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REGULACION DEL DESARROLLO Y EL REGISTRO DE Basic non-clinical requirements for registration of new REGULACION DEL DESARROLLO Y EL REGISTRO DE Basic non-clinical requirements for registration of new drugs. MEDICAMENTOS CSIC 6 de octubre de 2009 • Legal Basis Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Belén Gracia Moneva Servicio Evaluación Fármaco-toxicológica Agencia Española de Medicamentos y Productos Sanitarios

Development-Registration Pre-Clinical Pharmacology Safety Assessment Toxicology Process R&D Chem Eng. R&D Manufacturing Drug Metabolism Development-Registration Pre-Clinical Pharmacology Safety Assessment Toxicology Process R&D Chem Eng. R&D Manufacturing Drug Metabolism (ADME) Pharmaceutical R&D Formulation Clinical Investigator & patient Clinical Pharmacology Clinical Research Clinical Statistics & Epidemiology Data Coordination Research Information Systems Information Services Bio Process R&D Regulatory Affairs Project Planning & Management Marketing

Target selection Studies of Disease Mechanisms Discovery Target -receptor; -ion channel; -transporter; -enzyme; - Target selection Studies of Disease Mechanisms Discovery Target -receptor; -ion channel; -transporter; -enzyme; - signalling molecule Lead Search Molecular Studies -Develop assays (use of automation) -Chemical diversity -Highly iterative process Animal Studies - relevant species - transgenic KO mice - conditional KOs - agonists/antagonists - antibodies - antisense - RNAi Lead optimization -selectivity -efficacy in animal models -tolerability: AEs mechanismbased or structure-based? -pharmacokinetics -highly iterative process Development Drug Candidate safety testing Human Studies Phases I, III Drug Approval and Registration

Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Normativa legal Europea: Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Normativa legal Europea: -DIR 2001/20/EC Of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. -Autorización por cada Estado Miembro -Comisión publicará guías sobre pruebas toxicológicas y farmacológicas

Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Nacional: RD 223/2004 Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Nacional: RD 223/2004 de 6 de febrero, por el que se regulan los ensayos clínicos con medicamentos

Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Detailed Guidance for Requisitos toxicológicos y farmacológicos para el inicio de la investigación clínica Detailed Guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial (Oct 05) http: //ec. europa. eu/enterprise/pharmaceutic als/eudralex/vol 3_en. htm

Detailed Guidance for the request for authorisation of a clinical trial on a medicinal Detailed Guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial (Oct 05) Investigational Medicinal Product Dossier (IMPD) 4. 1. 6. 1. 2 Non-clinical pharmacology and toxicology data

IMPD -Resumen de los datos farmacológicos y toxicológicos del medicamento en investigación usado en IMPD -Resumen de los datos farmacológicos y toxicológicos del medicamento en investigación usado en el ensayo clínico o justificación. -Listado de los estudios y referencias bibliográficas. -Análisis crítico de los datos disponibles/evaluación seguridad del medicamento

IMPD -GLP - Medicamento representativo cuali/cuantitativamente en términos de impurezas IMPD -GLP - Medicamento representativo cuali/cuantitativamente en términos de impurezas

Community Guidelines (Vol 3 of Eudralex) http: //ec. europa. eu/enterprise/pharmac euticals/eudralex/vol 3_en. htm www. Community Guidelines (Vol 3 of Eudralex) http: //ec. europa. eu/enterprise/pharmac euticals/eudralex/vol 3_en. htm www. emea. eu. int

CPMP/ICH/135/95 Normas de la Buena Práctica Clínica Manual del investigador Datos clínicos y no CPMP/ICH/135/95 Normas de la Buena Práctica Clínica Manual del investigador Datos clínicos y no clínicos relevantes para el estudio de los medicamentos en investigación en el ser humano

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador Resultados de todos los estudios Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador Resultados de todos los estudios no clínicos relevantes sobre la farmacología, toxicología, fca y el metabolismo de medicamento en investigación

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador Considerar la metodología utilizada, los Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador Considerar la metodología utilizada, los resultados y una discusión de la relevancia de los hallazgos para la indicación terapéutica investigada y los posibles efectos adversos y no intencionados en humanos

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador • • • Especies estudiadas Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador • • • Especies estudiadas Número y sexo de los animales en cada grupo Unidad de dosis Intervalo de dosis Vía de administración Intervalo dosificación Información sobre la distribución sistémica Duración del seguimiento posterior a la exposición Resultados

Normas de Buena Practica Clínica CPMP/ICH/135/95 Manual del investigador Resultados: • • • Naturaleza Normas de Buena Practica Clínica CPMP/ICH/135/95 Manual del investigador Resultados: • • • Naturaleza y frecuencia de los efectos farmacológicos o tóxicos Severidad o intensidad de los efectos farmacológicos o tóxicos Tiempo transcurrido hasta la aparición de los efectos Reversibilidad de los efectos Duración de los efectos Relación dosis respuesta

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador a) Farmacología no clínica Resumen Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador a) Farmacología no clínica Resumen de los aspectos farmacológicos del medicamento en investigación y si es necesario, de los metabolitos más importantes en animales. Estudios que evalúen la actividad terapéutica potencial (modelos de eficacia, unión a R y especificidad) y aquellos que evalúen seguridad

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador b) Farmacocinética y Metabolismo en Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador b) Farmacocinética y Metabolismo en animales Resumen del metabolismo y eliminación fca del medicamento en investigación en todas las especies estudiadas. Su relación con hallazgos farmacológicos y toxicológicos en las especies animales

Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador c) Toxicología • • • Normas de Buena Práctica Clínica CPMP/ICH/135/95 Manual del investigador c) Toxicología • • • Dosis única Dosis repetidas Carcinogénesis Estudios especiales Toxicidad reproductiva Genotoxicidad

Community Guidelines Non-clinical safety studies for the conduct of human clinical trials and Marketing Community Guidelines Non-clinical safety studies for the conduct of human clinical trials and Marketing Authorisation for Pharmaceuticals (CPMP/ICH/286/95)

Community Guidelines Non-clinical safety studies for the conduct of human clinical trilas (CPMP/ICH/286/95) Community Guidelines Non-clinical safety studies for the conduct of human clinical trilas (CPMP/ICH/286/95)

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Objective To recommend international standards for, and promote harmonisation of, the nonclinical safety studies recommended to support human clinical trials of a given scope and duration as well as marketing authorization for pharmaceuticals

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Pharmacology studies- effects on CVS, CNS and RESP systems conducted prior to human exposure Toxicokinetic and pharmacokinetic studies- in vitro metabolic data for animals and humans conducted prior to initiating human clinical trials

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Acute toxicity studies-Define a maximum tolerated dose in the general toxicity test species Repeated dose toxicity studies- duration related to the duration, therapeutic indication and scope of the proposed clinical trial. Two mammalian sp (one non -rodent)

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Non-clinical studies to support exploratory clinical investigations (early phase 1): -Microdose studies -Single dose studies up to sub-therapeutic or intended therapeutic range -Multiple dose studies

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Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Local tolerance studies – by intended therapeutic route as part of the general toxicity studies

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Genotoxicity studies. Single dose clinical trials- assay for gene mutation Multiple dose clinical trials- chromosomal damage in a mammalian system added Phase II trials- complete battery of tests Exploratory studies- case by case assessment

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Carcinogenicity studies Only cause for concern for carcinogenic risk should the study results be submitted to support clinical trials

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Reproduction toxicity studies Conducted as is appropriate for the population that is to be exposed: -Men Phase I/II: evaluation of male reproductive organs Phase III: male fertility study -Women not of childbearing potential -Women of childbearing potential- reprotox bat or prevent pregnancy. Fertility prior to phae III -Pregnant women- genotox bat, all reprod tox

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Clinical trials in Pediatric population -Case by case assessment -Safety data from previous adult human experience -Results from repeated-dose toxicity studies of appropriate duration in adult animals -Core safety pharmacology package -Standard battery of genotoxicity tests -Reproduction tox studies relevant to age and gender (fertility, pre-post natal development studies, embryofetal developmental studies) -Juvenile animal toxicity studies- previous animal data and human safety data insufficient

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals CPMP/ICH/286/95 Immunotoxicity Completed before exposure of large population of patients (Phase III) Photosafety testing 1)- Photochemical properties 2)- Information on the phototoxic potential of chemically related compounds 3)-tissue distribution 4)-Clinical or non-clinical findings indicative of phototoxicity

Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (EMEA/CHMP/SWP/28367/07)

(EMEA/CHMP/SWP/28367/07) Quality aspects Non-clinical aspects Clinical testing strategies and designs First-in-human clinical trials (EMEA/CHMP/SWP/28367/07) Quality aspects Non-clinical aspects Clinical testing strategies and designs First-in-human clinical trials

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Identify potential factors for risk -Limitations -All new chemical and biological (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Identify potential factors for risk -Limitations -All new chemical and biological investigational medicinal product (except gene and cell therapy)

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Factors of risk 1) mode of action 2) nature of the (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Factors of risk 1) mode of action 2) nature of the target 3) relevance of animal model

(EMEA/CHMP/SWP/28367/07) -Factors of risk 1) mode of action Novel mechanism of action: target connected (EMEA/CHMP/SWP/28367/07) -Factors of risk 1) mode of action Novel mechanism of action: target connected to multiple signalling pathways (immune system), cytokine release. Previous exposure of human to compounds with related modes of action. Evidence from animal models. Novelty of the molecular structure of the active substance.

(EMEA/CHMP/SWP/28367/07) -Factors of risk 2) nature of target knowledge of structure, tissue distribution, cell (EMEA/CHMP/SWP/28367/07) -Factors of risk 2) nature of target knowledge of structure, tissue distribution, cell specificity, disease specificity, regulation, level of expression, biological function of the human target, variations between individuals in different populations healthy/patients, polymorphisms of target in relevant animal species and humans and its impact on pharmacological effects

(EMEA/CHMP/SWP/28367/07) -Factors of risk 3) relevance of animal species and models: target, its structural (EMEA/CHMP/SWP/28367/07) -Factors of risk 3) relevance of animal species and models: target, its structural homology, distribution, signal transduction pathways and nature of pharmacological effects, affinity for molecular targets. Qualitative and quantitative differences in biological responses. questionable relevance Risk

(EMEA/CHMP/SWP/28367/07) -Factors of risk 3) relevance of animal species and models: highly species-specific medicinal (EMEA/CHMP/SWP/28367/07) -Factors of risk 3) relevance of animal species and models: highly species-specific medicinal products may: * NOT reproduce the intended pharmacoligical effect in humans * GIVE RISE to misinterpretation of pharmacokinetic and pharmacodynamic results * NOT identify relevant toxic effects

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Demonstration of relevance of the animal model -Pharmacodynamics -Pharmacokinetics -Safety pharmacology (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Demonstration of relevance of the animal model -Pharmacodynamics -Pharmacokinetics -Safety pharmacology -Toxicology -Estimation of the first dose in human

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Pharmacodynamics. Mode of action, biology of target, pharmacological effects: Primary and (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Pharmacodynamics. Mode of action, biology of target, pharmacological effects: Primary and secondary pharmacodynamics in in vitro animal and human and in vivo in animal models (receptor binding and occupancy, duration of effect and dose-rsponse). Dose/concentration-response curve

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Pharmacokinetics- standard p. K/tk data available in all species used for (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Pharmacokinetics- standard p. K/tk data available in all species used for safety studies before into human

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Safety pharmacology standard core battery data available before into humans (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Safety pharmacology standard core battery data available before into humans

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Toxicology programme in relevant animal species. Toxicity in non-relevant sp are (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Toxicology programme in relevant animal species. Toxicity in non-relevant sp are discouraged Human specific proteins likely to be immunogenic in animal species

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Estimation of the first dose in human Case-by-case basis NOAEL (No (EMEA/CHMP/SWP/28367/07) Non-clinical aspects -Estimation of the first dose in human Case-by-case basis NOAEL (No observed Adverse effect Level)+ SF MABEL (Minimal Anticipated Biological Effect Level)+ SF

(EMEA/CHMP/SWP/28367/07) Non-clinical aspects MABEL: i) target binding and receptor occupancy studies in vitro in (EMEA/CHMP/SWP/28367/07) Non-clinical aspects MABEL: i) target binding and receptor occupancy studies in vitro in target cells from human and relevant sp ii) concentration-response curves in vitro in target cells from human and the relevant animal species and dose/exposure-response in vivo in the relevant animal species iii) Exposures at pharmacological doses in the relevant animal species PK/PD

Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/125459/2006) Gene therapy: plasmid DNA, viral , non-viral vectors, genetically modified viruses , genetically modified cells developed for treatment or prevention of human diseases.

(EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy (EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products Minimal requirements for non-clinical studies before first in human subjects: 1)-pharmacodynamic proof of concept in non-clinical models (in vivo/in vitro). Expression, specific control of expression and production of correct transgene product in appropriate target organ must be demonstrated 2)-biodistribution data on all organs target or not

(EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy (EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products Minimal requirements for non-clinical studies before first in human subjects: 3)-Studies to stablish dose: Based on the rationale for the use of a gene therapy medicinal product in human subjects Based on results of toxicity studies number of genes integrated in cell/dose of GTMP

(EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy (EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products Minimal requirements for non-clinical studies before first in human subjects: 4)-Toxicity studies. Duration, sp, dosing, route mimic clinical situation Single tox study Repeated-dose tox study Biomarkers predictive of toxicity in animal models

(EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy (EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products Minimal requirements for non-clinical studies before first in human subjects: 5) Integration studies 6) Germline transmission 7) Target tissue selectivity 8) Immunogenicity and immunotoxicity

(EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy (EMEA/CHMP/GTWP/125459/2006) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products Minimal requirements for non-clinical studies before first in human subjects: 9) Delivery devices 10) Reproductive toxicology 11) Genotoxicity studies 12)Carcinogenicity/oncogenicity/tumorigenici ty studies

Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96)-Rev Safety Pharmacology Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96)-Rev Safety Pharmacology Stand-alone safety pharmacology studies need not be conducted to support studies in patients with advanced cancer. . .

Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Genotoxicity studies Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with advanced cancer.

Note for Guidance on the pre-clinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Start Dose Note for Guidance on the pre-clinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Start Dose for first administration in human Dose expected to have pharmacologic effects and is reasonably safe to use. 1/10 STD severely toxic dose in 10% of animals in rodents (STD 10) 1/6 HNSTD highest non-severely toxic dose in non-rodents

Note for Guidance on the pre-clinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) General toxicology Note for Guidance on the pre-clinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) General toxicology NOAEL- not essential -MTD (Maximum tolerated dose)/DLT (dose limiting toxicity) - Incorporate a recovery period if toxicological findings

Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Reproduction toxicology Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Reproduction toxicology Embryofetal/fertility/peri-post natal toxicity studies of anticancer pharmaceuticals not essential to support clinical trials in patients with advanced cancer

Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Duration o Note for Guidance on the preclinical evaluation of anticancer medicinal products (CPMP/SWP/997/96) Duration o support initial clinical trials Phase I clinical trials continue according patient response Phase III- up to 3 months duration

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