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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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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