General Regulatory aspects Non-clinical and clinical evaluation Biosimilars in the EU General Regulatory aspects Non-clinical and clinical evaluation Dr. Gonzalo Calvo and Dr. Sol Ruiz CHMP members, European Medicines Agency (EMA) Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)

EVOLUTION OF MAN … in Europe

Well, that's the EU, in green the 15 courtiers forming the EU until 18 days ago. In Yellow the 10 countries joining the EU since one month ago. And Norway and Iceland, that although not officially member states of the EU actively participate in the drug regulatory process. That's seems nice, one country, the EU, one Drug Agency, the EMEA. Full stop But ...

Well, that's the EU, in green the 15 courtiers forming the EU until 18 days ago. In Yellow the 10 countries joining the EU since one month ago. And Norway and Iceland, that although not officially member states of the EU actively participate in the drug regulatory process. That's seems nice, one country, the EU, one Drug Agency, the EMEA. Full stop But ...

Evaluación científica Director Ejecutivo Dpt. Administración Comunicación Dpt. Legal Dpt. Inspecciones y QC Coordinación Med Uso Humano (Pre-Autorización) Med Uso Humano (Post-Autorización) Med Uso Veterinario CHMP Evaluación científica

PROCEDIMIENTOS DE REGISTRO EN LA UE CENTRALIZADO DESCENTRALIZADOS Reconocimiento mutuo Descentralizado

EL 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 1995 2005 2008

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

CHMP Chairman (Dr Eric Abadie) & Vice-Chairman (Tomas Salmonson)                                                                                                                                                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)

CENTRALISED PROCEDURE (new product) “Pre-submission meeting”: Meeting at the EMEA to discuss procedural, regulatory or legal aspects of the submission. A “Project Team Leader” (PTL) is appointed by the EMEA Appointment of Rapporteur/Co-Rapporteur and their assessment teams: 7 months prior to the intended submission date (at the CHMP meeting) Decision of the invented name Submission of the dossier Validation of the application Start of the procedure. Timetable: 270 day

Centralised Procedure Day 0 - 120 CLOCK STOP Pre-submission Primary evaluation Day 121 – 210 Secondary Opinion/ Decision evaluation Post authorisation Activities LAUNCH

Well, that's the EU, in green the 15 courtiers forming the EU until 18 days ago. In Yellow the 10 countries joining the EU since one month ago. And Norway and Iceland, that although not officially member states of the EU actively participate in the drug regulatory process. That's seems nice, one country, the EU, one Drug Agency, the EMEA. Full stop But ...

Well, that's the EU, in green the 15 courtiers forming the EU until 18 days ago. In Yellow the 10 countries joining the EU since one month ago. And Norway and Iceland, that although not officially member states of the EU actively participate in the drug regulatory process. That's seems nice, one country, the EU, one Drug Agency, the EMEA. Full stop But ...

PhVWP GTWP BWP CTWP SWP CHMP SAWP BMWP BPWP EWP VWP QWP Other WPs

eCTD package Not part of CTD C T D Module Module 3 Module 5 4 Quality Regional Info Module 2 NC Overview NC Summary Clinical Overview Summary Overall summary Quality C T D Module 3 Quality Module 4 Non-clinical Module 5 clinical

Abridged application – generic (no data exclusivity) Healthy Human Volunteer trials Reference Product Bioequivalence Study

Abridged application – Biosimilar (bio-generic) (No data exclusivity) Non clinical studies Clinical studies Reference Product

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

General aspects (2) Comparative “in vitro” e “in vivo” non-clinical studies PK PD Immunogenicity Toxicity Efficacy and safety data ensuring clinical comparability Imunogenicity Risk Management Plan

Biosimilar References Overarching Guideline (CHMP/437/04). “Guideline on Similar Biological Medicinal Products” Defines principles Biotechnology- derived proteins Quality General guidelines Quality / Safety Efficacy Non-clinical Clinical Guideline on general principles: Clinical equivalence, Safety studies, Immunogenicity, (Pharmacovigilance) Annexes provide specific (non)clinical data requirements Insulin Somatropin GCSF Epoetin IFN- LMMH Product class specific data requirements Non-clinical Non-clinical Non-clinical Non-clinical Non-clinical Non-clinical Clinical Clinical Clinical Clinical Clinical Clinical

In principle, the concept of “similar biological medicinal products” applies to any biological medicine. Guideline CPMP/BWP/437/04 Insulin Somatropin GCSF Epoetin IFN-A Non-clinical Clinical LMWH Non-clinical Non-clinical Non-clinical Non-clinical Non-clinical Clinical Clinical Clinical Clinical Clinical B-IFN mAbs More complex Feasible? Possible?

Risk – – RISK MANAGEMENT + Benefit

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? www.lucky-lions.com Idea: C. Nick

Thank goodness! I got it! El sentido común es, posiblemente, el elemento más importante a la hora de evaluar y utilizar herramients terapéuticas.