Biosimilars in the EU General Regulatory aspects Non-clinical and clinical evaluation Dr. Gonzalo...
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Biosimilars in the EUBiosimilars in the EUGeneral Regulatory aspectsGeneral Regulatory aspects
Non-clinical and clinical Non-clinical and clinical evaluationevaluation
Dr. Gonzalo Calvo and Dr. Sol RuizCHMP members, European Medicines Agency (EMA)Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)
EVOLUTION OF MAN … in Europe
Director Ejecutivo
Dpt. Administración Comunicación
Dpt. Legal Dpt. Inspecciones y QC
Med Uso Humano
(Pre-Autorización)
Med Uso Humano
(Post-Autorización)
Med Uso Veterinario
CHMP
Coord
inaci
ón
Evalu
aci
ón
cien
tífica
PROCEDIMIENTOS DE REGISTRO EN LA UEPROCEDIMIENTOS DE REGISTRO EN LA UE
• CENTRALIZADO
• DESCENTRALIZADOS• Reconocimiento mutuo• Descentralizado
EL PROCEDIMIENTO CENTRALIZADO ES OBLIGATORIOEL PROCEDIMIENTO CENTRALIZADO ES OBLIGATORIO....
• Tecnología del ADNr
• Introducción de una etapa biotecnológica
• Terapia génica (incluye vectores)
• Terapia celular
• HIV
• Oncológicos
• Enfermedades neurodegenerativas
• Diabetes
• Enf autoinmunitarias
• Enf. virales
2005
2008
1995
Centralised Procedure
• Regulatory review Process
• 1 Marketing Authorisation valid EU
• 1 Invented name (Tradename)
• 1 Common Labelling (22 languages identical)
• Summary of Product Characteristics (SPC)
• User Package Leaflet & Package Labelling
• Maximum time limit• 210 days Evaluation ---> Opinion
• Chairman (Dr Eric Abadie) & Vice-Chairman (Tomas Salmonson)• 1 scientific expert member nominated by each MS and 1 alternate • 1 scientific expert member from NO and IS and 1 alternate (observers)• 5 co-opted members (ES, UK, NL, LU, DE)
CHMP
CENTRALISED PROCEDURE (new product)
1. “Pre-submission meeting”: Meeting at the EMEA to discuss procedural, regulatory or legal aspects of the submission.
2. A “Project Team Leader” (PTL) is appointed by the EMEA
3. Appointment of Rapporteur/Co-Rapporteur and their assessment teams: 7 months prior to the intended submission date (at the CHMP meeting)
4. Decision of the invented name
5. Submission of the dossier
6. Validation of the application
7. Start of the procedure. Timetable: 270 day
Day 121 – 210Day 121 – 210
CLOCKCLOCK STOPSTOP
Pre-Pre-submissionsubmission
PrimaryPrimary evaluationevaluation
Day 0 - 120Day 0 - 120
SecondarySecondary Opinion/ Opinion/ Decision Decision evaluation evaluation
Post Post authorisation authorisation
ActivitiesActivitiesLAUNCH
Centralised Procedure
EWP
SWP
SAWP BMWP
BPWP
BWP
CHMP
PhVWP
QWPVWP
GTWP
CTWP
Other WPs
Module 4
Non-clinical
Module 5
clinical
Module 3
Quality
Qua
lity
Ove
rall
sum
mar
y NC Overvie
wNC
Summary
Mod 1
ClinicalOverview
Clinical Summary
Module 2
C
T
D
Not part of CTD
eCTD package
Regional Info
Abridged application – generic(no data exclusivity)
Reference Product
Healthy Human
Volunteer trials
Bioequivalence Study
Abridged application – Biosimilar
(bio-generic) (No data exclusivity)
Reference Product
Non clinical studies
Clinical
studies
General aspects (1)
• Centralised procedure• Biosimilar: = phrmaceutical form, dosis and route of
administration• It is ot possible in principle to extrapolate between different
routes of administration• Reference product must be the same troughought the
dossier and be available in the EU
• Comparative “in vitro” e “in vivo” non-clinical studies• PK• PD• Immunogenicity• Toxicity
• Efficacy and safety data ensuring clinical comparability• Imunogenicity• Risk Management Plan
General aspects (2)
Overarching Guideline (CHMP/437/04).“Guideline on Similar Biological Medicinal Products”
Biotechnology- derived proteins
IFN-Epoetin LMMH
Quality
Non-clinical
Clinical
Non-clinical
Clinical
Non-clinical
Clinical
Product class specific data requirements
Biosimilar References
GCSF
Non-clinical
Clinical
Non-clinical
Clinical
Non-clinical
Clinical
Somatropin
General guidelines
Quality / Safety Efficacy
Defines principles
Non-clinical
Clinical
Insulin
In principle, the concept of “similar biological medicinal products” applies to any biological medicine. Guideline CPMP/BWP/437/04
Epoetin LMWH
Non-clinical
Clinical
IFN-A
Non-clinical
Clinical
GCSF
Non-clinical
Clinical
Non-clinical
Clinical
Non-clinical
Clinical
Somatropin
Non-clinical
Clinical
Insulin
mAbs More complex
Feasible?
Possible?
B-IFN
Risk
Benefit
– –
– +
RISK MANAGEMENT
Sistema de Farmacovigilancia y Plan de Gestión de Riesgos
• Riesgos identificados• Riesgos potenciales
• De clase• Individuales
• Programa para• Detectar• Cuantificar• Minimizar• Evaluar el impacto de las medidas
• Efectos de clase• Immunogenicidad
• Notificación espontánea• Estudios epidemiológicos• Registros
• TRAZABILIDAD!
Factors potnetially influencing the immunogenicity of a particular product
Structure
Nature of the protein
Glycosilation
Other factors
Assay metods
Impurities
Formulation
Route of adminitration
Dose and treatment duration
Patients characteristics
Concomitant treatments
???
Consequences
Loss of efficacy
Neutralisation of native proteins
General immunological effects
In summary …
• The legal framework in the EU is relatively clear• The concept of essential similarity and interchangeability is not
applicable, today, in most EU conuntries• In general. Therapeutic equivalence in at least the most
sensitive indication is the rule• Clinical immunogenicity data must be provided pre-marketing• A RMP should be provided as for an innovator product• Challenging future!
Biosimilar thinking has evolved
How much „similarity“ do we need?
How much do we need to know?
Idea: C. Nick
ww
w.lu
cky-
lions
.com
Thank goodness!
I got it!
El sentido común es, posiblemente, el elemento más importante a la hora de evaluar y utilizar herramients terapéuticas.