obtaining information a study on fixed-dose · fdc case study focusing on estimation of interaction...

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)

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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

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

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

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

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

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

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

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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

Data created from general characteristics

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ggsave

A: Alimentary tract and metabolism J: Antiinfectives for systemic use R: Respiratory system

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

Glyxambi – Clinical efficacy

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• Patients • Trials

Glyxambi – Clinical efficacy

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• Design • Amount of doses tested

Glyxambi – Clinical efficacy

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• Patients • Trials • Design • Amount of doses tested

Glyxambi – Clinical efficacy

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• Patients • Arm level

• Trials • Design • Amount of

doses tested

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

Data created from clinical efficacy

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AD: Approved drug NME: New molecular entity

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

Conclusion

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The positive

Conclusion

Transparency

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EMA

People Industry

Academia

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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