Protocol Design & Development: What You Need to Know to Ensure a Successful Study

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Protocol Design & Development What You Need to Know to Ensure a Successful Study

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Protocol QuotesYour protocol has more amendments than it does subjectsUnfortunately there is no control experiment for writing a protocolIt takes 10 weeks to develop an effective protocolWhy would I want to have anyone else look at MY protocol?A poorly conceived or poorly executed clinical trial can result in misinformation, which is worse than no information70 percent of the money expended in drug development is wasted.

Commercial Protocol DevelopmentObjective Depends on the PhasePhase 1 safetyPhase 2 proof of concept of efficacy and safetyPhase 3 validation of efficacy and safety

The Ultimate Objective is to Provide Data to Either Support a Marketing Application for a Product or Render it Unsafe or Ineffective

Scientific Protocol DevelopmentObjective is Often to Advance Understanding of Science or Current TherapyTherapy-based mechanistic studiesMore marketed products than investigational productsCommonly small FDA targeted studies on investigational products (Investigator INDs)Intent is to publish study results in a peer-reviewed journal to further scientific and clinical knowledge

IntroductionProtocol Design and Development PrinciplesElements Included in Development of Protocol ObjectivesElements Included in Development of Statistical Analysis PlansElements of Other Protocol SectionsSteps in the Design and Development of a Successful ProtocolProcess to Develop a Successful ProtocolTiming of Protocol Development in the Process of Clinical Trial ConductPitfalls to Avoid in the Development of a ProtocolA Path Forward

Protocol Development PrinciplesState Everything OnceAvoids redundant editing and conflicting informationWrite Objectives First for Early Stage ProtocolsComprehensive and specific objectivesWrite Statistical Analysis Plan (SAP) First for Late Stage ProtocolsSAP constructs data base, case report forms, and protocol simultaneouslyPlan Up Front and Avoid Protocol AmendmentsAmendments cost time and money

Protocol Development Principles(continued)Scientists (Clinical, Integrated Product Development / Regulatory, Research, Clinical Pharmacology)StatisticiansPhysiciansClinical Research AssociatesClinical Operations

Data ManagersSafety ExpertsRandomization ExpertsRegulatory OperationsSite Investigators and Study CoordinatorsMarketing PersonnelReimbursement Experts

Protocol Development is an Interdisciplinary Process

Protocol Development Principles(continued)Start Development Process with 5 - 10 Page Protocol Synopsis (or Outline or Summary)Get Agreement on Critical Issues before Expanding to Full ProtocolPut the Logistical Details in a Study Procedures Manual (Fewer Protocol Amendments)

Protocol Development Principles(continued)Write Specific Objectives in Early Stages of DevelopmentNO!!!!: The objective of this study is to determine the safety and efficacy of drug X in Y diseaseYES!!!!: To evaluate the effects of a twice daily intravenous dose of medicine A in population B on the clinical endpoint C by recording the measurement D at time period E relative to baseline versus a placebo.

Elements of a Clinical ProtocolObjectivesStatistical Methods (Statistical Analysis Plan)IntroductionStudy DesignStudy TreatmentsSubject EnrollmentStudy Assessments

Reporting Adverse EventsData Handling and Quality AssuranceAdministrative ConsiderationsInvestigator StatementReferencesStopping Rules

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Elements of a Clinical ProtocolObjectivesStatistical Methods (Statistical Analysis Plan)IntroductionStudy DesignStudy TreatmentsSubject EnrollmentStudy Assessments

Reporting Adverse EventsData Handling and Quality AssuranceAdministrative ConsiderationsInvestigator StatementReferencesStopping Rules

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Objectives by Phase of DevelopmentPhase 1Primary SafetySecondary Pharmacodynamics, Pharmacokinetics, Efficacy (rarely)Phase 2Primary Efficacy (at a defined dose)Secondary SafetyPhase 3Primary Validation of EfficacySecondary - Safety

ObjectivesQuintessence of the Early Stage (usually Phase 1 or 2) ProtocolRequires Consultation with Interdisciplinary TeamScientific, Statistical, Clinical, Integrated Product Development / Regulatory, CRA, CRF Development, Data Management, Investigator, Study CoordinatorConduct document Kickoff Meeting with interdisciplinary teamShould Take Several Days of Due Diligence to Finalize ObjectivesEarly Phase Protocol Synopsis and Protocol Should Flow From Objectives

Approach to Early Stage Clinical Trial Planning

PROTOCOLSTRATEGYMEETING

Statistical andRegulatory

Study Variables

Science andMedicine

Study Design

Study Objectives

Protocol

Draft CRFs

Database Setup

SAS Programming

Study Conduct

DataManagement,Statistics

FINAL REPORT

Elements Included in the Development of Protocol ObjectivesProductPatient PopulationGeneric Dosing RegimenClinical EndpointEfficacy AnalysesSafety AnalysesPhaseNOT THE DOSE

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Product Development ProcessChemistryPharmaceuticsPharmacology andPharmacokineticsToxicologyRegulatoryClinicalProduction

DrugSelection18+ Mo.18 Mo.6 Mo.10 Mo.12 Mo.12 Mo.24 Mo.

Phase 1Phase 2Phase 3Data AnalysisISS/ISE/ERsPhase 4Safety inhealthyvolunteersEfficacy& safetysmallGroup ofpatientsEfficacy & safetylargeGroup ofpatientsNDA PrepareSubmitFDA ReviewNDAApprovalPost-marketSurveillanceINDPrepareSubmit PilotPlantGMP Plant ProductionStability, Validation ProductionFormulation, Dose & AdministrationStability, Tech Transfer, ValidationHealthyhumansHumanpatientsADME (animal)MutagenicityAcute ToxicitySub-acute ToxicityLong-term Feeding Studies (chronic toxicity and carcinogenicity)Reproductive Toxicology8 Years

PRODUCT DEVELOPMENT

PopPKDISCOVERY

1O Pharm2O Pharm

1 Year +

Representative Phase 2 ObjectiveThe primary objective of this study is to determine the dose of XXX that controls active bleeding in successive cohorts of thrombocytopenic patients using the result-based dose adjustment design depicted below:

Result-based Dose Adjustment Design

Data Analyses by PhasePhase 1:Safety evaluated by Treatment Emergent Adverse Events (TEAEs)Pharmacokinetics evaluated with T1/2, AUC, Cmax, Tmax, etc. variablesDrug/Drug Interactions evaluated with TEAEsOccasional pharmacodynamic or efficacy endpoint evaluated statisticallyStatistical methods: largely descriptive

Data Analyses by Phase (continued)Phase 2:Survey of clinical endpoints, doses, regimens, etc.Continued safety evaluationStatistical methods: rigorous enough to convince yourself result is realPhase 3:Prospective definition of efficacy on well-defined, regulatorily-acceptable, clinical endpointContinued safety evaluationStatistical Methods: rigorous enough to convince the regulators result is real

Elements of a Clinical ProtocolObjectivesStatistical Methods (Statistical Analysis Plan)IntroductionStudy DesignStudy TreatmentsSubject EnrollmentStudy Assessments

Reporting Adverse EventsData Handling and Quality AssuranceAdministrative ConsiderationsInvestigator StatementReferencesStopping Rules

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Statistical Analysis Plan (SAP)Quintessence of the Late Stage ProtocolRequires Consultation with Interdisciplinary TeamMedical, Scientific, Statistical, Integrated Product Development / Regulatory, CRA, CRF Developer, Data ManagerConduct Document Initiation Meeting with Interdisciplinary TeamShould Take Several Days to Weeks to Perform Due Diligence and Finalize SAPClinical Data Base, Case Report Form, Protocol Synopsis, and Protocol Should Flow From SAP

Approach to Late Stage Clinical Trial Planning

STRATEGYMEETING

Study Objectives

Study Variables

Science,Medicine,Statistical, &Regulatory

Study Design

STATISTICAL

ANALYSIS PLAN

Protocol

Draft CRFs

Database Setup

SAS Programming

Study Conduct

DataManagement,Statistics

FINAL REPORT

Elements Included in the Development of Statistical Analysis PlansEfficacy AnalysesPrimary AnalysisSecondary AnalysesSafety AnalysesAnalyses Addressing Adverse EventsAnalyses of Clinical Laboratory DataSample SizeMissing Value Handling and Subject Evaluability

Elements Included in the Development of SAPs (continued)Group Comparability at BaselineInterim Analysis and Stopping RulesStatistical Adjustments for Multiple EndpointsApproach to Multicenter AnalysisSupplemental AnalysesSubgroup Analyses

Elements of a Clinical ProtocolObjectivesStatistical Methods (Statistical Analysis Plan/Study Endpoints)IntroductionStudy DesignStudy TreatmentsSubject EnrollmentStudy Visits

Study AssessmentsReporting Adverse EventsData Handling and Quality AssuranceAdministrative ConsiderationsInvestigator StatementReferencesStopping Rules

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IntroductionBRIEF Description of TechnologyBRIEF Description of Previous Nonclinical and Human ExperienceRationale for Conduct of the Study in the Context of Overall Development ProgramDosing RationaleStudy JustificationShould Get Shorter the Further Development Proceeds

Dosing RationaleInitially Based on Nonclinical Data: Phase 1/2Eventually Based on Previous Clinical Data: Phase 2/3Spend Time Thinking About It Needed for Marketing ApplicationDont Just Go With a Dose that WorksInclude in the Introduction

Study DesignShould Flow From Objectives (early stage) or SAP (late stage)Design: Dose Escalation/Parallel/Crossover/etcEfficacy or PK/PD AssessmentsType of ControlSingle center/Multi-centerStudy Periods/Study DurationNOT THE PACKAGING INSTRUCTIONS / LABELING / OR EXPERIMENTAL PROCEDURES

I know the Roman empire crumbled in large part because their number system did not contain the number zero, nevertheless.

Day Zero - Verboten

DAY ZERO

Week Zero - Verboten

WEEK ZERO

All You Need is.

LOVE and

A Time Zero on Day 1D-2; Day-1; Day 1 (with Time Zero); Day2Product is administered at Time Zero on Day 1Week -1 contains Day -1 through Day -7Week 1 contains Day 1 through Day 7D-7D-6D-5D-4D-3D-2D-1D 1D 2D 3D 4D 5D 6D 7

Week -1Week 1

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Study TreatmentsName of Investigational ProductDosage Forms (Active and Control)Size of Unit DoseDrug Administration InstructionsDecoding ProceduresDrug Packaging, Storage, Dispensing, and Disposition of Unused Drug

Subject EnrollmentInclusion/Exclusion Criteria

Randomization/Blinding

Subject Withdrawal

Inclusion/Exclusion CriteriaPhase 1Healthy Volunteers Exceptions: e.g., Oncology, HIV, some life-threatening rare diseasesPhase 2Optimized for Successful Demonstration of EfficacyPhase 3Broadened to Approximate Target Population for Marketing

Randomization and BlindingActive:Control1:1 (always preferred from a scientific perspective)2:13:1 (always preferred from a monetary perspective)Double BlindSingle BlindOpen Label

Subject WithdrawalCriteria for Discontinuation

Replacement of Dropouts

NOT STOPPING RULES (Warrants its own section)

Study AssessmentsWhat Is Done When (usually by Day)

Time and Events Table

Textual Format

Ensure Tabular and Textual Information is ConsistentStudy coordinators are different

Reporting Adverse EventsPresent Requirements in Excess of RegulationsTabular Format UsefulKeep it SimpleStress the Importance of this Aspect to InvestigatorsStandardized Template Text (not required to be reviewed for each protocol)

Stopping RulesSection is Not Always RequiredUsually for novel products or potentially toxic products

Designed to Give the Investigator and the Regulators Comfort that You are Proceeding Safely (not too quickly)

One of the Most Difficult Sections to WriteNeed a lot of experienced regulatory/medical/statistical inputUse of standard toxicological scales

Generic Stopping RulesClear Evidence of Harm or Harmful Side-Effects of the Treatment No Likelihood of Demonstrating Treatment Benefit Overwhelming Evidence of the Benefit of the TreatmentUsually associated with an interim analysis Trial is Stopped While Data is Reviewed for Safety Concern

Suspension GuidelinesSet of Conditions which Require a Review Team to Convene and Review the Data

Meant to Prevent Stopping Study for Inappropriate Reason

Can be more General to Cover Unexpected Adverse Experiences because youre not Requiring the Study to Stop

Data Handling and Quality Assurance Case Report Form Instructions

Monitoring Procedures

Inspection of Records

Study Record Retention Instructions

Standardized Template Text

Administrative ConsiderationsConfidentiality IssuesIEC/IRB ProceduresProtocol Modification ProceduresInformed Consent ProceduresProtocol Deviations/ViolationsStudy Reporting RequirementsFinancial Disclosure and ObligationsInvestigator DocumentationStudy Conduct GuidelinesPublication Policy

Investigator StatementSigned Commitment by the Investigator

Must Have Read and Understood the Protocol

Must Conduct the Study in Accordance with the Applicable Regulations

References

Pertinent References from Introduction, Statistical Methods, etc.

It is not a scientific paper!

Pitfalls in Protocol DevelopmentInitially Drafting Complete ProtocolNot Spending Sufficient Effort on Objectives or SAPSubmitting SAP After Study Has StartedPeppering Protocol with Redundant InformationNot Checking Tables and Text for ConsistencyNot Soliciting Sufficient Interdisciplinary InputNot Identifying Final Decision Making AuthorityAllowing Endless Reviews

The Solution?????

The Future of Protocol DevelopmentTreat your protocol as if it were data.

Phase II Study of the Efficacy, Safety, Tolerability and Immunogenicity of Subcutaneously Administered Dynavax Amb a 1 Immunostimulatory Oligodeoxyribonucleotide Conjugate (AIC) in Ragweed-allergic Adults: A Three-arm, Phase II, Observer blinded, Randomized, Placebo-controlled Study

The Future of Protocol DevelopmentTreat your protocol as if it were data.

Phase II Study of the Efficacy, Safety, Tolerability and Immunogenicity of Subcutaneously Administered Dynavax Amb a 1 Immunostimulatory Oligodeoxyribonucleotide Conjugate (AIC) in Ragweed-allergic Adults: A Three-arm, Phase II, Observer blinded, Randomized, Placebo-controlled Study

CDISC Protocol Representation Model (PRM)Clinical Data Interchange Standards Consortium (CDISC) Founded 1997Non profit standards development organization aimed at facilitating product development and approval by regulatory agencies

Protocol Representation Model (PRM) 2010Useful Format for Information Management and Re-useTagged informational units that are machine-readableStructuring information by meta information

Protocol Representation ModelStandard Concepts Stored in a Database

Some 300 Agreed-upon Standard Data Fields and Values:ObjectivePhaseDegree of blindSubject age rangeSubject population definition

Structures Concepts by Identifying them as Common Across Protocols

PRMBenefits CDISC Says: . . . protocol information can be readily entered into an information system or online registry that allows key protocol information to be searched, shared, analyzed, reported on, and reused.

Thousands of Uses:Automatically Updated Study Summaries for WebsitesTransfer of Study Structure to CTMS and EDCSearchable DBs of Study Designs and CompoundsPropagate Data into Protocol and CSR Templates

PRMHow To CDISC Toolkit: Makes it Easy for Protocol Authors to Reap Benefits of PRMhttp://www.cdisc.org/cdisc-prm-toolset-version-1.0Study Outline for Basic FieldsStudy Outline Concepts List Describes Each Field

Wizard Being Developed

ConclusionsProtocol Development is Multidisciplinary ProcessProtocol Development Benefits From Compartmentalization and Employing SystemsSuccessful Clinical Studies Require a Well-Planned ProtocolUnfortunately there is no control experiment for writing a protocol

Questions?

textXXX 6.0 mg/kg(n=5)orPlatelets(n=5)XXX 4.0 mg/kg(n=5)orPlatelets(n=5)BleedingControlled?XXX 6.0 mg/kg x 2*(n=5)orPlatelets(n=5)BleedingControlled?BleedingControlled?XXX 2.0 mg/kg(n=5)orPlatelets(n=5)XXX 5.0 mg/kg(n=5)orPlatelets(n=5)XXX 4.0 mg/kg x 2*(n=5)orPlatelets(n=5)Terminate StudyYESNOYESNOYESNO