No data left behind – making the case with datasets or “evidence synthesis for learning about real world effectiveness” 17 th June 2016 Matthias Egger, University of Bern Chrissie Fletcher, Amgen The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. www.imi.europa.eu
Disclaimer (Chrissie Fletcher) • The views expressed herein represent those of the presenter and do not necessarily represent the views or practices of Amgen or the views of the general Pharmaceutical Industry. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework 2 Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 2 www.imi.europa.eu
Agenda • Key questions we’re addressing • Latest thinking on methods and guidance for evidence synthesis and predicting effectiveness • Case study illustrations – Combining Randomised Controlled Trials (RCTs) and Observational Data: Schizophrenia – Predicting effectiveness from efficacy: RA • Software & tools to aid implementation • Information and materials for stakeholders • How you can help and provide feedback The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 3 www.imi.europa.eu
Key questions we’re addressing The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 4 www.imi.europa.eu
Questions Outcomes Applicability Data sources Evidence synthesis Conditions 1) How efficacious and safe Efficacy, Typical patients Phase II/III Clinical trials, Study is this drug? safety included in randomised standard meta- conditions clinical trials clinical trials analysis 2) How efficacious and safe Relative efficacy, Typical patients Phase II/III Network meta- Study is this drug compared to relative safety included in randomised analysis conditions alternative therapies? clinical trials clinical trials 3) How effective and safe is Relative Patients Phase II/III Individual patient Study this drug compared to effectiveness, predicted to randomised data (IPD) network conditions alternative therapies, in relative safety in receive the drug clinical trials, meta-analysis and the patients who will predicted study post-launch clinical databases meta-regression likely receive it post- populations and registries launch? 4) How effective and safe is Relative Patients Phase II/III Mathematical Real world this drug compared to effectiveness, predicted to randomised modelling conditions alternative therapies, in relative safety in receive the drug clinical trials, the patients who will predicted real post-launch in a clinical databases likely receive it in the real world given health and registries, world of a health care populations care system expert opinion, system? patient Egger, Fletcher, Moons. JRSM 2016 preferences The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 5 5 Egger, Fletcher, Moons. JRSM 2016 www.imi.europa.eu
Latest thinking on methods and guidance for evidence synthesis and predicting effectiveness The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 6 www.imi.europa.eu
We performed three systematic reviews on methods for: network meta-analysis (NMA) individual participant data (IPD) meta-analysis mathematical modelling to predict real-world effectiveness based on evidence from randomized controlled trials (RCTs) Our aim was to identify and describe state-of-the-art methods in these three research areas, to summarize methodological challenges and limitations and to give recommendations on the use of the discussed methods. All three reviews were accepted for publication in the Research Synthesis Methods journal The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 7 www.imi.europa.eu
1. Get Real in network meta-analysis: a review of the methodology Orestis Efthimiou, , Thomas P. A. Debray, Gert van Valkenhoef, Sven Trelle, Klea Panayidou, Karel G. M. Moons, Johannes B. Reitsma, Aijing Shang and Georgia Salanti The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 8 www.imi.europa.eu
• Guidance: Presented the advantages and limitations of alternative approaches. Discussed in depth methods to assess the validity of the underlying assumptions Provided technical details regarding a series of special issues: network meta- regression, accounting for the risk of bias, multiple outcomes and repeated measures, defining the number of nodes, planning future studies, etc. Listed software tools for fitting NMA and for assessing its assumptions. • Our review constitutes the most comprehensive collection of methods for NMA to date and can be a valuable tool for both experienced researchers as well as researchers taking their first steps in NMA Efthimiou, O., Debray, T. P. A., van Valkenhoef, G., Trelle, S., Panayidou, K., Moons, K. G. M.,Reitsma, J. B., Shang, A., Salanti, G., GetReal in network meta-analysis: a review of the methodology. Res. Syn. Meth. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 9 www.imi.europa.eu
Assumption in NMA Transitivity, congruence, consistency…. When you extract the In the outset When you find the studies outcomes The treatments The groups of Direct and we compare are studies that indirect in principle compare them treatment effects jointly do not differ with are in statistical randomizable respect to the agreement distribution of They have the same Various statistical tests effect modifiers indication, I can imagine a mega-trial with all Cipriani A et al. Conceptual and You can test this assumption Technical Challenges in Network treatments being if you have enough studies Meta-analysis compared etc per comparison Annals of Internal Medicine 2013 The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 10 www.imi.europa.eu
2. GetReal in meta-analysis of individual participant data: a review of the methodology Thomas P. A. Debray, Karel G. M. Moons, Gert van Valkenhoef, Orestis Efthimiou, Noemi Hummel, Rolf H. H. Groenwold, Johannes B. Reitsma The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union ’ s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ’ in kind contribution. 11 www.imi.europa.eu
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