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.