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
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 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
Manual del investigador
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
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
• 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
Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for
pharmaceuticalsCPMP/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 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 testsExploratory studies- case by case assessment
Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for
pharmaceuticalsCPMP/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
pharmaceuticalsCPMP/ICH/286/95
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
Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for
pharmaceuticalsCPMP/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, embryo-fetal 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 pharmaceuticals
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
Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals
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
(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 risk1) mode of action2) nature of the target3) relevance of animal model
(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 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
(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 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 pK/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
-Toxicology
Toxicology programme in relevant animal species.Toxicity in non-relevant sp are discouragedHuman 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 basisNOAEL (No observed Adverse effect Level)+ SFMABEL (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 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
(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 subjectsBased 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 medicinal products
Minimal requirements for non-clinical studies before first in human subjects:
4)-Toxicity studies. Duration, sp, dosing, route mimic clinical situationSingle tox studyRepeated-dose tox studyBiomarkers 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 medicinal products
Minimal requirements for non-clinical studies before first in human subjects:
5) Integration studies6) Germline transmission7) Target tissue selectivity8) Immunogenicity and immunotoxicity
(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 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.
Note for Guidance on the pre-clinical evaluation of anticancer medicinal products(CPMP/SWP/997/96)
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
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 pre-clinical 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 pre-clinical evaluation of anticancer medicinal products(CPMP/SWP/997/96)
Duration o support initial clinical trialsPhase I clinical trials continue according patient responsePhase III- up to 3 months duration
GRACIAS!