writing clinical research protocols part 1: preparation and process jonathan mccall, ba editor dcri...

Writing Clinical Writing Clinical Research Protocols Research Protocols Part 1: Part 1: Preparation and Preparation and ProcessProcess

Jonathan McCall, BAJonathan McCall, BAEditorEditorDCRI CommunicationsDCRI Communications

The Protocol-writing ProcessThe Protocol-writing Process


■ Clinical Protocols: an OverviewClinical Protocols: an Overview

■ Preparatory StepsPreparatory Steps

■ Assembling a Protocol TeamAssembling a Protocol Team

■ Managing the ProcessManaging the Process

■ Resources and GuidanceResources and Guidance

Protocol WritingProtocol Writing

““The validity, accuracy, and coherency of the The validity, accuracy, and coherency of the [protocol] document can have a huge [protocol] document can have a huge influence on the treatment administration and influence on the treatment administration and on the interpretability of the results. on the interpretability of the results.

If we wish to improve the quality of clinical If we wish to improve the quality of clinical trial protocols, we should improve the…trial protocols, we should improve the…writing process.”writing process.”

Gennari JH, Medinfo, 2004Gennari JH, Medinfo, 2004

Protocol Writing: a Collaborative Protocol Writing: a Collaborative ProcessProcess

Clinical research protocols often (always?) Clinical research protocols often (always?) require the input of many knowledgeable require the input of many knowledgeable people, including physicians, nurses, CRAs, people, including physicians, nurses, CRAs, regulatory experts, statisticians, information regulatory experts, statisticians, information technology experts, and even sometimes technology experts, and even sometimes editors…editors…

Protocol Writing: a Collaborative Protocol Writing: a Collaborative ProcessProcess

““[protocol writing] is an [protocol writing] is an intellectualintellectual and and creative group taskcreative group task…”…”

Weng C, Medinfo, 2004Weng C, Medinfo, 2004

Protocol Writing: an Iterative ProcessProtocol Writing: an Iterative Process

■ Protocols are in constant flux*:Protocols are in constant flux*:

■ Content changes due to multiple contributorsContent changes due to multiple contributors

■ Content changes in response to review or Content changes in response to review or critiquecritique

■ Content changes necessitated by new clinical Content changes necessitated by new clinical informationinformation

■ Content changes dictated by an evolving Content changes dictated by an evolving regulatory and ethical landscaperegulatory and ethical landscape

*van der Lei J, What’s in a Protocol (position paper), 2000*van der Lei J, What’s in a Protocol (position paper), 2000

Passing MusterPassing Muster

You probably thought having an earthshaking You probably thought having an earthshaking idea that could advance scientific knowledge idea that could advance scientific knowledge and change clinical practice was the hard part.and change clinical practice was the hard part.


■ Between the bright idea and successfully Between the bright idea and successfully completed study, your protocol will have to completed study, your protocol will have to pass muster with the following people:pass muster with the following people:

■ Other physiciansOther physicians

■ NursesNurses

■ Patients Patients

■ Reviewers (including IRBs)Reviewers (including IRBs)


■ Thinking ahead about challenges—scientific, Thinking ahead about challenges—scientific, regulatory, cultural, and logistical—may mean regulatory, cultural, and logistical—may mean the difference between a successful protocol the difference between a successful protocol and one that never makes it out of the and one that never makes it out of the preliminary review committee.preliminary review committee.

Some Questions to Ask Before Some Questions to Ask Before BeginningBeginning

■ Basic Feasibility:Basic Feasibility:

■ Are there enough potential subjects to meet Are there enough potential subjects to meet my accrual goal?my accrual goal?

■ Are there competing trials? (Remember: a trial Are there competing trials? (Remember: a trial may compete not only for patients but for may compete not only for patients but for access to drugs and devices.)access to drugs and devices.)

■ Is there (note: NOT “should there be”) clinical Is there (note: NOT “should there be”) clinical equipoise regarding this research question?equipoise regarding this research question?


■ Physicians and institutions:Physicians and institutions:

■ Are other physicians likely to be receptive to Are other physicians likely to be receptive to this study idea?this study idea?

■ Would participating in this study require special Would participating in this study require special resources or entail financial drains on a resources or entail financial drains on a practice?practice?

■ Are other institutions likely to have the Are other institutions likely to have the technology/expertise/support technology/expertise/support infrastructure/levels of training needed?infrastructure/levels of training needed?


■ Patients:Patients:

■ Are patients likely to find this study interesting Are patients likely to find this study interesting or acceptable?or acceptable?

■ How will patients learn about this study?How will patients learn about this study?

■ What risk or costs might patients have to bear What risk or costs might patients have to bear in participating in this study?in participating in this study?


■ LogisticsLogistics

■ How will we accomplish randomization, drug How will we accomplish randomization, drug shipments, unblinding, etc? shipments, unblinding, etc?

■ How will specimens be collected, stored, How will specimens be collected, stored, shipped, banked, read?shipped, banked, read?

■ How will we audit for performance?How will we audit for performance?■ How will data be collected, transferred, stored How will data be collected, transferred, stored

and analyzed?and analyzed?■ How will we respond to “help desk” issues?How will we respond to “help desk” issues?

Representing the Relevant Areas of Representing the Relevant Areas of KnowledgeKnowledge

■ Principal InvestigatorsPrincipal Investigators

■ Specialists (Imaging, Specialists (Imaging, Nuclear Med, Surgery)Nuclear Med, Surgery)

■ Nursing/CRANursing/CRA

■ RegulatoryRegulatory

■ SafetySafety

■ StatisticsStatistics

■ Data managementData management

■ Patient advocacyPatient advocacy

■ Study coordinatorStudy coordinator

■ Protocol editorProtocol editor

Creating a Realistic TimetableCreating a Realistic Timetable

■ The typical process:The typical process:

1.1. ““Submit an initial proposal,Submit an initial proposal,

2.2. Generate the first complete draft,Generate the first complete draft,

3.3. Iteratively review and revise the drafts,Iteratively review and revise the drafts,

4.4. Submit final draft to the [reviewing body] for Submit final draft to the [reviewing body] for approval.approval.

However, the details within step #3 are quite However, the details within step #3 are quite complex.”complex.”



““However, the details within step #3 are quite However, the details within step #3 are quite complex.”complex.”


NB: NB: UNDERSTATEMENTUNDERSTATEMENT


■ However long you think it will take, it will take However long you think it will take, it will take longer.longer.

■ Be aware of the intersection of:Be aware of the intersection of:

■ Your own and others’ schedulesYour own and others’ schedules

■ Project benchmarks and timetablesProject benchmarks and timetables

■ Review cyclesReview cycles

Clear ChannelsClear Channels

■ Establish the lines of communications:Establish the lines of communications:

■ Who’s in charge?Who’s in charge?

■ Who has final responsibility for a given task?Who has final responsibility for a given task?

■ How are consensus decisions made?How are consensus decisions made?

■ How is information communicated a) among How is information communicated a) among the protocol group, b) between the protocol the protocol group, b) between the protocol group and outside entities?group and outside entities?

Clear ChannelsClear Channels

“…“…participants involved in protocol participants involved in protocol development have development have different levels of different levels of statusstatus….the ….the clinician researcherclinician researcher is usually is usually treated as the treated as the highest-level authority.highest-level authority. Thus, it is often Thus, it is often hard or impossiblehard or impossible for others for others (eg, the protocol editors) to (eg, the protocol editors) to make demandsmake demands on on these researchers.”these researchers.”






■ Managing the Writing ProcessManaging the Writing Process


Some Problems that Plague the Some Problems that Plague the Process…Process…

■ Ineffective or excessive review and revisionIneffective or excessive review and revision

■ Poor version controlPoor version control

■ Integrating input from other contributorsIntegrating input from other contributors

■ Poor coordinationPoor coordination

Weng C, Medinfo, 2004Weng C, Medinfo, 2004

……and Some Possible Solutions:and Some Possible Solutions:

■ Identify the person responsible for the Identify the person responsible for the content.content.

■ Identify the person responsible for integrating Identify the person responsible for integrating the content into the protocol.the content into the protocol.

■ Establish a process for deciding on accepting Establish a process for deciding on accepting or rejecting critiques or suggestions.or rejecting critiques or suggestions.

■ Keep detailed minutes/records of all meetings Keep detailed minutes/records of all meetings or project discussions; mandate or project discussions; mandate acknowledgment of receipt of important acknowledgment of receipt of important communicationscommunications

Technological SolutionsTechnological Solutions

■ Researchers with the available resources may Researchers with the available resources may be interested in exploring technological be interested in exploring technological solutions, including software packages for solutions, including software packages for multi-contributor projects, or develop an “in-multi-contributor projects, or develop an “in-house” system.house” system.

■ These solutions may offer particular help in These solutions may offer particular help in managing communication flow.managing communication flow.

Be Mindful of ConstraintsBe Mindful of Constraints

■ Protocols have a way of growing into “fishing Protocols have a way of growing into “fishing expeditions.”expeditions.”

■ ““Mission creep” should be sharply Mission creep” should be sharply constrainedconstrained——don’t succumb to “kitchen sink” don’t succumb to “kitchen sink” data collection.data collection.

■ Keep the protocol lean.Keep the protocol lean.

Maintaining ControlMaintaining Control

■ The “single-scriber” approach*:The “single-scriber” approach*:

■ A single person (usually the protocol editor) is A single person (usually the protocol editor) is charged with integrating contributions, charged with integrating contributions, maintaining a master file, and controlling file maintaining a master file, and controlling file access during the draft process.access during the draft process.

■ This person also usually takes responsibility This person also usually takes responsibility for draft circulation and dissemination.for draft circulation and dissemination.

*Gennari JH, Medinfo, 2004*Gennari JH, Medinfo, 2004

Maintaining ControlMaintaining Control

■ A procedure for collecting sign-off on a draft A procedure for collecting sign-off on a draft document should be established.document should be established.

■ A protocol checklist enumerating required A protocol checklist enumerating required items can be useful.*items can be useful.*

■ Remember: regardless of procedures, final Remember: regardless of procedures, final responsibility rests with the PI.†responsibility rests with the PI.†

*CTEP Investigators’ Handbook, 2002 (Appendix VII)*CTEP Investigators’ Handbook, 2002 (Appendix VII)

††Protomechanics, Chapter 1, 2005 Protomechanics, Chapter 1, 2005 (www.cc.nih.gov.protomechanics )(www.cc.nih.gov.protomechanics )

IterationsIterations

■ The cyclical process of drafting the protocol The cyclical process of drafting the protocol extends through the protocol submission and extends through the protocol submission and review process.review process.

■ The PI, protocol editor, and study coordinator The PI, protocol editor, and study coordinator are usually responsible for most duties are usually responsible for most duties relating to submission and critique.relating to submission and critique.

A Typical Review CycleA Typical Review Cycle

2: Final draft 2: Final draft created by created by

team; team; submitted submitted for higher-for higher-

level review level review

4: Draft 4: Draft modified per modified per

reviewer reviewer comments; comments;

reply draftedreply drafted

1: Draft 1: Draft study study

approved by approved by local local

research research committeecommittee

3: Protocol 3: Protocol returned with returned with

comments comments requiring requiring

response or response or modificationmodification

Phase II/III Phase II/III StudyStudy

Phase II/III Phase II/III StudyStudy

NIH (Protomechanics)NIH (Protomechanics)

http://www.cc.nih.gov/ccc/protomechanics/http://www.cc.nih.gov/ccc/protomechanics/

These are the NIH’s guidance documents for These are the NIH’s guidance documents for protocols proposed for the Warren Grant protocols proposed for the Warren Grant Magnuson Clinical Center. Subjects include:Magnuson Clinical Center. Subjects include:

■ Protocol contentProtocol content

■ Roles and responsibilitiesRoles and responsibilities

■ Regulatory compliance Regulatory compliance

■ Scientific and statistical designScientific and statistical design

■ Compensation and reimbursement issuesCompensation and reimbursement issues

Cancer Therapy Evaluation Program Cancer Therapy Evaluation Program (CTEP)(CTEP)

http://ctep.cancer.gov/guidelines/http://ctep.cancer.gov/guidelines/

Contains guidelines and resources for clinical Contains guidelines and resources for clinical cancer trials conducted under NCI auspices, cancer trials conducted under NCI auspices, including:including:

■ Investigators’ HandbookInvestigators’ Handbook

■ Protocol templates (phase I, II, & III)Protocol templates (phase I, II, & III)

■ Regulatory and process guidanceRegulatory and process guidance

NIH Roadmap FundingNIH Roadmap Funding

http://nihroadmap.nih.gov/grants/index.asphttp://nihroadmap.nih.gov/grants/index.asp

Contains listing of NIH Roadmap funding Contains listing of NIH Roadmap funding opportunities for basic/correlative sciences.opportunities for basic/correlative sciences.

Office of Human Research Protection Office of Human Research Protection (OHRP)(OHRP)

http://www.hhs.gov/ohrp/policy/index.htmlhttp://www.hhs.gov/ohrp/policy/index.html

This is a DHHS site that houses regulatory This is a DHHS site that houses regulatory guidance documents for conducting clinical guidance documents for conducting clinical trials in human subjects.trials in human subjects.

Office of Human Subjects Research Office of Human Subjects Research (OHSR)(OHSR)

http://ohsr.od.nih.gov/info/info.htmlhttp://ohsr.od.nih.gov/info/info.html

List of OHSR guidance documents, including:List of OHSR guidance documents, including:

http://ohsr.od.nih.gov/info/sheet5.htmlhttp://ohsr.od.nih.gov/info/sheet5.html

Guidelines for writing research protocolsGuidelines for writing research protocols

http://ohsr.od.nih.gov/info/sheet6.htmlhttp://ohsr.od.nih.gov/info/sheet6.html

Guidelines for writing informed consent Guidelines for writing informed consent documentsdocuments

SummarySummary

■ Proper preparation can make the difference Proper preparation can make the difference between success and failure in protocol between success and failure in protocol development.development.

■ Protocols are the work of many handsProtocols are the work of many hands—and —and as such, require some care to ensure as such, require some care to ensure coordination and cooperation among coordination and cooperation among contributors.contributors.

Questions?Questions?

writing clinical research protocols part 1: preparation and process jonathan mccall, ba editor dcri...

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