1. ECBS: Vaccines and Biotherapeutic products Dr Ivana Knezevic TSN/EMP/HIS WHO, Geneva, 31 st October 2013 EMP Technical Briefing Seminar EMP Technical Briefing Seminar

2. Ivana Knezevic | 2 |2 | Outline WHO International Standards - written (eg, Guidelines, Recommendations) - measurement (Int. Standards and Reference Preparations) ECBS 2013 – main outcomes Biotherapeutic Products (BTP) Similar Biotherapeutic Products (Biosimilars) Collaborating Centers Strategic issues

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 Guidelines/ recommendations under development/ revision ECBS 2013 – main outcomes – Biotherapeutic Products made by rDNA technology - ADOPTED – Typhoid conjugate - ADOPTED – Nonclinical evaluation of adjuvanted vaccines - ADOPTED Plan for ECBS 2014 – IPV – Regulatory evaluation of post-approval changes – Regulatory Risk Assessment in the case of Adventitious Agents in already licensed vaccines – "Scientific Considerations" rather than Guidelines Plan for ECBS 2015 – GMP for biologicals – HPV – Regulatory Risk Assessment of Biotherapeutic Products – Regulatory expectations for Controlled Temperature Chain

7. Informal consultation ECBS submission Implementation workshop Timeline for WHO Written Standards

8. Ivana Knezevic Timeline for Written Standards Projects with unclear timeline Meningitis B Flu vaccines for regulators in non-producing countries Vector based vaccines Update of guidelines on clinical evaluation of vaccines Product Specific Guidelines on Similar Biotherapeutic Products (SBP)

9. Ivana Knezevic | 9 |9 | 2013 2008 20092010 2011 Development of measurement standards for biotherapeutics, 2008 - 2013 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) 1.TNF alpha (3rd IS) 2.Peg G-CSF (1st IS)

10. Ivana Knezevic Biotherapeutic Products (BTP) including Similar Biotherapeutic Products (SBP) WHO survey on regulation of BTP and SBP: to understand situation in various regions/countries: – Diversity of national regulatory requirements in the region – Obstacles in developing and regulating BTP – Required clinical data for already licensed products – Definitions used for "originator" product and "copy product" in the case of SBP Following networks have been involved: – PANDRH, AVAREF – APEC, ASEAN – Russian speaking countries A possibility for survey for Industry Common objectives of all networks: 1) expertise and capacity building 2) regulatory convergence and 3) efficient sharing of information and knowledge Expertise/ experience for evaluation of BTP is essential - need for technical assistance

12. Ivana Knezevic Similar Biotherapeutic Products (SBP) 3 rd implementation workshop on SBP: 14-16 May 2014 in Korea: – Focus on clinical evaluation of SBP – Special considerations for evaluation of mabs – Case studies on selected topics Regulators from APEC and ASEAN expressed interest for joint workshop on BTP and SBP Follow up actions with PAHO in addressing the need for assistance to PANDRH Regulatory risk assessment of products licensed without clinical data: case studies from countries (eg, Thailand, Brazil) and maybe Guidelines Main theme of pre-ICDRA meeting in 2014: Biosimilars

13. Ivana Knezevic Implementation of standards - concept Following adoption of WHO Guidelines or Recommendations, a need for facilitating implementation of guiding principles into regulatory and manufacturing practice is addressed: – Usually, the issues that are complex and/ or difficult for regulators to implement, are identified during the consultation process – Drafting Group is presenting a proposal for facilitating implementation to the ECBS or the Committee identifies a need for helping regulators General Topics – Stability Evaluation of Vaccines, Vaccine Lot Release, Evaluation of Cell Substrates – Evaluation of Biotherapeutic Products, including SBP Specific issues related to Vaccines or Biotherapeutic Products – Selected vaccines with complex issues such as: potency testing of rota vaccine, HPV evaluation of combined vaccines based on DTP, typhoid conjugate, IPV BTP: mabs, EPO, SBP: Reference Product, comparability studies, quality parameters, extrapolation of indication

15. Ivana Knezevic Implementation of standards - tools Implementation workshops: – Lectures on selected topics – Case studies – Work in groups of 6-8 participants where regulators and manufacturers discuss application of guiding principles to specific examples – Facilitators help clarifying the points needed for discussion and each group comes up with a conclusion and key arguments that support their opinion – In some cases, there is no consensus but options for proceeding further – Good learning opportunity but limited to certain number of workshop participants (eg. 30-40 participants) Publications – meeting reports, case studies from implementation workshops – Special issue in Biologicals – Vaccine Stability and Similar Biotherapeutic Products E-learning tools, Webinars

18. Ivana Knezevic Collaborating Centers Recent designations: – NIFDC – Jan 2013 – PEI – Aug 2013 Recent re-designation: – NIBSC – July 2013 Current status: 8 CCs for standardization and evaluation of vaccines Additional expertise and broader experience available in CCs which has increased capacity for responding to expectations of the users of standards Concept of global CC with technical support to various regional and inter- country networks of regulators Information on WHO web site for biologicals – revision of the page for CCs to provide regular update on the activities of CCs

20. Ivana Knezevic Strategic issues – Regulatory Science as a basis for Regulation of Biologicals – Role of WHO standards in facilitating regulatory convergence Provision of the most needed standards on time Right balance between general principles and examples – unique role of WHO Science based regulation, consensus on critical aspects – Making standards available is important but not enough. In addition: Regular communication with the users of WHO standards Input from regulators, manufacturers and academia in developing and implementing WHO standards Involvement of WHO Collaborating Centers Collaboration with other standard setting bodies -Evolving concept Great expectations in terms of broadening the scope to include cell therapy, gene therapy but limited resources

21. Ivana Knezevic | 21 | Key strategic drivers WHO context WHO reform EMP reorganization ICDRA 2014 Global public health Universal health coverage Regulatory convergence Regulatory science

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