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Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dr. Dirk Mentzer, MD, PhD
Consultant General Paediatrics
Head of Pharmacovigilance unit
Chair of PDCO at EMA
Paul-Ehrlich-Institut
Federal Institute for Vaccines
and Biomedicines, Germany
Disclaimer
• The views and opinions expressed in the following PowerPoint slides are those of the
individual presenter and should not be attributed to the Paul-Ehrlich-Institut or to the
European Medicines Agency (EMA).
• My employee is the Paul-Ehrlich-Institut, a national regulatory agency, and I have
nothing to disclose.
• By education, I am a paediatrician with limited experience in paediatric oncology
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20181
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20182
The target should have an effect to all children
in need for treatment!
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20183
• PDCO has to serve all children needs
• PDCO/ EMA role and influence
• Paediatric needs and trial feasibility
• International cooperation
• New methodologies
Medicinal product development
Initial PIP application:
• PIP Opinion after 60 day or
• Clock stop to respond to request
for supplementary Information
• Assessment of responses (60d)
• Final PIP opinion at D120
Request for Modification
of an agreed PIP opinion
• Assessment of changes
proposed to PIP
• PDCO opinion on
changes after 60 days
Final Compliance check
• Validation of submitted
study reports of studies
agreed in the PIP
• PDCO opinion on
compliance after 60 days
Paediatric
Indication
Theory
Adult clinical trial program
Post-marketingPIP opinion and paediatric clinical trial program
PK/PD
Safety & efficacy
Non-clinical studies
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20184
MAA
Problem: Timely availability of marketed medicines for children
Deferrals
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20185
Problem: PIP submission
Deferred studies in PIPs
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20186
Medicinal product development
Initial PIP application:
• PIP Opinion after 60 day or
• Clock stop to respond to request
for supplementary Information
• Assessment of responses (60d)
• Final PIP opinion at D120
Request for Modification
of an agreed PIP opinion
• Assessment of changes
proposed to PIP
• PDCO opinion on
changes after 60 days
Final Compliance check
• Validation of submitted
study reports of studies
agreed in the PIP
• PDCO opinion on
compliance after 60 days
Paediatric
Indication
Reality
Adult clinical trial program
Post-marketingPIP opinion and paediatric clinical trial program
PK/PD
Safety & efficacy
Non-clinical studies
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20187
DeferredNot deferred
Studies deferred
VariationInitial MAA Variation
Medicinal product development
Initial PIP application:
• PIP Opinion after 60 day or
• Clock stop to respond to request
for supplementary Information
• Assessment of responses (60d)
• Final PIP opinion at D120
Request for Modification
of an agreed PIP opinion
• Assessment of changes
proposed to PIP
• PDCO opinion on
changes after 60 days
Final Compliance check
• Validation of submitted
study reports of studies
agreed in the PIP
• PDCO opinion on
compliance after 60 days
Paediatric
Indication
Theory
Adult clinical trial program
Post-marketingPIP opinion and paediatric clinical trial program
PK/PD
Safety & efficacy
Non-clinical studies
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20188
MAA
Medicinal product development
Initial PIP application:
• PIP Opinion after 60 day or
• Clock stop to respond to request
for supplementary Information
• Assessment of responses (60d)
• Final PIP opinion at D120
Request for Modification
of an agreed PIP opinion
• Assessment of changes
proposed to PIP
• PDCO opinion on
changes after 60 days
Final Compliance check
• Validation of submitted
study reports of studies
agreed in the PIP
• PDCO opinion on
compliance after 60 days
Paediatric
Indication
Reality
Adult clinical trial program
Post-marketingPIP opinion and paediatric clinical trial program
PK/PD
Safety & efficacy
Non-clinical studies
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.20189
DeferredNot deferred
Studies deferred
VariationInitial MAA Variation
Initial MAA
End P1
• Timing of first submission of PIP
(e.g. early versus late)
• Condition/ indication (therapeutic area)
(e.g. PAH, MS, Diabetes, Asthma)
• Unmet therapeutic needs in paediatrics
(by population like neonates/ oncology)
(by needs like epilepsy, psychiatry)
(by mechanism of action)
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201810
Initial MAA
End P1
• Timing of first submission of PIP
(e.g. early versus late)
• Condition/ indication (therapeutic area)
(e.g. PAH, MS, Diabetes, Asthma)
• Unmet therapeutic needs in paediatrics
(by population like neonates/ oncology)
(by needs like epilepsy, psychiatry)
(by mechanism of action)
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201811
Stakeholder
Meeting at EMA
End P1
Strategy by timing of submission
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201812
End P1Science based plan, Cy to come back with more robust
information in due course, MODs to come, no deferrals
Paediatric
Indication
Deferal for
completion
Define Population, need for formulation, trials (non
clinical and clinical, dose finding, extrapolation)Experience
from PRIME
Strategy by timing of submission Initial MAA
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201813
End P1
During P2
Science based plan, Cy to come back with more robust
information in due course, MODs to come, no deferrals
More detailed opinion,
no deferrals on initiation CT
Paediatric
Indication
Deferal for
completion
Deferal for
completion
Define Population, need for formulation, trials (non
clinical and clinical, dose finding, extrapolation)
non clinical, dose finding,
before initial MAA
Experience
from PRIME
Strategy by timing of submission Initial MAA
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201814
End P1
During P2
Close to MAA
Science based plan, Cy to come back with more robust
information in due course, MODs to come, no deferrals
More detailed opinion,
no deferrals on initiation CT
Paediatric
Indication
Deferal for
completion
Deferal for initiation
completion
Deferal for
completion
Define Population, need for formulation, trials (non
clinical and clinical, dose finding, extrapolation)
non clinical, dose finding,
before initial MAA
Experience
from PRIME
Strategy by timing of submission Initial MAA
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201815
End P1
During P2
Close to MAA
Science based plan, Cy to come back with more robust
information in due course, MODs to come, no deferrals
More detailed opinion,
no deferrals on initiation CT
Paediatric
Indication
Deferal for
completion
Deferal for initiation
completion
Deferal for
completion
Define Population, need for formulation, trials (non
clinical and clinical, dose finding, extrapolation)
non clinical, dose finding,
before initial MAA
Risk for delay of initial MAA
Interaction with CHMP/ PRAC is needed to define the
need for treatment in adults versus likelihood for off-label-
use in paediatrics risking the completion of the PIP.
Experience
from PRIME
Strategy by timing of submission Initial MAA
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201816
Preterm newborn Term newborn
(0 to 28 days)
Infants and toddlers
(29 days to 23 months)
Children
(2 to 11 years)
Adolescents
(12 to 18 years)
Significant therapeutic benefit for the Paediatric population
Defining the need for treatment per subpopulation
Standard or care – approved alternatives
Paediatric clinical Trial methodology
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201817
18
Modelling & Simulation followed by Extrapolation
Adult=> Adolescence => Children=>Neonate/ Pre-term
PD (Extrapolation, Biomarker)
PK (Bridging, Pop-PK, Extrapolation, modelling)
Efficacy and Safety
Dose finding
Endpoints, Monitoring of risks
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201818
19
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201819
PD (Extrapolation, Biomarker)
PK (Bridging, Pop-PK, Extrapolation, modelling)
Efficacy and Safety
Dose finding
Endpoints, Monitoring of risks
20
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201820
From benchScience
Research
development
Market forces
To bedsideResearch
Patient health
Paediatric needs
RegulatorsPIPs
Waiver
Deferrals
guidelines
• Decision on minimal information available on paediatric medicinal
product development at time initial MAA (e.g. Non-clinical, PK,
dose-finding, sub-population)
• PIP related to medicinal products, where adult needs are covered
(authorised and available for adults in the EU), deferrals should
strictly be related to technical (formulation) or safety issues
• Justifications for requesting deferral for initiation and completion
(after initial MAA) in late submissions needs to be reflected
against the unmet paediatric medical need. (MAA for adults
potentially delayed)
• ? Inclusion of adolescence in initial MAA (extrapolation) ?
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201821
Let us move to the next gear!
Thank you for your attention
Improving new drug development for paediatric cancer: the EMA and PDCO vision
Dirk Mentzer | Brussels | 08.02.201822