Writing Clinical Research Protocols, Part 2: Writing and Editing Clinical Research Protocols

Writing Clinical Writing Clinical Research Protocols, Research Protocols, Part 2: Part 2: Writing and Editing Writing and Editing Clinical Research Clinical Research ProtocolsProtocols

Jonathan McCall, BAJonathan McCall, BAEditorEditorDCRI CommunicationsDCRI Communications

Writing Clinical Research ProtocolsWriting Clinical Research Protocols


■ General ConsiderationsGeneral Considerations

■ Parts of the ProtocolParts of the Protocol

■ Good Writing MattersGood Writing Matters

■ Looking AheadLooking Ahead

■ Resources and GuidanceResources and Guidance

Who Reads Protocols?Who Reads Protocols?

■ Keep the “audience” in mind:Keep the “audience” in mind:

■ Other physiciansOther physicians

■ Nurses/CRAsNurses/CRAs

■ Patients and their familiesPatients and their families

■ Patient advocatesPatient advocates

■ IRB membersIRB members

■ Scientific reviewersScientific reviewers

Using TemplatesUsing Templates

■ Many NIH programs encourage or require the Many NIH programs encourage or require the use of protocol templates, such as the ones use of protocol templates, such as the ones available here:available here:

■ http://ctep.cancer.gov/guidelines/templates.htmlhttp://ctep.cancer.gov/guidelines/templates.html

■ Following template guidelines can help guide Following template guidelines can help guide authors, but not every part of a template will authors, but not every part of a template will necessarily apply in a given study.necessarily apply in a given study.

Parts of the ProtocolParts of the Protocol

■ IntroductionIntroduction

■ Objectives (including Objectives (including study schema)study schema)

■ Eligibility criteriaEligibility criteria

■ Study design/methods Study design/methods (including drug/device (including drug/device info)info)

■ Safety/adverse eventsSafety/adverse events

■ Regulatory guidanceRegulatory guidance

■ Statistical section Statistical section (including analysis and (including analysis and monitoring)monitoring)

■ Human subjects Human subjects protection/informed protection/informed consentconsent

Adapted from: Adapted from: Protomechanics: Chapter 1 (http://www.cc.nih.gov/ccc/protomechanics/),Protomechanics: Chapter 1 (http://www.cc.nih.gov/ccc/protomechanics/),

CTEP Investigators’ Handbook, 2002 CTEP Investigators’ Handbook, 2002 (http://ctep.cancer.gov/forms/Hndbk.pdf )(http://ctep.cancer.gov/forms/Hndbk.pdf )

Background and RationaleBackground and Rationale

■ All protocols require a section detailing the All protocols require a section detailing the scientific rationale for a protocol and the scientific rationale for a protocol and the justification in medical and scientific literature justification in medical and scientific literature for the hypothesis being proposed.for the hypothesis being proposed.

■ Introductory section should be as succinct as Introductory section should be as succinct as possible and should be organized in a logical, possible and should be organized in a logical, sequential flow.sequential flow.

Background and RationaleBackground and Rationale

■ Double check all citations:Double check all citations:

■ ““Bibliographic inaccuracies harm the citing Bibliographic inaccuracies harm the citing author and may cast doubt on the quality of the author and may cast doubt on the quality of the research being reported…”research being reported…”

Wyles DF, Behavioral and Social Sciences Librarian, 2004Wyles DF, Behavioral and Social Sciences Librarian, 2004

■ “…“…[A]uthors should verify references against [A]uthors should verify references against the original document.”the original document.”

Uniform Requirements for Manuscripts Submitted to Uniform Requirements for Manuscripts Submitted to Biomedical Biomedical Journals, ICMJE, 2005 (http://www.icmje.org/)Journals, ICMJE, 2005 (http://www.icmje.org/)

ObjectivesObjectives

■ Objectives should be stated clearly as Objectives should be stated clearly as hypotheses to be tested.hypotheses to be tested.

■ Each objective should have a corresponding Each objective should have a corresponding discussion in the statistical section.discussion in the statistical section.

CTEP Investigators’ Handbook, 2002 CTEP Investigators’ Handbook, 2002 (http://ctep.cancer.gov/handbook/index.html)(http://ctep.cancer.gov/handbook/index.html)

Writing Eligibility CriteriaWriting Eligibility Criteria

STOP BEFORE YOU WRITE!STOP BEFORE YOU WRITE!

■ Eligibility criteria are the largest barrier to Eligibility criteria are the largest barrier to accrual to clinical trials.accrual to clinical trials.11

■ Poorly written or poorly conceived criteria Poorly written or poorly conceived criteria may undermine a trial’s generalizability and may undermine a trial’s generalizability and scientific validity.scientific validity.22

11Fuks A, J Clin Epidemiol, 1998Fuks A, J Clin Epidemiol, 199822George SL, J Clin Oncol, 1996George SL, J Clin Oncol, 1996


■ Eligibility criteria—stated as either exclusion Eligibility criteria—stated as either exclusion or inclusion criteria—define and limit the or inclusion criteria—define and limit the kinds of patients that can participate in a kinds of patients that can participate in a clinical trial.clinical trial.

■ Reasons for imposing eligibility criteria can Reasons for imposing eligibility criteria can include scientific rationales, safety concerns, include scientific rationales, safety concerns, regulatory issues, and practical regulatory issues, and practical considerations.considerations.

George SL, J Clin Oncol, 1996George SL, J Clin Oncol, 1996


■ Problems with restrictive criteria:Problems with restrictive criteria:

■ Limitations of generalizabilityLimitations of generalizability

■ Failure to mimic clinical practiceFailure to mimic clinical practice

■ Increased study complexityIncreased study complexity

■ Increased costsIncreased costs

■ Decreased patient accrualDecreased patient accrual

George SL, J Clin Oncol, 1996George SL, J Clin Oncol, 1996


■ Recommendations:Recommendations:

■ The number of eligibility criteria should be kept The number of eligibility criteria should be kept to a minimum.to a minimum.

■ Criteria should include only those absolutely Criteria should include only those absolutely necessary to ensure scientific validity and necessary to ensure scientific validity and patient safety.patient safety.

■ Eligibility criteria should be clearly defined and Eligibility criteria should be clearly defined and verifiable by an external auditor.verifiable by an external auditor.

Adapted from:Adapted from:

George SL, J Clin Oncol, 1996George SL, J Clin Oncol, 1996Fuks A, J Clin Epidemiol, 1998Fuks A, J Clin Epidemiol, 1998


■ Eligibility criteria should be straightforward Eligibility criteria should be straightforward and unambiguous. Which of these criteria and unambiguous. Which of these criteria would you choose?would you choose?

■ Pregnant and/or nursing women are not eligible.Pregnant and/or nursing women are not eligible.■ All women of childbearing age are required to All women of childbearing age are required to

have a serum pregnancy test.have a serum pregnancy test.■ Pregnant and/or nursing women are not eligible for Pregnant and/or nursing women are not eligible for

this study. All women of childbearing potential this study. All women of childbearing potential (defined as…) must have a negative pregnancy (defined as…) must have a negative pregnancy test (serum or urine) within 2 weeks of study test (serum or urine) within 2 weeks of study enrollment.enrollment.


■ However, be aware of the consequences of However, be aware of the consequences of highly specific criteria:highly specific criteria:

■ For example: consider the issues that will For example: consider the issues that will follow from mandating a particular serum follow from mandating a particular serum concentration of some marker, rather than concentration of some marker, rather than building the definition around institutional building the definition around institutional upper limits of normal. upper limits of normal.

Study DesignStudy Design

■ The study design section of the protocol The study design section of the protocol should contain a stepwise description of all should contain a stepwise description of all procedures required by the study.procedures required by the study.

■ A good study design section includes A good study design section includes sufficient information for the participating site sufficient information for the participating site to develop a comprehensive clinical pathway to develop a comprehensive clinical pathway for study patients.for study patients.

Study DesignStudy Design

■ Parts of the study design section may include:Parts of the study design section may include:

■ Initial evaluationsInitial evaluations

■ Screening testsScreening tests

■ Required lab testsRequired lab tests

■ Details of treatment and ancillary proceduresDetails of treatment and ancillary procedures

■ Agent information or device specificationsAgent information or device specifications

■ Dose scheduling and modificationDose scheduling and modification

■ CalendarsCalendars

Adapted from: Protomechanics: Chapter 1 Adapted from: Protomechanics: Chapter 1 (http://www.cc.nih.gov/ccc/protomechanics/)(http://www.cc.nih.gov/ccc/protomechanics/)

SafetySafety

■ The Safety (or Adverse Events) section should The Safety (or Adverse Events) section should include:include:

■ Detailed information for reporting adverse Detailed information for reporting adverse events, including reporting to the FDA and/or events, including reporting to the FDA and/or the sponsorthe sponsor

■ Unblinding processes (if applicable)Unblinding processes (if applicable)

■ Lists of expected adverse eventsLists of expected adverse events

Human Subjects ProtectionHuman Subjects Protection

■ This section includes discussion of:This section includes discussion of:

■ Subject selection and exclusionSubject selection and exclusion

■ Proposed methods of patient recruitmentProposed methods of patient recruitment

■ Minority representation Minority representation

■ Recruitment (or exclusion) of special subjects, Recruitment (or exclusion) of special subjects, including vulnerable subjectsincluding vulnerable subjects

■ Lists of potential risks and benefits, including Lists of potential risks and benefits, including justification for risksjustification for risks

Adapted from: OHSR Information Sheet 5: Guidelines for Writing Adapted from: OHSR Information Sheet 5: Guidelines for Writing Research Protocols (ohsr.od.nih.gov/info/sheet5.html )Research Protocols (ohsr.od.nih.gov/info/sheet5.html )

Model Informed ConsentModel Informed Consent

■ The Office of Human Subjects Research The Office of Human Subjects Research recognizes 3 fundamental conditions for a recognizes 3 fundamental conditions for a valid informed consent:valid informed consent:

■ Disclosure of relevant information to Disclosure of relevant information to prospective research subjectsprospective research subjects

■ Comprehension of the information providedComprehension of the information provided

■ Voluntary agreement of the subject, free from Voluntary agreement of the subject, free from coercioncoercion

Adapted from: OHSR Information Sheet 6: Guidelines for Writing Adapted from: OHSR Information Sheet 6: Guidelines for Writing Informed Consents (ohsr.od.nih.gov/info/sheet6.html )Informed Consents (ohsr.od.nih.gov/info/sheet6.html )


■ To these ends, the protocol model informed To these ends, the protocol model informed consent document must:consent document must:

■ Be thorough and completeBe thorough and complete

■ Be written in simple, nontechnical languageBe written in simple, nontechnical language

■ Be carefully worded to avoid potentially Be carefully worded to avoid potentially coercive phrasingcoercive phrasing


■ OHSR recommends the following be included:OHSR recommends the following be included:

■ Statement that the study involves researchStatement that the study involves research

■ Purpose of the research and the length of the studyPurpose of the research and the length of the study

■ Description of risks and benefitsDescription of risks and benefits

■ Discussion of alternative therapiesDiscussion of alternative therapies

■ Confidentiality policyConfidentiality policy

■ Compensation for injuryCompensation for injury

■ Contact for further questions/informationContact for further questions/information

■ Statement of voluntary participationStatement of voluntary participation

Adapted from: OHSR Information Sheet 6: Guidelines for Writing Adapted from: OHSR Information Sheet 6: Guidelines for Writing Informed Consents (ohsr.od.nih.gov/info/sheet6.html )Informed Consents (ohsr.od.nih.gov/info/sheet6.html )


■ Writing a good MIC is a balancing act between Writing a good MIC is a balancing act between being thorough, being accurate, and being as being thorough, being accurate, and being as concise and simple as possible.concise and simple as possible.

■ Patient advocates may offer invaluable Patient advocates may offer invaluable experience and insight during the drafting and experience and insight during the drafting and review phase of an MIC.review phase of an MIC.

Correlative StudiesCorrelative Studies

■ Integrating correlative studies/basic science Integrating correlative studies/basic science is a priority for the NIH:is a priority for the NIH:

■ ““NIH Roadmap” initiativeNIH Roadmap” initiative

■ Examples of correlative studies include:Examples of correlative studies include:

■ GenomicsGenomics

■ ProteomicsProteomics

■ PharmacokineticsPharmacokinetics

■ Decision-analysis studiesDecision-analysis studies

Correlative StudiesCorrelative Studies

■ A “protocol within a protocol,” with a similar A “protocol within a protocol,” with a similar structure listing rationale, methods, design, structure listing rationale, methods, design, and analysis plans? Or,and analysis plans? Or,

■ Integrated into the main body of the protocol?Integrated into the main body of the protocol?

The Statistical SectionThe Statistical Section

■ Make sure that study objectives and study Make sure that study objectives and study design elements in the statistical section design elements in the statistical section mirror those in described in the Objectives mirror those in described in the Objectives section!section!

■ If the study involves stopping rules, make If the study involves stopping rules, make sure that descriptions and definitions of sure that descriptions and definitions of toxicities in the statistical section match those toxicities in the statistical section match those in the Safety/AE section.in the Safety/AE section.

Good Writing MattersGood Writing Matters

“…“…Many existing clinical trials contain Many existing clinical trials contain problems such as problems such as incompletenessincompleteness, , ambiguityambiguity, , and and inconsistencyinconsistency. Most of the errors are . Most of the errors are introduced during the protocol writing introduced during the protocol writing processprocess…”…”

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


■ Errors, omissions, or inaccurate or unclear Errors, omissions, or inaccurate or unclear material in technical writing can potentially material in technical writing can potentially result in:result in:

■ Monetary lossMonetary loss

■ Damage to equipmentDamage to equipment

■ Loss of timeLoss of time

■ Loss of scientific value of researchLoss of scientific value of research

■ Physical harmPhysical harm

Blake G and Bly R, “Fundamentals of Effective Technical Writing,” Blake G and Bly R, “Fundamentals of Effective Technical Writing,” The Elements of Technical Writing, 1993The Elements of Technical Writing, 1993


■ Costs of a badly written protocol?Costs of a badly written protocol?

■ Poorly written inclusion criteria have resulted in Poorly written inclusion criteria have resulted in a number of ineligible and inevaluable patients a number of ineligible and inevaluable patients being enrolled to a study.being enrolled to a study.

NOW WHAT?NOW WHAT?


■ To fix this problem, the protocol has to be To fix this problem, the protocol has to be amended. Remember:amended. Remember:

““Any change to the protocol document or Any change to the protocol document or Informed Consent that affects the Informed Consent that affects the scientific scientific intentintent, , study designstudy design, , patient safetypatient safety, or , or human subject protectionhuman subject protection is considered an is considered an amendment, and therefore amendment, and therefore mustmust be approved be approved by CTEP and your IRB…”by CTEP and your IRB…”

NCI CTEP Amendment Request Submission Policy, Version Date NCI CTEP Amendment Request Submission Policy, Version Date May 14, 2004 (http://ctep.cancer.gov/guidelines/templates.html)May 14, 2004 (http://ctep.cancer.gov/guidelines/templates.html)


■ What are some potential costs in this What are some potential costs in this scenario?scenario?

■ Patient distressPatient distress

■ Study design compromisedStudy design compromised

■ Accrual delay (possibly measured in months)Accrual delay (possibly measured in months)

■ Administrative costs of submitting and Administrative costs of submitting and approving amendment (coordinating center approving amendment (coordinating center and sites)and sites)

■ Site goodwillSite goodwill

Tools for Better WritingTools for Better Writing

■ Appoint a dedicated editor to oversee the Appoint a dedicated editor to oversee the drafting and compilation of a protocol.drafting and compilation of a protocol.

■ Adopt standard references for your protocol.Adopt standard references for your protocol.

■ Many eyes make accurate work: review both Many eyes make accurate work: review both among and outside of the team can make the among and outside of the team can make the difference.difference.

Tools for Better Writing:Tools for Better Writing:Style SheetsStyle Sheets

■ Establishing a list of common style elements Establishing a list of common style elements can help maintain uniformity and consistency can help maintain uniformity and consistency in protocols:in protocols:

■ Preferred punctuationPreferred punctuation

■ Preferred citation stylePreferred citation style

■ Layout and organization of protocolsLayout and organization of protocols

■ Templates for calendars and schedulesTemplates for calendars and schedules

■ Common data elementsCommon data elements

Tools for Better Writing: ProofreadingTools for Better Writing: Proofreading

■ Make time for proofreadingMake time for proofreading

■ Don’t make last-minute changes and submit a Don’t make last-minute changes and submit a document for review or approval without document for review or approval without subjecting it to a formal proofreading.subjecting it to a formal proofreading.

■ Once is not enoughOnce is not enough

■ Remember: protocols are lengthy, complex Remember: protocols are lengthy, complex documents. You will need more than single documents. You will need more than single review to catch all mistakes.review to catch all mistakes.

Tools for Better Writing: ProofreadingTools for Better Writing: Proofreading

■ Fresh eyesFresh eyes

■ Working too long on a protocol may habituate Working too long on a protocol may habituate eyes and brains to mistakes, simply because eyes and brains to mistakes, simply because they’ve been there all along. Get an “outside” they’ve been there all along. Get an “outside” reviewer!reviewer!

■ Spell-checkers, etc.Spell-checkers, etc.

■ A document that has been “checked” by A document that has been “checked” by automatic software has NOT been proofread.automatic software has NOT been proofread.

Avoiding Pitfalls: InconsistencyAvoiding Pitfalls: Inconsistency

■ Adopt and apply standards for:Adopt and apply standards for:

■ Procedure namesProcedure names

■ Agents and devices (Remember: avoid trade Agents and devices (Remember: avoid trade names!)names!)

■ AbbreviationsAbbreviations

■ UnitsUnits

Avoiding Pitfalls: AmbiguityAvoiding Pitfalls: Ambiguity

■ Use precise language.Use precise language.

■ Are spans of time inclusive or exclusive?Are spans of time inclusive or exclusive?

■ Identify procedures as specifically as possible Identify procedures as specifically as possible (eg, “balloon angioplasty” rather than “heart (eg, “balloon angioplasty” rather than “heart surgery”).surgery”).

Looking AheadLooking Ahead

■ Even the best protocols may have to be Even the best protocols may have to be amended, due to:amended, due to:

■ Changes in the scientific or clinical landscapeChanges in the scientific or clinical landscape

■ Regulatory changes, including updated Regulatory changes, including updated proceduresprocedures

■ Unforeseen clinical developments that may Unforeseen clinical developments that may affect patient safety or study validityaffect patient safety or study validity


■ Avoid being “reactive” when amending Avoid being “reactive” when amending protocolsprotocols

■ Seize the opportunity to review the entire Seize the opportunity to review the entire protocol; this “continuing review” may uncover protocol; this “continuing review” may uncover errors or omissions that passed through earlier errors or omissions that passed through earlier reviews.reviews.

■ Don’t just make a “point” change to a protocol; Don’t just make a “point” change to a protocol; check the entire document for ramifications.check the entire document for ramifications.


■ Remember: maintain version control!Remember: maintain version control!

■ Archive EVERYTHING!Archive EVERYTHING!

■ Control access to materials:Control access to materials:

■ Have a defined procedure for creating or Have a defined procedure for creating or modifying filesmodifying files

■ Limit write-access to files, where appropriateLimit write-access to files, where appropriate

NIH Guidance on Protocol WritingNIH Guidance on Protocol Writing

■ Protomechanics:Protomechanics:

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

■ The Office of Human Subjects Research:The Office of Human Subjects Research:

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

■ The NCI Investigators’ Handbook:The NCI Investigators’ Handbook:

http://ctep.cancer.gov/handbook/index.htmlhttp://ctep.cancer.gov/handbook/index.html

TemplatesTemplates

■ The NIH phase III template:The NIH phase III template:

http://www.ninds.nih.gov/funding/research/http://www.ninds.nih.gov/funding/research/clinical_research/ProtocolTemplate.htmclinical_research/ProtocolTemplate.htm

■ The Cancer Therapy Evaluation Program The Cancer Therapy Evaluation Program (CTEP) Templates (phases I–III; based on NIH (CTEP) Templates (phases I–III; based on NIH model):model):

http://ctep.cancer.gov/guidelines/templates.htmlhttp://ctep.cancer.gov/guidelines/templates.html

Informed ConsentsInformed Consents

■ Office of Human Subjects ResearchOffice of Human Subjects Research http://ohsr.od.nih.gov/info/info.htmlhttp://ohsr.od.nih.gov/info/info.html

■ The Office for Human Research Protections The Office for Human Research Protections (OHRP):(OHRP):

http://www.hhs.gov/ohrp/policy/index.html#informedhttp://www.hhs.gov/ohrp/policy/index.html#informed

Writing ResourcesWriting Resources

■ The International Committee of Medical The International Committee of Medical Journal Editors (ICJME) Uniform Journal Editors (ICJME) Uniform Requirements for Manuscripts Submitted to Requirements for Manuscripts Submitted to Biomedical JournalsBiomedical Journals

http://www.icmje.org/http://www.icmje.org/

Writing ResourcesWriting Resources

■ The American Medical Association style The American Medical Association style manual may provide a useful “default” manual may provide a useful “default” reference for protocol writing:reference for protocol writing:

Cheryl Iverson, ChairCheryl Iverson, Chair. The American Medical. The American MedicalAssociation Manual of StyleAssociation Manual of Style. 9. 9thth ed. Lippincott ed. Lippincott Williams and Wilkins; 1998.Williams and Wilkins; 1998.

■ The Duke University Medical Center Library The Duke University Medical Center Library maintains a select bibliography of style guides maintains a select bibliography of style guides at:at:

http://www.mclibrary.duke.edu/subject/stylehttp://www.mclibrary.duke.edu/subject/style

SummarySummary

■ Writing a clinical protocol is an elaborate, Writing a clinical protocol is an elaborate, collaborative task that will require the talents collaborative task that will require the talents of many contributors to ensure a result that is of many contributors to ensure a result that is scientifically sound and logistically scientifically sound and logistically practicable.practicable.

■ The quality of writing in a protocol and the The quality of writing in a protocol and the quality of the protocol itself are inseparable.quality of the protocol itself are inseparable.

Questions?Questions?

Writing Clinical Research Protocols, Part 2: Writing and Editing Clinical Research Protocols

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