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: nv@ipharma.ruWeb-site: www.ipharma.ru

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