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

STANDARD COURSE IN CLINICAL TRIALSTANDARD COURSE IN CLINICAL TRIAL

PIENGTHONG NARAKORN

May 23, 2008

OUTLINE: March 24, 2008OUTLINE: 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

OUTLINE: March 25, 2008OUTLINE: 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

OUTLINE: March 26, 2008OUTLINE: 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

From R&D to product licensing From R&D to product licensing

Requirements on Quality– Active substance

General information, ManufactureControl of active substance, Stability

– Finished productFormulation productControl of excipients and finished

product, stability

Registration application for generic product require:

– Product quality

– Literature references

– Bioequivalence study

From R&D to product licensing From R&D to product licensing

Innovator products should be fulfilled all these tests:

– Pharmaceutical tests

– Non-clinical test

– Clinical trials

– Potential environment risks

From R&D to product licensing From R&D to product licensing

Study design&methodologyStudy design&methodology

Descriptive studyEpidemiology studyAnalytic studyIntervention studyExperimental study:phase I,II, IIIObservational study:phase IV(Non-experimental)

Study design&methodologyStudy design&methodology

Efficacy: phase III Effectiveness (ประสิ�ทธิ�ผล): phase IV Efficiency (ประสิ�ทธิ�ภาพ):

Clinical trialsClinical 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

Clinical trialsClinical 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

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

Proposal DevelopmentProposal Development

Proposal DevelopmentProposal 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

Finding GrantsFinding 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

Management of Multicenter TrialManagement 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

Management of Multicenter TrialManagement 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

To set globally applicable standards for the conduct of such biomedical

research on human subjects

Good Clinical Practice(การปฏิ�บั�ติ�การวิ�จั�ยทางคล�นิ�กท��ดี�)

Good Clinical Practice(การปฏิ�บั�ติ�การวิ�จั�ยทางคล�นิ�กท��ดี�)

GCPGCP

GLP

S-Scientific valid

E-Ethically oriented

A-Accuracy

T-Traceability

Good Clinical PracticeGood Clinical Practice

Good Clinical PracticeGood 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

Good Clinical PracticeGood 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

Tools for Conducting a clinical trialTools 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

Informed consentInformed consent

กระบัวินิการท��ย�นิย�นิควิามสิม�ครใจัของอาสิาสิม�ครในิการติ�ดีสิ�นิใจัเข!าร"วิมในิโครงการวิ�จั�ยภาย หล�งจัากไดี!ร�บัข!อม'ลเก��ยวิก�บัการวิ�จั�ยอย"างละเอ�ยดี

ใช้!ภาษาท��บั*คคลท��วิไปเข!าใจัไดี!ง"าย ควิรหล�กเล��ยงการใช้!ศั�พท,ทางการแพทย, ควิรขอควิามย�นิยอมจัากเดี.ก (ถ้!าติ!องวิ�จั�ยในิเดี.ก) ควิรระบั*ไวิ!ดี!วิย วิ"า การไม"เข!าร"วิมโครงการไม"ถ้�อเป0นิควิาม“

ผ�ดี” งานิวิ�จั�ยท��ยกเวิ!นิการขอควิามย�นิยอม: พฤติ�กรรมทางเพศั

ยาเสิพติ�ดี งานิวิ�จั�ยในิช้*มช้นิบัางแห"งของประเทศัก2าล�งพ�ฒนิา

Informed consentInformed 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

Principle of Electronic Data Management in Clinical TrialsPrinciple 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

Role of InvestigatorRole 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

Role of CRORole 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.

Role of CRARole 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

Responsibilities of research pharmacistResponsibilities of research pharmacist

Ordering; companies/import Storage; temp., humidity Inventory control; monthly check Distribution; control storage condition Dispensing & Accountability Disposal

Practical Points of IRB Review in Clinical TrialsPractical 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

AEs

– Any untoward medical occurrence, not related to the medicinal product

– Do not include:Medical or surgical proceduresPre-existing disease or conditions

present at the start of the study

Safety & the Safety Reporting ProcessSafety & the Safety Reporting Process

Safety & the Safety Reporting ProcessSafety & the Safety Reporting Process

SAEs

– Results in death

– Is life-threatening

– Require/prolong hospitalization

– Results in incapacity

– Is a congenital anomaly/birth defect

Investigational New Drug RegulationInvestigational New Drug Regulation

Might allow parallel application with EC submission : จั*ฬาฯ ศั�ร�ราช้ฯ รามาฯ มช้. มอ. มข. เวิช้ศัาสิติร,เขติร!อนิ กรมแพทย,ทหารบัก กระทรวิงสิาธิารณสิ*ข

Need:– Drug label– Drug leaflet– IB– Patient information sheet– Clinical Trial Protocol– Information on Drug Quality & GMP

Requirement:– GCP– GMP

Accepted ECs

GCP Inspection

International Clinical Trial RegistrationInternational 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)

Common Pitfalls of GCP TrialsCommon Pitfalls of GCP Trials

Safety reporting Consent: Wrong ICF, no date, time,

witness Inclusion/Exclusion criteria Investigational product: storage,

accountability

Common Pitfalls in PharmacyCommon 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