Sponsor Responsibilities ICH E6 Good Clinical Practice Guidance

1. NIDCR CROMS Clinical Research Operations and Management Support Rho, Inc., Federal Division National Institute of Dental and Craniofacial Research National Institutes of Health Sponsor ResponsibilitiesICH E6 Good Clinical Practice Guidance 2012-12-16

2. Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management and/or financing of a clinical trial

3. Quality Assurance /Quality Control (ICH 5.1) • Implement and maintain QA and QC systems with written SOPs to ensure GCP compliance • Secure agreements from all sites for monitoring, auditing, and inspections • QC of data handling • Reliable • Processed correctly • All agreements should be in writing

4. Contract Research Organization (CRO) • A person or an organization contracted by the sponsor to perform one of more of a sponsor’s trial related duties and functions • Commercial • Academic • Other

5. Contract Research Organization (CRO)(ICH 5.2) • Sponsor may transfer all or some trial duties/functions to a CRO • Ultimate responsibility lies with the sponsor • Transferred duties should be specified in writing • Not specified = retained by sponsor • References to sponsor apply to CRO for duties that are transferred

6. Medical Expertise (ICH 5.3) Designate qualified medical personnel to advise on trial questions or problems Outside consultants may be appointed if needed

7. Trial Design (ICH 5.4) • Utilize qualified individuals: Biostatisticians, Clinical pharmacologists, Physicians • Use as appropriate through all trial stages • Protocol design • CRF development • Analysis (planning/preparing study reports) • For further guidance: • Clinical Trial Protocol and Protocol Amendments (Sec. 6)

8. Trial Management, Data Handling, and Recordkeeping (ICH 5.5) • Utilize qualified individuals to supervise conduct of trial, handle and verify data, conduct statistical analysis, and prepare trial reports • Can create independent data monitoring committee (IDMC) to assess progress • Safety data and critical efficacy endpoints • Recommendations to sponsor: continue, modify or stop trial • IDMC should have SOPs and maintain written records of meetings

9. Trial Management, Data Handling, and Recordkeeping (ICH 5.5) • When handling electronic trial data: • Data processing system should conform to sponsor requirements • Maintain SOPs • Permit changes that are documented(audit trail) • Maintain a security system to prevent unauthorized access • Maintain list of individuals authorized to make changes • Maintain data backup • Safeguard blinding (if applicable) during data entry/processing

10. Trial Management, Data Handling, and Recordkeeping (ICH 5.5) • Possible to compare original data to processed data • Use an unambiguous subject identification code • Retain all essential documents pertaining to trialand regulatory requirements • If clinical development of an investigational product is discontinued: • Retain essential documents for up to 2 years • Notify site investigators and appropriate regulatory authorities • Transfer of ownership of data should be reported to appropriate authorities, as per applicable regulatory requirements

11. Trial Management, Data Handling, and Recordkeeping (ICH 5.5) • Retain sponsor-specific essential documents until: • At least 2 years after the last approval of a marketing application in an ICH region , and until there are no pending or contemplated marketing applications in an ICH region, OR • At least 2 years after formal discontinuation of clinical development of the investigational product • Retain longer if required by applicable regulatory requirements or needed by the sponsor • Sponsor should communicate in writing to investigator/institutions: • Inform of the need for record retention • Notify when the trial-related records are no longer needed

12. Investigator Selection(ICH 5.6) • Sponsor selects investigators and/or institutions • Provide protocol and up-to-date Investigator’s Brochure • Ensure time to review before agreement • Obtain agreement to: • Conduct trial in compliance with GCP • Comply with data recording procedures • Permit monitoring, auditing and inspection • Retain essential documents

13. Allocation of Duties and Functions (ICH 5.7) • Before the trial begins, ensure that all duties and functions are: • Defined • Established • Allocated

14. Compensation of Subjects and Investigators (ICH 5.8) Provide insurance or indemnify the investigator/institution (if required) Policies and procedures should address costs of treatment for trial-related injuries Method and manner of compensation should comply with regulatory requirements

15. Financing (ICH 5.9) Documented in agreement between sponsor and investigator/institution

16. Notification/Submission to Regulatory Authority(ies) (ICH 5.10) • Before initiating trial, the sponsor (or sponsor & investigator) should submit required applications to appropriate authorities for: • Review • Acceptance • Permission • Any submission should be dated and include protocol identifiers

17. Confirmation of Review by IRB/IEC (ICH 5.11) • Obtain IRB/IEC documentation from investigator • IRB/IEC name and address • Statement that IRB/IEC is organized and compliant with GCP and applicable regulations • Documented approval to begin study • If requested by the sponsor: • Copy of protocol, written informed consent and other written information to be provided to subjects • Subject recruiting procedures • Documents related to subject payment

18. Confirmation of Review by IRB/IEC continued (ICH 5.11) • Obtain copy of modifications made and date of IRB/IEC approval : • Modification to protocol • Written informed consent • Other written information to subjects • Obtain documentation and dates of re-approvals/re-evaluations or withdrawals/suspensions

19. Information on Investigational Products (IP) (ICH 5.12) • During planning, ensure that safety and efficacy data are available to support human exposure • By the route • At the dosages • For the duration • In the trial population • Update Investigator’s Brochure as new information becomes available

20. Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13) Manufactured in accordance with applicable GMP Coded and labeled to protect blinding, if applicable Labeling complies with regulatory requirements Determine acceptable storage temperatures and conditions and inform involved parties

21. Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13) • Product packaged to prevent contamination and unacceptable deterioration • Blinded trials should include a mechanism for rapid product identification (in case of medical emergency) • Should not permit undetectable breaks • Results of studies on significant formulation changes should be assessed before new clinical trials

22. Supplying and Handling Investigational Products (IP) (ICH 5.14) Obtain all required documentation Supply investigator/institution with the products Ensure that written procedures include instructions for handling and storage of IP Ensure timely delivery Maintain records of IP shipment receipt, disposition, return, and destruction Maintain system for disposition of unused product Ensure that product is stable over period of use

23. Record Access (ICH 5.15) • Protocol or other written agreement should state that investigator will provide direct access to source data for monitoring, audits, IRB review and regulatory inspection • Verify that each subject consented to direct access to medical records • Must be in writing

24. Safety Information (ICH 5.16) • Responsible for ongoing safety evaluation of the IP • Should promptly notify all investigators/institutions and regulatory authorities of findings that could: • adversely affect safety of subjects • impact conduct of trial • alter IRB approval

25. Adverse Drug Reaction Reporting (ICH 5.17) • Expedite reporting of adverse drug reactions to: • Concerned investigators/institutions, • IRBs/IECs • Regulatory authorities • Expedited reports should comply with applicable regulatory requirements and ICH Guidance • Submit to regulatory authorities required safety updates and reports

26. Monitoring: Purpose(ICH 5.18) • Verify that: • The rights and well-being of human subjects are protected • The reported trial data are accurate, complete, and verifiable from source documents • Conduct of trial is in compliance with: • Approved protocol/amendments • GCP • Applicable regulatory requirements

27. Monitoring: Selection and Qualification of Monitors (ICH 5.18) • Monitors should be appointed by sponsor • Appropriately trained; have the needed scientific and/or clinical knowledge • Qualifications should be documented • Familiar with: • Investigational product • Protocol, written informed consent form, and other written information for subjects • SOPs • GCP and applicable regulatory requirements

28. Monitoring: Extent and Nature of Monitoring (ICH 5.18) • Ensure trials are adequately monitored • Determine extent and nature of monitoring based on: • Objective , Purpose and Endpoints • Size, Design and Complexity • Blinding • On-site monitoring before, during, and after the trial • Central monitoring in exceptional circumstances

29. Monitoring: Monitor’s Responsibilities (ICH 5.18) • Main line of communication between sponsor and investigator • Verify investigator qualifications & resources • Verify staff and facilities are adequate to safely and properly conduct the trial • Verify investigational products • Acceptable storage times and conditions and sufficient supplies • Supplied only to eligible subjects and at protocol-specified dose • Subjects provided with instruction before use • IP receipt, use and return is controlled and documented • Disposition of unused product complies with requirements

30. Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18) Verify that investigator follows approved protocol and amendments Verify that written informed consent is obtained before participation Ensure that investigator receives current Investigator’s Brochure and all documents/supplies needed Ensure that investigator and trial staff are informed about the trial

31. Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18) Verify that trial staff are performing specified trial functions in accordance with protocol Verify that only eligible subjects are being enrolled Report the subject recruitment rate Verify documents and records are complete and up-to-date Verify that investigator provides all reports, notifications, applications and submissions

32. Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18) • Check accuracy and completeness of CRF entries • Data required by protocol are reported accurately • Dose/therapy modifications are well-documented • Adverse events, concomitant medications, and intercurrent are reported • Missed visits, tests, and examinations are reported • Withdrawals and dropouts are reported

33. Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18) • Inform investigator of CRF entry error, omission, or illegibility • Ensure that corrections, additions, or deletions are made, dated, explained, and initialed • Determine if adverse events are reported appropriately • Determine if the investigator is maintaining essential documents

34. Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18) Communicate deviations from the protocol, SOPs, GCP, and regulatory requirements to the investigator Take appropriate action designed to prevent recurrence of the detected deviations.

35. Monitoring: Monitoring Procedures (ICH 5.18) Follow the sponsor’s written SOPs and procedures set by the sponsor for a specific trial

36. Monitoring: Monitoring Report (ICH 5.18) • Submit written report to sponsor after each trial-related visit/communication • Date, site, name of monitor, name of investigator • Summary of review, monitor statements on findings, facts, deviations, deficiencies, conclusions, actions taken, and actions recommended • Review and follow up of the report should be documented by sponsor’s designated representative

37. Audit: Purpose (ICH 5.19) An audit is independent of and separate from routine monitoring or quality control functions Evaluate trial conduct and compliance with the protocol, SOPs, GCP, and regulatory requirements

38. Audit: Selection and Qualification of Auditors(ICH 5.19) • Sponsor appoints individuals, independent of the clinical trial • Ensure auditors are qualified by training and experience • Qualifications should be documented

39. Audit: Auditing Procedures (ICH 5.19) • Conducted in accordance with sponsor’s written procedures • What to audit • How to audit • Frequency, form, and content

40. Audit: Auditing Procedures (continued )(ICH 5.19) • Audit plan and procedures should be guided by: • Importance of trial to submission to regulatory authorities • Number of subjects • Type and complexity • Levels of risks • Any identified problems • Observations and findings should be documented • When required, provide and audit certificate

41. Noncompliance (ICH 5.20) Defined as noncompliance with protocol, SOPs, GCP, and/or regulatory requirements Should lead to prompt action by the sponsor to secure compliance If monitoring or auditing identifies serious or persistent noncompliance, sponsor should terminate participate in the trial and notify regulatory authorities

42. Premature Termination or Suspension of a Trial (ICH 5.21) • Inform and provide reasons • Investigators/institutions, and regulatory authorities • IRB/IEC

43. Clinical Trial/Study Reports (ICH 5.22) Ensure clinical trial/study reports are prepared and provided to regulatory agencies as required Reports in marketing applications should meet the standards of the ICH Guidance for Structure and Content of Clinical Study Reports

44. Multicenter Trials (ICH 5.23) All investigators conduct the trial in strict compliance with protocol CRFs are designed to capture data at all multicenter sites Supplemental CRFs should be provided for investigators who are collecting additional information Responsibilities of coordinating investigators are documented prior to start of trial

45. Multicenter Trials (continued)(ICH 5.23) • All investigators are given instructions on following: • The protocol • Compliance with uniform standards for the assessment of clinical and laboratory findings • Completing the CRFs • Facilitate communication between investigators

46. Questions?