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A study on fixed-dose combinations
Asbjørn Nøhr-Nielsen, Ph.D. stud. Department of drug design and pharmacology and Copenhagen Centre for Regulatory Science 2nd October 2017
Obtaining information –European public assessment reports (EPARs)
11/10/2017 1
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Introduction
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Aim: Using modelling and simulations we aim to optimize the clinical development for FDC products with focus on requirements from the EU health authorities.
Project 1:
Review of clinical
development studies for FDC products using
European public
assessment reports (EPARs)
Project 2:
Simulation- project using a FDC case study
focusing on estimation of interaction
parameters and optimal
distribution of patients
Project 3:
Modelling using a FDC
case study with two well-defined
components, combining old data with new
studies
Project 4:
Modelling using a FDC case study
focusing on surface-
modelling of effect and
side-effects
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Agenda
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Aim: Using modelling and simulations we aim to optimize the clinical development for FDC products with focus on requirements from the EU health authorities.
Project 1:
Review of clinical
development studies for FDC products using
European public
assessment reports (EPARs)
Project 2:
Simulation- project using a FDC case study
focusing on estimation of interaction
parameters and optimal
distribution of patients
Project 3:
Modelling using a FDC
case study with two well-defined
components, combining old data with new
studies
Project 4:
Modelling using a FDC case study
focusing on surface-
modelling of effect and
side-effects
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The idea
Project 1:
Review of clinical development requirements for FDC products using European public assessment reports (EPARs).
Citation from Guideline on clinical development of fixed combination medicinal products:
“A factorial design study may support the pharmacological additive effects or synergism of the proposed combinations, especially when different effective dose levels of the individual active substances exist”.
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The hypothesis
Project 1:
Review of clinical development requirements for FDC products using European public assessment reports (EPARs).
We hypothesize that the interpretation of the guidelines can lead to non-optimal investigations in the clinical
development program for FDCs
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Fixed-dose combinations
• Combination of two or more active pharmaceutical ingredients in a single dosage form
• Specific set of guidelines (Guideline on clinical development of fixed combination medicinal products)
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Fixed-dose combinations - Advantages
Improving patient care
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Compliance - Keeping track
of several medications
- Reduction in pill burden
Novel treatment entity - Potential for
synergism between components
- Combined profiles for effect and adverse effect
Safety - Extensive
DDI studies
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Fixed-dose combinations - Advantages Improving patient care
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Compliance Novel treatment entity
Safety
Advantages for the industry
New drugs in pipeline - Improved efficacy - Improved Safety
profile
Patent protection - Extend proprietary
rights and marketability of a drug product
Enabling the GP - Optimized dose
relationship
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Fixed-dose combinations - Disadvantages
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Disadvantages of FDCs
Customization - Inability to
customize the dose regimen
Safety - Difficult to identify the
active pharmaceutical ingredient responsible for the adverse reaction
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We hypothesize that the interpretation of the guidelines can lead to non-optimal investigations
in the clinical development program for FDCs
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Body of clinical evidence • Patients • Trials • Combinations of
known/unknown drugs
General characteristics • Therapeutic area • Authorization date
Approaches applied in the development • Design • Amount of doses
tested
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EPARs – Retrieving the data
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EPARs – Retrieving the data
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EPARs – Retrieving the data
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EPARs - Spreadsheet
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We hypothesize that the interpretation of the guidelines can lead to non-optimal investigations
in the clinical development program for FDCs
11/10/2017 15
Body of clinical evidence • Patients • Trials • Combinations of
known/unknown drugs
General characteristics • Therapeutic area • Authorization date
Approaches applied in the development • Design • Amount of doses
tested
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Data created from general characteristics
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ggsave
A: Alimentary tract and metabolism J: Antiinfectives for systemic use R: Respiratory system
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Data created from general characteristics
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Glyxambi - an example
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Glyxambi – table of contents of EPAR
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Glyxambi – table of contents of EPAR
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Glyxambi – Quality aspects
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• Combinations of known/unknown drugs
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Glyxambi – Clinical efficacy
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• Patients • Trials
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Glyxambi – Clinical efficacy
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• Design • Amount of doses tested
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Glyxambi – Clinical efficacy
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• Patients • Trials • Design • Amount of doses tested
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Glyxambi – Clinical efficacy
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• Patients • Arm level
• Trials • Design • Amount of
doses tested
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We hypothesize that the interpretation of the guidelines can lead to non-optimal investigations
in the clinical development program for FDCs
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Body of clinical evidence • Patients • Trials • Combinations of
known/unknown drugs
General characteristics • Therapeutic area • Authorization date
Approaches applied in the development • Design • Amount of doses
tested
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Data created from clinical efficacy
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AD: Approved drug NME: New molecular entity
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Data created from clinical efficacy
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Conclusion
The positive
• Easily accessible
• Provides an overview • Data at the arm level of
clinical trials
• Enables some types of research
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The negative
• Can be lacking in depth and detail • No information at patient
level of clinical trials
• Sparse information on the use of modeling
• No defined structure for the data
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Conclusion
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The positive
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Conclusion
Transparency
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EMA
People Industry
Academia
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Acknowledgements
Supervisor
Trine Melgaard Lund, Assoc. Prof. Dept. of Drug Design and Pharmacology University of Copenhagen
Co-supervisors
Christian Bressen Pipper, Assoc. Prof. Section of Biostatistics University of Copenhagen
Marieke De Bruin, Prof. Copenhagen Centre for Regulatory Science (CORS) University of Copenhagen
Ole Jannik Bjerrum, Prof. emeritus Dept. of Drug Design and Pharmacology University of Copenhagen
Mikael Thomsen Drug Development Specialist Contera Pharma
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