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 Member Member and and SWP SWP Chair Chair CHMP, CAT, SAWP
NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES The ultimate aim The ultimate aim The ultimate aim Efficiently and effectively justify / support safe Efficiently and effectively justify / support safe introduction in clinical trials & furher furher progression progression introduction in clinical trials & • through clinical evaluation • through clinical evaluation • to registration • to registration • TO MARKET • TO MARKET B.Silva Lima, EMEA,Febrauary 2009
NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES Supportive Role on Early Clinical Trials Supportive Role on Early Clinical Trials For Decisions on eg eg For Decisions on For Decisions on eg – FIM dose estimation based on FIM dose estimation based on – – FIM dose estimation based on • Pharmacology Pharmacology • • Pharmacology • Safety Safety • • Safety – Safety Pharmacology Safety Pharmacology – – Safety Pharmacology – Toxicology Toxicology – – Toxicology – Highlights on safety aspects to monitor Highlights on safety aspects to monitor – – Highlights on safety aspects to monitor • eg eg liver; CNS; dermal; renal; liver; CNS; dermal; renal; … … • • eg liver; CNS; dermal; renal; … – … … … … … … – – … … … B.Silva Lima, EMEA,Febrauary 2009
FIM: Safe Starting Dose in Man Should Be Driven by Pharmacology & Toxicology B.Silva Lima, EMEA,Febrauary 2009
NONCLINICAL STUDIES FOR NEW DRUG CANDIDATES Subsequent CTs CTs :Stepwise NC program Subsequent :Stepwise NC program Subsequent CTs :Stepwise NC program Adjusted to the Clinical Study Adjusted to the Clinical Study Adjusted to the Clinical Study • Subjects Subjects • • Subjects – Health status – Health status – Health status – Age Age – – Age ICH M3; CPMP/ICH/286/95 ICH M3; CPMP/ICH/286/95 – Gender Gender – – Gender Under Revision Under Revision • Duration of the Study Duration of the Study • • Duration of the Study • Extension of Extension of Traget Traget Population Population • • Extension of Traget Population • Disease Disease • • Disease – Incidence Incidence – – Incidence – severity – severity – severity B.Silva Lima, EMEA,Febrauary 2009
The « «Core Core» » Nonclinical The Nonclinical Package (MA) Package (MA) • Proof of concept Proof of concept • • Proof of concept Pharmacodynamics Pharmacodynamics • Secondary effects Secondary effects • • Secondary effects • Safety Pharmacology Safety Pharmacology • • Safety Pharmacology • ADME Pharmacokinetics Pharmacokinetics • Species selection • Human Extrapolation Toxicology Toxicology • Predictive • Mechanistic (?) B.Silva Lima, EMEA,Febrauary 2009
Toxicology Toxicology Toxicology General Toxicity General Toxicity Superseded by human data Superseded by human data Superseded by human data Special Toxicity Special Toxicity NOT superseded by human data superseded by human data NOT NOT superseded by human data B.Silva Lima, EMEA,Febrauary 2009
Toxicology Toxicology Toxicology Acute Acute Acute Toxicity Toxicity Toxicity 6 months 6 months 2-4 weeks 2-4 weeks Repeated Dose Repeated Dose Repeated Dose 1 month 1 month Studies Studies Studies 3 months 3 months 9 (12) months 9 (12) months Special Toxicity Special Toxicity NOT superseded by human data NOT superseded by human data NOT superseded by human data B.Silva Lima, EMEA,Febrauary 2009
Toxicology Toxicology Toxicology Acute Acute Acute Toxicity Toxicity Toxicity 6 months 6 months 2-4 Weeks 2-4 Weeks Repeated Dose Repeated Dose Repeated Dose 1 month 1 month Studies Studies Studies 3 months 3 months 9 (12) months 9 (12) months Carcinogenicity Carcinogenicity Reproduction Toxicology Reproduction Toxicology Genotoxicity Genotoxicity • fertility fertility 1 life- -span span • fertility 1 life 1 life-span • in vitro in vitro • in vitro • embryofetal toxicity embryofetal toxicity + • + • embryofetal toxicity + • in vivo in vivo • • in vivo 1 additional model 1 additional model 1 additional model • peri peri- -post natal toxicity post natal toxicity • • peri-post natal toxicity B.Silva Lima, EMEA,Febrauary 2009
Rates & Causes for Drug Drug Failure During Rates & Causes for Failure During Development Development 20% 20% Non- -Clinical Clinical Non 20% toxicity 20% toxicity 20% efficacy efficacy 20% Clinical Clinical Marketing Marketing Marketing Authorization Authorization Authorization Phase I Phase I Phase II Phase II Phase III Phase III B.Silva Lima, EMEA,Febrauary 2009
Question for NC and Clinical Scientists Question for NC and Clinical Scientists Question for NC and Clinical Scientists How to Improve? How to Improve? How to Improve? Main Reasons For (Late) Attrition, in Clinical Main Reasons For (Late) Attrition, in Clinical Trials, eg eg Trials, •Further In silico/in vitro ? – Poor kinetics •Exploratory Clinical Trials? •Role for PhGenetics? – Insufficient efficacy •Role for Omics? •Role for Biomarkers? – Unpredicted safety aspects •More relevant studies? B.Silva Lima, EMEA,Febrauary 2009
ICH M3; CPMP/ICH/286/95 ICH M3; CPMP/ICH/286/95 ICH M3; CPMP/ICH/286/95 Early- -Phase I Phase I Early Early-Phase I (ICH 3 Guideline Ongoing Revison Revison) ) (ICH 3 Guideline Ongoing (ICH 3 Guideline Ongoing Revison) Low (PD range) dose studies Low (PD range) dose studies PK/PD: microdose microdose studies studies PK/PD: PK/PD: microdose studies better/faster selection better/faster selection Adapted Adapted Adapted of «promising» molecules? of «promising» molecules? NC package package NC NC package - Safety pharmacology - Safety pharmacology - Local tolerance - Local tolerance - Genotoxicity Genotoxicity in vitro in vitro - Phase I Phase I - Acute Toxicity Acute Toxicity - - Repeated dose Repeated dose tox tox. (2W) . (2W) - male reproductive organs male reproductive organs B.Silva Lima, EMEA,Febrauary 2009 B.Silva Lima B.Silva Lima B.Silva Lima
Some Reasons Some Reasons for Poor for Poor Safety Safety Prediction Prediction of of NC studies NC studies •Development Development Programs Programs Regulatory Regulatory – – Driven Driven Only Only • •Development Programs Regulatory – Driven Only •Innapropriate Innapropriate Study Study Planning Planning • •Innapropriate Study Planning •Irrelevant Irrelevant Animal Animal Models Models Used Used • •Irrelevant Animal Models Used B.Silva Lima, EMEA,Febrauary 2009
HOW To “Optimise” HOW To “Optimise” Predictivity Predictivity of of NC ? NC ? •Use Use Relevant Relevant Species Species / / Models Models •Use Relevant Species / Models • Small molecules vs Biopharmaceuticals vs Advanced Therapies •Adapt Adapt Study Study Design ( Design (into into human human situation situation) ) •Adapt Study Design (into human situation) • •Study Human Relevance of Study Human Relevance of • Same General Principles Through •Study Human Relevance of Different Strategies Relevant Nonclinical Nonclinical Findings Findings Relevant Relevant Nonclinical Findings B.Silva Lima, EMEA,Febrauary 2009
HOW To “Optimise” HOW To “Optimise” Predictivity Predictivity of of NC ? NC ? •Use Use Relevant Relevant Species Species / / Models Models ! ! •Use Relevant Species / 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 Biologics Small Molecules •Sructural similarities Interspecies similarities on •Target expression •Metabolism •Target Biology •Distribution •Drug-target interaction •Excretion •Pathophysiology B.Silva Lima, EMEA,Febrauary 2009
HOW To “Optimise” HOW To “Optimise” Predictivity Predictivity of of NC ? NC ? •In In Case Case of of Poor Poor/ /Non Non- -Relevant Relevant Species Species ? ? •In Case of Poor/Non-Relevant Species ? • •Use Homologue Molecule •eg Human specific Metabolite: •Use Transgenic Model •Test Isolate Metabolite? •… •… … Biologics Small Molecules •Sructural similarities Interspecies similarities on •Target expression •Metabolism •Target Biology •Distribution •Drug-target interaction •Excretion •Pathophysiology B.Silva Lima, EMEA,Febrauary 2009
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