Identifying gaps and signposting solutions for efficacy and - - PowerPoint PPT Presentation

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Identifying “gaps” and signposting solutions for efficacy and effectiveness

Chris Chinn, Sanofi Lucien Abenhaim, LASER Analytica

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

W hat are the m ain goals of the presentation?

• Give an overview of WP2 work
• Describe the decision-making approach WP2 has developed

for R&D, when developing a new compound (“Gap Analyser”)

• Receive feedback

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

W hat can/ should the audience do after seeing the presentation?

• Understand the concept of drivers of effectiveness and

systematic methods to identify them early during the drug development

• Be aware of tools and analytical techniques available to

support study designs aiming to assess effectiveness

• Identify opportunities to apply concepts within their
• rganisations

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Overview of W P2 w ork

• Main objective

– To better understand the gap between efficacy and effectiveness so as to provide a framework – And tools to address it during the drug development process

• Analytical and statistical approaches were combined, and a

decision-making perspective was used

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

W hat 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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Effectiveness is the result of interactions of different factors on efficacy

 One must know what factors are likely to influence the efficacy of the drug (Build your theoretical model)  The distribution of the factors in the target populations must be studied

• Coverage
• Medical Practices
• Screening policies
• Age, gender
• Behavioral factors
• Baseline Risk
• Genetics
• Dose, posology
• Duration of use
• Adherence
• Co-prescriptions
• Past experience

‘Interactions’ ‘Interactions’

• Disease stage
• Comorbidities

Good News  Not so many drivers

• f effectiveness

 Interacting effects are mostly universal Don’t confound Interactions and confounding

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

‘Inteactions’ ‘Interactions’

W hat 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

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Drivers of effectiveness

• How can we IDENTIFY drivers of effectiveness?
• How can we ADDRESS drivers of effectiveness In clinical

research?

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

GapAnalysis and New Solutions

Systematic approach to understand and address “drivers of effectiveness”: those factors that determine how efficacy translates into real world outcomes

• Guidance on a range of methodologies

useful to assess the drivers of effectiveness within a disease area

• Exploring statistical and analytical

issues arising from designing trials to provide information on the impact of specific drivers of effectiveness

Analytics of trial design: population, power, outcome assessment

Physician Choices Healthcare system resources & policies Patient Factors & Behaviours

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Drivers of effectiveness

• Is it possible to identify drivers of effectiveness before

launch?

– Yes

• Systematic or Focused Literature reviews
• Experts interview
• Aggregate data analyses (≈meta-analyses)
• Patient-level data analyses

– Examples

• Antipsychotic drugs in schizophrenia: duration of disease
• Anticancer drugs in Hodgkin’s Lymphoma: age, toxicity

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

• Is there a risk for an efficacy-effectiveness

gap?

Prior to phase 2b Develop overall evidence plan Prior to phase 3 Detailed plan for RCTS, other studies and analyses Prior to launch Focus on analyses for submissions & phase IV commitments

Why should I generate real-world evidence?

Comparator

NMA modelling techniques

Population

Identification of drivers of effectiveness: literature review, experts insight, data analyses

Outcome

Qualitative research, Patient insights

How could I understand the issue?

Intervention

X

• Is there a compelling need to generate

evidence of effectiveness, over and above RCTs for registration?

X

SCIENTIFIC ADVICE HTA CASE HISTORIES COMMERCIAL FORECAST

How could I understand the issue?

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

Drivers of effectiveness

• How to use knowledge on drivers of effectiveness before launch?

– Drivers of effectiveness related to patient characteristics

• If the distribution of these key characteristics is different in RCTs as in

real-life, the efficacy measured will differ from effectiveness

• patients with a key characteristic are often excluded (older age, shorter

duration of illness, comorbidity, etc.)

• One solution is to include a small sample of these patients otherwise

excluded (enriched RCT) + predictive modelling to predict the effectiveness in a wider population – Drivers of effectiveness from healthcare setting level or actual use of drug

• Another solution is to perform a pragmatic trial reflecting actual clinical

conditions and behaviours

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

• Methodological options for an integrated

“effectiveness evidence generation plan” (design parameters and analyses)

Prior to phase 2b Develop overall evidence plan Prior to phase 3 Detailed plan for RCTS, other studies and analyses Prior to launch Focus on analyses for submissions & phase IV commitments

What should I do? Pragmatic trial

• Shall we plan for PCT?
• Which aspect of PICO should

be more pragmatic?

• Which are the statistical

challenges

Phase 3 RCT

• Can I use enriched RCT

design, to improve the heterogeneity in population and gain knowledge on effectiveness?

Generation of evidence on effectiveness: options Post-launch observational study

• Is there a risk of channelling bias ?
• How to correct for this risk?

IF YES

How could I address the issue?

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

TOOLBOX

• f study design and analytical tools, with options and recommendations
• Which pre-authorization RCTs actually explored

effectiveness and how?

• Which design parameters and analytical tools are

available for pragmatic trials?

• A methods to improve heterogeneity of population in

RCTs (The “enriched RCT” design)

ANALYTICAL APPROACH

Identifying drivers of effectiveness

• Best methods to

adjust for indication bias

• Development of

methods to identify a risk for channelling bias using 3 case studies

• 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

Mapping-out existing design parameters and analytical tools

• 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

Improving analytical tools for the assessment of effectiveness through Pragmatic Trials or post- authorization studies Implementing knowledge on drivers of effectiveness in RCTs

• Dealing with imbalance

in selection bias in TwiCS trial designs

• Dealing with

heterogeneity in the comparator arm

STATISTICAL APPROACH

Pragmatic trials Post-authorization

• bservational studies

Mapping-out the rationale for effectiveness evidence generation

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 (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu

W hat can/ should the audience do after seeing the presentation?

• How can DoE Analysis be incorporated into early drug

development?

• Can a common framework of DoE be used by Industry,

Regulatory and HTA bodies within the framework of early / joint scientific advice?

• How can best practice be defined to ensure acceptability of

new information supporting effectiveness assessment at launch (e.g. REA and initial HTA assessments)

• How can the framework be used to inform evidence planning

within adaptive pathways