Regulation of Vaccines in Low- and Middle-Income Countries

COVID-19

The largest-ever pandemic of COVID-19 virus in 2020 and epidemic of Ebola virus disease in 2014–2015 triggered an unprecedented accelerated vaccine development process. New production platforms, innovative clinical trial designs, flexible and agile regulatory pathways, and relying on advanced regulatory systems and WHO were successfully used to evaluate complex vaccine constructs ^, in countries with very limited regulatory resources and little or no experience in assessing vaccine clinical trial applications. Nevertheless, appropriate regulatory oversight was exercised in part because of the willingness of better-resourced regulatory agencies to provide peer-to-peer scientific support to the regulatory agencies in the affected countries. A key lesson learned from the 2014–2015 Ebola virus disease epidemic is that regulatory preparedness for infectious disease threats needs to be strengthened in all countries, especially in low- and middle-income countries (LMICs), and especially for regulation of vaccines.

When WHO declared a public health emergency of international concern (PHEIC) on January 30, 2020, the etiological agent causing the new respiratory disease later called COVID-19 had just been isolated (January 7), and the first genomic sequence was completed on January 10. Therefore, it was only after the declaration of the PHEIC that scientific/academic institutions and manufacturers started to work on the development of COVID-19 vaccines. This chronology of facts has challenged public health systems worldwide, and regulatory bodies are no exception. Even those regulatory authorities with mechanisms in place to authorize the use of investigational products were forced to create guidelines, task forces, procedures, and alliances to maximize the efficiency of assessment, review, and authorizations of medical products. Vaccines are undoubtedly the most complex medical products to develop, from concept to a stage where sufficient evidence of quality, safety, and efficacy are collected to provide an assurance that their use will provide more benefits than risks when used in the context of a public health emergency.

Vaccines for routine use are manufactured in a subset (between 40 and 45) of the 194 member states of the WHO. They are used, without exception, in every member state. A growing proportion of vaccines that are used to immunize the world’s population are manufactured in LMICs. Appropriate regulatory oversight of vaccines in the developing world is critical not only to ensure the quality, safety and efficacy of vaccines used in national immunization programs in the country of manufacture but also to protect and enhance investments in the global immunization enterprise.

The WHO establishes international standards for the regulation of vaccines and assesses implementation of these standards. The regulatory capacity of National Regulatory Authorities (NRAs) in key vaccine-producing LMICs is improving, but further work is needed (e.g., to strengthen health systems to embed the gains made). The NRAs of LMICs that import vaccines are, in some cases, not resourced to provide specialist regulatory oversight of vaccines. The most appropriate strategy for such countries is to leverage the regulatory evaluations performed elsewhere.

REGULATION OF VACCINES IN LOW- AND MIDDLE-INCOME COUNTRIES

Safe and effective vaccines are universally recognized as essential public health tools. Consistent production of safe and effective vaccines is difficult and doing so at an affordable price even more so. Vaccines are regulated by pharmaceutical medical products law and are among the most complex medical products available today. Informed decision making for vaccines requires specialist regulatory expertise. Risk-based regulatory evaluations for vaccines requires an understanding of, first, biological production and quality control processes and, second, the implications (in the case of preventive vaccines) of administering products derived from living systems, often to very young infants, at a population scale. Regulatory authorities must always be ready to evaluate new information on potential or real risks and benefits of vaccines and change decisions as needed. Adapting and implementing regulatory pathways and procedures that facilitate countries’ preparedness for public health emergencies, such as the COVID-19 pandemic, should ideally be in place before the emergency occurs. Regulatory adaptation is critical during public health emergencies; hence NRAs are encouraged to modify a traditional, reactive control system into a proactive, risk-based approach to speed up the public’s access to life-saving vaccines.

Box 82.1 provides an example of the type of problem confronting regulators and how they have reacted to it.

LMIC vaccine manufacturers are an attractive option to supply the global market, but currently the potential of such suppliers is not fully realized. One obstacle is confidence in the quality of vaccines from such suppliers. National regulatory authorities are the gatekeepers of the supply chain of medical products, and they have a mandate to ensure the quality, safety and efficacy of medicines, vaccines, blood, and blood products, medical devices, including diagnostics and traditional, or herbal medicines. However, the majority of the world’s regulators are still struggling to reach a level of maturity, whereby they have a stable, well-functioning, and integrated regulatory system.

When a national regulatory system is independent, efficient, science based, transparent, and well managed, it supports robust and effective vaccine regulation, and vaccines entering the market are safe, efficacious, and of assured quality. This in turn protects the population from harm due to unregulated supplies, including substandard and falsified vaccines, and thus fosters confidence in the health care delivery system. A well-functioning NRA creates an environment in which medical products are appropriately manufactured, stored, distributed, and dispensed. It supports local production of vaccines, which is key to affordability, helps create a transparent, and well-organized market for pharmaceuticals and other medical products, and enables postmarketing surveillance and integrity of the supply chain. All these facets of regulation help ensure timely access to vaccines and enable NRAs to be prepared for better response to emergencies. Moreover, at its best, a strong NRA will perform all of these functions without creating an unnecessary regulatory burden on itself and any of the stakeholders.

WHO supports its member states in strengthening their regulatory systems for medical products by setting norms and standards, promoting smart regulation, identifying strengths and gaps, providing specialized technical assistance, and capacity-building opportunities and advising them on issues related to quality assurance of medicines for national and international markets.

In 1997, WHO began benchmarking regulatory systems as part of its regulatory system-strengthening program, initially using a set of indicators designed to evaluate regulatory oversight for vaccines. This was to address the pressing challenge of how to ensure that vaccines meet the appropriate standards of quality, safety and efficacy, whether they were used domestically in the country of manufacture, or in receiving countries. Later on, WHO expanded this program to evaluate regulatory oversight for medicines, blood and blood products and medical devices. In 2013, WHO started to unify these parallel programs and integrate various tools developed in this regard through the development of a harmonized tool, the Global Benchmarking Tool (GBT), representing the primary means by which the WHO objectively evaluates regulatory systems.

One of the aims of this program is to ensure that the NRA in each vaccine producing country is meeting the requirements of a maturity level 3 against international standards for vaccine regulation. The maturity level 3 (previously called functional) is assessed by WHO-led benchmarking. ^,

Between 1997 and 2020, more than 100 assessments were conducted, including the NRAs of all vaccine-producing countries.

In addition to the national regulatory system component that provides the framework, there are eight core regulatory functions, defined by the WHO for an NRA to provide comprehensive regulatory oversight of vaccines. Comprehensive regulatory oversight should be in place in countries that manufacture vaccines. Regulatory systems in these countries should have a legal framework and a mandate to enforce the eight regulatory functions recommended by the WHO. These functions are: (a) Registration and Marketing Authorization, (b) Vigilance, (c) Market Surveillance and Control, (d) Licensing Establishments, (e) Regulatory Inspection, (f) Laboratory Testing, (g) Clinical Trials Oversight, and (h) National Regulatory Authority Lot Release. ^,

However, for the majority of countries that import their vaccines, only a subset of regulatory functions need be in place. Stratification of the needed regulatory functions by source of vaccine has proved an effective and pragmatic strategy to guide countries regarding the level of investment that is appropriate to their context.

A “vaccine of assured quality” is defined as a vaccine that has been produced in a country with a functional NRA and has a positive benefit/risk evaluation for use in the target populations. WHO recommends that 100% of vaccines that are used in national immunization programs are of assured quality.

VACCINES OF ASSURED QUALITY AND FUNCTIONALITY OF NATIONAL REGULATORY AUTHORITIES: GLOBAL STATUS AND TRENDS

WHO and its partners strive to ensure all countries have access to sufficient doses of vaccine that are of assured quality. Stable, well-functioning, and integrated regulatory systems (maturity level 3) with streamlined processes and predictable timelines are key to facilitate this access.

Based on data available to the WHO, in 2019, more than 98.5% of the globally available vaccine doses used in National Immunization Programs were of assured quality, up 2.5% from 2017. This contrasts with the situation in early 1990, when it is estimated that less than 50% of vaccines were of assured quality. Additional vaccine-producing countries with functional NRAs are expected to reduce the remaining 1.5% gap in the coming years.

Sustaining the gains made in vaccine-producing countries is constantly challenging, however. WHO is monitoring and following up on the status in countries at risk and may provide technical assistance when needed. Special capacity-building and monitoring programs may be proposed to address regulatory matters urgently.

The WHO Global Benchmarking Tool (GBT)

The GBT enables regulatory authorities to self-evaluate their own strengths and areas for improvement; facilitates the formulation of an institutional development plan to build upon strengths and address the identified gaps, and prioritizes interventions. In addition, it facilitates the monitoring of progress and achievements. It helps countries to develop strong legal foundations and political leadership to underpin a regulatory system with a clear focus on patient safety and transparency in decision-making and to identify and develop a core set of regulatory functions to meet country and regional needs.

The GBT evolved through a process of wide and deep consultation with WHO member states and other stakeholders, and piloting in different regulatory settings. The GBT was field-tested in 2018 and the first uses of the current version were conducted in March and April 2019 in Ghana and El Salvador, respectively.

One of the significant additions to the latest version of the tool, GBT Rev VI, is benchmarking modules that look at the NRA’s ability to tackle the problem of substandard and falsified medical products. This is covered under several modules of the tool including the national regulatory system, market surveillance, and laboratory testing, as well as regulatory inspection, and marketing authorization. The latest revision of the tool also promotes other principles of Good Regulatory Practices, including legality, impartiality, consistency, proportionality, flexibility, effectiveness, efficiency, clarity, and transparency as well as the need for implementation of risk and quality management in regulatory systems, and regulatory preparedness to face emergencies. ^, Several subindicators in the tool look at the NRA capacity and preparedness for managing emergencies.

The WHO Regulatory Systems Strengthening program, which aims to strengthen capacity of regional, subregional, and national regulatory systems, works with countries to apply the GBT, as part of a five-step approach to improvement and NRA capacity building, with priority given to regulatory systems strengthening for developing countries ( Fig. 82.1 ).

The GBT is divided into four levels: (1) national regulatory system and regulatory functions (e.g., Registration and Marketing Authorization), (2) indicators (e.g., MA04 Procedures established and implemented to perform registration and/or marketing authorization, (3) subindicators (e.g., MA04.01: Documented procedures and tools are implemented for the assessment of the different parts of the application [i.e., quality and efficacy] and for the assessment of specific requirements applicable to specific classes of medical products or MA04.07: There are documented mechanisms to handle nonroutine registration or MA requirements in special situations), and (4) fact sheets. In addition to the national regulatory system component that provides the framework, there are eight core regulatory functions, which between them cover the whole product life cycle of medical products. Core functions are agreed upon during the consultation process with the NRA and include the following: