretation 3. Verification. Principles of ICH GCP continued 34. 11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory compliance. Principles of ICH GCP continued 35. 12. Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing Practice (GMP). They should be used in accordance with the approved protocol. Principles of ICH GCP continued Good Manufacturing Practice 36. 12. Systems with procedures that assure the quality of every aspects of the trial should be implemented. Principles of ICH GCP continued Quality 37. Areas Addressed in the GCP Gu idelin es IRB/EC Investigator Responsibilities Investigators Brochure Clinical Trial Protocol Sponsor Responsibilities Essential Documents Principles of GCP 38. IRB/Ethics Committee All studies must be approved prior to recruiting participants IRB must review all documents given to participants Composition of the IRB Reporting from protocol to the IRB Maintenance of Records IRB/EC 39. Review Approval Recruiting IRB must review all documents given to participants All studies must be approved Reporting from protocol to the IRB IRB/EC IRB/Ethics Committee All studies must be approved prior to recruiting participants IRB must review all documents given to participants Composition of the IRB Reporting from protocol to the IRB Maintenance of Records 40. SCENE Investigator Responsibilities Qualifications & Agreements 1 2 3 Up to date CV Compliance with GCP Familiar with investigational product Permit of monitoring by sponsor Maintenance of a list of qualified personnel 4 5 41. What counts as qualified? Education Training Experience 42. What counts as qualified? Education Training Experience There is no GCP qualification 43. Education Individuals must be educated to be able to competently perform their specific trial task Clinicians must be clinically qualified Statisticians must be qualified Managers must be appropriately educated 44. Training There are variety of courses and seminars currently available Employer orientation courses Industry courses E-learning (some Institute of Clinical Research) Private courses (usually run by self-employed consultant) Host institution courses Trial specific workshops Investigators meetings 45. Experience On-the-job learning Discovering what is required Doing the job (sometimes wrongly) Following information and knowledge through teams/units Talking to other trialists 46. Adequate Resources Time Staff Informed Recruitment Investigator Responsibilities SCENE 47. Adequate Resources Time Staff Informed Recruitment Investigator Responsibilities SCENE Time 48. Adequate Resources Time Staff Informed Recruitment Investigator Responsibilities SCENE 49. Adequate Resources Time Staff Informed Recruitment Investigator Responsibilities SCENE Time 50. Medical Care Investigator Responsibilities 51. Medical Care A qualified MD (or dentist) responsible for trial-related medical decisions Provide adequate medical care for AEs or other significant medical condition Inform subject's primary physician about participation in trial Make a reasonable effort to ascertain why participant withdrawals from study Medical Care Investigator Responsibilities 52. Medical Care A qualified MD (or dentist) responsible for trial-related medical decisions Provide adequate medical care for AEs or other significant medical condition Inform subject's primary physician about participation in trial Make a reasonable effort to ascertain why participant withdrawals from study Medical Care Investigator Responsibilities 53. Medical Care A qualified MD (or dentist) responsible for trial-related medical decisions Provide adequate medical care for AEs or other significant medical condition Inform subject's primary physician about participation in trial Make a reasonable effort to ascertain why participant withdrawals from study Medical Care Investigator Responsibilities 54. Medical Care A qualified MD (or dentist) responsible for trial-related medical decisions Provide adequate medical care for AEs or other significant medical condition Inform subject's primary physician about participation in trial Make a reasonable effort to ascertain why participant withdrawals from study Medical Care Investigator Responsibilities 55. The investigator/institution should have: Written and dated approval opinion from the IRB/IEC for the trial protocol, Written informed consent form, consent form updates, Subject recruitment procedures Any other written information to be provided to subjects. The investigator/institution Should provide to the IRB/IEC all documents subject to review. The investigator's/institution should provide the IRB/IEC with a current copy of the Investigator's Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Brochure to the IRB/IEC. Investigator Responsibilities Communication with IRB Before the Trial During the Trial Investigator`s Brochure 56. Protocol If deviations occur, they should be reported Investigator Responsibilities Compliance with protocol The investigator may implement a deviation As soon as possible should be submitted: a) to the IRB/IEC for review and approval opinion, b) to the sponsor for agreement and, if required, c) to the regulatory authorities. 57. Investigator Responsibilities Investigational Product Records Storing Using Explaining Responsibility 58. Participant should be given a copy Informed Consent All contents of the informed consent Informed Consent Signed & dated by participant Informed Consent Provide ample time to review & ask questions Informed Consent Ubderstandable Language Informed Consent No language of a waiver of legal rights Informed Consent Fully inform participant of all aspects of the trial Informed Consent Investigator Responsibilities Informed Consent No coercion No influence Informed Consent Written Can be revised Informed Consent GCP IRB Informed Consent 59. Investigator Responsibilities Records & Reports Accuracy, Completeness, Legibility & Timeliness of data reported CRF consistent with Source documentation Changes to CRF should be Dated, Singed & Explained Maintain Trial documents Financial aspects noted in contract Make available all records for monitor, auditor, IRB, or other regulatory authority 60. Investigator Responsibilities Progress Report IRB Annually If requested 61. Investigator Responsibilities Progress Report IRB Annually If requested 62. Investigator Responsibilities Progress Report IRB Sponsor Authorities Annually If requested 63. 1. Quality Assurance & Quality Control 2. Contract Research Organization (CRO) 3. Medical Expertise 4. Trial Design Sponsor Responsibilities Provide written Standard Operating Procedures (SOP)s Secures agreement between all parties Data handling Hired by the sponsor to implement trial- related duties Designated medical personnel to advise on trial-related medical questions and problems Designs Case Report Form (CRF)s Planning analyses 64. 5. Management, Data Handling, Recordkeeping, & Data Monitoring Committee 6. Investigator Selection 7. Allocation of Duties & Functions 8. Compensation to Subjects & Investigators Sponsor Responsibilities Qualified personnel to supervise overall conduct of the study DMC assesses the progress of the clinical trial Maintain SOPs for electronic data processing Inform Investigator of guidelines for record retention Qualifications by training and experience Sponsor should define, establish and allocate all trial-related duties and functions Insure investigator/institution against claims arising from the trial Coverage for the cost of treatment Compensation for the subject 65. 9. Financing 10. Notification/Submission to Regulatory Authorities 11. Confirmation of Review by IRB 12. Information on Investigational Products Sponsor Responsibilities Submission of required applications to authorities for review, acceptance, and/or permission to begin trial Sufficient safety & efficacy data from non- clinical studies are available to support human exposure Update Investigators Brochure as new info becomes available Should obtain name & address of institutional IRB, statement that they comply with GCPs and applicable laws and regulations Documentation of approval Financing 66. 13. Manufacturing, Packaging, Labeling, & Coding Investigational Products 14. Supplying & Handling Investigational Products 15. Record Access 16. Safety Information Sponsor Responsibilities Timely delivery of product Maintenance of records (shipment, receipt, return) System for disposition of unused product Ongoing safety evaluation Sponsor should have access to records Manufactured in accordance with GMPs Coded and labeled in a manner that protects blinding PI should be informed of storage information 67. 17. Adverse Drug Reaction Reporting 18. Monitoring 19. Auditing 20. Noncompliance Sponsor Responsibilities Rights and well being of human subjects are protected Trial data are accurate and complete Noncompliance Evaluate trial conduct and compliance with protocol, SOPs, GCPs and other regulatory requirements Report all adverse drug reactions that are serious and unexpected Submit all safety updates and DSM reports 68. 21. Premature Termination or Suspension of a Trial 22. Clinical Trial/Study Reports 23. Multicenter Trials Sponsor Responsibilities Communication is facilitated between all investigators Clinical Trial/Study Reports Promptly notify investigators/institution with reason for the termination 69. Resources http://www.fda.gov/oc/gcp/guidance.htm http://www.clinicaltrials.gov/ http://www.fda.gov/oc/ohrt/irbs/websites.html http://ohrp.osophs.dhhs.gov/ http://privacyruleandresearch.nih.gov/