Basic nonclinical requirements for registration of new drugs'

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Basic non-clinical requirements for registration
of new drugs.
REGULACION DEL DESARROLLO Y EL REGISTRO DE
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 Ag
encia Española de Medicamentos y Productos
Sanitarios
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Development-Registration
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(No Transcript)
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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

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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

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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/eud
  ralex/vol3_en.htm

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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

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• 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/evaluac
  ión seguridad del medicamento

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• IMPD
• -GLP
• - Medicamento representativo cuali/cuantitativamen
  te en términos de impurezas

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• Community Guidelines (Vol 3 of Eudralex)
• http//ec.europa.eu/enterprise/pharmaceuticals/eud
  ralex/vol3_en.htm
• www.emea.eu.int

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• 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

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Normas de Buena Práctica ClínicaCPMP/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

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• Normas de Buena Práctica ClínicaCPMP/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

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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

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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

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Normas de Buena Práctica Clínica
CPMP/ICH/135/95Manual del investigador

• 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

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

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Normas de Buena Práctica Clínica
CPMP/ICH/135/95Manual del investigador

• c) Toxicología
• Dosis única
• Dosis repetidas
• Carcinogénesis
• Estudios especiales
• Toxicidad reproductiva
• Genotoxicidad

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

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

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

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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

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

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

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Non-clinical safety studies for the conduct of
human clinical trials and marketing authorisation
for pharmaceuticalsCPMP/ICH/286/95
Reproduction toxicity studies Conducted as is
appropriate for the population that is to be
exposed -Men Phase I/IIevaluation 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 studies
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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

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Non-clinical safety studies for the conduct of
human clinical trials and marketing authorisation
for pharmaceuticalsCPMP/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
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• Guideline on strategies to identify and mitigate
  risks for first-in-human clinical trials with
  investigational medicinal products
  (EMEA/CHMP/SWP/28367/07)

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(EMEA/CHMP/SWP/28367/07)

• Quality aspects
• Non-clinical aspects
• Clinical testing strategies and designs
• First-in-human clinical trials

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(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)

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(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

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(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.

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(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

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(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

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(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

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(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

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(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-re
  sponse curve

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(EMEA/CHMP/SWP/28367/07)

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

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(EMEA/CHMP/SWP/28367/07)

• Non-clinical aspects
• -Safety pharmacology standard core battery data
  available before into humans

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(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

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(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

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(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

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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.

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(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

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(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

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(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

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(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

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(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/tumorigenicity
  studies

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Note for Guidance on the pre-clinical evaluation
of anticancer medicinal products(CPMP/SWP/997/96)
-RevSafety PharmacologyStand-alone safety
pharmacology studies need not be conducted to
support studies in patients with advanced
cancer...

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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.

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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

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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

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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

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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

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GRACIAS!