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STANDARD COURSE IN CLINICAL TRIAL

STANDARD COURSE IN CLINICAL TRIAL. PIENGTHONG NARAKORN May 23, 2008. OUTLINE: March 24, 2008. From R&D product to licensing Study design & research methodology for clinical trials Proposal development Grant hunting, fund management, research administration & human resource management

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STANDARD COURSE IN CLINICAL TRIAL

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  1. STANDARD COURSE IN CLINICAL TRIAL PIENGTHONG NARAKORN May 23, 2008

  2. OUTLINE: March 24, 2008 • From R&D product to licensing • Study design & research methodology for clinical trials • Proposal development • Grant hunting, fund management, research administration & human resource management • Management of multi-center trials

  3. OUTLINE: March 25, 2008 • GCP&ICH-GCP • Tools for conducting GCP • Challenges with large-scale, phase III • Principle of electronic data management • Role of CRO&CRA • Common pitfalls in pharmacy • Common pitfalls in GLP

  4. OUTLINE: March 26, 2008 • Symposium: Challenges in ethical approval of clinical trials • International clinical trial registration • Symposium: Practical points of IRB review in clinical trials • Investigational new drug • Interactive session: Case study& common pitfalls of GCP trial

  5. From R&D to product licensing • Requirements on Quality • Active substance • General information, Manufacture • Control of active substance, Stability • Finished product • Formulation product • Control of excipients and finished product, stability

  6. From R&D to product licensing • Registration application for generic product require: • Product quality • Literature references • Bioequivalence study

  7. From R&D to product licensing • Innovator products should be fulfilled all these tests: • Pharmaceutical tests • Non-clinical test • Clinical trials • Potential environment risks

  8. Study design&methodology • Descriptive study • Epidemiology study • Analytic study • Intervention study • Experimental study:phase I,II, III • Observational study:phase IV (Non-experimental)

  9. Study design&methodology • Efficacy: phase III • Effectiveness (ประสิทธิผล): phase IV • Efficiency (ประสิทธิภาพ):

  10. Clinical trials • Phase I • PK, safety, healthy volunteers • Phase II • Placebo controlled design, dose-response relationship, short-term safety, patients • Phase III • Larger patient groups, efficacy, short & long term safety • Phase IV • Post marketing surveillance

  11. Clinical trials • Research Involving Children • The research might not equally well be carried out with adults • The purpose of the research is to obtain knowledge relevant to the health needs of children • A parent or legal representative of each child has or given permission • Children’s refusal to participate or continue in the research will be respected

  12. Proposal Development • Good Idea: target, question • Good Timing: 3-6 months • Good Presentation: What, Why, How, Outcome • Good Support: Mentors, Collaborators, General reader • Good Luck • Good Grantsmanship

  13. Proposal Development • General & background information • Trial objectives & purpose • Benefits • Study location • Trial design • Selection and withdrawal of subjects • Treatment of subjects • Assessment of Efficacy • Assessment of Safety • Statistics • Project plan • Timeline • Direct access to source data/documents • Quality Control • Ethics • Data handling & record keeping • Instruments • Financing and insurance • Publication policy • CV of investigators • Institutional declaration

  14. Finding Grants • Pharmaceutical Companies • Ready-made protocols • Investigator-initiated • National Research Council of Thailand • International Organizations • U.S. NIH • U.S. CDC • WHO • Japanese government • Wellcome Trust • Bill&Melinda Gates Foundation

  15. Management of Multicenter Trial • Sample size>1000 subjects • > 10 sites • Timely and In-time result is needed-speed • Many people involved • Central Coordinator Center; PI, Co-Investigator, IRB, Administrative support, Data systems, Project Coordination, Statistical analysis, Computer support, • Study Protocol & Design

  16. Management of Multicenter Trial • Pre-study Activities; Investigator selection, Site qualification, Pre-study visit • Monitoring • Close out visit • Database management issues • Statistical considerations • Sponsor reports • Investigator reports • Budget & contract • Data Safety and Monitoring Board • Rewards & Incentives

  17. Good Clinical Practice(การปฏิบัติการวิจัยทางคลินิกที่ดี) To set globally applicable standards for the conduct of such biomedical research on human subjects

  18. Good Clinical Practice S-Scientific valid E-Ethically oriented A-Accuracy T-Traceability GCP GLP

  19. Good Clinical Practice • ICH GCP:1-13 (Principles, IRB/IEC, Investigator, Sponsor, Protocol, IB, IP • Process in a Clinical Trial; • Developing a study protocol • Blinded study (Single, Double, Triple)/Open • Randomization • Comparative • Co-intervention • Ethical approval • Sign a contract • Get FDA approval • Pre-trial meeting • Screening/enrollment • Complete CRF

  20. Good Clinical Practice • Process in a Clinical Trial; • Monitoring • Audit of trail • Data cleaning, entering • Data analysis: interim, final • Compliance/Adherence • AEs, SAEs • Data and Safety Monitoring Committee • Standard Operating Procedure (SOP) • Intention-to treat Analysis • Per Protocol Analysis • Contamination: community trial • Writing report • Presentation & publication

  21. Tools for Conducting a clinical trial • Protocol • CRF; record within 48 hrs • Source documents -hospital records, Lab. note, -memorandum -subject’s diaries -questionnaires -pharmacy dispensing records -recorded data from automated instruments -x-rays film • Records & reports • IB • Product insert

  22. Informed consent • กระบวนการที่ยืนยันความสมัครใจของอาสาสมัครในการตัดสินใจเข้าร่วมในโครงการวิจัยภาย หลังจากได้รับข้อมูลเกี่ยวกับการวิจัยอย่างละเอียด • ใช้ภาษาที่บุคคลทั่วไปเข้าใจได้ง่าย • ควรหลีกเลี่ยงการใช้ศัพท์ทางการแพทย์ • ควรขอความยินยอมจากเด็ก (ถ้าต้องวิจัยในเด็ก) • ควรระบุไว้ด้วย ว่า “การไม่เข้าร่วมโครงการไม่ถือเป็นความผิด” • งานวิจัยที่ยกเว้นการขอความยินยอม: พฤติกรรมทางเพศ ยาเสพติด งานวิจัยในชุมชนบางแห่งของประเทศกำลังพัฒนา

  23. Informed consent • A copy should be offered to the subject • Purpose of the research • Procedures that will be followed, including total time • Risks and discomforts • Benefits of the research • Compensation, if any • Alternatives to participation

  24. Principle of Electronic Data Management in Clinical Trials • Good Data Management Practices: 21 CFR 11 • Data manager • CRF development: • Started when draft protocol became available • 6 week • 100% reflect protocol • Use multiple choice • Medical term • Data Entry • Start data cleaning ASAP • Medical review • Data review meeting • Database lock

  25. Role of Investigator • Conduct clinical trial; high responsibility, medical training &experience, have sufficient time, facilities, compliance with GCP & Protocol, potential for recruiting • Contact with IRB • Review protocol • Take an informed consent • Know Lab. Specimens • Record & report to sponsor/IRB/Regulatory authorities • Provide medical care of subjects • Write final report and submit to sponsor/IRB/Regulatory

  26. Role of CRO • Contract Research Organization (CRO); CT plan, site management, monitoring • 1110 CROs, 6 biggest companies (Quintiles, Covance, PPD, Charles River Labs., Parexel, MDS Pharma) • Provide speed, larger enrollment (China, India), efficiency • Younger work force than academic • IATEC & CUIPIF:Ratchadamri Rd.

  27. Role of CRA • Protocol editing • Writing patient information/consent form • Site identification • Lab. identification • CRF editing • Regulatory document collection & submission • Ordering & shipping IP • Pre-study, Initiation, Monitoring, Close out visit • AEs/SAEs follow-up • CRA cannot take on investigator responsibilities, patients care

  28. Responsibilities of research pharmacist • Ordering; companies/import • Storage; temp., humidity • Inventory control; monthly check • Distribution; control storage condition • Dispensing & Accountability • Disposal

  29. Practical Points of IRB Review in Clinical Trials • Competent and properly trained committees • Managing of Conflicts of Interest • Compliance with related SOPs • Independent review • Appropriateness of the scientific design of a study • Subject selection • Risk & benefit • Informed consent: free from pressure • Data protection plan • Examine qualifications of investigators & staff • Evaluate study site • Continuing review • High risk: very 4 months • Moderate risk: every 6 months • Minimal risk: every 1 year • Retain all records 3 years after completion

  30. Safety & the Safety Reporting Process • AEs • Any untoward medical occurrence, not related to the medicinal product • Do not include: • Medical or surgical procedures • Pre-existing disease or conditions present at the start of the study

  31. Safety & the Safety Reporting Process • SAEs • Results in death • Is life-threatening • Require/prolong hospitalization • Results in incapacity • Is a congenital anomaly/birth defect

  32. Investigational New Drug Regulation • Might allow parallel application with EC submission : จุฬาฯ ศิริราชฯ รามาฯ มช. มอ. มข. เวชศาสตร์เขตร้อน กรมแพทย์ทหารบก กระทรวงสาธารณสุข • Need: • Drug label • Drug leaflet • IB • Patient information sheet • Clinical Trial Protocol • Information on Drug Quality & GMP • Requirement: • GCP • GMP • Accepted ECs • GCP Inspection

  33. International Clinical Trial Registration • To promote public awareness • To ensures that the results of all trials can be tracked down • To reduce unnecessary duplication of research • Manuscript to be reviewed by International Committee of Medical Journal Editors (ICMJE) • All interventional clinical trials should be registered • PI/lead PI is responsible for registering • Chula IRB review now includes a section asking whether a clinical trial has been or will be registered • Eligible registries for ICMJE • www.clinicaltrials.gov (USA): free • www.ISRCTN.org (UK) • www.actr.org.au (Australia) • www.trialregister.nl (Netherlands)

  34. Common Pitfalls of GCP Trials • Safety reporting • Consent: Wrong ICF, no date, time, witness • Inclusion/Exclusion criteria • Investigational product: storage, accountability

  35. Common Pitfalls in Pharmacy • Protocol out of date, incomplete • Incomplete prescription • Correction made without signature/date • Mixed-up between active stock & expired stock • Easy access for unauthorized persons • Temp./humidity out of range • Error correction

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