1. Ivana Knezevic | 1 |1 | VII PANDRH Conference Implementation of WHO standards for regulatory evaluation of similar biotherapeutic products SBPs Ottawa, 6 th September 2013 Dr Ivana Knezevic, WHO/HIS/EMP

2. Ivana Knezevic | 2 |2 | Outline WHO International Standards - written (eg, Guidelines, Recommendations) - measurement (Int. Standards and Reference Preparations) Similar Biotherapeutic Products – Implementation workshops – Clinical evaluation of SBPs Biotherapeutic Products (BTP) – Guidelines on BTP made by rDNA technology – ECBS 2013 – Regulatory Risk Assessment of Biotherapeutic Products

3. Ivana Knezevic | 3 |3 | World Health Organization (WHO) WHO is a specialised agency of the UN serving as the directing and coordinating authority for international health matters and public health on behalf of its 194 Member States. Principle objective - the attainment by all people of the highest possible level of health. WHO is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries and monitoring and assessing health trends. Setting norms and standards and promoting their implementation is affirmed as a core function of WHO for the period 2008-2013.

4. Ivana Knezevic | 4 |4 | WHO Biological Standardization WHO has played a key role for over 60 years in establishing the WHO Biological Reference Materials necessary to standardize biological materials as well as developing WHO guidelines and recommendations to assure the quality, safety, and efficacy of biological products. These norms and standards, based on scientific consensus achieved through international consultations, assist WHO Member States in ensuring the quality and safety of biological medicines and related in vitro biological diagnostic tests worldwide. The Organization accomplishes this biological standardization work through – its biological programme coordinated by a Secretariat at WHO HQ; – the WHO Expert Committee on Biological Standardization (ECBS) selected from an Expert Advisory Panel on Biological Standardization; and – WHO Collaborating Centres for Biological Standardization.

5. Ivana Knezevic | 5 |5 | WHO norms and standards for biologicals Global written standards Global measurement standards standards Scientific evidence Measurement standards: essential elements for development, licensing and lot release 1)Standardization of assays 2)Further development and refinement of QC tests 3) Scientific basis for setting specifications Reference preparations for vaccines and biotherapeutics www.who.int/biologicals

6. Ivana Knezevic 6 |6 | Available WHO International Standards or Reference Reagents used for potency assessment of Biosimilars The list is available on the following links: 1)WHO web http://www.who.int/bloodproducts/catalogue/CytoFeb2013.pdf 2) NIBSC web http://www.nibsc.ac.uk/products/biological_reference_materials/product_c atalogue.aspx Recently published review article by Thorpe R, Wadhwa M, Biologicals 2011. http://www.sciencedirect.com/science/article/pii/S1045105611000704

7. Ivana Knezevic | 7 |7 | 2008 2009 2010 2011 Development of measurement standards for biotherapeutics, 2008 - 2012 2012 1. Urinary follicle stimulating hormone and urinary luteinizing hormone (5 th IS) 2. Erythropoetin, recombinant for bioassay (3rd IS) 3. High molecular weight urokinase (2nd IS) 4. IL 29 (1st RR) 5. IL 2 (2nd IS) 1. Thyroid stimulating antibody (2 nd IS) 2. Follicle stimulating hormone (2 nd IS) 3. Sex hormone binding globulin (2 nd IS) 4. G-CSF (2 nd IS) 1. Chorionic gonadotrophin (5 th IS) 2. Parathyroid hormone, 1-84 (1st IS) 1. Insulin-like growth factor (2 nd IS) 1. Dihydrostreptomycin (3 rd IS) 2. TGF beta-3 (1st IS)

8. Ivana Knezevic | 8 |8 | WHO Guidelines on SBPs and other publications 1. The final version of the Guidelines on evaluation of similar biotherapeutic products (SBPs) is available on WHO Biologicals website (http://www.who.int/biologicals/en/) since April 2010.http://www.who.int/biologicals/en/ The document was adopted by the 60th meeting of the WHO Expert Committee on Biological Standardization, in October 2009. 2. Web pages related to biotherapeutics: http://www.who.int/biologicals/vaccines/biotherapeutic- products/en/index.html http://www.who.int/biologicals/vaccines/biotherapeutic- products/en/index.html 3. Link to special issue in Biologicals (2011), 39 devoted to SBPs: 25 articles with WHO experience in working with regulators worldwide: http://www.sciencedirect.com/science/journal/10451056/39/5 http://www.sciencedirect.com/science/journal/10451056/39/5

10. Ivana Knezevic | 10 | WHO Guidelines on SBPs – implementation workshop in Bogota, 21-23 March 2012 1) 16 Latin American countries represented: ARG; BOL; BRA; CAN; COL; CHI; COR; CUB; DOR; ECU; ELS; HON; MEX; PAN; PER; VEN 2) PANDRH BIO WG was well represented 3) Facilitators and speakers from Health Canada and WHO 4) Issues discussed: - Concept of the Guidelines, Scope and key definitions, key principles for licensing SBPs, Reference Biotherapeutic Product (RBP) - Q, NC and clinical evaluation of SBPs - Country reports - results of the survey conducted in 2012

11. Ivana Knezevic | 11 | Further information and contact Biological standardization website: www.who.int/biologicals Immunization website: www.who.int/immunization Contact details: Dr Ivana Knezevic (email: knezevici@who.int)knezevici@who.int

12. Ivana Knezevic | 12 | Key principles for the licensing of SBPs SBPs are not generic medicines and many characteristics associated with the authorization process and marketed use of generic medicines generally do not apply. Effective regulatory oversight: critical for assuring Q, S, E of SBPs Stepwise approach -Demonstration of similarity of SBP to RBP in terms of quality is a prerequisite for the reduction of the non-clinical and clinical data set required for licensure. -If major differences are found in the quality, non-clinical and clinical studies, the product should not be considered as "similar" and, therefore, other options for its further development and licensing (eg, stand alone) should be considered. Important to note that biotherapeutics which are not shown to be similar to a RBP should not be described as "similar", nor called a "SBP".

13. Ivana Knezevic | 13 | Licensure requirements– amount of data and applicability Full dossier (Stand alone approach) Similar Biotherapeutic Products (SBPs) Applicable to all biologicals Existing knowledge, full, comparative characterization, plus Comparative BUT reduced non-clinical, clinical data Applicable to well characterized biologicals only Generic For chemical entities only Not applicable to biologicals

14. Ivana Knezevic | 14 | Reference Biotherapeutic Product (RBP) RBPs should have been marketed for a suitable duration and have a volume of marketed use RBPs should be licensed based on a full Q, S and E data set The same RBP used throughout the development of the SBP An SBP should not be considered as a choice for RBP The active substance of the RBP and the SBP must be shown to be similar The dosage form and route of administration of the SBP should be the same as that of the RBP NRAs may need to consider establishing additional criteria to guide the acceptability of using a RBP licensed or resourced in other countries

15. Ivana Knezevic | 15 | ICDRA Recommendations 2010 (to countries) NRAs (Member States) should Regulate biosimilars as biologicals. Therefore, a generic medicines ("biogeneric") regulatory approach is not appropriate and should not be used. Implement WHO Guidelines as a whole. This means that only products licensed on the basis of the full comparability study (Q, NC, C) should be considered, and named as SBPs (biosimilars). Strengthen clinical and statistical expertise to improve evaluation of the data submitted by the manufacturers for licensing. Additional efforts are needed to address specific issues related to pharmacovigilance of biosimilars.

16. Ivana Knezevic | 16 | ICDRA Recommendations 2010 (to WHO) WHO should Consider developing guidelines on risk management strategies for copy products already licensed as "biogeneric". Develop a template for Member States to share information on the scientific basis for licensing biosimilars. Supplement its guidance on evaluation of similar biotherapeutic products by providing up-to-date Guidelines for evaluation of biotherapeutic products in general. Conduct a review of existing international reference preparations for assay of biotherapeuctics. Identify gaps and take action to fill the gap.

17. Ivana Knezevic | 17 | Clinical evaluation of SBPs – key points for regulators Clinical data should be meaningful for the product in question and intended use Methodology of clinical trials is very important and all aspects of the design, conduct, statistical analysis and interpretation of results should be carefully considered. Collaboration between clinical reviewers and statisticians in reviewing the various aspects of clinical trials is strongly encouraged. Designed to demonstrate comparable safety and efficacy of SBP to RBP and, therefore, need to employ testing strategies that are sensitive enough to detect relevant differences between the products. – A trial that lacks assay sensitivity cannot detect differences between products that may exist, and could lead to an erroneous conclusion of equivalence or non-inferiority. Assay sensitivity is established based on historical data with the RBP(evaluated before the trial begins at the trial design stage), and the conduct of the current trial (evaluated after the trial is completed).

18. Ivana Knezevic | 18 | Clinical evaluation of SBPs – guiding principles Clinical comparability exercise: stepwise procedure; PK and PD studies followed by the pivotal clinical trials Efficacy studies – No dose-finding studies – Demonstrate in adequately powered, randomized, and parallel group clinical trial (ICH E9 and E10) – Equivalence or non-inferiority studies may be acceptable for the comparison of efficacy and safety of the SBP with the RBP; equivalence/non-inferiority margins have to be pre-specified and justified taking into account historical data with the RBP, and relevant clinical and statistical considerations.

19. Ivana Knezevic | 19 | Safety – Usually, safety data obtained from the efficacy trials will suffice – Comparison with the RBP should include type, frequency and severity of AEs Extrapolation – Prerequisites: – Similarity shown in a sensitive model preferably based on an equivalence trial. – Mechanism of action/receptor the same – Safety and immunogenicity sufficiently characterized in the evaluated population Clinical evaluation of SBPs

20. Ivana Knezevic | 20 | Clinical evaluation – validation of data Validation of data is one of the critical steps which is sometimes forgotten. Overall, it is an important step in determining the validity of the conclusions that are made from a clinical trial, and includes a careful assessment of the following: a) the completeness and accuracy with which data were collected; b) any potential biases that could have arisen during trial conduct and data analysis; c) the extent and impact of protocol violations; d) the extent, timing and patterns of missing data and early withdrawals from the trial; e) the suitability of the primary method for handling missing data and early withdrawals, including the suitability of any sensitivity analyses performed to assess the robustness of the study results; Collaboration with a statistician is important in validating the data from a clinical trial.  Decision making process for clinical regulatory reviewers includes all the above and many other important issues.

21. Ivana Knezevic | 21 | Challenges 1. Regulatory framework for biotherapeutics: diversity of approaches 1.Most of the biotherapeutics in developing countries belong to the category of known biological entity that have been licensed through the stand alone pathway with reduced data package rather than through SBP pathway. 2.Some countries have regulatory pathway for "non-innovative biotherapeutic products" but requirements are not always clear. 2. Lack of expertise and capacity for evaluation of biotherapeutics at NRA 3. Comparability studies with RBP: concept not well understood and used in developing countries 5. PhV system in many countries: needs to be developed/ improved 6. Additional responsibilities of NRAs and other national authorities: 1.IP issues 2.Interchangeability and substitutability 3.Labelling and prescribing information

22. Ivana Knezevic | 22 | Call for comments on WHO Guidelines for Biotherapeutic products

23. Ivana Knezevic | 23 | Regulatory Risk Assessment (RRA) for biotherapeutic products licensed with insufficient/ inappropriate data -Draft Guidelines in preparation, public consultation planned for Q4 2013 -NRAs need to consider a risk based approach in dealing with BTP already on the market but known to have been licensed with insufficient/ inappropriate data -Issues to be considered in deciding appropriate regulatory actions: -Nature of products, potential alternatives, importance of products for treating diseases and consequences of treating or non-treating, seriousness of a potential lack of efficacy, as well as possible safety issues and ability of the PhV system in the country to monitor and determine problems associated with these products etc. -regulatory evaluation by experienced NRA for biologicals, BTP in particular -compliance to WHO recommendations for BTP - One of the options is to leave such products on the market for a specified period, such as four years, during which time manufacturers would be required to submit appropriate quality, nonclinical, and clinical data, and risk management plan for regulatory evaluation to support the continuation of the license. - Example of Thai FDA regulatory actions: re-evaluation of all licensed EPO is ongoing, starting with an update of Quality part and Risk Management Plan. Additional clinical trials may be needed. It may happen that none of EPO products will be SBP. Supply shortage may be an issue.

24. Ivana Knezevic | 24 | Points for discussion – Collaboration with regional networks of regulators Input into the development of WHO standards: –e.g., call for comments/ feedback on Guidelines on BTP made by rDNA technology – by 20 th Sep 2013 Options for facilitating implementation of WHO standards into regulatory and manufacturers' practices e.g., implementation workshops on selected topics such as clinical evaluation of BTP (2014)

25. Ivana Knezevic | 25 | Further information and contact Biological standardization website: www.who.int/biologicals Immunization website: www.who.int/immunization Contact details: Dr Ivana Knezevic (email: knezevici@who.int)knezevici@who.int