IMI Get Real using real world evidence in

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IMI Get. Real - using real world evidence in R&D and healthcare decision making

IMI Get. Real - using real world evidence in R&D and healthcare decision making Chrissie Fletcher, Amgen Ltd on behalf of IMI Get. Real The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

Disclaimer • The views expressed herein represent those of the presenter and do not

Disclaimer • 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 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

What is effectiveness • Effectiveness may be defined as the impact of drug efficacy,

What is effectiveness • Effectiveness may be defined as the impact of drug efficacy, when all “interactions” are at play – Interaction being used in the broad sense of “interaction” and “effect modification” • 3 levels of interaction are considered – The real/actual use of drug – The patient/disease-related characteristics – The healthcare system-related characteristics The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

What is effectiveness research • The purpose of Effectiveness Research is to assess these

What is effectiveness research • The purpose of Effectiveness Research is to assess these “interactions”: – – Which ones are “universal” How do they distribute locally What is the magnitude of their impact What is the mechanism of Action • This covers the entire span of epidemiologic and public health research methods ‘Interactions’ The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

Increasing Focus on Comparative Effectiveness Earlier understanding of effectiveness of new products. Better targeting

Increasing Focus on Comparative Effectiveness Earlier understanding of effectiveness of new products. Better targeting to patients who will gain the greatest benefits. Increasing interest. Potential for improving public health if efficacyeffectiveness gap identified. Require evidence of benefit of treatment compared with standard of care in own jurisdiction. “Effectiveness challenges” Population Study population not consistent with the population for which reimbursement is being sought Uncertainty of treatment effects in subgroups based on pivotal trial populations *Illustrative examples Intervention Comparator Study comparator(s) do not include current standard of care (SOC) for the reimbursement population Outcome Study medication schedule (dose, dose titration/ escalation, frequency, route of admin, monitoring) inconsistent with routine Indirect comparison vs SOC Study underpowered to practice is uncertain due to a small deliver meaningful results Effectiveness likely number of trials from which for outcomes of interest impacted by adherence (of to form a valid network (e. g. HRQo. L) intervention and/or The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant comparators) in routine agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. practice www. imi. europa. eu Primary Study outcomes of limited interest from reimbursement perspective,

Prior to phase 3 Detailed plan for RCTS, other studies and analyses Prior to

Prior to phase 3 Detailed plan for RCTS, other studies and analyses Prior to phase 2 b Develop overall evidence plan Prior to launch Focus on analyses for submissions & phase IV commitments Why should I generate real-world evidence? • Is there a risk for an efficacy-effectiveness gap? • Is there a compelling need to generate evidence of effectiveness, over and above RCTs for registration? How could I understand the issue? Identification of drivers of effectiveness: literature review, experts insight, data analyses NMA modelling techniques Qualitative research, Patient insights Population X Intervention Comparator Outcome HTA CASE HISTORIES X SCIENTIFIC ADVICE COMMERCIAL FORECAST The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

What should I do? • Methodological options for an integrated “effectiveness evidence generation plan”

What should I do? • Methodological options for an integrated “effectiveness evidence generation plan” (design parameters and analyses) Prior to phase 2 b Develop overall evidence plan How could I address the issue? Prior to phase 3 Detailed plan for RCTS, other studies and analyses Prior to launch Focus on analyses for submissions & phase IV commitments Generation of evidence on effectiveness: options Phase 3 RCT Pragmatic trial • Can I use enriched RCT design, to improve the heterogeneity in population and gain knowledge on effectiveness? • Shall we plan for PCT? • Which aspect of PICO should be more pragmatic? • Which are the statistical challenges Post-launch observational study • Is there a risk of channelling bias ? • How to correct for this risk? NMA modelling techniques The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

ANALYTICAL APPROACH Mapping-out the rationale for effectiveness evidence generation - Reviewing 60 authorization dossiers

ANALYTICAL APPROACH Mapping-out the rationale for effectiveness evidence generation - Reviewing 60 authorization dossiers and HTA reviews (HAS), to understand the importance of providing evidence on effectiveness before launch and explore how to improve in pre-registration studies STATISTICAL APPROACH Mapping-out existing design parameters and analytical tools - Identifying drivers of effectiveness - - How is the “efficacy-to-effectiveness gap” understood and conceptualized? The concept of Drivers of Effectiveness Development of methods to identify drivers of effectiveness using 3 case studies Implementing knowledge on drivers of effectiveness in RCTs A methods to improve heterogeneity of population in RCTs (The “enriched RCT” design) Which pre-authorization RCTs actually explored effectiveness and how? Which design parameters and analytical tools are available for pragmatic trials? Improving analytical tools for the assessment of effectiveness through Pragmatic Trials or postauthorization studies Post-authorization observational studies Pragmatic trials - Dealing with imbalance in selection bias in Twi. CS trial designs Dealing with heterogeneity in the comparator arm - Best methods to adjust for indication bias Development of methods to identify a risk for channelling bias using 3 case studies TOOLBOX of study design and analytical tools, with options and recommendations The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

Why pragmatic trials? v Real World Evidence (RWE) on relative effectiveness needed to guide

Why pragmatic trials? v Real World Evidence (RWE) on relative effectiveness needed to guide physicians/policy makers in their decisions v Traditional RCTs and observational studies have limitations in providing RWE on relative effectiveness v Pragmatic trials combine the strength of RCTs ( addresses confounding through randomization), while generating results that are generalizable to the real world • BUT: they have to be well designed and executed The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu Calvert et al. J Clin Epidemiol 2011, Hemkens LG, BMJ 2016;

PRECIS-2 Pragmatic Trials on a continuum The research leading to these results has received

PRECIS-2 Pragmatic Trials on a continuum The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant *PRagmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) wheel. (Loudon K et al. BMJ 2015; 350: h 2147) agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The goal of PCTs Minimize bias/variability: § § Use preference design? Blinding outcome assessment?

The goal of PCTs Minimize bias/variability: § § Use preference design? Blinding outcome assessment? Use ‘objective outcomes’/training/standardizing? Use realistic/flexible treatment strategies? Maximize Generalizability/Feasibility: § § § § Randomization at cluster level? Select real life sites/settings? , Use realistic/flexible treatment strategies? , Outcomes as in practice? , Integrate data collection with care systems? , Minimize ‘Hawthorne effect’? Discuss design in early phase with all stakeholders? The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

http: //www. imi-getreal. eu/Portals/1/Documents/01%20 deliverables/2017 -03 -30%20 -%20 WP 4%20%20 Methodological%20 guidance%2 C%20 recommendations%20

http: //www. imi-getreal. eu/Portals/1/Documents/01%20 deliverables/2017 -03 -30%20 -%20 WP 4%20%20 Methodological%20 guidance%2 C%20 recommendations%20 and%20 illustrative%20 case%20 studies. pdf The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

Get. Real Outputs Methods • • Original research • • Drivers of effectiveness Analytical

Get. Real Outputs Methods • • Original research • • Drivers of effectiveness Analytical methods Prediction models Methodological guidance Detection of bias Adjustment of bias Aggregate RWD in NMAs Individual patent RWD in NMAs Tools Summaries • • Study types Sources of data Methods Literature reviews Case studies • • • Retrospective analyses of relative effectiveness issues Disease area specific issues Stakeholder views • • • Software Checklists & templates Design options for pragmatic clinical trials *Illustrative examples – not a complete list of Get. Real outputs The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

What the navigator provides The research leading to these results has received support from

What the navigator provides The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

ADDIS – Get. Real software platform The research leading to these results has received

ADDIS – Get. Real software platform The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu 24

The research leading to these results has received support from the Innovative Medicines Initiative

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu

ADDIS – web based user interface The research leading to these results has received

ADDIS – web based user interface The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu 26

The Get. Real-World Evidence Framework: A Resource for Everyone! A shared platform addressing the

The Get. Real-World Evidence Framework: A Resource for Everyone! A shared platform addressing the inclusion of alternative study designs in medicine development strategies Reflects stakeholder perspectives as far as possible A comprehensive resource regarding alternative evidence development pathways An index of study designs, data sources and policies relating to real -world evidence Educational resource, clarifying potential effectiveness challenges and identifying potential RWE options Signposts to authoritative resources, tools and policies relevant to real-world evidence The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115546, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP 7/2007 -2013) and EFPIA companies’ in kind contribution. www. imi. europa. eu