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The Fundamentals of The Fundamentals of International Clinical Research International Clinical Research

Writing a Protocol: Writing a Protocol: From Proposal to IRBFrom Proposal to IRB--ReadyReady

Deborah HilgenbergDeborah HilgenbergFamily Health InternationalFamily Health International

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What is a Protocol?What is a Protocol?

ICH Guidelines:ICH Guidelines:

““A document that describes the A document that describes the objectives, design, methodology, objectives, design, methodology, statistical considerations and statistical considerations and organization of a trialorganization of a trial””---- E6, Section 1.44E6, Section 1.44

Written by sponsor, investigator or teamWritten by sponsor, investigator or team

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What is the difference between a What is the difference between a Grant ProposalGrant Proposal and a Protocol?and a Protocol?

Grant proposalGrant proposal ::

Purpose:Purpose: Obtain fundingObtain funding

Focus: Focus: Describes Aims, methods,Describes Aims, methods,hypotheseshypotheses

Feasibility:Feasibility: Costs, staffing, equipmentCosts, staffing, equipment

Review by:Review by: Scientific review committee, fundersScientific review committee, funders

Tone:Tone: PersuasivePersuasive

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What is the difference between a What is the difference between a Grant Proposal and a Grant Proposal and a ProtocolProtocol??

Protocol: Protocol: a a regulatoryregulatory documentdocument

Purpose:Purpose: Describes a single studyDescribes a single study in detailin detail

Focus: Focus: Organized around specific objectivesOrganized around specific objectives

Feasibility: Specifics of enrolling, implementation Feasibility: Specifics of enrolling, implementation detailsdetails

Reviewed by: Scientists, Sponsor, IRBs Reviewed by: Scientists, Sponsor, IRBs

Tone: Tone: Informative; focused on Informative; focused on detailsdetails

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Start with the Scientific Start with the Scientific QuestionQuestion

Clear idea of the primary research Clear idea of the primary research question being asked question being asked Clearly stated objective(s): Clearly stated objective(s): –– SpecificSpecific–– MeasurableMeasurable–– RelevantRelevant–– FeasibleFeasible–– EthicalEthical

Everything in protocol relates back to Everything in protocol relates back to research questionresearch question

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General InformationGeneral InformationICH E6, Section 6.1ICH E6, Section 6.1

Protocol title, identifying number,

version number and date

Investigator responsible for the study

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Statement of ComplianceStatement of Compliance

Signed statement by Principal Signed statement by Principal Investigator that study will be Investigator that study will be conducted in compliance with protocol, conducted in compliance with protocol, GCP, and applicable regulatory GCP, and applicable regulatory requirement(s).requirement(s).

ICH E6, Section 6.2.5ICH E6, Section 6.2.5

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Protocol Summary/SchemaProtocol Summary/Schema

Last section actually written:Last section actually written:

Concise overviewConcise overview——population, population, duration, number of sitesduration, number of sitesBriefly describe designBriefly describe designList objectivesList objectives——clear and specificclear and specificProvide schematicProvide schematic

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Background/RationaleBackground/Rationale

Review findings of other researchReview findings of other researchRationaleRationale——why your study needs to be why your study needs to be donedoneDescribe designDescribe design——observational, observational, randomizedrandomizedKnown or potential risks and benefitsKnown or potential risks and benefits——applies to any type of studyapplies to any type of studyIf using intervention, describeIf using intervention, describe

E6, Section 6.2E6, Section 6.2

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Objectives Objectives

Clearly state primary and secondary objectivesClearly state primary and secondary objectives——the fewer the the fewer the better!better!

Typically include Typically include ““actionaction”” word, such as assess, measure, word, such as assess, measure, compare, etc.compare, etc.–– Example: To define levels of serotypeExample: To define levels of serotype--specific neutralizing Abs specific neutralizing Abs

associated with protective immunity against dengueassociated with protective immunity against dengue

Method by which objective is met, outcome measuresMethod by which objective is met, outcome measures–– Example: Neutralizing Ab titers in blood samples collected from Example: Neutralizing Ab titers in blood samples collected from infants infants

before DV infection, and predicted neutralizing Ab titers at timbefore DV infection, and predicted neutralizing Ab titers at time of illness, e of illness, will be correlated with disease severity and peak viremia levelswill be correlated with disease severity and peak viremia levels. . Neutralizing Ab titers at which infants developed symptomatic deNeutralizing Ab titers at which infants developed symptomatic dengue ngue will be determined.will be determined.

ICH E6, Section 6.3

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DesignDesign

Type of study, e.g., observational, caseType of study, e.g., observational, case--controlcontrolSpecific outcomes/endpoints to be Specific outcomes/endpoints to be measured measured andand methods of data collectionmethods of data collectionHow many participants, in which groupsHow many participants, in which groupsTime to complete enrollmentTime to complete enrollmentDescribe study groups/armsDescribe study groups/armsExpected duration of trialExpected duration of trial periodsperiods including including followfollow--upup

ICH E6, Section 6.4ICH E6, Section 6.4

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Study Population: Study Population: Selection and WithdrawalSelection and WithdrawalDefine population from which participants will Define population from which participants will be drawnbe drawnDescribe recruitment strategiesDescribe recruitment strategiesState estimated number of participants needed State estimated number of participants needed in each group/armin each group/armDefine age, gender, ethnicityDefine age, gender, ethnicityExample: Example: 1050 male and female patients at ______ Hospital, 1050 male and female patients at ______ Hospital, age 6 months through 15 years, who are DVage 6 months through 15 years, who are DV--RTRT--PCR positivePCR positive

ICH E6, Section 6.5ICH E6, Section 6.5

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Study PopulationStudy Population

Vulnerable populations require Vulnerable populations require special considerations:special considerations:–– ChildrenChildren–– Pregnant womenPregnant women–– PrisonersPrisoners–– Other vulnerable populationsOther vulnerable populations

http://www.hhs.gov/ohrp/humahttp://www.hhs.gov/ohrp/humansubjects/guidancensubjects/guidance

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Study PopulationStudy Population

List inclusion criteriaList inclusion criteria–– describe characteristics and conditions necessary for eligible pdescribe characteristics and conditions necessary for eligible persons to be includedersons to be included–– Include willingness to provide consentInclude willingness to provide consent

List exclusion criteriaList exclusion criteria–– describe characteristics that would disqualify otherwise eligibldescribe characteristics that would disqualify otherwise eligible e

participantsparticipants–– Include exclusionary concomitant medicationsInclude exclusionary concomitant medications

Risks of study should structure in/ex criteriaRisks of study should structure in/ex criteria–– Example: if intervention is risky for pregnant women, ensure thaExample: if intervention is risky for pregnant women, ensure that t

women who are enrolled are women who are enrolled are notnot pregnant and use effective pregnant and use effective contraceptivecontraceptive during studyduring study

ICH E6, Section 6.5ICH E6, Section 6.5

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Study Procedures/Evaluations Study Procedures/Evaluations at Each Contactat Each Contact

Obtain consentObtain consentMedical history, physical exam, specimen Medical history, physical exam, specimen collectioncollectionInterview/questionnaireInterview/questionnaireEnvironmental survey, e.g., water sample, Environmental survey, e.g., water sample, insect collection, etc.insect collection, etc.Counseling proceduresCounseling proceduresMedications/treatments permitted and not Medications/treatments permitted and not permittedpermitted

ICH E6, Section 6.6ICH E6, Section 6.6

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Study Procedures/EvaluationsStudy Procedures/Evaluations

Screening: what happens to participant at Screening: what happens to participant at first contact, including consentfirst contact, including consent

Enrollment: baseline assessment, Enrollment: baseline assessment, randomization procedures, etc.randomization procedures, etc.

FollowFollow--up Visits: plan for retentionup Visits: plan for retention

What and how data are collected at each What and how data are collected at each visitvisit

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Study Procedures/EvaluationsStudy Procedures/Evaluations

Laboratory EvaluationsLaboratory Evaluations– Include specific test components and estimated

volume and type of specimens needed for each test

– Specify laboratory methods

List special assays or proceduresrequired (e.g., immunology assays, sputum specimens, photographs)

Instructions for specimen preparation, handling, storage, and shipment

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Schedule of EventsSchedule of Events----requiredrequired

XXXXXXXXAssess AEAssess AE

XXXXXXXXInterventionIntervention

XXXXXXHematologyHematology

XXXXXXChemistryChemistry

XXXXXXXXUrinalysisUrinalysis

XXSymptom Symptom directeddirected

XXPhysical ExamPhysical Exam

XXXXXXXXXXReview Con Review Con MedsMeds

updateupdateXXMedical HistoryMedical History

XXXXSign ConsentSign Consent

FinalFinalTime 2Time 2Time 1 Time 1 Enroll/Enroll/BaselineBaseline

ScreenScreenProceduresProcedures

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Safety Assessment Safety Assessment (other (other than minimal risk protocol)than minimal risk protocol)

Define adverse events (AEs) and serious Define adverse events (AEs) and serious adverse events (SAEs)adverse events (SAEs)Describe types of AEs that may occur, including Describe types of AEs that may occur, including lab valueslab valuesProcedures to follow if AE occursProcedures to follow if AE occursDescribe methods used to track AEsDescribe methods used to track AEsReport pregnanciesReport pregnanciesHalting rulesHalting rules

ICH E6, Section 6.8ICH E6, Section 6.8

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Statistical ConsiderationsStatistical Considerations

Written as Written as ““selfself--containedcontained”” sectionsection

Clearly linked to study objectivesClearly linked to study objectivesAssumed number of dropAssumed number of drop--outs, withdrawals, outs, withdrawals, missing data, etc.missing data, etc.Criteria for terminating study/participantsCriteria for terminating study/participantsProcedures for deviationsProcedures for deviationsParticipants to be analyzedParticipants to be analyzed

ICH E6, Section 6.9ICH E6, Section 6.9

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Analysis Plan SummaryAnalysis Plan Summary

Adequate for reviewers to decide if Adequate for reviewers to decide if planned primary analyses are planned primary analyses are appropriate for the studyappropriate for the study

Include the way in which anticipated Include the way in which anticipated analysis problems will be handledanalysis problems will be handled

Describe how safety measures Describe how safety measures monitoredmonitored

Full plan done Full plan done prior toprior to any analysesany analyses

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Data ManagementData Management

Describe source documentsDescribe source documents–– Refer to DMID Source Documentation StandardsRefer to DMID Source Documentation Standards

Indicate schedule for data reports, and final Indicate schedule for data reports, and final study reportsstudy reportsDescribe how documents/data maintainedDescribe how documents/data maintainedStatement about who will have accessStatement about who will have accessSpecify length of time for retention of study Specify length of time for retention of study recordsrecords

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Ethics/Protection of Ethics/Protection of ParticipantsParticipants

Discuss Discuss –– ethical reviewethical review–– risks/benefitsrisks/benefits–– participant compensationparticipant compensation–– confidentiality, especially limits of confidentiality, especially limits of

include any communicable disease reporting include any communicable disease reporting requirementsrequirements

–– study discontinuationstudy discontinuationICH E6, Section 6.12ICH E6, Section 6.12

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Informed Consent ProcessInformed Consent Process

Refer to ICH E6, Section 4.8Refer to ICH E6, Section 4.8Describe process of obtaining consentDescribe process of obtaining consent–– Special attention for minors, different languages, Special attention for minors, different languages,

and low literacy and low literacy

Identify if more than one consent usedIdentify if more than one consent used, , i.e., for screening, for enrollment, for i.e., for screening, for enrollment, for specimen storagespecimen storageMust be approved by IRB(s) prior to useMust be approved by IRB(s) prior to use

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Other Sections Other Sections (if required by (if required by DMID)DMID)

Quality Control and AssuranceQuality Control and AssuranceFinancing and InsuranceFinancing and InsurancePublication PolicyPublication PolicySupplements/AppendicesSupplements/Appendices

ICH E6, Section 6.11ICH E6, Section 6.11--6.166.16

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AppendicesAppendices

Sample informed consentsSample informed consents----requiredrequiredSchedule of events/visitsSchedule of events/visits----requiredrequiredData Management Plan Data Management Plan Site Monitoring PlanSite Monitoring PlanManual of ProceduresManual of Procedures

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Protocol Writing Tips: Protocol Writing Tips: Getting StartedGetting Started

Writing a protocol is Writing a protocol is –– a team effort, not individuala team effort, not individual–– takes takes timetime, with , with manymany draftsdrafts

Recommended coRecommended co--authors or reviewers authors or reviewers include:include:–– Statistician(s)Statistician(s)–– Data managerData manager–– Clinicians or epidemiologistClinicians or epidemiologist–– Study coordinator/implementation expert(s)Study coordinator/implementation expert(s)–– Community representative(s)Community representative(s)

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Protocol Writing: Getting Protocol Writing: Getting StartedStarted

Use of a template is recommended by DMIDAssign writing tasks to others, especially statistician, data manager, lab expert

Expect multiple reviews from sponsor Expect multiple reviews from sponsor and IRBsand IRBs

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Protocol Writing TipsProtocol Writing Tips

Spell out abbreviations and acronyms at first useSpell out abbreviations and acronyms at first use– abbreviations should be added to the list in the front of the

protocol

Version number and date are required;– Follow DMID version control guidelines

Posted on the ICSSC website (http://www.icssc.org/templates_resources.htmhttp://www.icssc.org/templates_resources.htm/)

Use bulleted lists where helpful Use bulleted lists where helpful

Header/Footer: pagination; version number; Header/Footer: pagination; version number; short title; date.short title; date.

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Back it up!Back it up!

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SummarySummary

Clear objectives and endpoints are Clear objectives and endpoints are essentialessentialAll procedures/data contribute to answer All procedures/data contribute to answer primary questionprimary questionTemplates ensure sponsorTemplates ensure sponsor’’s needs are s needs are met and all pieces are includedmet and all pieces are includedWriting a study protocol is a team effortWriting a study protocol is a team effortThink ahead to the implementationThink ahead to the implementation

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Finally, remember why we Finally, remember why we do researchdo research