The African vaccine regulatory forum´s role in research and development during public health emergencies: past, present, and future

¹Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo, ²Regulation and Safety Unit, World Health Organization, Head Quarters, Geneva, Switzerland, ³Regulatory Convergence and Networks, World Health Organization, Head Quarters, Geneva, Switzerland

^&Corresponding author
Chinwe Iwu-jaja, Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo

Essay    

The African continent faces frequent disease outbreaks and epidemics [1]. For example, nearly half the countries of the continent experience at least one major disease outbreak annually [2]. In the last decade alone, African countries have been affected by outbreaks of Ebola Virus Disease and, more recently, mpox, which have gone on to be declared as public health emergencies of international concern by the World Health Organization (WHO) [3,4]. In addition, outbreaks of measles, vaccine-derived poliovirus, and other vaccine-preventable diseases continue to occur on the continent [5,6]. Some of the reasons for these outbreaks include low coverage with vaccines for vaccine-preventable diseases, poor understanding of the epidemiology and transmission, weak disease surveillance and control systems, and inadequate sanitation and hygiene [7]. As a continent with low investments in health infrastructure, Africa lacks the readiness to respond to disease outbreaks, epidemics, and pandemics for several reasons, including but not limited to weak healthcare infrastructure, limited disease surveillance systems and early warning capabilities, limited research capacity for emerging diseases, poor resource allocation, and economic instability [4,8,9].

Africa accounts for only 3% of global clinical trials despite representing 19% of the world's population [10]. Clinical trials are vital indicators of a region's research, development, and innovation capabilities. Increasing Africa's participation in clinical trials would strengthen the continent's research ecosystem and enhance its capacity for developing new health products. Through research and development (R&D), Africa could create innovative therapies and vaccines to prevent, control, and eliminate diseases. However, this R&D potential remains unrealized, thereby limiting Africa's ability to effectively address disease outbreaks.

Over the decades, the WHO, working with partners, has attempted to address these challenges. One of these efforts was the establishment of the African Vaccine Regulatory Forum (AVAREF) in 2006, which has focused on strengthening regulatory and ethics capacity for the oversight of clinical research [11]. This has resulted in better human resources and technical capacity for research and development of therapeutics and vaccines during disease outbreaks and epidemics. The current manuscript highlights AVAREF´s role in supporting R&D during the Ebola epidemic and the COVID-19 pandemic, sharing valuable lessons learned from both public health emergencies. The article explains how AVAREF set timelines for clinical trial applications (CTAs) and product review, strengthened the capacities of ethics committees (ECs) and national regulatory authorities (NRAs) through training, and introduced innovations to regulatory approvals and oversight. These activities were built upon networking, adoption of common processes, and harmonization to improve access - all in the context of the Ebola outbreaks and the COVID-19 pandemic. The paper also identifies the outstanding challenges and demonstrates how AVAREF can help to overcome these challenges. Also, it shows how AVAREF is repositioning itself to accelerate R&D during such emergencies without hindering the overall response to the diseases.

Lessons from Ebola: the first step was leveraging the WHO´s convening authority to hold a meeting of all the national regulatory authorities of the continent, national ethics committees, and product development partners in November 2014 in South Africa. The meeting of regulators and stakeholders in 2014 under the auspices of AVAREF produced recommendations that were implemented in support of the R&D of vaccines against Ebola Zaire. The purpose was to build global solidarity, identify vaccine candidates that are ready for human clinical trials, and agree on a regulatory pathway (review and approval processes, post-approval risk management). The vaccine candidates that were ready for clinical trials were recombinant vesticular stomatitis virus containing the glycoprotein of Ebola Zaire, human adenovirus type 16 containing glycoprotein of Ebola Zaire in prime boost with vaccinia Ankara, and chimpanzee adenovirus type 3 containing adenovirus of Ebola Zaire. It was also agreed that submissions of clinical trial protocols and reviews would use AVAREF tools and follow the AVAREF-defined pathways with joint reviews for multi-country studies. AVAREF would also be involved in jointly overseeing post-approval risk management.

The second step involved the organization of three joint reviews and a scientific advice session of clinical trial applications of the candidate vaccines against Ebola Zaire. The first joint review was held in December 2014 in Geneva, Switzerland. The proposed studies involved Liberia, Sierra Leone, and Guinea, using the three candidate vaccines identified by AVAREF. The second joint review was held in Arusha in 2015 for the trial of the Ad26.ZEBOV/MVA-BN-Filo vaccine in Ghana, Tanzania, Kenya, and Uganda. Three of the countries provided regulatory decisions within 32 days. There was a delay in the fourth country, leading to the withdrawal of the application. A third joint review was held in Ghana in 2015 for Liberia and Ghana for the Ad26.ZEBOV/MVA-BN-Filo vaccine. In December 2014, a scientific advice session was held with developers and principal investigators (PIs) of the three candidate vaccines against Ebola. This session brought experts in epidemiology, immunology, and other areas to review the clinical trial design for these three candidate vaccines and to provide advice to the PIs and developers [12]. The third step involved the joint collaborative registration of two vaccines (rVSV ZEBOV, Ad26.ZEBOV/MVA-BN-Filo /vaccinia Ankara prime boost) against Ebola, which are now available for use against outbreaks. The AVAREF Secretariat organized meetings to facilitate the joint registration of two vaccines against Ebola. These vaccines were subsequently prequalified by WHO [13].

Lessons from the COVID-19 pandemic

Pre-pandemic preparatory work: AVAREF organized a tabletop exercise in November 2017 simulating an outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) and charged a group of health professionals, scientists, staff of regulatory authorities and ethics committees and global health partners with coming up with the best way for AVAREF to accelerate product development during a pandemic. The group produced a set of recommendations, which were approved by the AVAREF assembly constituted of heads of NRAs and Chairpersons of the national ECs. A hypothetical scenario involving MERS-CoV was developed as a case study for the exercise. The aim was to encourage dialogue on how regulatory networks and the AVAREF joint review guideline could be leveraged most effectively to facilitate the accelerated development and deployment of promising vaccine candidates and in vitro diagnostic tools. Through this exercise, the AVAREF joint review guideline was determined to be suitable for its intended purpose. The group put forth several recommendations for AVAREF, suggesting enhancements to the Guideline and addressing the wider challenges that were recognized during the discussions. The second step was discussions and repurposing of Bill and Melinda Gates Foundation (BMGF) grants to the WHO to address COVID-19. Within this proposal, a clear capacity-building plan was developed. The plan set targets for capacity building to address research and development of therapeutics and vaccines against COVID-19. Critical activities were identified, with key outputs and results, aimed at desirable impacts on the pandemic. The next step was the development and implementation of the AVAREF emergency response plan to COVID-19. This plan aimed to create an appropriate forum for all R&D stakeholders to facilitate accelerated development of products against COVID-19 through targeted partner funding, enhanced capacity of regulators and ethics committees, engagement of researchers, sponsors, and product developers, as well as promotion of partnerships and dedicated information sharing. It was hoped that at least one vaccine and one therapeutic product against COVID-19 would be developed by the end of 2020. To implement this Action Plan, there were clearly defined work packages as follows:

Work package 1: supporting the implementation and documenting timelines for the “AVAREF Strategy and Guidance for Emergency Preparedness”. The pre-pandemic tabletop exercise of 2015 resulted in important recommendations in support of an emergency procedure and timeline for regulatory review and decision-making for clinical trials during the pandemic. These recommendations were used to develop the AVAREF emergency procedure. The timeline for ethics and regulatory review for a clinical trial application (CTA) of any licensed product is 10 days, and for a new product 14 days. The procedure was developed by the AVAREF Technical Coordinating Committee (TCC) and endorsed by the Steering Committee.

Work package 2: joint review of CTAs through emergency review process and scientific advice. The AVAREF joint review model [11] and scientific advice were extended to Product Development Partnerships (PDPs), sponsors, ECs, and NRAs. Due to restrictions on movement because of COVID-19, online meetings were organized by the secretariat for the stakeholders.

Work package 3: implement a strategy in collaboration with the African Union Development Agency-New Partnership for Africa´s Development (AUDA-NEPAD), Regional Economic Committees (RECs) and Africa CDC for Joint Review of COVID-19 vaccines under Emergency Use Listing (EUL) or Emergency Use Authorization (EUA) by NRAs through emergency review process and scientific advice. Through consultations with NRAs and their stakeholders, different scenarios were established for different COVID-19 vaccines and therapeutics. For scenario one, products on the WHO EUL would not require detailed reviews by NRAs before approval. Products not meeting EUL requirements or choosing not to undergo EUL evaluation but approved by stringent NRAs (United States Food and Drug Administration [USFDA] and European Medicines Agency [EMA]) would belong to Scenario two. Scenario two products would be evaluated minimally by a panel of experts from AVAREF. Scenario three products, not belonging to any of the other scenarios, would be evaluated by panels of experts selected by NRAs with external expertise from WHO Prequalification (PQ), the EMA, and others providing support.

Work package 4: joint monitoring of the safety of experimental products for COVID-19. AVAREF, working with AUDA-NEPAD as well as the BMGF, supported Ghana, Ethiopia, and South Africa to establish a common database for adverse events following immunizations (AEFIs) and to conduct joint signal detection for all vaccines against COVID-19.

Work package 5: COVID-19 AVAREF Virtual Forum for Regulators and Ethics Committees and Partners. To ensure that there was a frequent exchange of knowledge and information in general about COVID-19 as a new disease, frequent webinars were organized by the AVAREF secretariat. These meetings brought scientists working on COVID-19 to present the results of their work to regulators and ECs.

Work package 6: virtual webinars with research scientists, PDPs, and sponsors. The AVAREF secretariat also organized webinars to disseminate information about AVAREF products and services to PDPs and sponsors.

Work package 7: separate capacity building web-based training for Regulators and Ethics Committees. To ensure that, the capacity of ethics committees was also strengthened, and specific online training was offered to ECs. In addition to this, an online Good Clinical Practice (GCP) course, including GCP inspection of clinical trials, was developed.

Work package 8: communication and advocacy. The AVAREF secretariat took the opportunity to call for more resources in support of regulators. AFRO senior management played a critical role in the advocacy for AVAREF.

Table 1 and Table 1.1 depict the capacity-building activities that were planned in 2020, their expected outputs, expected results, estimated level of capacity built, and actual level of capacity built. Overall, it was hoped that these activities, when implemented, would result in the availability of at least one therapeutic and one vaccine for emergency use against COVID-19. However, by the end of 2020, no vaccine or therapeutic was implemented on the continent. Therefore, the target of availability and use of a vaccine or therapeutic for the disease was missed. The reasons for the inability to meet the expected levels of capacity have been highlighted in the Table. The reasons include delays in the initiation and completion of some of the activities. In addition, there were also delays by PIs, sponsors, and developers of these products. The percentages assigned to different activities are based on their potential contributions to the implementation of clinical trials, EUL, and the eventual availability of vaccines and therapeutics. From the two major clinical trials of antivirals that were tested on the continent using the AVAREF emergency procedure, four out of 11 countries met the AVAREF emergency timeline of 15 days, and five successfully reviewed and provided decisions between 16 and 30 days. Only two countries took a longer time of more than 30 days. For the chloroquine/hydroxychloroquine clinical trials, one out of 4 countries made it within 15 days, another one between 16 and 30 days, and the last two countries exceeded 30 days. Thus, clinical trials of these antivirals, whose results were eagerly awaited early in the COVID-19 pandemic, commenced within a couple of months under the AVAREF emergency review procedure.

AVAREF convened technical workshops to support member states on the EUA of all WHO EUL vaccines, as shown in the figure below. These technical workshops provided a platform for WHO prequalification teams of assessors to describe the assessment process and to provide details of the assessment report to facilitate subsequent national registration or approvals of COVID-19 vaccines within 14-30 days post EUL. They improved the harmonization of the review and processing of COVID-19 clinical trials and product authorizations. As of February 2023, 54 African countries (46 from the WHO African Region (AFR)) have authorized more than one COVID-19 vaccine, and 52 (44 from AFR) have authorized more than two vaccines.

The total number of authorizations provided by the NRAs for the COVID-19 Vaccines Global Access (COVAX) donated doses, all COVID-19 vaccines was 1287. Some of the NRAs do not issue EUAs but only issue import permits for the donation doses. Approximately 176 import permits were issued by the respective NRAs for a variety of COVID-19 vaccines. Figure 1 shows technical workshops focused on COVID-19 and other vaccine development conducted between 2021 and 2022. The real value of AVAREF is in its ability to support and accelerate R&D during epidemics and pandemics. This was demonstrated during the Ebola outbreak of 2014, the 2018-2019 Ebola outbreak (the world´s second-largest Ebola epidemic on record), and the COVID-19 pandemic [14-16]. AVAREF is best suited for this purpose due to several reasons. The network is agile and flexible, and recommendations are made and implemented across several countries without a binding treaty as compared to other networks. The partnership between WHO, the Gates Foundation, and others ensures that AVAREF receives support from a pool of experts while undertaking efforts to accelerate R&D. The governance model of AVAREF allows for its technical coordinating committee, with the support of the secretariat and other experts, to develop and implement their guidance documents and templates. Work sharing and the recognition of the decisions of each other´s expertise facilitate joint reviews and scientific advice, which are key during R&D in emergencies. It came as no surprise that during the review of the response to Ebola by the US National Academies of Sciences, Engineering and Medicine, the R&D for vaccines component that AVAREF participated in was assessed as the most successful [17].

Of the three Ebola vaccine candidates that received technical advice and underwent joint or assisted reviews, one played the key role in the ring vaccination trial that helped to control and eventually stop the Ebola epidemic in West Africa [18]. Similarly, despite earlier anxiety about African NRAs to reach decisions on COVID-19 vaccines in time for their introductions, all the vaccines that received WHO EU listing were duly approved and introduced across the continent, resulting in a vaccine glut. Although the implementation of the activities for capacity building for AVAREF did not result in the use of any COVID-19 vaccine in 2020 on the continent, by the first quarter of 2021, African countries had begun the implementation of COVID-19 vaccines under the WHO EUL. Delays in the implementation of some of the activities meant that very few clinical trials of vaccines against COVID-19 were conducted in Africa. More needs to be done to make AVAREF a more efficient platform in emergency R&D. In anticipation of a future pandemic, AVAREF undertook pre-pandemic preparation through a tabletop exercise in November 2017. The choice of SARS-COV-1 as the pathogen was appropriate and enabled the participants from research institutions, pharmaceutical companies, Ministries of Health, NRAs, and other partner organisations to discuss and agree on how they would respond to such an outbreak with the development of vaccines and therapeutics. The recommendations from this tabletop exercise would later be transformed into the AVAREF emergency procedure, which would be used during the COVID-19 pandemic. Preparatory work, including tabletop exercises, can play a meaningful role in contributing to capacity building for R&D, especially during epidemics and pandemics.

Additionally, the AVAREF response to COVID-19 covered the essentials for accelerating R&D, namely capacity building and knowledge sharing, online joint reviews and scientific advice, adoption of shorter timelines for reviews and decision making and close collaboration with other external NRAs. For instance, using the AVAREF emergency procedure with its shorter timelines, two major clinical trials of antivirals were successfully undertaken. While some countries met the emergency timelines for ethics and regulatory review followed by decision making, a few others completed the procedure after an additional two weeks or more. The sponsors and principal investigators of these trials expressed satisfaction with the performance of most of the countries. As a result, several products with potential antiviral effects were successfully screened, and the results were disseminated. Typically, these countries would normally have taken at least six months to review and provide decisions on clinical trial applications. AVAREF could use its platform as an approach for enhancing NRA capacity and effectiveness in research and development. By working with institutions, researchers, funders, and governments, AVAREF could facilitate the development of a continental R&D strategy that would enable progress during inter-outbreak/pandemic periods to provide viable options for addressing public health emergencies

Conclusion     

AVAREF has demonstrated its ability to accelerate R&D, resulting in the development and availability of therapeutics and vaccines in epidemics and pandemics. WHO-AFRO is able to leverage the AVAREF infrastructure to further enhance research and development. The tools and processes are available and can be used by other regional networks during any epidemic or pandemic.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Bartholomew Dicky Akanmori designed the study and prepared the initial draft. All authors provided significant input to subsequent revisions. Chinwe Iwu-Jaja completed and submitted the manuscript, overseeing the entire submission process. All authors have read, reviewed, and approved the final version.

Tables and figure     

Table 1: level of capacity built from planned activities to strengthen regulatory capacity for R&D of therapeutics and vaccines for COVID-19 by AVAREF in 2020

Table 2: level of capacity built from planned activities to strengthen regulatory capacity for R&D of therapeutics and vaccines for COVID-19 by AVAREF in 2020

Figure 1: AVAREF facilitated technical workshops for COVID-19 vaccines and other vaccines from 2021 to 2022

References