The program will begin promptly at 10:00 am EDT

THANK YOU FOR JOINING ISMPP U TODAY!

August 20, 2013

ISMPP WOULD LIKE TO THANK…..

…the following Corporate Platinum Sponsors for their ongoing support of the society

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ISMPP ANNOUNCEMENTS

• Mark your calendars! The 2013 European Meeting of ISMPP is on 22–23 January 2013, ETC Venues, 200 Aldersgate, St Paul's, London, UK. Registration is now open

• Call for Abstracts is now open for the 2013 European Meeting. Submission deadline is October 12th at 5:00pm EST

• A Suggestions Document developed by ISMPP’s Sunshine Act Task Force for interpretation and implementation of the legislation is available on the ISMPP website

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IGNORE AT YOUR PERIL!

WHY PUBLICATION PROFESSIONALS DO NEED TO KNOW ABOUT SPIRIT GUIDELINES FOR PROTOCOLS

Speaker: An-Wen Chan, MD, DPhil, FRCPC

Speaker: Julie A. Ely, MA, PhD, CMPP™

Moderator: Serina Stretton, BSc Hons, PhD, CMPPTM

Image source: 1007-07-98 / Freefoto.comImage source: Paul Downey Flickr`

IGNORE AT YOUR PERIL!(no matter where you live…)

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OBJECTIVES

• At the end of this session, attendees should be able to:– Discuss the SPIRIT 2013 Statement and why it is needed – Understand the appropriate use of the 33-item checklist – Understand how the SPIRIT 2013 Statement benefits professional

medical publication planning

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INTRODUCTIONS

• Speaker: An-Wen Chan, MD, DPhil, FRCPC– Phelan Scientist and Mohs Surgeon, Women's

College Research Institute; Assistant Prof. of Medicine at the University of Toronto, in Canada

– Special Advisor to the Clinical Trials Unit of the Canadian Institutes of Health Research, helped coordinate the WHO International Clinical Trials Registry Platform in Geneva

– Chair, SPIRIT Initiative to improve the quality of clinical trial protocols

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INTRODUCTIONS

• Speaker: Julie A. Ely, MA, PhD, CMPP™– Senior Medical Writer, ProScribe Medical

Communications, Sydney, Australia– PhD, University of California– Many years of experience working in international

pharma and biotechnology companies in all areas of drug development, from discovery research to phase IV clinical trials ; 9 years as a medical writer

– Has conducted multiple training sessions on SPIRIT in the USA and the Asia-Pacific region

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INTRODUCTIONS

• Moderator: Serina Stretton, BSc Hons PhD, CMPPTM

– Head of Medical Writing, ProScribe Medical Communications, Sydney, Australia

– PhD, Flinders University of South Australia– Many years of experience across the spectrum of

medical communications in the Asia-Pacific region, from protocols to publication planning to patient information; > 15 years as a medical writer

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DISCLOSURES

• The information presented reflects the personal knowledge and opinion of the presenters and does not represent those of their current or past employers or those of ISMPP

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THE SPIRIT INITIATIVE: DEFINING STANDARD PROTOCOL ITEMS

AUGUST 20, 2013

An-Wen Chan, MD DPhilWomen’s College Hospital & Research InstituteUniversity of Toronto

IMPORTANCE OF TRIAL PROTOCOLS

Trial ‘roadmap’

Scientific & ethics review

Origin of subsequent reportingJournals

Trial registries

Ethics boards

Funders

Regulators/ Policymakers

Patients &Trial participants

Healthcare providers

Trialists

Transparency

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CURRENT LANDSCAPE

• >15,000 trials completed annually

• Protocols are often suboptimal

– Incomplete information

– Variable format

– Variable standards

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Harms reporting system

Power calculation

Primary outcome

Blinding

Allocation concealment

PROTOCOLS LACK IMPORTANT INFORMATION

0% 20% 40% 60% 80% 100%

25%

40%

59%

41%

34%

% of protocols with inadequate information

Allocation concealment

Primary outcomes

Power calculation

Blinding

Harms reporting system

Mhaskar R et al, J Clin Epid 2012; Chan AW et al, BMJ 2008, JAMA 2004; Scharf O, J Clin Oncol 2006; Pildal J, BMJ 2005; Hróbjartsson A et al, J Clin Epid 2009

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0% 20% 40% 60% 80% 100%

Subgroup analyses

Adjusted analyses

Handling of protocol deviations

Handling of missing data

Primary outcome analysis

PROTOCOLS LACK IMPORTANT INFORMATION

Adjusted analyses

Subgroup analyses

1º outcome analysis

Handling of missing data

Handling of deviations

Chan AW et al, BMJ 2008; Al-Marzouki S et al, Lancet 2008

20%

47%

77%

95%

67%

% of protocols with inadequate information

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SYSTEMATIC REVIEW OF PROTOCOL GUIDELINES

• 40 guidelines → >380 protocol elements

– Most elements found in only 1 guideline

• No systematic methods or use of evidence

Tetzlaff J et al, Systematic Reviews 2012

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BURDEN OF REVISIONS

Among 288 industry trials submitted for ethics approval:

• REB requested revisions to 92%

– Protocol content (45%)

– Other related information (20%)

Russ H, German Med Sci 2009

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BURDEN OF AMENDMENTS

Among >3,400 industry protocols:

• 50% were amended– 16 changes per trial

• One third classified as ‘avoidable’

Getz KA, Drug Info J 2011; Decullier E, BMC Med Ethics 2005

= 9 weeks of trial delay= 3.5 hrs of REB time1 amendment

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OBJECTIVE• To improve content and quality of clinical trial

protocols through evidence-based guidance

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DEFINITION OF PROTOCOL

• Pre-trial document submitted for ethics approval – Background & objectives– Population & interventions– Methods & statistical analyses– Ethical and administrative aspects

• Evolving document– Transparent audit trail

• Related documents (SAP, contracts)

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SPIRIT 2013 Checklist

Explanatory document

METHODS

Delphi consensus survey

Systematic reviews: Existing protocol guidelines Evidence for key protocol items

Consensus meetings

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DELPHI CONSENSUS SURVEY

• Preliminary checklist based on systematic review

• 3 survey rounds from Aug – Nov 2007– 96 participants from 17 countries

• Items rated from 1-10– Ratings and comments circulated in each round– Median ≥ 8 → Included– Median ≤ 5 → Excluded

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Tetzlaff J et al, Trials 2012

CONSENSUS MEETINGS (DECEMBER 2007 AND SEPTEMBER 2009)

• 20 participants– Trialists, methodologists, industry, ethicists, funders, journal

editors

• Review of protocol items from Delphi survey

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SYSTEMATIC REVIEW OF EVIDENCE

2433 articles reviewed

10725 citations screened(MEDLINE, EMBASE, Cochrane Methodology Register)

376 methodologic articles included

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EVOLUTION OF SPIRIT CHECKLIST

Delphi consensus survey

Systematic review of protocol guidelines

Consensus meetings

Systematic review of evidence

59 items

71 items

33 items

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SPIRIT 2013 CHECKLIST

• 33 items in five categories– Administrative information– Introduction– Study methods– Ethical considerations & dissemination– Appendices

Chan AW et al, Annals Intern Med 2013

SCHEMATIC PARTICIPANT TIMELINE

Study period

Pre-allocation

Randomization

Post-allocation follow-up

Close-out

TIMEPOINT

ENROLLMENT

INTERVENTIONS

ASSESSMENTS

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SCOPE

• All clinical trials

• Minimum content

• Relevant information from contracts & operations

manuals

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RELATION TO OTHER GUIDANCE

• Declaration of Helsinki

• Good Clinical Practice

• CDISC Protocol Representation Group

• PRACTIHC (Pragmatic RCTs In Health Care)

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SPIRIT EXPLANATION & ELABORATION

• Model example

• Rationale and explanation

• References to empirical evidence and further

reading

Chan AW et al, BMJ 2013

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TRIAL TEAM Better trial implementation Faster REB approval Fewer amendments

Improved protocol completeness

EXTERNAL REVIEWERS Increased protocol consistency More efficient review Fewer amendments

Standard guidance(SPIRIT Statement)

Educational resource(SPIRIT Explanatory paper)

Saved time & resourcesHigh quality trials

Chan AW et al, Lancet 2013 31

ENDORSEMENTS

• WAME, Lancet, BMJ, Annals

• Clinical trial groups (NCIC, MRC, UCL)

• Academic institutions

• GSK, J&J

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33

SEPTRE

• SPIRIT Electronic Protocol Tool & Resource

• Key features– Evidence-based SPIRIT content– Consistency across protocols– Compatibility with trial registries and IRB platforms– Cost savings (fewer amendments; faster ethics review)

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USERS

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CONCLUSIONS

• SPIRIT checklist aims to improve protocol quality

• Potential impact on efficiency of protocol drafting,

registration, submission, and review

• Opportunities for broad adoption

www.spirit-statement.org

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Trialists/Methodologists/Statisticians An-Wen Chan (Chair), Univ of Toronto Jennifer Tetzlaff, University of Ottawa David Moher, University of Ottawa Doug Altman, University of Oxford Kay Dickersin, Johns Hopkins University Caroline Doré, UK MRC Peter Gøtzsche, Nordic Cochrane Centre Asbjørn Hŕobjartsson, Nordic Cochrane Wendy Parulekar, NCIC CTG Ken Schulz, Family Health International Andreas Laupacis, University of TorontoIndustry Jesse Berlin, Johnson & Johnson Frank Rockhold, GSK

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Journal editors Trish Groves, BMJ Bill Summerskill, Lancet Drummond Rennie, JAMA Hal Sox, Annals of Internal Medicine

Government funders Karmela Krleža-Jerić, Canadian

Institutes of Health Research

Ethicists Howard Mann, University of Utah Genevieve Dubois-Flynn, Canadian

Institutes of Health Research

A SPIRITed approachHow publication professionals can use SPIRIT

Dr Julie A. Ely, PhD, CMPP™

ProScribe Medical Communications, Sydney, Australia

OVERVIEW

• Why do we need SPIRIT?• Protocol checklist items for publication professionals• How publication professionals / medical writers can use SPIRIT• Summary

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WHY DO WE NEED SPIRIT?

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INCONSISTENCY ACROSS CLINICAL TRIAL DOCUMENTS

• Incomplete / inconsistent information in clinical study reports vs registry data vs peer-reviewed publications

• Incomplete / biased reporting of results

InformationClinical Study

Report Completeness

Registry ReportCompleteness

Journal Publication

Completeness

Study methods 88% (533/606)

31% (147/468)

40% (458/1152)

Primary endpoint 76% (77/101)

56% (44/78)

31% (60/192)

Wieseler et al. BMJ 2012;344:d8141

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IN THE BEGINNING…ICH E6 GOOD CLINICAL PRACTICE GUIDELINES

• Published in 1996• Widely used international

guideline on protocol content• Provides minimal guidance

about results dissemination (Section 6.15)

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LANDSCAPE HAS CHANGED….

• Focus is now on transparency disclose results!– 1997: FDA Modernization Act required trial registration for therapies used to

treat “serious or life-threatening diseases”

– 2005: ICMJE (International Committee of Medical Journal Editors) requirement for trial registration to publish in ICMJE member journals

– 2007: FDA Amendments Act (FDAAA) requirement for trial registration & results posting

– 2011: EMA requirement for trial registration & results posting

– 2012 (draft): FDA TEST Act (Trial and Experimental Studies Transparency) expands the scope of trials requiring registration & results posting

– Corporate Integrity Agreements1

1Rodino F. Therapeutic Innovation & Regulatory Science 2013;47:50-56 43

FIXING THE LINCHPINWRITE BETTER PROTOCOLS!

• SPIRIT 2013 is an opportunity to:– Enhance protocol quality, improve standardization of clinical research– Document EARLY and STRONG commitment to trial registration and

results dissemination– Increase consistency

• Protocol, registry, results database, publications

– Build trust and transparency• Right thing to do for participants!• Educate the public

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WHAT EVERY PUBLICATION PROFESSIONAL NEEDS TO KNOW….ABOUT SPIRIT

• What’s new and unique in SPIRIT 2013 checklist1?• Protocol checklist items of particular relevance to:

– Publication professionals– Regulatory medical writers

1Word version of checklist available at: www.spirit-statement.org/publications-downloads/ 45

TRIAL REGISTRATION DATA SET

• Item 2b: include a table with the minimum trial registration dataset (World Health Organization-compliant)– Promotes complete and transparent trial registration– Provides a structured synopsis of the trial – If protocol amendments include registry items, registration data set

table will serve as handy reminder to update registry information

Chan et al. Ann Int Med 2013;158:200 46

ROLE & RESPONSIBILITIES OF SPONSOR / FUNDER

• Item 5c: Role of study sponsor and funders– Study design– Collection, management, analysis, and interpretation of data– Writing of clinical study report– Decision to submit the report for publication*– State if sponsor/funder has ultimate authority over any of these activities

*International Federation of Pharmaceutical Manufacturers & Associations (IFPMA): A Joint Position on Publications requirement

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INVESTIGATOR ACCESS TO TRIAL DATA

• Item 29: Access to the final trial dataset & disclosure of any agreements that limit investigator access to the data• Who will have access to raw/cleaned data sets?• Description of any restrictions to data access• Storage location for data

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RESULTS DISSEMINATION POLICY

• Item 31a: Communicating trial results to participants, healthcare professionals, and the public

• Emphasis on early planning for:– Publications (ie, publication planning, publication steering committee)– Any conditions relating to the Investigator’s right to publish (ie, should be

Good Publication Practices 2 [GPP2]-compliant)• Warning: 1 in 4 trials on www.clinicaltrials.gov had non-compliant information, and

40% of these trials involved the Asia-Pacific region! 1

– Results disclosure databases– Other data-sharing arrangements

1Stretton et al. Seventh International Congress on Peer Review & Biomedical Publication; September 8-10, 2013, Chicago, IL 49

AUTHORSHIP POLICY

• Item 31b: Authorship/contributorship– Based on ICMJE Uniform Requirements for Manuscripts– Plans for the use of professional medical writers and funding source– No ghost authorship, guest/gift authorship, or ghostwriters!

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PUBLIC ACCESS

• Item 31c: any plans for granting public access to:– Full study protocol– Clinical study report (CSR)– Participant-level datasets (de-identified)– Statistical code (to allow verification and replication of analyses)– Precedence for public access to participant-level data sets and

CSRs• New & draft EMA regulatory policies1

• GlaxoSmithKline; NIH NIAID Immune Tolerance Network2

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1 EMA Policy 0043 (2010); EMA Draft Policy 70 (2013); 2N Engl J Med. 2013;369:468-469, 475-478 51

SPIRIT AND PUBLICATION PROFESSIONALS:WHAT CAN WE DO?

• EARLY planning for trial registration, results dissemination, and publication strategy– Publication planning committee; sufficient budget available– GPP2-compliant publication agreements

• Provide input during the protocol writing phase – Protocol review committee; protocol quality review– May add time to protocol review cycle; benefits outweigh risks

• Review/update your organization’s protocol template/protocol template instructions

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WHAT CAN PUBLICATION PROFESSIONALS DO?

• Increase awareness of SPIRIT in your organization– Provide SPIRIT checklist to your colleagues– Implement global training on use of checklist (esp. Asia-Pacific region)

• SPIRIT 2013 Explanation & Elaboration publication1

• Real-life examples for each checklist item

– Translations of checklist currently underway• Chinese, Italian, German

• Japanese (?), Hindi (?)

1Chan et al. BMJ 2013;346:e7586; Available at: www.spirit-statement.org 53

WHAT CAN PUBLICATION PROFESSIONALS DO?

• Use SPIRIT checklist as a tool for education and audits– Non-proprietary; checklist freely available to download

• Service providers (a must for protocol writers?)

• Investigator use (a must for funding support of investigator-initiated trials?)

• Ethics committees (evidence-based rationale for protocol content)

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SUMMARY

• Using the SPIRIT 2013 checklist should:– Improve protocol quality – Enhance timely trial registration & results dissemination– Minimise publication bias– Increase transparency– Enhance public trust in clinical research

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QUESTIONS......

To ask a question, please type your query into the ‘Q&A’ chat box at the bottom left of your screen. Every attempt will be made to answer all questions.

NEXT ISMPP U PRESENTATIONS

• Date: September 18• Topic: Report on 7th International Congress on Peer

Review and Biomedical Publication• Presenters to be announced

• Date: to be announced• Encore presentation of Sunshine Act ISMPP U with live Q&A

session for members unable to attend on August 14

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THANK YOU FOR ATTENDING!

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