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

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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

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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