basic non-clinical requirements for registration of new drugs. legal basis regulacion del desarrollo...

Basic non-clinical requirements for registration of new drugs.

• Legal Basis

REGULACION DEL DESARROLLO Y EL REGISTRO DE MEDICAMENTOS

CSIC 6 de octubre de 2009

Requisitos toxicológicos y farmacológicos para el inicio de la

investigación clínica

Belén Gracia MonevaServicio Evaluación Fármaco-toxicológica

Agencia Española de Medicamentos y Productos Sanitarios

Development-RegistrationDevelopment-Registration

Pharmaceutical R&DFormulation

Clinical Investigator& patient

Clinical PharmacologyClinical Research

Statistics & EpidemiologyData CoordinationResearch Information SystemsInformation Services

Regulatory AffairsProject Planning & ManagementMarketing

Process R&DChem Eng. R&DManufacturing

Bio Process R&D

Safety AssessmentToxicology

Drug Metabolism(ADME)

PharmacologyPre-Clinical

Clinical

Drug Candidatesafety testing

Animal Studies- relevant species

- transgenic KO mice- conditional KOs

- agonists/antagonists- antibodies- antisense

- RNAi

Studies ofDisease Mechanisms

Human Studies Phases I,II, III

Target-receptor; -ion channel; -transporter;

-enzyme; - signalling molecule

Lead Search-Develop assays (use of automation) -Chemical diversity-Highly iterative processMolecular Studies

Lead optimization-selectivity -efficacy in animal models-tolerability: AEs mechanism- based or structure-based?-pharmacokinetics-highly iterative process

Drug Approvaland Registration

Target selection Discovery Development


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


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 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/pharmaceuticals/eudralex/vol3_en.htm

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 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

Community Guidelines (Vol 3 of Eudralex)

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/

vol3_en.htmwww.emea.eu.int

CPMP/ICH/135/95Normas de la Buena Práctica Clínica

Manual del investigadorDatos clínicos y no clínicos

relevantes para el estudio de los medicamentos en investigación en el ser humano

Normas de Buena Práctica ClínicaCPMP/ICH/135/95

Manual del investigadorResultados 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 investigadorConsiderar 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/135/95Manual 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 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


a) Farmacología no clínicaResumen 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



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



c) Toxicología

• Dosis única• Dosis repetidas • Carcinogénesis • Estudios especiales• Toxicidad reproductiva• Genotoxicidad

Community GuidelinesNon-clinical safety studies for the conduct of human clinical trials and

Marketing Authorisation for Pharmaceuticals

(CPMP/ICH/286/95)

Community GuidelinesNon-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 pharmaceuticalsCPMP/ICH/286/95

ObjectiveTo 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 pharmaceuticalsCPMP/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

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 pharmaceuticals

CPMP/ICH/286/95

Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for

pharmaceuticalsCPMP/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



Local tolerance studies – by intended therapeutic route as part of the general toxicity studies


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 testsExploratory studies- case by case assessment



Carcinogenicity studies

Only cause for concern for carcinogenic risk should the study results be submitted to support clinical trials



Reproduction toxicity studiesConducted as is appropriate for the population that is to be exposed:

-MenPhase I/II:evaluation of male

reproductive organsPhase 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 studies



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, embryo-fetal developmental studies)-Juvenile animal toxicity studies- previous animal data and human safety data insufficient


CPMP/ICH/286/95

Immunotoxicity Completed before exposure of large population of

patients (Phase III)

Photosafety testing1)- Photochemical properties2)- Information on the phototoxic potential of chemically related compounds3)-tissue distribution4)-Clinical or non-clinical findings indicative of phototoxicity


CPMP/ICH/286/95

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 aspectsNon-clinical aspectsClinical testing strategies and designs

First-in-human clinical trials


Non-clinical aspects

-Identify potential factors for risk-Limitations-All new chemical and biological investigational

medicinal product (except gene and cell therapy)



-Factors of risk1) mode of action2) nature of the target3) relevance of animal model


-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.


-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 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 products may:

* NOT reproduce the intended pharmacoligical effect in humans

* GIVE RISE to misinterpretation of pharmacokinetic and pharmacodynamic results

* NOT identify relevant toxic effects



-Demonstration of relevance of the animal model

-Pharmacodynamics-Pharmacokinetics-Safety pharmacology-Toxicology-Estimation of the first dose in human



-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



-Pharmacokinetics- standard pK/tk data available in all species used for safety studies before into human



-Safety pharmacology standard core battery data available before into humans



-Toxicology

Toxicology programme in relevant animal species.Toxicity in non-relevant sp are discouragedHuman specific proteins likely to be immunogenic in animal species



-Estimation of the first dose in human

Case-by-case basisNOAEL (No observed Adverse effect Level)+ SFMABEL (Minimal Anticipated Biological Effect Level)+ SF



MABEL:

i) target binding and receptor occupancy studies in vitro in target cells from human and relevant spii) 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 speciesiii) 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 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 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)-biodistributiondata on all organs target or not




3)-Studies to stablish dose:Based on the rationale for the use of a gene therapy

medicinal product in human subjectsBased on results of toxicity studies

number of genes integrated in cell/dose of GTMP




4)-Toxicity studies. Duration, sp, dosing, route mimic clinical situationSingle tox studyRepeated-dose tox studyBiomarkers predictive of toxicity in animal models




5) Integration studies6) Germline transmission7) Target tissue selectivity8) Immunogenicity and immunotoxicity




9) Delivery devices10) Reproductive toxicology11) Genotoxicity studies12)Carcinogenicity/oncogenicity/

tumorigenicity studies

Note for Guidance on the pre-clinical 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 pre-clinical 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.


Start Dose for first administration in humanDose expected to have pharmacologic effects and is reasonably safe to use.1/10 STD severely toxic dose in 10% of animals in rodents (STD10)1/6 HNSTD highest non-severely toxic dose in non-rodents


General toxicology

NOAEL- not essential -MTD (Maximum tolerated dose)/DLT (dose limiting toxicity)- Incorporate a recovery period if toxicological findings


Reproduction toxicology

Embryofetal/fertility/peri-post natal toxicity studies of anticancer pharmaceuticals not essential to support clinical trials in patients with advanced cancer


Duration o support initial clinical trialsPhase I clinical trials continue according patient responsePhase III- up to 3 months duration

GRACIAS!

basic non-clinical requirements for registration of new drugs. legal basis regulacion del desarrollo...

Documents

of eudralexhttp

the competent

medicinal product for

investigacin normas

clinical trial on

investigacin clnica

datos farmacolgicos

buena prctica clnicamanual