Meta-análisis - Web de Ferran Torres

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Heterogeneity and external validity Are the study populations sufficiently representative of a common target population (dosage, duration, severity etc)? Are there any reason to suspect a clinically relevant interaction? Suspected interactions and major clinical differences among the individual studies should be evaluated in alternative analyses. 2007 Ferran.Torres@uab.es 91 Pooled analyses of safety endpoints Less sophisticated pooling of data from variable sources. Strigent meta-analysis analysis for in depth evaluation of safety signals from less reliable analyses. Special attention to the inclusion of studies that are likely to dilute potential negative effect. Intra-study comparisons a minimum requirement. 2007 Ferran.Torres@uab.es 92 ICH E9 Statistical principles for Clinical Trials, , 1998 What is the crucial question? ”The results of the confirmatory trial(s) should be robust.” ”In some circumstances the weight of evidence from a single confirmatory trial may be sufficient.” Do we have enough studies? or Do we have enough data? 2007 Ferran.Torres@uab.es 93 2007 Ferran.Torres@uab.es 94 Arguments for replication More than one study provides a broader basis for generalisation of the results. Protection against fraud Reduced risk for some hidden systematic bias The general demand for replication of scientific results Fundamental requirement on the phase III documentation Adequate and well-controlled data of good quality A sufficient number of patients, with a sufficient variety and disease conditions, collected by a sufficent number of investigators, demonstrating a positive risk/benefit in the intended population at the intended dose and manner of use. Minimum requirement: One controlled study with sta-tistically tistically compelling and clinically relevant results. 2007 Ferran.Torres@uab.es 95 2007 Ferran.Torres@uab.es 96 16
Reasons to plan for more than one study Lack of pharmacological rationale A new pharmocological principle Phase I and phase II data limited or unconvincing A therapeutic area with a history of failed studies or failures to confirm seemingly convincing results Any other need to address additional questions in the phase III program Crucial issues in the one pivotal study situation Internal and external validity. Clinical relevance. . The treatment benefit must be large enough to be clinically relevant. Statistical significance. Passing the conventional 5% significance level is usually not sufficient. 2007 Ferran.Torres@uab.es 97 2007 Ferran.Torres@uab.es 98 Crucial issues in the one pivotal study situation Data quality Internal consistency. Similar findings in pre-specified sub-populations and for different endpoints. Center effects. Plausibility of the hypothesis tested. Scientific advice on One confirmatory study Sponsors’ argument New/extended extended indication, pediatric indication New formulation Effects on survival Serious disease (e.g. cancer) Life-long disease without cure No therapy currently available Rare disease (orphan drug) One study in each of two indications Placebo controlled dose-finding study positive 2007 Ferran.Torres@uab.es 99 2007 Ferran.Torres@uab.es 100 Conclusion on One Pivotal study There is no formal requirement to include two or more pivotal studies in the phase III program. In most cases several studies is the most feasible way to provide the data needed. In the exceptional event of a one pivotal study application, theis study has to be particularly compelling. 2007 Ferran.Torres@uab.es 101 17
Page 1 and 2: Preguntas básicasb Meta-an anális
Page 3 and 4: CARACTERÍSTICAS Datos: - Tipos de
Page 5 and 6: Unbiased Hedges’ g estimate Corre
Page 7 and 8: Funnel plot Funnel plot SAMPLE SIZE
Page 9 and 10: Statistical issues on the results (
Page 11 and 12: Study ANDERSON 1988 BELL 1989 BELL
Page 13 and 14: 10.4%-14.2% = 3.8% 2007 Ferran.Torr
Page 15: Pre-specification specification: :

Meta-análisis - Web de Ferran Torres

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