1. Good Clinical Practice A Review for OCRA US RAC Study Group September 2005 Ginger Clasby, MS Promedica International gclasby@promedica-intl.com 714-799-1617 x 25 gclasby@promedica-intl.com

2. GCP What It Is An international ethical & scientific quality standard for designing, conducting, recording & reporting human clinical studies – EU – Japan – US Applies to registration studies that may have an impact on safety & welfare of human subjects

3. GCP Participating Parties IRB/Ethics Committee Investigators Sponsor Regulatory Authorities

4. GCP Key Documents Investigator Brochure Study Protocol Informed Consent Document

5. GCP Principles 1.Studies in accordance with Declaration of Helsinki; consistent with GCP & applicable regulatory requirements 2.Studies initiated & continued only if anticipated benefits outweigh risks 3.Rights, safety & welfare of human subjects take priority over interests of science & society 4.Available non-clinical & clinical info on product adequate to support study

6. GCP Principles 5.Studies scientifically sound; described in clear, detailed protocol 6.Study in compliance with IRB/EC approved protocol 7.Medical care given to subjects is the responsibility of qualified medical professional(s) 8.Individuals conducting studies qualified by education, training & experience 9.Freely given informed consent obtained from every subject prior to study participation

7. GCP Principles 10.Study information recorded, handled & stored to allow accurate reporting, interpretation & verification 11.Confidentiality of subject records protected in accordance with applicable regulatory requirements 12.Investigational products manufactured, handled & stored in accordance with GCP & used in accordance with approved protocol 13.Systems/procedures implemented to assure quality of study

8. IRB/EC Roles & Responsibilities To safeguard study subjects’ rights & welfare by: Evaluation/disposition of study proposal Evaluation of proposed subject consent materials Evaluation of emergency use consent methodology Evaluation of investigator qualifications Ongoing review of study progress (at least yearly) Evaluation of proposed subject compensation plans

9. IRB/EC Composition & Operations Membership has qualifications & experience to evaluate science, medical aspects & ethics of proposed study – ≥ 5 members – ≥ 1 member whose primary interest in nonscientific – ≥ 1 member independent of institution or study site Written SOPs & records Decisions rendered at announced meetings with quorum in attendance

10. IRB/EC Composition & Operations Only members participating in review should vote Investigator may provide info on study, but should not be involved in review or vote Nonmembers with expertise in special areas may be invited to assist with review (but cannot vote)

11. IRB/EC Procedures Document group membership & qualifications Schedule meetings & notify members Conduct initial & ongoing review of studies Determine ongoing review frequency Provide expedited review of minor study changes, in accordance with regulatory requirements Specify that no subject should be enrolled in study prior to IRB/EC approval

12. IRB/EC Procedures Specify that no deviations from protocol should be initiated without prior IRB/EC approval – Emergency situations require immediate notification of IRB/EC after the fact Specify that Investigator should promptly report: – Protocol deviations – Changes increasing subject risk or study procedures – Serious and unexpected adverse events

13. IRB/EC Procedures Notify Investigator promptly of: – Study-related decisions – Reason for decisions – Procedures for appeal of decisions

14. IRB/EC Required Records Relevant records maintained ≥ 3 yr after study completion Records available for review by regulatory authorities

15. IRB/EC What is Reviewed Investigator Brochure or Report of Prior Investigations Study protocol & amendments Investigator qualifications Informed consent documents, including subject recruiting tools Other written information provided to subjects Subject compensation plans Adverse events Protocol deviations

16. IRB/EC When Reviews Occur Prior to study initiation at site At least yearly during study During study, as necessitated by: – Changes in protocol, consent documents, etc. – Changes in study investigator – Reports of serious or unanticipated device-related adverse events At study completion or termination

17. Investigator Roles & Responsibilities Qualified to conduct study Have adequate resources to conduct study Provide medical care to study subjects Regular communication with IRB/EC reviewing study Compliance with study protocol Maintenance of investigational product accountability Compliance with study randomization & unmasking procedures Provide informed consent to study subjects

18. Investigator Responsibilities Appropriate Qualifications Training & experience demonstrated via: – Medical license – CV – Specialized study training – GCP training If study responsibilities delegated, need a list of qualified persons to whom responsibilities are delegated

19. Investigator Responsibilities Adequate Resources Suitable staff & good methods for keeping them apprised Suitable facilities Appropriate patient population – Access to disease or condition – Volume of patients with disease or condition

20. Investigator Responsibilities Medical Care Make medical decisions regarding patient treatment Adequate care for study-related adverse events Diligence in ascertaining reason(s) for subject withdrawals from study

21. Investigator Responsibilities IRB/EC Communications IRB/EC approval prior to study initiation IRB/EC kept apprised of events & progress during study

22. Investigator Responsibilities Protocol Compliance Conduct study in accordance with protocol May not deviate from protocol without Sponsor/IRB approval Document deviations from protocol

23. Investigator Responsibilities Investigational Product Accountability Maintain accountability at study site Document product receipt & disposition Maintain product in a secure area Use product only in accordance with protocol Disallow use of product by anyone not registered with study

24. Investigator Responsibilities Randomization Procedures & Unmasking Follow study randomization procedures Unmask only in accordance with protocol Document noncompliance or premature unmasking

25. Investigator Responsibilities Subject Informed Consent Comply with regulatory requirements Update consent documents as necessary Inform subject that study involves “investigational” product May not coerce subject to participate May not waive subject’s legal rights Keep subject informed of new information regarding study

26. Investigator Responsibilities Subject Informed Consent Provide informed consent in understandable language Give subject the chance to ask questions If subject can’t read, need impartial witness If subject is “disadvantaged”, need legally authorized witness Get subject consent in writing prior to initiation of study procedures Give subject a copy of signed consent document

27. Investigator Responsibilities Required Records & Reports Essential regulatory document file(s) – Protocol & amendments – Approved informed consent documents – Product accountability documentation – Investigator qualifications & agreements – IRB correspondence – Study delegation list – Subject screening/enrollment logs – Study monitoring reports – Calibration/maintenance logs – Memos to file

28. Investigator Responsibilities Required Records & Reports Source documentation Data capture forms (study-specific) Data clarification forms Fully executed informed consent documents

29. Investigator Responsibilities Required Records & Reports Written periodic status reports to IRB/EC Written reports of protocol deviations to Sponsor & IRB/EC Serious or unanticipated product-related adverse events to Sponsor & IRB/EC Notification of study suspension or termination to IRB/EC Final study report to IRB/EC Retain ≥ 2 yr

30. Sponsor Roles & Responsibilities Study quality assurance Appropriately qualified medical personnel to advise on study Utilization of qualified personnel in study design & operations Study management, data handling & record keeping Investigator selection & training Definition/allocation of study responsibilities

31. Sponsor Roles & Responsibilities Facilitation of communications between Investigators Study compensation (investigators and/or subjects) & financing Regulatory authority notification/submission Confirmation of IRB/EC review/approval Investigational product information Investigational product manufacturing, packaging, labeling & coding Investigational product supply & handling

32. Sponsor Roles & Responsibilities Record access Ongoing safety evaluation & reporting Serious/unanticipated adverse event reporting Study monitoring Study noncompliance procedures Study termination or suspension notification Study reports

33. Sponsor Roles & Responsibilities Sponsor may transfer responsibilities to CRO – Transfer must be documented in writing – Sponsor still has ultimate responsibility for study quality and data integrity

34. Study Protocol Components General administrative info Background Study purpose & objectives Study design Subject eligibility requirements How subjects will be treated How safety & efficacy will be assessed Sample size justification & statistical analysis methods

35. Study Protocol Components How data will be captured & maintained Monitoring procedures Proposed informed consent document

36. Informed Consent Document Components Statement that study involves “research” & product “experimental” (if applicable) Study purpose Number of expected study subjects to be enrolled Study treatment(s) & probability for random assignment Study exams & procedures for duration of trial Subject’s responsibilities Foreseeable risks to subject (embryo, fetus, nursing infant)

37. Informed Consent Document Components Expected benefits Alternatives procedures or therapies & associated risk/benefit Compensation available in event of study-related injury or sickness Anticipated payments to subject for study participation Anticipated expenses to subject for study participation Statement that participation is voluntary

38. Informed Consent Document Components Description of extent to which confidentiality can be assured Commitment to keep subject apprised on new information that may affect subject’s willingness to participate in study Contact info for questions re: subject rights; trial- related adverse events Circumstances under which subject’s participation may be terminated

39. Investigator Brochure What It Is A compilation of clinical & non-clinical data on the product that is relevant to the product’s study in humans Necessary for Investigator & IRB/EC review to assess the risks/benefits associated with study

40. Investigator Brochure Components Product formulation summary Introduction/background info regarding product & investigational plan Investigational product physical, chemical & pharmaceutical properties & formulation Non-clinical studies Human clinical studies Summary of data & guidance for Investigator

41. Good Clinical Practice Reference Documents & Links ICH - E6: Guideline for Good Clinical Practice 21 CFR 50 - Informed Consent 21 CFR 56 - Institutional Review Board http://www.ich.org/cache/compo/276-254-1.html http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrs earch.cfm http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrs earch.cfm