EMA EFPIA workshop EMA EFPIA workshop Break- -out session no. - - PowerPoint PPT Presentation

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EMA EFPIA workshop EMA EFPIA workshop Break- -out session no. - - PowerPoint PPT Presentation

Feb 01, 2023 35 likes •165 views

EMA EFPIA workshop EMA EFPIA workshop Break- -out session no. out session no. 2 2 Break Case Study Title: Dose Finding under Model Dose Finding under Model Case Study Title: Uncertainty A case study based on a multi-

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EMA EFPIA workshop EMA EFPIA workshop Break Break-

  • out session no.
  • ut session no. 2

2

Case Study Title: Case Study Title: Dose Finding under Model Dose Finding under Model Uncertainty Uncertainty – – A case study based on a multi A case study based on a multi-

  • regional

regional clinical trial clinical trial

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BOS2: Position statement

M&S analysis results should be the primary analysis to establish the dose(s) for phase II/III

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Background & Rationale Background & Rationale

Case study

  • COPD, Phase II, global development
  • Endpoint: trough FEV1 at week 2 (change from baseline)
  • No prior PK/PD model
  • Goal – Select dose to bring forward into Phase III

Finding the right dose is not that simple

  • True shape of dose-response model is typically unknown
  • Choice of a working model may have a substantial impact on dose

selection

  • Model selection using observed data needs to account for model

uncertainty and associated multiplicity issues

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Objectives of the M&S work Objectives of the M&S work

Primary objectives

  • Proof of concept (PoC): any evidence of treatment effect
  • Dose selection – which dose to take into phase III

 Incorporating uncertainty

  • Design

Dose levels investigated Sample size

  • Analysis

Adjusting for multiplicity Incorporating model uncertainty Exploring ethnicity effect (particularly Japanese)

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Available Data / Prior Models

After discussion with clinical team

Placebo + 4 doses + active control Max treatment effect: 150 mL (improvement over placebo) Absolute clinically relevant differences ( = 120 mL) Five candidate models

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Methods –

MCP-Mod

Set of candidate models

  • Optimize trial design: doses investigated
  • Investigate trial operating characteristics

(including robustness and sensitivity)

  • Construct optimal contrast coefficients (PoC)

Test dose-response signal (PoC) Select dose-response model: model selection or averaging Possibly combined with external data Dose estimation (MED, EDx …)

Design Analysis

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M&S Assumptions M&S Assumptions

  • True underlying DR is equally

likely to be any of the five candidate models

  • Japanese and non-Japanese

share the same dose-response form

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M&S Results M&S Results – –

design design

  • 4

active doses were chosen among 7 available

  • operating characteristics were investigated
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M&S Results M&S Results – –

DR profiles DR profiles

  • Weighted

dose-response curves – based on the goodness-of-fit

  • f 4 fitted models (linear, quadratic, emax and logistic)
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SLIDE 10

M&S Results M&S Results – –

dose selection dose selection

Dose selected: 1 mg

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Conclusions Conclusions

  • Our approach emphasizes modeling/estimation

(learning) as opposed to hypothesis testing (confirming) of the conventional approach

  • Uncertainty was incorporated at both trial design

and data analysis phases

  • Evaluate operational characteristics of alternative

designs and methods via simulation study to make recommendations on their use in practice

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Generalisation Generalisation

To ensure robust and sensible designs and analysis methods, modeling and simulations should be employed routinely

Uncertainty should be accounted for decision making

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