Regulatory overview of biological products in Brazil

Transcription

1 Regulatory overview of biological products in Brazil Vanessa Lucas Xavier Office of Biological Products Brazilian Health Regulatory Agency ANVISA June, 2016

2 ANVISA S MISSION To protect and promote the public health and to intervene in the risks caused by the production and use of products subject to health surveillance, in coordination with the states, municipalities and the Federal District, according to the Brazilian Health System principles, in order to improve the quality of life of the population.

3 REGULATORY ACTS CONCERNING BIOLOGICAL PRODUCTS Labelling RDC 47/2009 RDC 60/2012 Package insert RDC 71/2009 RDC 61/2012 Import RDC 81/2008 Quality control RDC 234/2005 Good manufacturing practices RDC 17/2010 Law 6.360/1976 Decree 8.077/2013 Marketing Authorization RDC 55/2010 Post-approval changes RDC 49/2011 Stability studies RDC 50/2011 Allergens RDC 233/2005 Probiotics RDC 323/2003 Pre-meeting submission Ordinance 219/2015

4 BIOLOGICAL PRODUCTS According to RDC 55/2010: - Recombinant proteins; - Monoclonal antibodies; - Products derived from biological fluids; - Medicines containing live, attenuated or dead microorganisms; - Vaccines; - Antivenom immunoglobulins; - Blood products; - Probiotics; - Allergens.

5 BIOLOGICAL PRODUCTS RDC 55/2010: Classification of Biological Products: - New Biological Product: is the biological drug containing a molecule with known biological activity, not licensed in Brazil yet. Innovative biological products - Biological Product: is the biological drug that is not new, containing a molecule with known biological activity, already licensed in Brazil. Non-innovative biological products

6 GENERAL CONSIDERATIONS - Brazilian regulation for biological and biosimilar products is aligned with WHO recommendations; - To license any biological medicine in Brazil is essential to demonstrate quality, safety and efficacy.

7 BIOLOGICAL PRODUCTS PATHWAYS RDC 55/2010 New Biological Product Classical regulatory pathway Full registration dossier Quality, Safety and Efficacy

8 STAND ALONE APPROACH - It is necessary to present full data on the development, production, quality control and non-clinical and clinical trials. - Production and quality control data should meet the quality standards already established for the Innovative biological product.

9 STAND ALONE APPROACH - Phase I and II clinical trials are not necessarily comparative. - Phase III studies will be always necessary and must be comparative to the Innovative biological product. - The extrapolation of indications is not applicable for biological products licensed by the Stand Alone pathway.

10 COMPARABILITY DEVELOPMENT PATHWAY BIOSIMILAR APPROACH Comparator Biological Product: a biological product that must be licensed by Anvisa, based on submission of a full dossier and that has already been authorized to be on the Brazilian market (Reference Product)

11 COMPARABILITY DEVELOPMENT PATHWAY BIOSIMILAR APPROACH - The same comparator must be used in all stages of the comparability exercise. - Non-clinical and clinical data can be reduced. - Phase III study has to demonstrate similar efficacy and safety compared to the reference product.

12 COMPARABILITY DEVELOPMENT PATHWAY BIOSIMILAR APPROACH - Clinical comparability exercise Stepwise procedure PK and PD studies followed by pivotal clinical trials - Clinical efficacy studies are required The selection of a sensitive population and adequate endpoints is a critical consideration. Immunogenicity comparative study is necessary.

13 COMPARABILITY DEVELOPMENT PATHWAY BIOSIMILAR APPROACH - Phase III Design - Equivalence is recommended - Non-inferiority, if justified - Post authorization studies may be required (phase IV);

14 RDC 55/2010 COMPARABILITY DEVELOPMENT PATHWAY BIOSIMILAR APPROACH Head-to-head comparison Comparability exercise Quality Comparator product Biosimilar Physicochemical characterization Biological characterization Non-clinical Clinical Non-clinical PK/PD Clinical Full registration dossier Comparable Quality, Efficacy and Safety

15 GUIDELINE FOR COMPARABILITY EXERCISE ANVISA - The comparability exercise must always use the same Comparator biological product. - Primary structure of the biosimilar must be identical to the Comparator. - Full characterization: primary and higherorder structure, post-translational modifications, biological activity, purity and impurities, product related substances and immunochemical properties.

16 BIOSIMILAR PRODUCTS IN BRAZIL First Biological Product licensed by Comparability Development Pathway REFERENCE PRODUCT REMICADE (infliximab) BIOSIMILAR STATUS EXTRAPOLATION OF INDICATIONS REMSIMA (infliximab) APPROVED (April 2015) YES

17 BIOSIMILAR PRODUCTS IN BRAZIL Second Biological Product licensed by Comparability Development Pathway REFERENCE PRODUCT GRANULOKINE (filgrastim) BIOSIMILAR STATUS EXTRAPOLATION OF INDICATIONS FIPRIMA (filgrastim) APPROVED (October 2015) NO

18 BIOLOGICAL PRODUCTS PATHWAYS RDC 55/2010 Stand-Alone Approach Development by Comparability NON-INNOVATIVE BIOLOGICAL PRODUCTs BIOSIMILARS Only biological products licensed on the basis of a full comparability package involving quality, nonclinical and clinical data

19 BIOSIMILAR APPROACH EXTRAPOLATION OF THERAPEUTIC INDICATIONS - A sensitive test model has to be used, which has to be able to detect potential differences between the biosimilar and the comparator. - The mechanism of action and/or involved receptor(s) must be the same. - Safety and immunogenicity have to be sufficiently characterized.

20 INTERCHANGEABILITY - In Brazil, interchangeability is under discussion. - Currently, Anvisa only considers interchangeability after a review of the clinical data obtained for this purpose. - It is necessary to conduct specific clinical trials. - The demonstration of interchangeability is not mandatory for the license of the biosimilar product

21 SUMMARY OF REGULATORY REQUIREMENTS

22 REQUIREMENTS FOR POST-APPROVAL CHANGES RDC 49/2011 Provides requirements for post-approval changes submissions of biological products and other provisions Post-approval changes classified by risk Level 1 change (minor change) Level 2 change (moderate change) Level 3 change (major change)

23 REQUIREMENTS FOR POST-APPROVAL CHANGES LEVEL 1 CHANGES Immediate implementation Refer to changes that have no impact on product s quality Usually included in pharmacopoeia or do not imply the need for analysis of the molecular structure

24 REQUIREMENTS FOR POST-APPROVAL CHANGES LEVEL 2 CHANGES Require prior approval from ANVISA Refer to changes that may impact on product quality, safety or efficacy and to modifications of non-compendial methodologies May imply the need of molecular structure analysis Molecular analysis has to be sufficient to demonstrate that the change does not affect product quality

25 REQUIREMENTS FOR POST-APPROVAL CHANGES LEVEL 3 CHANGES Require prior approval from ANVISA Refer to changes that have great chances to impact the molecular structure and / or that leads to the need of conducting clinical trials: major complexity Usually implies the need to perform a new molecular characterization If analytical techniques indicate impact on the molecular structure or are insufficient to assess it: need for non-clinical and/or clinical trials

26 GUIDELINE FOR ELABORATION OF CLINICAL STUDY REPORTS - BIOLOGICAL PRODUCTS - Clinical Trials must be conducted with biological product submitted - Clinical Trials must be approved by NRA in which country clinical trial was carried on - Clinical Trials conducted in Brazil must have previous ANVISA approval.

27 REGULATORY GUIDELINES Guideline for Non-clinical and clinical studies - Heparin Development by Comparability

28 REGULATORY GUIDELINES Guideline for Non-clinical and clinical studies - Interferon Alpha Development by Comparability

29 REGULATORY GUIDELINES Guideline for transport qualification of biological products (draft) NEW!

30 VACCINES - 94 Vaccines authorized by Anvisa : 1 st Dengue Vaccine in Brazil Evaluation prioritized - around 165 days of analysis.

31 TRANSPARENCY Drug Approval Letters - Drug letters are available on Anvisa s website. - They indicate causes that lead a determined product to be approved or refused by Anvisa.

32 CHALLENGES - Interchangeability - Extrapolation of indications - International non-proprietary name or INN (BQ)

33 PERSPECTIVES - Review current guidelines - Publish new guidelines (etanercept and insulin) - Review current legal framework - Strengthen international cooperation

34 INTERNATIONAL COOPERATION - EMA, United States, Canada, Korea, China, Japan, Portugal, Cuba and Argentina - PAHO Pan American Health Organization - WHO World Health Organization

35 THANK YOU!!! phone: SIA Trecho 5 - Área especial 57 - Lote 200 CEP: Brasília - DF Telefone: Anvisa Atende: ouvidoria@anvisa.gov.br