ispor workshop 08 april2016

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How can policy-makers and clinicians trust the results of a network meta-analysis? A workshop on how to apply the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) tool Prepared for : 2016 CADTH SymposiumApril 10, 2016

Knowledge Translation Program Li Ka Shing Knowledge InstituteSt. Michael's Hospital Toronto, Canada

Areti Angeliki Veroniki, MSc, PhDSharon E. Straus, MD, FRCPC, MScAndrea C. Tricco, MSc, PhD (contributor)

VeronikiA@smh.caSharon.Straus@utoronto.ca

TriccoA@smh.ca

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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We have no actual or potential conflict of interest in relation to this presentation

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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of the presentation

To gain knowledge about what a network meta-analysis (NMA) is What is the definition of NMA and how is it related to pairwise MA?

To gain knowledge and skills in assessing the validity of an NMA How do we know whether the NMA is credible?

To work in small groups to establish the credibility of a NMA Do we trust the results of this NMA?Is there anything missing?Could the authors have done things differently?3

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Network Meta-analysis (NMA)

NMA is an extension of pairwise meta-analysis that simultaneously compares multiple treatments for a medical condition from two or more studies that have one treatment in common

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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14 serotonin (5-HT3) receptor antagonists combinations for vomiting for patients undergoing surgery?

Placebo

Ondansetron

Granisetron

Dolasetron

Tropisetron

Ondansetron+Dexamethasone

Palonosetron

Ramosetron

Ondansetron+DroperidolIV

Ondan+Metoclopr IV

Granisetron+Dexamethasone

Palonosetron+Dexamethasone

Dolasetron+Dexamethasone

Dolasetron+DroperidolIV

Granisetron+DroperidolIV5238 RCTs and 33 meta-analysesTricco et al BMC Medicine 2015

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

17th Cochrane Colloquium 55

TerminologyNetwork meta-analysis (or multiple treatment meta-analysis or mixed treatment comparison)Combines direct and indirect data across a network of studies to infer the relative effectiveness/safety of 3 interventions in a single modelIndirect comparisonAllows the estimation of the relative effectiveness/safety of 2 treatments in the absence of head-to-head evidenceMixed comparisonCombines both direct and indirect evidence for a specific comparison to obtain a weighted average of the estimates for a single treatment comparison at the timeSalanti Res Syn Meth 2012

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Network Meta-analysis (NMA)Nikolakopoulou et al PLoS One 2013 Number of publications1997200020022003200420052006200720082009201020112012

01020304050

The number of published systematic reviews that employ NMA are increasing over time.Given the relevance of NMA to inform healthcare decision-making, it is of great interest to improve understanding of these studies by decision-makers and policy-makers.

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Example NMA published in BMJ OpenPlease read the following paperTricco et al BMJ Open 2015

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

Instead of giving them 7 minutes here, you could just ask them to read the abstract and then give them time during each item to read the relevant sections.

You could also divide them up so that each small group does one question and then report back to the larger group.8

Jansen et al 2014International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Questionnaire Items 2 main domainsRelevance (4 questions)

Credibility (22 questions)

Analysis (7 questions)

Reporting quality & transparency (6 questions)

Interpretation (1 question)

Conflict of interest (2 questions)

Evidence Base (6 questions)

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Scoring

Credibility and Relevance are scored separatelyQuestions are grouped by domain and each question is answered as yes/no/unclearEach domain can be rated as strong/weak/neutral

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseDid the researchers attempt to identify and include all relevant RCTs?Did the search strategy include terms for RCTs of all interventions of interest?Were multiple databases searched (e.g., MEDLINE, EMBASE, and Cochrane Central Registry of Trials)? Do the inclusion criteria include all RCTs of interest (if identified by the literature search)?Language limitations, search for unpublished materialA yes to the above implies an adequate attempt to include all available RCTs

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Systematic Review ConductThe same considerations as in a traditional systematic review and meta-analysis still apply!A well-conducted systematic review follows the Cochrane Collaboration methodology

Importance of clinical input on the systematic review conduct Need to ensure the team includes a range of expertise in systematic review methods, clinical, and statistical domains

Arguably more important to have a well-conducted underlying systematic review for NMANMA used to base policy decisions on the population level = affect many more people

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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A Systematic Review usually has.Comprehensive (2 databases) and PRESSed literature searchPre-defined inclusion and exclusion criteria (i.e., study eligibility criteria)Risk of bias appraisal (Cochrane tool for randomized clinical trials)Pre-defined data abstraction formSynthesis based on the totality of evidence and reported using PRISMADiscussion, providing limitations of included studies and review processProtocol using PRISMA-P, PROSPERO registry, published in an open access journal (e.g., Sys Rev journal, BMJ Open)Each step conducted by 2 reviewers, independentlyCochrane Handbook (editors: Higgins and Green) 2011, Shamseer BMJ 2015, Sampson JCE 2009, Moher BMJ 2009

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseTASK: Did the researchers attempt to identify and include all relevant RCTs?

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseDo the trials for the interventions of interest form one connected network of RCTs?Network geometry and connectedness

No_treat

ZIDO,AZT,ZDV

ZDV+3TC

Any_ART

ZDV+3TC+ABC

ZDV+3TC+NEVI

HAART

Any_treat

NEVI

EFAV

LAMIV,3TC

TENOF

d4T+3TC

ZDV+ddI+NEVI

No_treat

ZIDO,AZT,ZDV

ZDV+3TC

Any_ART

ZDV+3TC+ABC

ZDV+3TC+NEVI

HAART

TENOF

d4T+3TC

ZDV+ddI+NEVI

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseTASK: Do the trials for the interventions of interest form one connected network of RCTs?

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseIs it apparent that poor quality studies were included, thereby leading to bias?Cochrane ROB (Sensitivity analysis by components of ROB)1234567Random Sequence generationAllocation concealmentBlinding of participants and personnelBlinding of outcome assessmentIncomplete outcome dataSelective reportingOther bias

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseIs it apparent that poor quality studies were included, thereby leading to bias?Cochrane ROB (Sensitivity analysis by components of ROB)

Placebo

BUDE

FORM

INDAC

SAML

ACLI

GLYC

TIOT

FORM/BUDE

VILA/FLUT

SALM/FLUT

INDA/GLYCRandomization

Placebo

BUDE

FORM

INDAC

SAML

ACLI

GLYC

TIOT

FORM/BUDE

VILA/FLUT

SALM/FLUT

INDA/GLYCAllocation Concealment

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseTASK: Is it apparent that poor quality studies were included, thereby leading to bias?

Knowledge Translation, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada

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Evidence baseIs it likely that bias was induced by selective reporting of outcomes in the studies?Use the Cochrane ROB tool to help ascertain this

0

.5Standard error of log odds ratio

-2

-1

0