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EMA draft guideline on subgroups discussion

EMA draft guideline on subgroups discussion. April 2014 Kristian Windfeld, Biometrics , H. Lundbeck A/S. S cope. Guidance to assessors in interpretation of subgroup analyses and associated regulatory decision making

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EMA draft guideline on subgroups discussion

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  1. EMA draft guideline on subgroupsdiscussion April 2014 Kristian Windfeld, Biometrics, H. Lundbeck A/S

  2. Scope • Guidance to assessors in interpretation of subgroup analyses and associatedregulatory decision making • Possibleimplications for indication and inclusion of data in clinical studies section of SmPC “Enjoy the result you have found by exploratory data analysis, for you will not find it again” Confuseus

  3. Highlights of draft guideline • Frame for discussing and prioritisingsubgroups in protocol • Focus on exploratorysubgroupsratherthanthose part of confirmatory test strategy • Heterogeneity of target population • Methodologicalchallenges (false positives/negatives) • Credibility of subgroupfindings • Plausibility • Pre-specification • Replication • Common scenarios • Overall positive study with adversesubgroupfindings • Overall borderline/negative study, possible ID of subgroup with positive benefit/risk

  4. Definition of subgroups • Basedon pre-randomizationintrinsic/extrinsicfactors • Factor types • Unorderedcategorical (e.g. region) • Orderedcategorical (e.g. diseaseseverity) • Based on continuous measures • Usuallysubgroupsbased on single factor. Combinations maybe of interest • Risk scores • Based on biological measures – possiblemisclassification • Discussion: • How to pre-specify and justifycutpoints for continuous measures? Shouldyouusecutpoints in the firstplace for continuous variables? • Is it reasonable to studysubgroupsbased on one factor at a time? When/how to study factor combinations?

  5. The multiplicity problem • Multiple testing problem • Risk of false ”positives” is recognized – but noexcuse for not investigatingsubgroups… • Riskof approving drug in subgroups not benefittingalsoimportant • ”Cautionaryprinciple”: replicated evidence cannot be required to confirm credibility of an untoward effect of the experimental treatment • Discussion: • How canweachieveadequateprotectionagainst false ‘positive’ findingswhilesatisfying the need to studyhomogeneity of effect in population? • What do youthinkaboutprioritization of sensitivity of the investigation (by not adjusting for multiplicity) and the credibilityconsiderationsprovided to ensurespecificity of the approach? Is there a reasonable balance? Effective in subgroup Yes No Yes E1 Decision to approve in subgroup No E2

  6. Statistical methods • Statistical interaction tests appear not to beencouraged (said not to bewellunderstood…) • (unadjusted) p-values + plots with estimates and CIs (e.g. Forest plots) • Visual inspection of Forest plots; some guidance textaboutwhen to beconcerned given (Subgroups with CIs 2x or 3x width of overall effectthatare not overlapping with overall effect CI…) • Shrunkestimatesmaybeused to reduce the problem of extremerandomsubgroupfindings by chance • P-valueadjustment not recommendedbecause the subgroup analyses aretriggers for furtherinvestigation • Commonlyusedscale versus scale relevant for B-R decision (relative vs absolute) • Discussion: • What is your opinion aboutanalyzing the same outcome on both relative and absolutescale? (Statistical versus regulatory (B/R) considerations…) • How do you find the interpretability of unadjusted p-values/CIsin Forest-plots? How should difference between plausible vs exploratorysubgroupsbeaddressed? • Do yousee a role for ‘data mining’ methodssuch as recursivepartitioning, lasso, etc.?

  7. Prioritising the exploratory analyses • Addressingmultiplicity by prioritization: • Keysubgroup (used for stratification, plausibility) • Trulyexploratory (demographic, diseasecharacteristics,…) • Maximizea prioridiscussion to minimizea posteriori discussion… • Potential disincentive for sponsor to plan subgroup analyses, arguing for non-plausibility • Discussion: • Whyshould a sponsor pre-specify and prioritizepotentiallyprognostic and predictive factors with a potential label restriction as a consequence? Is it better to not pre-specify? • How do yousee the relevance of multiplicitycorrection for the plausible factor basedsubgroupinvestigations?

  8. Credibility of subgroupfindings • Keyconsiderationsregardingcredibility of subgroupfindings: • Plausibility (+pre-specification) • Replication • Possibility to look at ≥2 sources of evidencebetterthan a pooledestimate(!) • Sponsor mayuselack of pre-specification to argue for lack of credibility – not accepted (cf sponsor incentivediscussion…) • Discussion: • How do yousee the apparentpreference for doingsubgroup analyses by studyratherthanpooled, given the replicationconsideration?

  9. DSBS consolidatedcomments • We plan to submit DSBS consolidatedcomments via EFPIS • Pleaseemailyour (company/groupconsolidated) comments to krwi@lundbeck.com by 30 April 2014 • EFSPI deadline: April/May • EMA deadline: 31 July 2014

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