ECBS: Vaccines and Biotherapeutic products

Dr Ivana Knezevic TSN/EMP/HIS

WHO, Geneva, 5th November 2014

EMP Technical Briefing Seminar

EMP Technical Briefing Seminar

Ivana Knezevic | 2 |

Outline 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

Ivana Knezevic | 3 |

World Health Organization (WHO) 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.

Ivana Knezevic | 4 |

WHO Biological StandardizationWHO 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.

Ivana Knezevic | 5 |

Key strategic driversKey strategic drivers

WHO context

WHO reform

EMP reorganization

ICDRA 2014

New WHA resolutions

Scope of the ECBS

Global public health

Universal health coverage

Regulatory convergence

Regulatory science

Ivana Knezevic | 6 |

New Resolutions: BTP and RSSNew 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

Ivana Knezevic

16th ICDRA recommendations16th 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/DrugInformation2014_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

Ivana Knezevic | 8 |

WHO norms and standards for biologicals

WHO norms and standards for biologicals

Global written standards

Global measurement standards

Scientific evidence

Measurementstandards: essential elements for development, licensing and lot release

1) Standardization of assays2) Further development and refinement of QC tests3) Scientific basis for settingspecifications

Reference preparations for vaccines and biotherapeuticswww.who.int/

biologicals

Ivana Knezevic

2013 2014 2015

Development of measurement standards for Vaccines, 2013 - 2016

Development of measurement standards for Vaccines, 2013 - 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)

1 .Tetanus toxoid for flocculation assay (3rd IS)

2 .Anti-Toxoplasma Serum, Human (2nd IS)

3 .Typhoid Vi Polysaccharide (1st IS)

2016

1 .Trivalent inactivated polio vaccine (TIPV) for D antigen assay (3rd IS)

?

Ivana Knezevic

2013 2014 2015

Development of measurement standards for biotherapeutics, 2013

- 2016

Development of measurement standards for biotherapeutics, 2013

- 2016

1 .Luteinizing Hormone, human pituitary (3rd IS)

2 .Human proinsulin (1st IS)

1 .Etanercept (1st IS)2 .Human antibodies to EPO (1st

monoclonal antibody reference panel)

1 .Rituximab (1st RR)2 .Batroxobin (1st RR) 3 .Biosynthetic human

insulin (1st IS)

2016

1 .TNF alpha, recombinant, non-glycosylated (3rd IS)

2 .PEG G-CSF (1st IS)

Ivana Knezevic

Guidelines/ recommendations under development/ revision

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

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

Informal consultation

ECBS submission

Implementation workshop

Timeline for WHO Written Standards:Vaccines

MALDTPLRSTB LR

Ivana Knezevic

2014 2015 2016 2017

rDNA

RERA for BTP

SBP

Informal consultation

ECBS submission

Implementation workshop

Timeline for WHO Written Standards:

Biotherapeutics

Ivana Knezevic

Timeline for Written StandardsProjects with unclear timeline/ format

Timeline for Written StandardsProjects 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

Ivana Knezevic

Implementation of standards - toolsImplementation 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

Ivana Knezevic

Implementation of standards – 2013-2016

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

Ivana Knezevic

Implementation of standards – case studies

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 athttp://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

Ivana Knezevic

Collaborating Centers 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

Ivana Knezevic

WHO Network of Collaborating Centers 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

Ivana Knezevic

Further information and contactFurther 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)