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CLINICAL TRIAL PROTOCOL:
STRATEGY FOR SUCCESS
Natalia VostokovaChief Operating Officer
IPHARMA LLCNovember 20, 2014
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COST OF A
MISTAKE
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CLINICAL TRIAL PROTOCOL
• A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.
ICH GCP, GOST Р 52379-2005 «Good Clinical Practice»
• A document that defines objectives, organization and methodology of a clinical study, statistical methods of results analysis and measures to assure safety of clinical trial subjects.
Russian Federal Law dated April 12, 2010 N 61-ФЗ «On circulation of medicinal products»
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SO WHAT IS THE PROTOCOL?
Applied researchGuideline for InvestigatorTreatment and safety plan for patientSet of rules for monitor and auditorData collection and analysis schemeCost sheet for clinical trial worksBasis for clinical trial and drug registration
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THE ESSENCE OF A CLINICAL TRIAL PROTOCOL• Form: Clear structured guideline for all parties involved in a
clinical trial• Objective: To obtain appropriate data on clinical properties of
a drug within the shortest timeline and at minimal cost with due consideration of the following:• Medical and scientific relevance and justification• Treatment and/or safety assurance of patients• Regulatory requirements and GCP guidelines
• Outcome: Data sufficient to make a decision of drug registration, shift over to the next phase, additional research or ending of the clinical program
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10 ELEMENTS OF A SUCCESSFUL PROTOCOL1. Medical expertise2. Prior experience3. Hypothesis4. Endpoints and assessments5. Safety6. Credibility7. Rationality8. Structure9. Simplicity10. Legitimacy
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1. MEDICAL EXPERTISE• Standards of care
• International• Local• Treatment efficacy assessments• Treatment schemes• Basic treatment• New drugs• Market features
• Patient population• Prevalence• Course of disease: stages,
exacerbations, relapses• Medical history: concurrent
diseases, conditions, abnormalities in system organs
• Naïve and on standard treatment
• Sources:• Key opinion leaders• Web-sites of European, American, and Russian professional medical
associations• http://roszdravnadzor.ru «Orders and standards of medical care»
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2. PRIOR EXPERIENCE• Previous trials
• International standards for clinical trials conduct
• Local requirements to specific trials• Studies of drugs in the same
therapeutic area• Studies of drugs of the same class• Competing trials
• Drug properties• Preclinical data• Clinical data• Drugs of the same class
• Sources:• http://clinicaltrials.gov• http://grls.rosminzdrav.ru • http://www.ema.europa.eu/ema/ «Guideline on clinical investigation of
medicinal products in the treatment of …»• http
://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm
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3. HYPOTHESIS
• Primary endpoint• Frequency of event (binary outcome)• Value change (continuous outcome)
• Hypothesis• Superiority• Non-inferiority• Equivalence
Study objectiveMode of action
Primary endpoint*HypothesisН0 ↔ НаSample size calculation
Duration of treatment and follow-up
Data collection method
Decision making algorithm
Expected result in control group
* Essential parameter of efficacy, safety or PK
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4. ENDPOINTS AND ASSESSMENTS• Objectives and goals of the study
• Primary (one hypothesis)• Secondary• Exploratory
• Types of endpoints• Efficacy• Safety• Quality of life• Pharmacokinetics• Pharmacodynamics• Pharmacogenetics
• Methods of assessment• Interview• Physical• Laboratory• Instrumental• Scales, questionnaires, diaries
• Data source• Investigator• Laboratory• «Rater»• Patient• Treating physician• Caregiver
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5. SAFETY• Safety assurance
• Exclusion criteria• Criteria for early discontinuation• Concomitant medication• Rescue therapy• Prohibited medications• Food and activity restrictions• Contraception• Unscheduled visits• Follow-up period after the end of
the study treatment
• Safety reporting• Expected adverse reactions of
the investigational product, comparator and basic therapy
• AE/SAE/Pregnancy reporting procedure
• AE of special interest• Data Safety Monitoring Board• Unblinding procedure (for
double-blind studies)
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6. CREDIBILITY• Control
• Randomization• Double-blind design• Placebo control• Comparison with “gold standard”• Baseline definition• Run-in (placebo) period• Comparable groups• Homogenous population• Strict eligibility criteria• Stable basic treatment
• Instruments• Central lab• Validated methods• Calibration of equipment• Unified standards and methods of
calculation• Drug dosing and storage instructions• Validated scales• Central rater• Independent expertise• Data Monitoring Board• Training and education• Site Monitoring
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7. RATIONALITY• To implement
• Relevance• Feasibility• Consistency
• To save resources• Cost• Time• Efforts• Price-performance ratio
• To make a decision• To minimize risks• To monitor signals• To stop just in time
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8. STRUCTURE1. Background2. Objectives3. Study design4. Population5. Study drug6. Procedures7. Study visits8. Quality assurance9. Statistical methods10. Administrative procedures11. References
• Cover page• Protocol approval page• Investigator’s statement• Contact information• Synopsis• Abbreviations• Index• Appendix
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9. SIMPLICITY• Simple language easy to
understand, definition of terms and acronyms
• Unambiguous straightforward wording
• Get to the point, don’t overburden the text
«…perfection is attained not when there is nothing more to add, but when there is nothing more to remove»
Antoine de Saint Exupéry
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10. LEGITIMACY• Regulations• Ethical aspects• Distribution of
responsibilities• Documentation
maintenance• Quality assurance• Confidentiality• References and appendix
• Version and date of the document
• Signature of Sponsor and Investigator
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STEP-BY-STEP PROGRESSIONStep 1. REVIEW THE DATA
Therapeutic areaPrevious experiencePreclinical and clinical dataKOL opinion
Step 2. DEVELOP THE CONCEPT
Define the patient populationTreatment regimen and control groupStudy design, primary objective, endpointPose the hypothesis
Step 3. CREATE THE SYNOPSIS
Create the outline of the studyDescribe all substantial study aspectsWork through all study specific issuesDevelop the study chart
Step 4. DRAFT THE PROTOCOL
Elaborate all protocol sectionsWork into details as necessary
Step 5. FINALIZE THE PROTOCOL
Review and crosscheck the document
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THANK YOU FOR YOUR ATTENTION!Natalia VostokovaChief Operating OfficerIPHARMA LLC2a build. 1, Rabochaya str.Khimki, Moscow Region141400, RussiaPhone. +7 (495) 925-3074Mobile. +7 (926) 098-3633Email: [email protected]: www.ipharma.ru
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