Dr. Dirk Mentzer, MD, PhD Consultant General … · Improving new drug development for paediatric cancer: the EMA and PDCO vision Dr. Dirk Mentzer, MD, PhD Consultant General Paediatrics

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


Dirk Mentzer | Brussels | 08.02.20181



The target should have an effect to all children

in need for treatment!



• 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



MAA

Problem: Timely availability of marketed medicines for children

Deferrals



Problem: PIP submission

Deferred studies in PIPs













proposed to PIP

• PDCO opinion on





agreed in the PIP

• PDCO opinion on


Paediatric

Indication

Reality



PK/PD

Safety & efficacy




DeferredNot deferred

Studies deferred

VariationInitial MAA Variation











proposed to PIP

• PDCO opinion on





agreed in the PIP

• PDCO opinion on


Paediatric

Indication

Theory



PK/PD

Safety & efficacy




MAA











proposed to PIP

• PDCO opinion on





agreed in the PIP

• PDCO opinion on


Paediatric

Indication

Reality



PK/PD

Safety & efficacy




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)



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)



Stakeholder

Meeting at EMA

End P1

Strategy by timing of submission



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



End P1

During P2

Science based plan, Cy to come back with more robust


More detailed opinion,

no deferrals on initiation CT

Paediatric

Indication

Deferal for

completion

Deferal for

completion


clinical and clinical, dose finding, extrapolation)

non clinical, dose finding,

before initial MAA

Experience

from PRIME




End P1

During P2

Close to MAA





Paediatric

Indication

Deferal for

completion

Deferal for initiation

completion

Deferal for

completion




before initial MAA

Experience

from PRIME




End P1

During P2

Close to MAA





Paediatric

Indication

Deferal for

completion

Deferal for initiation

completion

Deferal for

completion




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




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



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



19



PD (Extrapolation, Biomarker)

PK (Bridging, Pop-PK, Extrapolation, modelling)

Efficacy and Safety

Dose finding

Endpoints, Monitoring of risks

20



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) ?



Let us move to the next gear!

Thank you for your attention



Documents

Dr. Dirk Mentzer, MD, PhD Consultant General … · Improving new drug development for paediatric cancer: the EMA and PDCO vision Dr. Dirk Mentzer, MD, PhD Consultant General Paediatrics