Global Development Challenges: Classical and Advanced Therapy - - PowerPoint PPT Presentation

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Global Development Challenges: Classical and Advanced Therapy - - PowerPoint PPT Presentation

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Global Development Challenges: Classical and Advanced Therapy Medicinal products Beatriz eatriz Silva Lima Silva Lima B iMED, , Lisbon Lisbon University University and and Infarmed Infarmed, Portugal , Portugal iMED CHMP, CAT, SAWP

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B Beatriz eatriz Silva Lima Silva Lima iMED iMED, , Lisbon Lisbon University University and and Infarmed Infarmed, Portugal , Portugal CHMP, CAT, SAWP CHMP, CAT, SAWP Member Member and and SWP SWP Chair Chair

Global Development Challenges: Classical and Advanced Therapy Medicinal products

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SLIDE 2

The ultimate aim The ultimate aim The ultimate aim

  • through clinical evaluation
  • to registration
  • TO MARKET
  • through clinical evaluation
  • to registration
  • TO MARKET

Efficiently and effectively justify / support safe Efficiently and effectively justify / support safe introduction in clinical trials & introduction in clinical trials & furher furher progression progression

NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 3

For Decisions on eg

– FIM dose estimation based on

  • Pharmacology
  • Safety

– Safety Pharmacology – Toxicology

– Highlights on safety aspects to monitor

  • eg liver; CNS; dermal; renal; …

– … … …

For Decisions on For Decisions on eg eg

– – FIM dose estimation based on FIM dose estimation based on

  • Pharmacology

Pharmacology

  • Safety

Safety

– – Safety Pharmacology Safety Pharmacology – – Toxicology Toxicology

– – Highlights on safety aspects to monitor Highlights on safety aspects to monitor

  • eg

eg liver; CNS; dermal; renal; liver; CNS; dermal; renal; … …

– – … … … … … …

Supportive Role on Early Clinical Trials Supportive Role on Early Clinical Trials

NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 4

FIM: Safe Starting Dose in Man Should Be Driven by Pharmacology & Toxicology

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 5

Adjusted to the Clinical Study

  • Subjects

– Health status – Age – Gender

  • Duration of the Study
  • Extension of Traget Population
  • Disease

– Incidence – severity

Adjusted to the Clinical Study Adjusted to the Clinical Study

  • Subjects

Subjects

– – Health status Health status – – Age Age – – Gender Gender

  • Duration of the Study

Duration of the Study

  • Extension of

Extension of Traget Traget Population Population

  • Disease

Disease

– – Incidence Incidence – – severity severity

Subsequent CTs :Stepwise NC program Subsequent Subsequent CTs CTs :Stepwise NC program :Stepwise NC program

ICH M3; CPMP/ICH/286/95 Under Revision ICH M3; CPMP/ICH/286/95 Under Revision

NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 6

The The « «Core Core» » Nonclinical Nonclinical Package (MA) Package (MA)

  • Pharmacodynamics
  • Pharmacodynamics
  • Pharmacokinetics
  • Pharmacokinetics
  • Toxicology
  • Toxicology
  • Proof of concept
  • Secondary effects
  • Safety Pharmacology
  • Proof of concept

Proof of concept

  • Secondary effects

Secondary effects

  • Safety Pharmacology

Safety Pharmacology

  • ADME
  • Species selection
  • Human Extrapolation
  • Predictive
  • Mechanistic (?)

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 7

Superseded by human data Superseded by human data Superseded by human data NOT superseded by human data NOT NOT superseded by human data superseded by human data General Toxicity General Toxicity Special Toxicity Special Toxicity

Toxicology Toxicology Toxicology

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 8

NOT superseded by human data NOT superseded by human data NOT superseded by human data Special Toxicity Special Toxicity

2-4 weeks 2-4 weeks 1 month 1 month 3 months 3 months Repeated Dose Studies Repeated Dose Repeated Dose Studies Studies 9 (12) months 9 (12) months 6 months 6 months Acute Toxicity Acute Acute Toxicity Toxicity

Toxicology Toxicology Toxicology

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 9

2-4 Weeks 2-4 Weeks 1 month 1 month 3 months 3 months Repeated Dose Studies Repeated Dose Repeated Dose Studies Studies 9 (12) months 9 (12) months 6 months 6 months

  • fertility
  • embryofetal toxicity
  • peri-post natal toxicity
  • fertility

fertility

  • embryofetal toxicity

embryofetal toxicity

  • peri

peri-

  • post natal toxicity

post natal toxicity Reproduction Toxicology Reproduction Toxicology 1 life-span + 1 additional model 1 life 1 life-

  • span

span + + 1 additional model 1 additional model Carcinogenicity Carcinogenicity

  • in vitro
  • in vivo
  • in vitro

in vitro

  • in vivo

in vivo Genotoxicity Genotoxicity Acute Toxicity Acute Acute Toxicity Toxicity

Toxicology Toxicology Toxicology

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 10

Marketing Authorization Marketing Marketing Authorization Authorization

Non Non-

  • Clinical

Clinical Clinical Clinical

Phase II Phase II Phase I Phase I Phase III Phase III

Rates & Causes for Rates & Causes for Drug Drug Failure Failure During During Development Development 20% 20%

20% 20% toxicity toxicity 20% 20% efficacy efficacy

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 11

How to Improve? How to Improve? How to Improve?

Question for NC and Clinical Scientists Question for NC and Clinical Scientists Question for NC and Clinical Scientists Main Reasons For (Late) Attrition, in Clinical Main Reasons For (Late) Attrition, in Clinical Trials, Trials, eg eg

– Poor kinetics – Insufficient efficacy – Unpredicted safety aspects

  • Further In silico/in vitro ?
  • Exploratory Clinical Trials?
  • Role for PhGenetics?
  • Role for Omics?
  • Role for Biomarkers?
  • More relevant studies?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 12
  • Acute Toxicity

Acute Toxicity

  • Repeated dose

Repeated dose tox

  • tox. (2W)

. (2W)

  • Genotoxicity

Genotoxicity in vitro in vitro

  • Safety pharmacology

Safety pharmacology

  • Local tolerance

Local tolerance

male reproductive organs male reproductive organs

Phase I Phase I

ICH M3; CPMP/ICH/286/95 ICH M3; CPMP/ICH/286/95 ICH M3; CPMP/ICH/286/95

B.Silva Lima B.Silva Lima B.Silva Lima

Early-Phase I (ICH 3 Guideline Ongoing Revison) Early Early-

  • Phase I

Phase I (ICH 3 Guideline Ongoing (ICH 3 Guideline Ongoing Revison Revison) ) Adapted NC package Adapted Adapted NC NC package package

PK/PD: microdose studies PK/PD: PK/PD: microdose microdose studies studies Low (PD range) dose studies better/faster selection

  • f «promising» molecules?

Low (PD range) dose studies better/faster selection

  • f «promising» molecules?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 13

Some Reasons for Poor Safety Prediction

  • f

NC studies Some Reasons for Poor Safety Prediction

  • f

NC studies

  • Development Programs Regulatory – Driven Only
  • Innapropriate Study Planning
  • Irrelevant Animal Models Used
  • Development

Development Programs Programs Regulatory Regulatory – – Driven Driven Only Only

  • Innapropriate

Innapropriate Study Study Planning Planning

  • Irrelevant

Irrelevant Animal Animal Models Models Used Used

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 14
  • Use Relevant Species / Models
  • Adapt Study Design (into human situation)
  • Study Human Relevance of

Relevant Nonclinical Findings

  • Use

Use Relevant Relevant Species Species / / Models Models

  • Adapt

Adapt Study Study Design ( Design (into into human human situation situation) )

  • Study Human Relevance of

Study Human Relevance of Relevant Relevant Nonclinical Nonclinical Findings Findings Small molecules vs Biopharmaceuticals vs Advanced Therapies Same General Principles Through Different Strategies

HOW To “Optimise” Predictivity

  • f

NC ? HOW To “Optimise” Predictivity

  • f

NC ?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 15
  • Use Relevant Species / Models !
  • Use

Use Relevant Relevant Species Species / / Models Models ! !

  • Similar to Human on

Similar to Human on

  • Pharmacodynamics

Pharmacodynamics

  • Kinetics (ADME)

Kinetics (ADME)

  • Pathophysiology

Pathophysiology

  • respecting ethics & animal welfare

respecting ethics & animal welfare

Small Molecules

Interspecies similarities on

  • Metabolism
  • Distribution
  • Excretion
  • Pathophysiology

Biologics

  • Sructural similarities
  • Target expression
  • Target Biology
  • Drug-target interaction

HOW To “Optimise” Predictivity

  • f

NC ? HOW To “Optimise” Predictivity

  • f

NC ?

B.Silva Lima, EMEA,Febrauary 2009

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  • In Case of Poor/Non-Relevant Species ?
  • In

In Case Case of

  • f Poor

Poor/ /Non Non-

  • Relevant

Relevant Species Species ? ?

  • eg Human specific Metabolite:
  • Test Isolate Metabolite?
  • … …

Small Molecules

Interspecies similarities on

  • Metabolism
  • Distribution
  • Excretion
  • Pathophysiology
  • Sructural similarities
  • Target expression
  • Target Biology
  • Drug-target interaction
  • Use Homologue Molecule
  • Use Transgenic Model
  • …

Biologics

HOW To “Optimise” Predictivity

  • f

NC ? HOW To “Optimise” Predictivity

  • f

NC ?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 17
  • Study Planning
  • Study

Study Planning Planning

  • In Relevant Species/Model
  • age (eg adult vs juvenile animals)
  • Gender
  • Disease status
  • Duration (ICH M3)

Administration Schedule (eg anticancer; ICH S9)

  • Early identification of need for mechanistic

approaches (eg biomarkers)

  • In

In Relevant Relevant Species Species/ /Model Model

  • age (

age (eg eg adult adult vs vs juvenile juvenile animals animals) )

  • Gender

Gender

  • Disease status

Disease status

  • Duration (ICH M3)

Duration (ICH M3) Administration Schedule ( Administration Schedule (eg eg anticancer; ICH S9) anticancer; ICH S9)

  • Early identification of need for mechanistic

Early identification of need for mechanistic approaches ( approaches (eg eg biomarkers) biomarkers)

Human relevance Human relevance

HOW To “Optimise” Predictivity

  • f

NC ? HOW To “Optimise” Predictivity

  • f

NC ?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 18
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!

Expectations on Nonclinical Program Expectations on Expectations on Nonclinical Nonclinical Program Program At the time of filing MAA At the time of filing MAA

  • IN THE IDEAL DEVELOPMENT!
  • IN THE IDEAL DEVELOPMENT!

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 19
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!

Expectations on Nonclinical Program Expectations on Expectations on Nonclinical Nonclinical Program Program At the time of filing MAA At the time of filing MAA

  • IN THE IDEAL DEVELOPMENT!
  • IN THE IDEAL DEVELOPMENT!

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 20
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!
  • MOST Concerns Should Have Been

Addressed and/or Solved/Considered for Risk Management

  • Major NC Problems Should NOT exist!

Expectations on Nonclinical Program Expectations on Expectations on Nonclinical Nonclinical Program Program At the time of filing MAA At the time of filing MAA

  • IN THE IDEAL DEVELOPMENT!
  • IN THE IDEAL DEVELOPMENT!

B.Silva Lima, EMEA,Febrauary 2009

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Concerns often Persist on eg.

– Carcinogenicity / genotoxicity – Genotoxic Impurities – Reproductive Toxicity – Hepatotoxicity – …

However, Still Are Raised for MAAs

– Poor justification of animal models – Insufficient Kinetics / Toxicokinetics

!? !?

SINCE THE IDEAL DOES NOT EXIST SINCE THE IDEAL DOES NOT EXIST … …

B.Silva Lima, EMEA,Febrauary 2009

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– Insufficient Nonclinical Programs? – Nonclinical (Animal) Models Irrelevant? – Nonclinical Signs Insufficiently Explored? – – Insufficient Insufficient Nonclinical Nonclinical Programs? Programs? – – Nonclinical Nonclinical (Animal) Models Irrelevant? (Animal) Models Irrelevant? – – Nonclinical Nonclinical Signs Insufficiently Explored? Signs Insufficiently Explored?

Questioning the Nonclinical Scientists Questioning the Questioning the Nonclinical Nonclinical Scientists Scientists

Too High Expectations for These To Be Clarified In Clinical Studies? Too High Expectations for These To Be Clarified In Clinical Studies?

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 23

Summaring: Major NC Challenges Summaring Summaring: Major NC : Major NC Challenges Challenges

  • New mechanisms of action
  • Human specific molecules (eg proteins, Abs, ...)
  • New Therapies/Technologies:(Cells/Biotech/Nano)
  • to understand the mode of action (MOA)
  • to pick up PD - related toxicological effects
  • to consider/adapt the MOA in the species used
  • use relevant species/model
  • use homologue molecules in the animal species
  • use animal models of the disease
  • use administration schedules and doses mimicking the

human situation

  • use of adapted approaches

B.Silva Lima, EMEA,Febrauary 2009

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Take as Starting Point Take as Starting Point… …

  • Experimental Models and Plans for NC Studies
  • carefully chosen,
  • scientifically justified
  • And, if needed, case-driven.

STRONGLY AVOID Irrelevant Nonclinical Studies SEEK FOR EARLY ADVICE BY REGULATORY AUTHORITIES

Major Challenges Major Major Challenges Challenges

Be Aware of 3Rs & GMP/GLP/GCP Thank YOU! Be Aware of 3Rs & GMP/GLP/GCP Thank YOU! Thank YOU!

B.Silva Lima, EMEA,Febrauary 2009

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SLIDE 25

Take as Starting Point Take as Starting Point… …

  • Experimental Models and Plans for NC Studies
  • carefully chosen,
  • scientifically justified
  • And, if needed, case-driven.

Avoid Irrelevant Nonclinical Studies SEEK FOR EARLY ADVICE BY REGULATORY AUTHORITIES

Major Challenges Major Major Challenges Challenges

Be Aware 3Rs & GMP/GLP/ Thank YO Be Aware 3Rs & GMP/GLP/ Thank YO Thank YO