Strengthening the regulation of health products through ......NRAs are mandated in their...

Strengthening the regulation of health products through networking, cooperation and

harmonization

Samvel Azatyan MD, PhD.Group LeadRegulatory Networks and Harmonization [RNH]Regulatory Systems Strengthening [RSS]Regulation of Medicines and Other Health Technologies [RHT]World Health OrganizationE-mail: [email protected]

WHO Technical Briefing Seminar

Medicines and Health Products

WHO Headquarters, Geneva, 4 – 8 November 2019

mailto:[email protected]

WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019

Access to medical products – global challenge

▪ In many low- and middle-income countries essential medicines are not always readily available and accessible;

▪ WHO estimate is that one third of the world’s population have no access to essential medicines (and more than half in some areas);

▪ Lack of essential medicines contributes to disparities in health and life-expectancy between low-income and high-income countries;

▪ Reasons for limited/insufficient access are different but one of them is inadequate regulatory capacity and lack of collaboration and work sharing in medicines regulation.

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Gap in Regulatory Capacity

▪ ≈30% of NMRAs globally have limited capacity to perform core regulatory functions

▪ Regulatory capacity gap between different countries (low- and high-income) in terms of:

• Human and financial resources;

• Regulatory functions effectively performed;

• Expertise available for fulfilling regulatory functions;

• Availability of proper systematic training for regulators;

• Applying quality management principles.

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Need for reliance – LMIC example

4

Summary observations:

▪ Guidelines and assessment procedures are not up to international standards and are often of an administrative rather than technical nature;

▪ Inadequate resources severely limit technical assessment of dossiers;

▪ In spite of resource constraints only few countries rely/refer on decisions made by other regulators (such as stringent NRAs or by the WHO PQ);

▪ Some countries had restrictive regulations not allowing reliance..

26 country studyin Africa


The concept of regulation is changing (1)

▪ NRAs are mandated in their jurisdictions to ensure timely access to safe, effective and quality medical products - in line with international standards;

▪ There is no clear vision or policy about HOW to set up regulatory systems in times when it is unrealistic to manage all functions in one national setting for most regulators – globalization of regulatory science;

▪ New products are likely more complex and sophisticated – demanding advanced health systems and "quality use“;

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Questions to answer:

▪ Can all national regulators assess and inspect all the product applications coming to their markets?

▪ Does repetitive assessments and inspections give any added value?

▪ How to build confidence in scientific assessments/ inspections carried out by other parties?

▪ How regulators can best contribute to the public health with the limited resources they have?

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▪ Health systems and health providers are varying in “strength” between countries:

• Not all new products coming to the markets equally fit for all types of health systems and health providers available;

• Benefit/risk assessment is not always taking into consideration health systems in which product is to be launched?

• Not always we know what exact competencies are needed for regulators to be able to perform their functions.

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Facilitating good quality decisions through reliance : WHO efforts

▪ Promoting good governance and transparency in medical products sector (GRP process);

▪ Promoting and facilitating building-up strong national regulatory systems as part of overall health systems strengthening;

▪ Promoting functional/adequate national regulatory systems as important contributor to achieving universal health coverage and able to address public health priorities (GBT process);

▪ Supporting regulatory workforce development – (Global Regulatory Curriculum);

▪ Promoting regulatory cooperation, convergence and harmonization – globally and regionally;

▪ Promoting work sharing – based on reliance on the work of trusted authorities – to inform regulatory decision-making.

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Regulatory convergence and harmonization initiatives

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Convergence and harmonization efforts should be able to diminish duplication, creating a "common language" for decision-making and facilitating cooperation, work-sharing and eventually reliance and/or

recognition


Areas of convergence and harmonization

Clinical trials –

▪ Harmonization of requirements for applications to conduct Clinical Trials;

▪ Recognition of Good Clinical Practice (GCP) audits;

▪ Clinical trial registries;

Medical product registration –

▪ Harmonization of technical guidelines & registration requirements;

▪ Reliance of Good Manufacturing Practices (GMP) audits & dossier assessments;

▪ Work-sharing of dossier assessments;

Post-market surveillance activities –

▪ Information-/work-sharing of Adverse Drug Reactions/safety assessments;

▪ Work-sharing/reliance on product testing results;

▪ Information-sharing on counterfeit medical products, product defects and GMP non-compliance of manufacturers.

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Sovereignty in regulatory cooperation

▪ Engaging in regulatory cooperation doesn't mean a loss of national sovereignty / autonomy;

▪ Use of collaborative and cooperative mechanisms, (e.g., joint assessments of marketing applications or sharing of inspection reports), does not imply collaborative decision-making!

▪ In all cases the regulatory decision itself remains firmly in the hands of sovereign nations.

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WHO views on Regulatory Cooperation

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Reliance and Recognition

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▪ Both reflect "taking account of’’ the output of other regulatory authorities;

▪ Increasing prevalence/necessity, even with most mature/resourced NRAs;

▪ Prerequisite: regulatory system and functions that can then be the object of reliance or recognition;

▪ May be both unilateral or mutual

▪ NB: sovereignty maintained in both cases

Reliance Recognition

Reduction:streamline/reduce internal work

Replacement:operationally, rely on decisions


Why WHO supports Regulatory Convergenceand Harmonization?

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NMRAsNational Government

DonorCommunity

Manufacturers(Local and

International)

Patients /consumers

• Greater process transparency• Reduced regulatory burden• Shorter time to approval• Greater incentive to prioritize dossier

submissions• Improved access to regional markets

• Potential for savings/greater reach via generic equivalents and increased competition

• Healthcare resources can be better managed

• Improved public health outcomes

Higher patient reach for a given level of support

• Increased capacity• More timely & cost effective

evaluation processes• Greater regulatory network, sharing

of best practices & experiences• More effective medicines control

• Quicker access to more affordable medical products of assured quality, especially for priority medicines

• Improved assurance that available medical products are safe


Regulatory Cooperation – regional efforts

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ASEAN SIAHR Project

PANDRH

African Vaccine Regulators Forum (AVAREF)

African Medicines Regulatory Harmonization Project (AMRH)


Options for making regulatory decision

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Unilaterial or mutual recognition: mutual recognition is based on treaties or equivalent, providing maximal benefits but partial loss of sovereignty with regard to decision-making

RecognitionReliance on regulatory decisions performed by other competent and trusted agencies and/or cooperation/collaboration with other regulators to reduce the workload, with independent final decision-making

Reliance

Work-sharing

Joint reviews

NRA makes independent decisions based on its own reviews or inspections

Normal/standard process

Regulatory cooperation based on convergence/ harmonization to improve the quality of decision making process

WHA resolution 67.20 (2014)


Registration pathways available for NRAs

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Verification, Secondary or tertiary reviews of primary reports from other agencies e.g. “SRA” or WHO PQ

e.g. EU decentralized procedure, ZAZIBONA

e.g. Reference NRAs, WHO PQ, EU Mutual recognition.

Work-sharing

Joint activities

e.g. EU centralised procedure, WHO-EAC joint assessments

Reliance

NRA capabilities

Recognition

Full assessment


Facilitated pathways to “transfer” regulatory information & knowledge

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WHO collaborative procedure

Vaccines: 2004Medicines: Started in 2012

Diagnostics: Pilot 2019Vector control: Pilot 2020

“SRA” collaborative procedure

• Sharing information / expertise (assessment, inspection and testing results or expertise) that serve as basis for national decisions – avoiding duplication.

• Voluntary participation – reference authorities, participating authorities and manufacturers/sponsors

Initiated in 2015European Medicines

Agency (EMA)Medicines and Healthcare

Products Regulatory Agency (MHRA)20 African NRAs

Regional networks

PRINCIPLES

African Medicines Regulatory

Harmonization Project (AMRH)

ASEAN SIAHR Project

**CRP-lite


WHO Prequalification of Medical Products

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Assessment of Dossier

Inspections

(API, FPP, CRO)

List of Prequalified

products

INPUTS PROCESS OUTPUTS

Assessment/

Inspection/Lab

Reports

WHO Public

Reports

Dossier

Expression of Interest

Assessors/ Inspectors

WHO Guidelines

Labs


Success story..

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65% of children globally are immunized with WHO prequalified vaccines through the GAVI alliance

PEOPLE ON ANTIRETROVIRAL THERAPY ACROSS THE GLOBE ARE TREATED WITH WHO PREQUALIFIED GENERIC MEDICINES


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How do WE get the prequalified product to these patients faster, and more efficient?

How do WE ensure continued supply of quality assured products post-registration?


Concept of facilitated registration (based on reliance)

To support the national registrations, regulators can benefit from already organized scientific assessments and inspections, if:

• Having access to regulatory expertise from trusted party (complete assessment and inspection reports);

• Having the same product;• Having same essential technical data;• Understanding validity of B/R for local

environment;• National legislation and sovereignty are not

affected;• Respect confidentiality of commercially

sensitive information;• Manage properly regulatory follow-up.

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If we share information (assessments, inspections, testing) for WHO PQ-ed or “SRA”-approved products

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THEN…

NRAs can rely on the shared information to facilitate national decisions

Re

lian

ce /

R

eco

gnit

ion

Timely access

to quality-

assured

products with

positive B/R

THEN…

Enhanced

NRA’s oversight

on other

products & sites

Re-allocate resources

• avoid duplications

• reduce regulatory burden

• assess B/R in local context

No

rmal

pat

hw

ay


How does the collaborative procedures works?

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Marketing authorisation

Submission

NRA

WHO PQ

SRA

NRA


KEY Principles of Facilitated Pathways

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• Voluntary;

• Product and registration dossier in countries are 'the same' as prequalified by WHO or approved by “SRAs”;

• Shared confidential information to support NRA decision making in exchange for accelerated registration process;

• 'Harmonized product status' is monitored and maintained.


Collaborative Registration Procedure:39 Participating NRAs - Medicines

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ArmeniaAzerbaijanBelarusBotswanaBurkina FasoBurundiCameroon*Caribbean Community (CARICOM)ComorosCote d'IvoireDem. Rep. CongoEritrea

PakistanPhilippinesSenegalSierra LeoneSouth AfricaSri LankaSudanTanzaniaThailandUgandaUkraineUzbekistanZambiaZanzibarZimbabwe

As of 26 Aug 2019

* CARICOMMember 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 TobagoAssociate Member States: Anguilla, Bermuda, British Virgin Islands, Cayman Islands and Turks and Caicos Islands

EthiopiaGeorgiaGhanaKazakhstanKenyaKyrgyzstanLao PDRMadagascarMalawiMaliMozambiqueNamibiaNigeria


Country registrations & therapeutic area

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Total registrations: 456(As of 26 Aug 2019)

15

36

61

80

125

106

33

6 12 15 16 20 20 110

20

40

60

80

100

120

140

2013 2014 2015 2016 2017 2018 2019

Registrations Countries

230

97

71

48

6 4

HIV/AIDS

Tuberculosis

Malaria

ReproductiveHealthHepatitis


Median time to registration

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*Including regulatory time and applicant time

81

93

7875

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

90 daysTARGET


Instead of conclusions:Timely access to medical products –never-ending challenge

1) Patients/consumers – wherever they are – deserve access to quality assured medical products with positive benefit-risk characteristics - UHC;

2) Not a single regulator anymore can fulfil all regulatory work alone;

3) Today’s reality and demand: to generate quality national decisions regulators globally MUST collaborate and MUST take into consideration the information available from other regulatory authorities;

4) Not using the outputs and outcomes from other regulatory authorities means lost opportunity, duplication of efforts, increased regulatory burden and waste of scarce resources..


Thank you!www.who.int/medicines

http://www.who.int/medicines

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