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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
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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WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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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WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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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WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
The concept of regulation is changing (2)
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?
6
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
The concept of regulation is changing (3)
▪ 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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WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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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WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Regulatory convergence and harmonization initiatives
9
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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.
10
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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 Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
WHO views on Regulatory Cooperation
12
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Reliance and Recognition
13
▪ 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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Why WHO supports Regulatory Convergenceand Harmonization?
14
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Regulatory Cooperation – regional efforts
15
ASEAN SIAHR Project
PANDRH
African Vaccine Regulators Forum (AVAREF)
African Medicines Regulatory Harmonization Project (AMRH)
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Options for making regulatory decision
16
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)
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Registration pathways available for NRAs
17
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Facilitated pathways to “transfer” regulatory information & knowledge
18
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 Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
WHO Prequalification of Medical Products
19
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Success story..
20
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
21
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?
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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.
22
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
If we share information (assessments, inspections, testing) for WHO PQ-ed or “SRA”-approved products
23
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
How does the collaborative procedures works?
24
Marketing authorisation
Submission
NRA
WHO PQ
SRA
NRA
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
KEY Principles of Facilitated Pathways
25
• 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.
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Collaborative Registration Procedure:39 Participating NRAs - Medicines
26
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Country registrations & therapeutic area
27
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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Median time to registration
28
*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
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
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..
WHO Technical Briefing Seminar: Medicines and Health ProductsWHO Headquarters, Geneva, 4 – 8 November 2019
Thank you!www.who.int/medicines