The future of AVAREF and its role, resources, and opportunities in contributing to the success of the emerging African Medicines Agency (AMA)

¹World Health Organization Regional Office for Africa, Brazzaville, Congo, ²African Medicines Agency, Kigali, Rwanda

^&Corresponding author
Kwasi Nyarko, World Health Organization Regional Office for Africa, Brazzaville, Congo

Essay    

The African Vaccine Regulatory Forum (AVAREF) was established in 2006 by the WHO as an informal network of member countries for regulatory and ethics capacity building. It has since been transformed, and now all 55 countries on the continent are members, with about 40 actively participating. This network, well known for its signature multi-country platform for joint reviews of clinical trial applications and registration of medicines during public health emergencies, has been instrumental in promoting harmonization and building regulatory and ethics capacity across Africa while supporting medicine developers [1,2].

Regulatory harmonization has been advocated internationally for years within the global regulatory ecosystem as a means of facilitating seamless and timely regulatory decision-making. Given the wide genetic diversity in Africa´s population, diverse landscape with 55 member states, four WHO languages, and significant administrative and legal differences, harmonization of laws, regulatory and ethics frameworks and processes is crucial for a seamless and timely regulatory decision making [3-5]. Other advantages of harmonization include ease of reliance between member states and integration with the international clinical trial ecosystem. Given the current comparatively low levels of clinical trials in Africa, the desire to attract more clinical trials, especially with African investigators, the promotion of harmonization of frameworks and establishment of reliance amongst member states is logical as no country, even the most resourced, can function solely without collaboration and information/resource sharing in this complex sector [6]. A pragmatic system for reliance and regulatory harmonization will address a major impediment: access to innovative medicines developed in Africa. On the other hand, it could be argued that a thriving local research and development with innovation, manufacturing pipelines would generate more clinical trials that in turn lead to advances in regulatory science and frameworks required for the registration of new medicines, vaccines, and health products.

The continent accounts for less than 3% of global clinical trial activity [7] despite its population of 1.5 billion representing 18.3% of the world's population [8]. Additionally, Africa bears 25% of the global disease burden with several diseases of epidemic and pandemic potential, and presents a suitable venue for clinical trials [9]. The continent possesses the widest and most variable genetic variation [10], which is particularly important as some therapeutic agents and vaccines are dependent on host genetic background for their efficacy and safety [11]. Obtaining safety, efficacy, and quality data from a genetically diverse study population suggests that medicines are more likely to be effective across numerous populations [12]. All these reasons highlight the challenges for the continent but also present unique opportunities for AVAREF and the AMA in the clinical trials arena. This paper examines AVAREF's evolution over nearly two decades, assesses its impact, and outlines its role in strengthening Africa's clinical trial capacity. Most importantly, we highlight the roles, responsibilities and resources AVAREF will bring to an emerging African Medicines Agency (AMA). It is envisaged that AVAREF will generate innovations and resources which include staff of NRAs who will be part of the AMA´s regulatory oversight of priority clinical trials.

Role of AVAREF: main accomplishments and contribution to the global R&D ecosystem

AVAREF has been instrumental in the authorization of numerous clinical trials and subsequent registrations for therapeutic products, including vaccines for meningococcal serogroup A meningitis, malaria, rotavirus, pneumococcal pneumonia, Ebola virus disease, COVID-19, Mpox, Lassa fever, Rift Valley Fever, and tuberculosis [1,2,13-16]. AVAREF has recently broadened its focus to include studies of neglected tropical diseases [1,2] while also supporting more complex trial designs, including adaptive protocols for severe malaria research, snakebite treatments, and controlled human challenge studies. The AVAREF Secretariat facilitates its activities by coordinating with the regional economic groups, NRAs, and NECs in gathering the nominee reviewers from multiple countries for activities such as the joint reviews, scientific advice, and facilitated registrations during emergencies. Using the same approach and platform, the AVAREF Secretariat also facilitates continuing education for reviewers, supports member states with ecosystem assessments to provide recommendations for systems strengthening for timely and high-quality clinical trials, and works with a wide range of partners, collaborators, and funders in the achievement of its goals, objectives, and outcomes. Furthermore, AVAREF members have developed a wide range of templates, tools, and guidelines for the assessment, review, and inspection of clinical trial applications. These include timelines for different review types from application to decision, procedures for joint reviews of clinical trial applications, frameworks for providing scientific advice to sponsors of clinical trials and principal investigators, and protocols for registration of therapeutic products, including during emergencies [1,17]. The network advances its primary directive of capacity building through partnerships and collaborators, providing expert technical support when required, and working along the innovation lifecycle. The AVAREF multi-country joint review procedure ensures timely decision making while providing an opportunity for reviewers to learn from each other, gain best practices, and develop trust - the foundation of reliance. The Secretariat has significantly contributed to harmonizing regulatory best practices and regulatory excellence in member states, supporting an increasing number of countries in attaining their desired maturity levels [1,18].

Current challenges

Despite progress, the capacity of NRAs and NECs on the continent remains relatively low, with eight out of 55 (about 14.5%) Member States-namely, Egypt, Ghana, Nigeria, Rwanda, Senegal, South Africa, Tanzania, and Zimbabwe-rated at maturity level 3 (ML-3 ) and considered functional based on the criteria of the WHO Global Benchmarking Tool [19] while 37 out of 55 (about 67%) at ML-1, and the remaining 19% at ML-2. Notably, only one francophone country and none of the lusophone countries in the region have reached ML-3 status. Furthermore, no country has achieved ML-4 status. The capacity and setting of ethics oversight through NECs and local/institutional ethics committees vary widely, and capacity building activities have been inconsistent across the continent [20]. Results from surveys and ecosystem assessments performed by the AVAREF Secretariat (unpublished data) suggest that many NRAs and NECs do not have documented processes, and among those that do, these processes are often not streamlined for efficiency. About 60% of reviews are conducted sequentially and rely heavily on standing committees, which may meet monthly or at much longer intervals. It was also reported that in most countries, regulatory decisions can be made by NRAs, NECs, both, or the Ministries of Health (MoH). Although most countries have dedicated units for CTAs, collaboration between NRAs and NECs is limited. Notably, there is limited capacity within NRAs for CTA review, with a small pool of evaluators (an average of approximately 2 FTEs for clinical trial reviews and 4 for NECs). Furthermore, there is a low volume of applications, with only six countries reporting the receipt of more than one application per month. A majority (93% of NRAs and ∼84% of NECs) requested support in digitally enabling their processes.

The needs: solutions, their drivers and the strategic operational and action plan for AVAREF

To address capacity gaps in clinical trials, including structural defects, technological deficiencies, and operational inefficiencies, a revised 2024-26 Strategic Operational and Action Plan for AVAREF has recently been developed. The plan is built on three supporting and reinforcing pillars, namely: partnerships for results; trusted expertise; and a life cycle approach on which the main function of excellence in capacity building rests, all aimed at increasing the quality and attracting more clinical trials on the continent. Ultimately, this will improve the timeliness of ethical and regulatory decision-making, yield enhanced results through effective collaborations and partnerships, involve trusted experts, and ensure the focus is not limited to NRAs and NECs [1]. The plan also outlines the priorities, areas of work, performance indicators, and expected outcomes. Thus far, its implementation has been instrumental in delivering expected results to member countries (Figure 1).

AVAREF´s priorities

AVAREF´s priority activities to boost clinical trial numbers include capacity strengthening for NRAs and NECs through staff training and continuing education in clinical trial application review (assessment), advising on the optimization of clinical trial processes through direct support to member states, and developing a cadre of expert reviewers for clinical trial applications and/or dossiers in collaboration with partners and expert support [1]. A key priority of AVAREF is to work with partners and collaborators in delivering its mandate; accordingly, the AVAREF Secretariat has prioritized partnerships that yield tangible results. To this effect, AVAREF is actively collaborating with the Gates Foundation, Wellcome Trust, CEPI, US FDA, PEI, EDTCP, AUDA-NEPAD, and others. In addition, efforts are being made to establish further alliances based on common objectives. Another key priority of AVAREF is to engage in what it refers to as an “ecosystem approach” to delivering on its mandate and priorities. Given that NRAs and NECs do not exist in isolation, actions must be designed, planned, and implemented with an ecosystem lens. This approach involves considering the impact of actions on other entities, which are not always in alignment operationally. Their mandates, objectives, and expectations may differ significantly, and could create discordance and inefficiencies if not proactively addressed. An ecosystem approach helps to bridge these gaps, seeking collaborations where appropriate to maximize the effectiveness of initiatives, ensuring that each stakeholder understands the role of the others and how their actions intersect, and encouraging the development of sectors that may not be directly within AVAREF´s mandate. Another priority for the AVAREF Secretariat is to identify a vehicle that enables its initiatives, projects, and programs to be tested, studied, and perfected. Hence, the proposal and implementation of the AVAREF Clinical Trial Pilot program-a pragmatic but ambitious project intended to address a wide range of shortcomings or irritants identified through existing processes and systems, with the expectation of increasing effectiveness and delivering tangible results.

AVAREF clinical trial pilot project

The objectives of the AVAREF Clinical Trial Pilot Project are to establish a viable framework for the regulatory and ethics oversight of clinical trials in Africa, in preparation for the operationalization of the African Medicines Agency (AMA). The key elements of the pilot include establishing a reliance network among 16 member states including Botswana, Burkina Faso, Egypt, Ethiopia, Gabon, Gambia, Ghana, Kenya, Malawi, Nigeria, Rwanda, Senegal, South Africa, Tanzania, Uganda, and Zimbabwe; developing a standardized (harmonized) framework and processes to enhance the quality and timeliness of clinical trial reviews; and targeted capacity building via continuing education, coaching, and mentoring. These countries were selected based on attainment of ML-3 status based on the WHO assessment tool, the number of clinical trials, equitable representation among the recognized regional economic groupings, inclusion of official WHO languages, and the willingness of the participating countries to be part of this reliance network [21]. A cadre of experienced clinical trial reviewers has been established with the aim of supporting the 16 selected countries. A centralized digital CTA submission and management system-enabling the submission, review, and decision-making of dossiers on a single platform is being developed and implemented. Ultimately, the pilot will lead to trusted scientific and technical support for the framework established to effectively process, assess, and provide regulatory oversight for clinical trials. By achieving these objectives, the AVAREF Clinical Trials Pilot Project aims to promote a standardized framework for regulatory and ethics oversight, enhance the quality of clinical trial application reviews, and improve regulatory efficiency through transparent and predictable decision-making processes. In turn, this could increase both the number and quality of clinical trials conducted in Africa and lead to improved access to novel and/or enhanced therapeutic products for the continent´s populations. Over two years, the AVAREF Clinical Trial Pilot Project intends to develop a pool of high-caliber reviewers from member countries by creating continent-specific intra-personal and inter-organizational reliance mechanisms that can be leveraged for the benefit of the continent. It is believed that these measures will help reduce decision times and support capacity building within member agencies.

Realizing AMA: strengthening the WHO-AFRO Partnership and shaping future plans

The African Medicines Agency (AMA) is a continental regulatory agency of the African Union, with a mandate to “enhance the capacity of states parties and regional economic communities (RECs) to regulate medical products to improve access to quality, safe, and efficacious medical products on the continent” [22]. The AMA treaty was adopted by heads of state and government during their 32^nd Ordinary Session of the Assembly on 11 February 2019 in Addis Ababa, Ethiopia. The African Medicines Agency (AMA) is expected to build on the foundational work established by the African Medicines Regulatory Harmonization (AMRH) initiative, which was launched in 2009 to promote the alignment of regulatory standards and practices among the national medicines authorities (NMRAs) of AU Member States [22-24]. AVAREF, serving as the AMRH technical coordinating committee for clinical trials, is the foundation for AMA with respect to regulatory and ethics oversight for clinical trials. A major consideration in AVAREF´s strategic plan is to strengthen member state regulatory systems to facilitate the seamless realization of AMA. While it might be tempting to adopt the system used by the European Medicines Agency (EMA) [25]-arguably the closest model to emulate-African countries must ensure that the selected model is pragmatic for the continent´s realities. Unlike the EMA, which was established when most of its member state NRAs were fully functional [25], AMA is being implemented in an environment where regulatory ‘maturity´ and/or ´performance´ is less prevalent; hence, adopting similar or equivalent structures may not support AMA´s objectives effectively.

Consequently, the future role of AVAREF will include ensuring that WHO´s technical and scientific support for member states is fully leveraged toward the realization and operationalization of AMA. In this regard, WHO-AFRO, through the AVAREF, is positioned to provide critical technical support, expertise, and linkages to member states. AVAREF´s support for AMA will build on the almost 2 decades of regulatory and ethics strengthening, AVAREF templates and methods that have been adopted by member states, AVAREF´s continuing support for reliance amongst member states, and the development of the cadre of expert reviewers to support AMA deliverables. Therefore, deliberate efforts should be made to establish and maintain a continuing relationship between WHO-AFRO and AMA. This partnership should be founded on the mutual goal of providing high-quality, safe, and effective medicines to member countries; it should encourage reliance, avoid duplication, and minimize inefficiencies and bureaucratic red tape. As a key unit within the emerging AMA, AVAREF must ensure that regional clinical trial oversight meets world-class standards-standards that are science-based, internationally recognized, pragmatic, and harmonized to ensure regulatory excellence. AVAREF´s success is critical to AMA´s potential to become a world-class continental regulatory organization [6]. The emergence of AMA naturally brings with it the expectation of an organization on par with world-class regulatory agencies like the EMA, FDA, or other mature regulatory bodies. AVAREF must focus on providing the much-needed high-quality continuing education and training of reviewers within the ecosystem and technical support not only to NRAs and NECs but also to other entities in the clinical trials chain to help achieve these objectives. In addition, the wide-ranging roster (Pool) of experts from the AVAREF Secretariat (WHO) would be available to AMA for its operationalization. Notably, AVAREF is prominently mentioned in the AMA Charter [22], underscoring its significant role not only in clinical trial oversight but also in the strategic and operational functioning of AMA. Efforts should be made to integrate AVAREF´s best practices, tools, and processes into the operationalization of AMA.

Outlook and predictions

The ecosystem and life-cycle approach being implemented aims to strengthen regulatory and ethics systems and capacities for clinical trials. If effectively applied, this approach could also support the operationalization of the AMA and contribute to the growth of the pharmaceutical and biopharmaceutical manufacturing systems in Africa, thereby enhancing access to safe, efficacious, affordable, and quality-assured medicines. Continued collaboration amongst partners, as outlined under the AVAREF´s partnerships for results pillar, should continue to facilitate a thriving R&D program in Africa. To ensure the realization of expected outcomes, AVAREF members need to address issues, including sustainable financing, which is linked to sovereignty and dignity. Finally, a focus on building the scientific and technical expertise required for the effective functioning of world-class regulatory functionality would contribute enormously to positive results. Potentially, Africa's share of global clinical trials could rise from the current 2.5% to 10% by 2035, such an increase representing a fourfold surge in R&D activity, currently valued at $70 billion globally, and could catalyse transformative changes throughout the continent. Managed appropriately, this growth could significantly spark a long-overdue biotechnology transformation and translate into reduced morbidity and mortality. Moreover, as clinical trials are pivotal to achieving Agenda 2063's vision of self-sufficiency in essential medicines, this surge would enhance access to affordable, safe, and effective treatments.

Research and development (R&D) is the gateway to innovative medicines, with clinical trials playing a crucial role. Therefore, a key aspect of AVAREF´s future strategy should be to prioritize R&D initiatives that lead to the development of new therapies. Given the current low levels of clinical trials on the continent, including early-phase and African-led studies, AVAREF must address these gaps to foster a thriving clinical trial environment. Currently, African countries are eager to develop a strong pharmaceutical manufacturing sector, as evidenced by the commitment to the goal of increasing local vaccine production from 1% to 60% by 2040 [26,27]. AVAREF´s role is critical to enabling the countries to achieve their objectives, ensuring that its efforts complement the operationalization of the AMA and contribute to a sustainable, innovative health landscape across the continent.

Conclusion     

AVAREF's evolution from a capacity-building network to a key enabler of regulatory excellence underscores its critical role in Africa's clinical trial ecosystem. By addressing regulatory inefficiencies, fostering harmonization, and strengthening partnerships, AVAREF has laid the groundwork for transformative growth. The Clinical Trial Pilot Project and the operationalization of AMA offer unprecedented opportunities to enhance regulatory systems, increase clinical trial activity, and support pharmaceutical manufacturing on the continent. AVAREF's strategic vision aligns with Africa's broader aspirations, ensuring a thriving R&D that delivers safe, effective, and affordable medicines to its population while positioning Africa as a global leader in therapeutic innovation.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All the authors read and approved the final version of this manuscript.

Figure     

Figure 1: summary of strategic operational and action plan for AVAREF

References