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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
(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
Discovery
Target
Studies of
Disease Mechanisms
-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,II, III
Drug Approval
and Registration
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/pharmaceutic
als/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/pharmac
euticals/eudralex/vol3_en.htm
www.emea.eu.int
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 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
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
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 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
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 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)
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 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 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 pharmaceuticals
CPMP/ICH/286/95
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
•
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 pharmaceuticals
CPMP/ICH/286/95
Genotoxicity studiesSingle 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 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 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 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 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
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)
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 target
3) 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 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 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 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 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)-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
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
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
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
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
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 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
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 (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 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 support initial clinical
trials
Phase I clinical trials continue
according patient response
Phase III- up to 3 months duration
GRACIAS!