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Presentation on theme: "STANDARD COURSE IN CLINICAL TRIAL"— Presentation transcript:


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 (USA): free (UK) (Australia) (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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