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TRANSCRIPT
WHO Technical Briefing Seminar
07 November 2019
WHO Regulatory Activities
Regulation of Medicines and other Health Technologies
Emer Cooke
Director, Regulation and Prequalification
Strategic Priorities
13th General Programme of Work 2019-2023
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WHO TransformationMajor reorganization of WHO to deliver the mission and strategic priorities of the 13th General Programme of Work
Mission
•Promote Health•Keep the World Safe•Serve the Vulnerable
Access to Medicines and Health Products
Health Products Policy
and Standards
Regulatory and
Prequalification
• Assistive technologies
• Blood Products
• Expert Committees
• INN
• Medical devices
• Pricing policy
• Regulatory Systems Strengthening
• Safety and vigilance related activities
• Prequalification
• Local production
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72nd World Health Assembly: some highlights
• Approval of “Access Roadmap for Access to Medicines, Vaccines and
other Health Technologies, 2019-2023”
• Resolution on Transparency “Improving the transparency of markets
for medicines, vaccines, and other health products”
• Launch of Interagency statement on “Promoting Local production of
Medicines and other Health Technologies”
• Launch of a Strategy for Prevention and Control of Snakebite
Envenoming
72nd WHA: Access Roadmap
• Aims to assist in achieving the Sustainable Development Goals by ensuring “availability, accessibility, acceptability and affordability” of health products of assured quality
• Based on existing WHO mandates in key Health Assembly resolutions of the last 10 years related to access to safe, effective and quality medicines, vaccines and health products
• outlines the programming of WHO’s work on access to medicines and vaccines for the period 2019–2023, including activities, actions and deliverable
Improving equitable access
• R&D that meets public health needs and improves access to health products• Application and management of IP to contribute to innovation and promote
public health• Evidence-based selection and fair and affordable pricing• Procurement and supply chain management• Appropriate prescribing, dispensing and rational use
Ensuring quality, safety and efficacy of health products
• Regulatory systems strengthening• Assessment of the quality, safety and efficacy of health products through
prequalification• Market surveillance of quality, safety and performance
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WHO 5-year action plan to improve the quality and safety of health products
https://www.who.int/medicines/news/2019/strong-reg-systems-to-reach-UHC/en/
Four strategic priorities aligned with WHO’s 13th
General Programme of Work
1) Strengthen country and regional systems in line with the drive toward UHC
2) Increase regulatory preparedness for public health emergencies
3) Strengthen and expand WHO prequalification and product risk assessment processes
4) Increase the impact of WHO’s Regulatory Supportive activities - efficiency, advocacy, knowledge sharing, joint planning
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Launch of Interagency Statement:Promoting Local production of Medicines and other Health Technologies
Evolving Science and Regulatory Challenges
1 3
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• Facilitating Access to safe, effective and quality assured innovative medical products
• Impact of globalization (outsourcing of clinical trials, manufacturing, product assembly and packaging)
• Increasingly complex technologies without clear regulatory approaches
• Transparency and Growing public expectations
• Lack of global regulatory resources (regulatory capacity – both scientific and administrative)
Impact of substandard/falsified productsNovember 2017 Literature review of 10 years of publications
** London School of Hygiene and Tropical Medicine
Estimations Impact models
Observed failure rate on medicines samples in low and middle income countries
US$ 30.5 billion
Estimated spending on SF medicines in LMIC, based on wholesale level sales
Caused by SF antibiotics in children under 5 suffering from pneumonia*
31,000 -116,000 deaths
US$ 38.5 Million
Caused by SF antimalarials in sub-Saharan Africa**
estimated spending on SF antimalarials in sub-Saharan Africa**
10.5% 72,430 - 169,271 DEATHS
* University of Edinburgh 8
More on this topic this afternoon
Current Status of Regulatory Systems WHO Global Benchmarking (for medicines and vaccines: as of October 2019)
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Advanced/referenceRegulatory Authorities
Can ensure the quality of products if rely on ML3 / ML4 regulatory systems
Target of WHA Resolution 67.2
100COUNTRIES
44COUNTRIES
50COUNTRIES 9
No formal approach
Reactive approach Stable formal system approach
Continual improvement emphasized
1 2 3 4
ISO
90
04
Regulatory system operating at advanced level of
performance and continuous improvement
Evolving national regulatory system
that partially performs essential regulatory functions
Stable, well-functioning and integrated regulatory system
Some elements of regulatory system exist
WH
O G
BT
More on this topic later
WHO Regulatory Activities: Focus on Access and Outcomes
• Increase knowledge of real life adverse events and coordinate actions taken against adverse events
• Mitigate risks and protect against substandard / falsified products
• Contain antimicrobial resistance
• Set global norms and standards (written & physical) and nomenclatures
• Increase common understanding on regulatory requirements by authority & manufacturer
• Standardize approach used by quality control labs
• Set effective and efficient regulatory systems in LMICs through collaborative & harmonized approaches with reliance principles
• Increase confidence in medical products produced in LMICs
• Assure safety, quality, appropriateness & efficacy of medical products used in LMICs: medicines, vaccines, medical devices, cold chain equipment, vector control products & in vitro diagnostics
• Increase competition to shape the market
Reduced mortality and morbidity
Decreasedregulatory burden
Decreased costof regulation
Reduced time for regulation
Increased regulatory capacity in LMIC
Technologies,
Standards and Norms
Regulatory Systems
Strengthening
Prequalification
TeamSafety & Vigilance
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Ensuring normative and technical excellence drives impact at country level
Strategic priority 1: some highlights
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• Global Benchmarking Tool version VI published December 2018
• WHO Listed Authorities concept moving towards operationalization
• Draft Framework to advance Universal Access to Safe, Effective and Quality-Assured Blood Products www.who.int/medicines/news/2019/DraftActionFrameworkUniversalAccessBlood-BloodComponents.June2019.pdf
• Support for countries transitioning out of GAVI and Global Fund
• WHO’s network of laboratories avoiding duplicative lot testing
• Assessing and improving impact of Guidelines – focus on biotherapeutics and lot release
• Regulatory approaches to cell and gene therapies
• Accelerating access through collaborative registration
Strengthen country and regional systems
Development of international norms and standards
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Guidelines cover areas such as:
• medicines• in vitro diagnostics• vaccines
• Development• Production• Distribution
Setting international norms and standards for:
• biotherapeutics • blood products• gene-therapy products• tissues and organs
• Inspection• Quality control and • other regulatory issues
Key factors required for the development of guidelines and standards:
• Close collaboration with other teams and relevant stakeholders
• Technical feedback on the existing guidelines and specifications
International norms and standards:
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The International Pharmacopoeia
WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP)
WHO Expert Committee on Biological Standardization (ECBS)
Presented on Monday, 04 November
To be presented on Friday, 08 November
No presentation on this topic, but visit www.who.int/biologicals/WHO_ECBS/en/
International Nonproprietary NamesNo presentation on this topic, but visit www.who.int/medicines/services/inn/en/
1• build regulatory capacity in Member States consistent
with good regulatory practices
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• promote regulatory cooperation, convergence and transparency through networking, work-sharing and reliance
Objectives of the WHO regulatory system strengthening programme
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WHA Resolution 67.20 in 2014
✓ recognized the importance of strong regulatory systems to a well-functioning healthcare system and the attainment of health-related SDGs and UHC.
More on this topic later
Regulatory decision making
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Regulatory cooperation based on convergence/ harmonization to improve the quality of decision making process
Recognition
RelianceWork-sharingJoint reviews
Normal/standard process
Unilateral or mutual recognition: based on treaties or equivalent, providing maximal benefits but partial loss of sovereignty with regard to decision-making
Reliance on regulatory decisionsPerformed by other competent and trusted agencies to reduce the workload, with independent final decision-making
Independent decisions based on its own reviews or inspections
Some key assumptions, facts and consequences
1 3
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Consequences:
• Costs are passed onto the healthcare system and/or patient
• Global complexity direct relation with shortages
• For smaller markets in particular - additional requirements hinder access and exacerbate shortages
Every distinct national regulatory requirement adds a cost and complexity to the global system
Reliance, work-sharing and cooperation can be a solutionBut do existing regulatory systems have the competencies to practice reliance effectively?
Accelerated registration through Collaborative Registration Procedures (CRP)Objectives:
• to facilitate the assessment and accelerate national registration of Prequalified products
• to accelerate registration of health products that have already received approval from a “stringent regulatory authority”
Principles:
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✓ Voluntary
✓ Sovereignty
✓ Identicality
✓ Co-operation
✓ Reliance
✓ Monitoring and maintenance
Sovereignty: Participating NRAs agree to respect principles, but national requirements still apply, decision remains national decision
Reliance: WHO PQT share the assessment reports, inspection reports and laboratory results with participating NRAs
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CRP median time for registrationfor medicines
456 registrations
Median = 93 daysincluding regulatory time and applicant time
40 plus countries
manufacturer
WHO
NRA
Before CRP – 2 months to 10 years
Median time to registration for Prequalified medicines – Over 450 approvals
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*Including regulatory time and applicant time
Days
81
93
78 75
93
113 114
93
0
20
40
60
80
100
120
2013(n=15)
2014(n=36)
2015(n=61)
2016(n=80)
2017(n=125)
2018(n=106)
2019(n=33)
All(n=456)
Cale
ndar
Days
As at 26 Aug 2019
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Collaborative Registration Procedure (CRP)Countries participating to medicines CRP
As at 26 Aug 2019
* CARICOM
Member States: Antigua and Barbuda, Bahamas, Belize, Dominica, Grenada, Haiti, Jamaica, Montserrat, Saint Lucia, St. Kitts and Nevis, St Vincent and the
Grenadines, Suriname and Trinidad and Tobago
Associate Member States: Anguilla, Bermuda, British Virgin Islands, Cayman Islands and Turks and Caicos Islands
Red: newly joined
Armenia
Azerbaijan
Belarus
Botswana
Burkina Faso
Burundi
Cameroon
*Caribbean Community
(CARICOM)
Comoros
Cote d'Ivoire
Malawi
Mali
Mozambique
Namibia
Nigeria
Pakistan
Philippines
Senegal
Sierra Leone
South Africa
Dem. Rep. Congo
Eritrea
Ethiopia
Georgia
Ghana
Kazakhstan
Kenya
Kyrgyzstan
Lao PDR
Madagascar
Sri Lanka
Sudan
Tanzania
Thailand
Uganda
Ukraine
Uzbekistan
Zambia
Zanzibar
Zimbabwe
A new proposal aimed at promoting reliance:
WHO Listed Authority (WLA):3
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• Term ‘Stringent Regulatory Authority (SRA)’:
o defined as original ICH member/observer,
o developed to guide procurement decisions
• Widely used and recognized
• However growing concerns with term SRA:
o with the fact that ICH doesn’t have remit or competence to assess regulatory capacity; coupled with expanding membership
• WHO expert committee asked WHO to develop new proposal in October 2017 – based on Global Benchmarking Tool assessments
• Extensive discussions and consultations, concept note published May 2019, stakeholder meeting 23 September 2019
WHO Listed Authorities
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• An objective and transparent approach to measuring and documenting regulator maturity
• Provides pathway for regulatory authorities to be globally recognized and thereby help guide reliance decisions on medical products
• Provides a robust framework to promote trust, confidence and reliance, enabling efficient use of regulatory resources
• Encourages investment in and continuous improvement of regulatory systems
• Expands the pool of regulatory authorities that can be used as “reference authorities”
• Creates an enabling regulatory environment for innovation and local production
WLA – Why and when?
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• Provides pathway for regulatory authorities to be globally recognized and thereby help guide procurement decisions on medical products, including for products not eligible for prequalification
• Provides a robust framework to promote trust, confidence and reliance, enabling efficient use of regulatory resources
• Encourages investment in and continuous improvement of regulatory systems
• Expands the pool of regulatory authorities contributing to efficiency of Prequalification program through increased use of abridged procedure
• Creates an enabling regulatory environment for innovation and local production
• Policy document and operational guidance under development
3
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• Roadmap for revision of emergency use procedures (EU(A)L) - nearly final
• Ebola Crisis DRC - accelerated access to investigational Ebola vaccines through assessments involving concerned regulators
• Roadmaps for introduction and roll-out of Ebola vaccines - Merck and J&J vaccines (discussions with other vaccine developers ongoing)
• Facilitating additional evidence generation through additional clinical trials and expanded access
• Use of EUL for novel Polio vaccines
• Recommendation for release into the global polio stockpile of mOPV2 vaccines
• Vigilance preparedness - Global Advisory Committee on Vaccine Safety (GACVS)
Strategic priority 2:Increase regulatory preparedness for public health emergencies
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WHO Regulatory work to prepare for Public Health Emergencies – integrated approach
• Support for WHO’s R & D Blueprint
• Technical guidelines and standards
• Emergency Use (Assessment) and Listing (EU(A)L)
• Safety monitoring
• Communication and coordination
• Regulatory Systems Strengthening (mapping of provisions and competences, table top exercise, support for guidelines and SOPs)
• Regulatory platforms to facilitate registration of drugs/vaccines through joint reviews
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Accelerating access to Ebola vaccines:Roadmap and licensing
• Roadmap published on licensing of Merck’s Ebola vaccine (VSV-ZEBOV) in countries at risk
https://www.who.int/medicines/news/2019/Merck_EVD_vax-intro-roadmap.pdf?ua=1
Background and Development
1) Initial discussions November 2018
2) Draft prepared January 2019
3) Consultation with FDA, EMA, AVAREF
4) Revised version published May 2019Purpose of the Roadmap:
• to facilitate the introduction and roll-out of a licensed Merck Ebola Vaccine in concerned African countries
• to describe the roles and responsibilities of different stakeholders
• to clarify the potential role of AVAREF as a platform
https://www.who.int/news-room/detail/18-10-2019-major-milestone-for-who-supported-ebola-vaccine
18 October: Positive EMA opinion (conditional) basis for accelerated PQ and licensing in affected countries
Pharmacovigilance Preparedness:Why is this important and what is WHO doing
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• Pharmacovigilance competence a key component to be evaluated as part of Benchmarking (GBT)
• But are approaches to pharmacovigilance in high- income countries applicable in low-income countries?
• Is there a need for more targeted monitoring – especially for new products?
• Are Risk Management Plans appropriate and implementable (experience with Article 58, Ebola vaccine, malaria vaccine)
• Can more experienced countries help less experienced countries?
• Smart Safety Surveillance pilot
More on this topic this afternoon
Prequalification (PQ) achievements:
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Diagnostics Medicines Vaccines Vector Control
Through the prequalification process, WHO has made available numerous quality-assured products to WHO Member State markets
*: cumulative numbers of products since inception
At the close of 2018, WHO had prequalified 1770 products* including
In vitro diagnostics & male circumcision device
Finished pharmaceutical product, active pharm
ingredient, quality control lab
Vaccines, Immunization device & cold chain
equipment
VC Products (VCPs: FPPs & APIs)
✓Larvicides✓Long-lasting
insecticidal nets ✓Indoor residual
spraying products✓Space spraying
products
✓24 priority diseases, covering vaccines required for routine immunization
✓Eligibility criteria for evaluation includes NRA functionality & programmatic suitability
✓HIV/AIDS✓Malaria ✓Tuberculosis✓Diarrhoea✓Influenza✓Reproductive Health✓Neglected tropical
diseases (NTDs)
✓HIV/AIDS✓Hep B✓Hep C✓HPV✓Malaria✓G6PD✓Cholera✓Syphilis
Presented on Wednesday, 06 November
Strategic priority 3:
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Strengthen and expand WHO prequalification and product risk assessment processes
• PQ pilot for Biosimilars in progress – exploring Human insulin
• First antivenom listed following risk assessment – May 2019
• Workshop for manufacturers in November 2019
• In-Vitro Diagnostics – Syphilis and HBV viral load assays – new eligibility criteria for IVDs
• Reproductive health? Other Cancer medical products? Antibiotics?
• What about digital tools, artificial intelligence?
• Ongoing collaboration on vaccines at all stages of development
• Use of information from WHO Listed Authorities (WLA) to facilitate prequalification
• In response to the growing burden of non-communicable diseases, such as cancer, a PQ pilot project launched in June 2018
• rituximab & trastuzumab: amongst the first monoclonal antibody therapies listed in the WHO Model List of Essential Medicines
• Two assessment pathways:
Full: Similar biotherapeutic products (SBP) that have already been registered
by non-Stringent regulatory authorities (SRA), using SRA-approved reference biotherapeutic products as comparator and marketed in the country of registration
Abridged: Originator products or SBPs for rituximab and trastuzumab that are
approved by SRA and marketed in the country of the SRA
• Applicants to commit to pursue “Collaborative Registration” in participating countries
• 23 Dossiers received
Update on PQ pilot of rituximab & trastuzumab (1) launched in June 2018
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Launch of a Strategy for Prevention and Control of Snakebite Envenoming:
www.who.int/snakebites/resources/9789241515641/en/
WHO targets 50% reduction in deaths and disabilities over the next 12 years
• work with countries to strengthen health systems towards achieving the SDGs
• ensure access to safe, effective and affordable treatment such as antivenoms and ancillary medical care
• Improve and strengthen production, supply and distribution of life-saving antivenoms and other commodities
• encourage research on new treatments, diagnostics and health device breakthroughs
Key messages
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• Strong and efficient Regulatory systems use concepts such as reliance, work-sharing and international collaboration
• Rich portfolio of concepts, tools, networks and enablers now exist –e.g.
• Particular relevant for new technologies and innovations
• Effective regulation is about enabling access to products – no impact if product doesn’t reach patient
• Requires integration across regulatory components but also across health care systems
o Good Regulatory Practices
o Collaborative Registration Procedures
o Joint reviews, Regional networks…
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Emer CookeDirector, Regulation of Medicines and other Health Technologies