ECBS: Vaccines and Biotherapeutic products EMP Technical Briefing Seminar ECBS: Vaccines and Biotherapeutic products Dr Ivana Knezevic TSN/EMP/HIS WHO, Geneva, 5th November 2014

Outline Norms and standards for biologicals in the context of WHO Strategic drivers and issues WHO International Standards - written (eg, Guidelines, Recommendations) - measurement (Int. Standards and Reference Preparations) ECBS 2014 – main outcomes Biotherapeutic Products (BTP) Similar Biotherapeutic Products (Biosimilars) Collaborating Centers

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 one of WHO core functions.

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.

Key strategic drivers Global public health WHO context Universal health coverage Regulatory convergence Regulatory science WHO context WHO reform EMP reorganization ICDRA 2014 New WHA resolutions Scope of the ECBS

New Resolutions: BTP and RSS New Resolution on biotherapeutic product (BTP) Discussed at the 134th Executive Board meeting, Jan 2014: EB134.R19 Decision/adoption to be made: by 67th World Health Assembly in May 2014: WHA67.21 http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R21-en.pdf New Resolution on RSS (Regulatory System Strengthening) http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R20-en.pdf

16th ICDRA recommendations Feedback from ICDRA and pre-ICDRA meetings are two sources of additional information regarding the regulatory practices in WHO member states: 16th meeting of the International Conference of Drug Regulatory Authorities (ICDRA) – held in Rio de Janeiro, 26-29 August 2014, hosted by ANVISA ICDRA recommendations published at:  http://www.who.int/medicines/publications/druginformation/issues/DrugInformat ion2014_Vol28-3/en/ Selected topics of interest: Strengthening regulatory systems for medicinal products Biosimilars Advanced therapies Clinical trial regulation Pre-ICDRA meeting on biosimilars – held on 24-25 August 2014 Info doc

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

Development of measurement standards for Vaccines, 2013 - 2016 1. Tetanus toxoid for flocculation assay (3rd IS) 2. Anti-Toxoplasma Serum, Human (2nd IS) 3. Typhoid Vi Polysaccharide (1st IS) 1. Trivalent inactivated polio vaccine (TIPV) for D antigen assay (3rd IS) 2013 2014 2015 2016 ? 1. Human serum anti-malaria Plasmodium falciparum (1st RR) 2. Haemophilus influenzae b polyribosylribitol phosphate polysaccharide (2nd IS) 1. Japanese Encephalitis Vaccine (1st IS) 2. Bordetella pertussis Toxin (2nd IS) 3. Rabies vaccines (7th IS) 4. Meningococcal serogroup X polysaccharide (1st IS) 5. Antibody to A (H7N9 Influenza virus (1st IS)

Development of measurement standards for biotherapeutics, 2013 - 2016 1. Etanercept (1st IS) 2. Human antibodies to EPO (1st monoclonal antibody reference panel) 1. TNF alpha, recombinant, non-glycosylated (3rd IS) 2. PEG G-CSF (1st IS) 2013 2014 2015 2016 1. Luteinizing Hormone, human pituitary (3rd IS) 2. Human proinsulin (1st IS) 1. Rituximab (1st RR) 2. Batroxobin (1st RR) 3. Biosynthetic human insulin (1st IS)

Guidelines/ recommendations under development/ revision ECBS 2014 Recommendations for IPV vaccines Regulatory evaluation of post-approval changes Regulatory Risk Evaluation on Finding an Adventitious Agent in a Marketed Vaccine - Scientific Principles to Consider ECBS 2015 GMP for biologicals HPV Regulatory Risk Assessment of Biotherapeutic Products Regulatory expectations for CTC ECBS 2016 Guidelines on clinical evaluation of vaccines Guidelines on flu vaccines for non-producing countries

Timeline for WHO Written Standards: Vaccines 2013 2014 2015 2016 Typhoid NC of adjuvanted IPV Rev of TRS 926 Post-app. Changes RRA for AAs GMP HPV CTC Clinical Flu label – Pregnant Flu – non-producing Cell substrates Others STB LR DTP MAL LR Informal consultation ECBS submission Implementation workshop

Timeline for WHO Written Standards: Biotherapeutics 2014 2015 2016 2017 rDNA RERA for BTP SBP Informal consultation ECBS submission Implementation workshop

Timeline for Written Standards Projects with unclear timeline/ format Vaccines Influenza vaccines for pregnant and lactating women Safe production of IPV – revision of TRS 926 Meningitis B, Meningitis X Vector based vaccines RSV Hep E Biotherapeutic Products Amendment on Similar Biotherapeutic Products (SBP) - mab Cell therapies/ Advanced therapies

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

Implementation of standards – 2013-2016 General Topics Stability Evaluation of Vaccines – 2013 Evaluation of Cell Substrates - 2013 Vaccine Lot Release - 2015 Post approval changes of vaccines - 2015 Specific issues related to Vaccines or Biotherapeutic Products Selected vaccines with complex issues such as: Evaluation of combined vaccines based on DTP – Indonesia, May, 2014 Typhoid conjugate vaccine – China, November, 2014 Malaria vaccine – South Africa, November, 2014 HPV - 2016 Evaluation of Biotherapeutic Products - 2014 Evaluation of SBP - 2014

Implementation of standards – case studies Implementation workshops provide: Good learning opportunity for participants Among all materials, case studies were recognized as preferred format for illustrating application of WHO guiding principles Publications: Meeting report from implementation workshop on evaluation of combined vaccines based on DTP – available at http://www.who.int/biologicals/areas/vaccines/combined_vaccines/en/ Case studies from implementation workshops on cell substrates – as an example Adventitious agents in viral vaccines: Lessons learnt from 4 case studies (Biologicals 42 (2014) 223-236) E-learning tools – to be developed for BTP, SBP, vaccine stability, cell substrates, vaccine lot release in 2015-2016; other topics to be considered

Collaborating Centers Recent designations: NIFDC – Jan 2013 PEI – Aug 2013 Recent re-designations: NIBSC – July 2013 NIID – Aug 2014 TGA – Aug 2014 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

WHO Network of Collaborating Centers 1st meeting held in April 2012 – meeting report published in Biologicals 40 (2012), 499-506 2nd meeting of the CC network on vaccine standardization, March 2014 at PEI, Langen, Germany: main issues discussed: 1) current ToR of individual CCs, 2) criteria for success of the CC network, 3) key areas where the network should focus its efforts and 4) priorities for coming years good opportunity for CCs to understand current approach and needs of one global and several regional regulatory networks that WHO supports agreed that the CC network should focus on standards, both written and measurement, as well as their practical application to support WHO initiative in promoting science based regulation of vaccines worldwide all CCs confirmed commitment to help WHO to improve efficiency in responding to the needs of its member states. In particular, development of new vaccines was recognized as an area where the CC network can provide more valuable support than the individual CCs. Consensus reached that the CC network will focus on the following: Improve approaches to support implementation of WHO standards into regulatory practice Improve the efficiency of the global standards setting process, and Identify gaps in WHO standards and set regulatory science agenda to address gaps

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)