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The ProtocolThe Protocol making it your guidemaking it your guide

Clinical Trials Quality AssuranceClinical Trials Quality AssuranceCompliance OfficeCompliance OfficeSchool of MedicineSchool of Medicine

Presenter: Sheda MooriPresenter: Sheda Moori

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Unappealing Aspects of Protocols Unappealing Aspects of Protocols

•A large amount of paperA large amount of paper•Incredibly long and complex Incredibly long and complex

title title •Technical languageTechnical language•Confidential and controlled Confidential and controlled

documentdocument

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Grant vs. ProtocolGrant vs. Protocol A grant is a document that details the rationale A grant is a document that details the rationale

and request for funding of research.and request for funding of research. A protocol is a document that details structure, A protocol is a document that details structure,

procedures and organization for research. procedures and organization for research.

• A protocol can be a part of a grant; made available via A protocol can be a part of a grant; made available via an agreement/contract; or created by the investigator.an agreement/contract; or created by the investigator.

• Grant funding can occur with the inclusion of a Grant funding can occur with the inclusion of a developed protocol or development may occur later in developed protocol or development may occur later in the process. the process.

• IRB submission of a grant for review and approval of 1 IRB submission of a grant for review and approval of 1 research plan (protocol) at a time.research plan (protocol) at a time.

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The Research in the Protocol The Research in the Protocol

CategoriesCategories

• BiomedicalBiomedical Study of the normal and abnormal physiology and Study of the normal and abnormal physiology and

development of humans.development of humans.

• BehavioralBehavioral Study of behavior of individuals or groups.Study of behavior of individuals or groups.

• SocialSocial Study of social and economic systems for use in planning Study of social and economic systems for use in planning

public policy.public policy.• Cost and benefits of alternate ways of providing health, Cost and benefits of alternate ways of providing health,

educational or welfare services at national, state or local leveleducational or welfare services at national, state or local level

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The Research in the Protocol The Research in the Protocol ObjectivesObjectives

• Collect Information Collect Information

• Initiate possible methods of preventionInitiate possible methods of prevention

• Evaluate Instruments and techniques for Evaluate Instruments and techniques for diagnosisdiagnosis

• Test Interventions (drug, device, biologic, Test Interventions (drug, device, biologic, procedure)procedure)

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The Research in the Protocol The Research in the Protocol

Ethics of including humans in the researchEthics of including humans in the research

• Is there true science?Is there true science?

• Does the research provide direct benefit? Does the research provide direct benefit?

• Does it minimize the risk?Does it minimize the risk? physicalphysical general welfare general welfare

• Does the research respect the “person”? Does the research respect the “person”?

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Protocol ContentProtocol Content Title page Signature page Content page List of Abbreviations and Definitions Summary Background/Rationale Research Objectives and Purpose Study Design Subject Population/Recruitment Research Intervention Randomization/Blinding Summary of Data to be collected Statistical Consideration Subject Compliance and Withdrawal Interim Analysis and Data Monitoring Ethical Considerations Finance and Insurance Reporting and Dissemination Appendix—Tables and References

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Today’s FocusToday’s Focus

Make the protocol your guideMake the protocol your guide•How to read the protocolHow to read the protocol•Understanding the protocolUnderstanding the protocol•How to utilize the protocolHow to utilize the protocol

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Reading a protocolReading a protocol Grouping the sections of the protocolGrouping the sections of the protocol

• Why is the research being conducted?Why is the research being conducted?• How will the research be conducted?How will the research be conducted?• What will be done with the data What will be done with the data

collected?collected?• Handle the “housekeeping sections” of Handle the “housekeeping sections” of

the protocol last. the protocol last.

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Reading a protocolReading a protocol Why is this research being conducted?Why is this research being conducted?

• SummarySummary• Background/RationaleBackground/Rationale• Research Objectives Research Objectives

The history of the research The history of the research

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Reading a protocolReading a protocol

Why is this research being conducted?Why is this research being conducted?

• Investigator brochureInvestigator brochure• Package insertsPackage inserts • Articles Articles

Part of the protocol (usually provided by a sponsor of a Part of the protocol (usually provided by a sponsor of a protocol)protocol)

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Reading a protocolReading a protocol How will the research be conducted?How will the research be conducted?

• Study DesignStudy Design• Subject Population/RecruitmentSubject Population/Recruitment• Subject Compliance/WithdrawalSubject Compliance/Withdrawal• Research Intervention Research Intervention • RandomizationRandomization• Methods to Avoid BiasMethods to Avoid Bias• Summary of Data to be CollectedSummary of Data to be Collected

Your InstructionsYour Instructions

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ProceduresProcedures

ObservationalObservational

Efficacy (only “response” in Phase I studies)Efficacy (only “response” in Phase I studies)

SafetySafety

Maintain Integrity and Avoid BiasMaintain Integrity and Avoid Bias• keep the research honestkeep the research honest

Note: Repository/Database procedures for future research are not relevant to a current Note: Repository/Database procedures for future research are not relevant to a current protocol’s research objective and require a separate consenting process. protocol’s research objective and require a separate consenting process.

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• ManualsManuals• MemosMemos• Case report forms (blank)Case report forms (blank)

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Reading a protocolReading a protocol What will be done with the data collected?What will be done with the data collected?

• Statistical ConsiderationStatistical Consideration• Interim AnalysisInterim Analysis• Data MonitoringData Monitoring

Collect Data Accurately Collect Data Accurately

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Reading a protocolReading a protocol What will be done with the data collected?What will be done with the data collected?

• Be aware of possible changes in the research.Be aware of possible changes in the research. Interim analysis/DSMBInterim analysis/DSMB Review and approval of changes in protocolReview and approval of changes in protocol Alert subjects to relevant changes (via consent)Alert subjects to relevant changes (via consent)

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Reading a protocolReading a protocol Handling the “housekeeping sections” last Handling the “housekeeping sections” last

• Abbreviations & DefinitionsAbbreviations & Definitions• Ethical ConsiderationsEthical Considerations• Financing and InsuranceFinancing and Insurance• Reporting and DisseminationReporting and Dissemination• Appendix—Tables and ReferencesAppendix—Tables and References

Save for Last!Save for Last!

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Reading a protocolReading a protocol ““Housekeeping” Considerations Housekeeping” Considerations

Consider the ethical, regulatory, practical and Consider the ethical, regulatory, practical and medical center policies as you read.medical center policies as you read.

• Make sure results can be duplicated.Make sure results can be duplicated.

• Decrease the risk of flawed data and ineffective Decrease the risk of flawed data and ineffective research.research.

• Integrate clinical standards with research standards.Integrate clinical standards with research standards.

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Understanding a protocolUnderstanding a protocolTitle of protocolTitle of protocol

The Body System/ Disease Process/Behavior/PolicyThe Body System/ Disease Process/Behavior/Policy

Intervention/Technique/Method/Intervention/Technique/Method/ Instrument/ProcedureInstrument/Procedure

Clinical research termsClinical research terms

Additional readingAdditional reading

Ask questionsAsk questions

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Understanding a protocolUnderstanding a protocolTitle of the ProtocolTitle of the Protocol

““A Multi-center, Randomized, Phase III A Multi-center, Randomized, Phase III Active Control Study Comparing Active Control Study Comparing ((investigational interventioninvestigational intervention) and () and (standard interventionstandard intervention) ) in in (subject population)”(subject population)”

Structure of the researchStructure of the research

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Understanding a protocolUnderstanding a protocol

““Walk the path of the researcherWalk the path of the researcher””

Knowledge of the Body system/Disease Knowledge of the Body system/Disease

process/Behavior/Policyprocess/Behavior/Policy

Knowledge of the Intervention/Technique/Method/Knowledge of the Intervention/Technique/Method/Instrument/ProcedureInstrument/Procedure

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Additional ReadingAdditional ReadingDuke Medical Center Library Online (Duke Medical Center Library Online (

http://www.mclibrary.duke.eduhttp://www.mclibrary.duke.edu))

MedlineMedline

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Defining research termsDefining research terms

Get to know the context and intentGet to know the context and intent

• Protocol glossary Protocol glossary (protocol specific)(protocol specific)

• CTQA coordinator guidebook CTQA coordinator guidebook (http://medschool.duke.edu/compliance)(http://medschool.duke.edu/compliance)

• Several online clinical research glossariesSeveral online clinical research glossaries

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Understanding a protocolUnderstanding a protocolSpeak up and ask questionsSpeak up and ask questions

The protocol is not a perfect documentThe protocol is not a perfect document..

Responsibility/AccountabilityResponsibility/Accountability

• Milgram experiment (Milgram experiment (Obedience to Authority Study)Obedience to Authority Study)

• Genovese syndrome (Genovese syndrome (Bystander effectBystander effect))

• The SThe Seinfeld einfeld finale finale (“Is Doing Nothing Something?”)

• Healthcare professionals are held to a higher standard.

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Utilizing a protocolUtilizing a protocol

Research set-upResearch set-up ReconcilingReconciling Explaining the researchExplaining the research

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Example #1Example #1

A coordinator is given a protocol written by a A coordinator is given a protocol written by a Duke investigator and it is his/her Duke investigator and it is his/her responsibility to obtain IRB approval and responsibility to obtain IRB approval and implement the research within the clinical implement the research within the clinical setting. setting.

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Utilizing a protocolUtilizing a protocolExample #1Example #1

A coordinator is given a protocol written by a Duke A coordinator is given a protocol written by a Duke investigator and it is his/her responsibility to obtain investigator and it is his/her responsibility to obtain IRB approval and implement the research within the IRB approval and implement the research within the clinical setting. clinical setting.

The protocol becomes the map of the The protocol becomes the map of the scientific/clinical details for writing the consent, scientific/clinical details for writing the consent, creating the IRB summary and designing the creating the IRB summary and designing the structure of the research within the clinic structure of the research within the clinic (budget, facility needs, personnel, etc.)(budget, facility needs, personnel, etc.)

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Example # 2Example # 2

Per the agreement for a pharmaceutically-Per the agreement for a pharmaceutically-sponsored protocol, the research has sponsored protocol, the research has competitive enrollment. Once the overall competitive enrollment. Once the overall target enrollment has been met via all sites, target enrollment has been met via all sites, the study will end regardless of individual the study will end regardless of individual site enrollment numbers. This same site enrollment numbers. This same protocol has details of long-term safety protocol has details of long-term safety procedures that must be performed for early procedures that must be performed for early withdrawal. withdrawal.

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Utilizing a protocolUtilizing a protocolExample # 2Example # 2 Per the agreement for a pharmaceutically-sponsored Per the agreement for a pharmaceutically-sponsored

protocol, the research has competitive enrollment. protocol, the research has competitive enrollment. Once the overall target enrollment has been met via Once the overall target enrollment has been met via all sites, the study will end regardless of individual all sites, the study will end regardless of individual site enrollment numbers. This same protocol has site enrollment numbers. This same protocol has details of safety procedures that must be performed details of safety procedures that must be performed for early withdrawal.. for early withdrawal..

The protocol becomes evidence that there is an The protocol becomes evidence that there is an inconsistency in the procedures for the research. inconsistency in the procedures for the research.

Questions that need to be addressed--What will Questions that need to be addressed--What will happen to active subjects if the overall study is happen to active subjects if the overall study is stopped? The safety procedures per the protocol are stopped? The safety procedures per the protocol are required….who will pay for these procedures if the required….who will pay for these procedures if the study prematurely ends? study prematurely ends?

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A nephrology protocol requires the use of a A nephrology protocol requires the use of a dialysis center and its staff. The staff will be dialysis center and its staff. The staff will be asked to collect and document data per the asked to collect and document data per the normal dialysis visit for the research.normal dialysis visit for the research.

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A nephrology protocol requires the use of a A nephrology protocol requires the use of a dialysis center and its staff. The staff will be dialysis center and its staff. The staff will be asked to collect and document data per the asked to collect and document data per the normal dialysis visit for the research.normal dialysis visit for the research.

The coordinator becomes the instructor for The coordinator becomes the instructor for the staff and the protocol becomes the the staff and the protocol becomes the textbooktextbook..

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The sponsor of a protocol sends safety reports The sponsor of a protocol sends safety reports regarding adverse events at other sites. regarding adverse events at other sites. Several reports of pneumonia are detailed. Several reports of pneumonia are detailed. Pneumonia was not documented as a Pneumonia was not documented as a possible adverse event for the research. possible adverse event for the research.

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The sponsor of a protocol sends safety reports The sponsor of a protocol sends safety reports regarding adverse events at other sites. regarding adverse events at other sites. Several reports for pneumonia are detailed Several reports for pneumonia are detailed that was not listed as a possible adverse that was not listed as a possible adverse event for the research. event for the research.

Comparing these reports to the protocol details Comparing these reports to the protocol details the continuing occurrence of an unexpected the continuing occurrence of an unexpected adverse event that could also be study-adverse event that could also be study-related. related.

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An OB-GYN research group is interested in a An OB-GYN research group is interested in a pharmaceutically-sponsored protocol pharmaceutically-sponsored protocol involving cervical dysplasia. involving cervical dysplasia.

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An OB-GYN research group is interested in a An OB-GYN research group is interested in a pharmaceutically-sponsored protocol pharmaceutically-sponsored protocol involving cervical dysplasia. involving cervical dysplasia.

The objective of past protocols The objective of past protocols become the “research resume” become the “research resume” for the group. for the group.

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SummarizeSummarize A protocol can seem intimidating.A protocol can seem intimidating. Approach the protocol answering the 3 main Approach the protocol answering the 3 main

questions.questions. Walk the path of the researcher.Walk the path of the researcher. Do some additional reading, define terms and ask Do some additional reading, define terms and ask

questions.questions. Be acquainted with all the procedures required.Be acquainted with all the procedures required. Learn to use the details of the protocol to help Learn to use the details of the protocol to help

with set-up and explanation of the research.with set-up and explanation of the research.

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Final ThoughtsFinal Thoughts

Not a nursing order Not a nursing order

Overall understanding for an Overall understanding for an easier process easier process

Scientific and Practical Review Scientific and Practical Review

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Final ThoughtsFinal Thoughts

““It’s the protocol, stupid!”It’s the protocol, stupid!”

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Contact Us:Contact Us:

Clinical Trials Quality Assurance SectionClinical Trials Quality Assurance Section

Compliance Office--School of MedicineCompliance Office--School of Medicine

2200 West Main Street2200 West Main Street

Suite 720 Wachovia Plaza at Erwin SquareSuite 720 Wachovia Plaza at Erwin Square

Durham, NC 27705Durham, NC 27705

Sheda’s phone number: (919) 684-6456 Sheda’s phone number: (919) 684-6456

Sheda’s email: [email protected] Sheda’s email: [email protected]

Fax: (919) 684-6105Fax: (919) 684-6105

Website: http://medschool.duke.edu/complianceWebsite: http://medschool.duke.edu/compliance

10/13/10 1 the protocol

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