Harmonizing regulatory processes for clinical trials: the AVAREF toolkit and footprint

¹Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo, ²Regulation and Safety Unit, World Health Organization, Headquarters, Geneva, Switzerland, ³Regulatory Affairs, Coalition for Epidemic Preparedness Innovations, London, England, United Kingdom

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

Essay    

The need for harmonization of national medicines regulatory systems and procedures dates back centuries to allow for comparison of new products [1]. Countries made the justification for establishing national regulatory authorities (NRAs), and subsequently, regulatory authorities were established in North America and later in Europe to spearhead the regulatory harmonization effort. The African continent was among the last to establish regulatory authorities, mostly through the European colonial government that ruled in these countries.

To better understand the African regulatory landscape, the World Health Organization (WHO) undertook a detailed assessment of the regulatory systems across forty-six African Member States at the 1^st African Medicines Regulatory Authorities Conference (AMRAC) meeting in 2005 [2]. The findings from this assessment revealed that only 30% of African countries had regulatory authorities, Clinical Trials were poorly regulated with little oversight, and a well-established secretariat with expertise and experience to support African regulators was lacking. Furthermore, there was no sustained partnership with financial and technical support, and most regulatory authorities did not have the required expertise to manage health products, especially biologicals. There was no clear strategy to support regulatory capacity strengthening across the continent. Other deficiencies identified were competing and overlapping harmonization initiatives, weak political commitment, and a lack of prioritization of regulatory work.

Consequently, the WHO, working with partners, undertook efforts to address the recommendations from the assessment of regulatory systems. The African Vaccine Regulatory Forum (AVAREF) was therefore established by the WHO a year later to support Clinical Trial oversight function on the continent [3]. The strategy adopted for AVAREF was a network approach to ethics and regulatory capacity building and harmonization. Later, the African Medicines Regulatory Harmonization (AMRH) initiative was launched to bring together countries through the regional economic communities under the auspices of the African Union [4].

The AVAREF Secretariat was established by WHO with scientists and experts to support the initial countries of the network. Partnerships with financial and technical support came from the European Union through the EDCTP, the Bill and Melinda Gates Foundation (BMGF) and the Canadian HIV vaccine Programme. It was also agreed that AVAREF will bring together NRAs, ECs, sponsors, and a Clinical Trial registration platform, collectively called Pan African Clinical Trials Alliance (PACTA). Additional expertise for the African NRAs was provided by the USFDA, MHRA, Health Canada, and the European Medicines Agency. The initial informal nature of the network provided flexibility and rapid adoption of recommendations from its meetings. Under AVAREF, the PACTA strategy [5] depends upon three key targets. They include: 1) Standard procedures and methodologies will be available for submissions and processing of Clinical Trials applications. 2) Standard procedures and methodologies for reviews, decisions, and timelines. 3) Various tools will be available for scientific advice and R&D in general for vaccines and other health technologies. Thus, AVAREF has gone on to develop such a toolkit, which supports the review of Clinical Trial applications and provides oversight. The present article, therefore, unpacks the AVAREF toolkit and provides evidence of its impact. The toolkit includes requirements and a checklist for a complete Clinical Trial application, review timelines for different diseases of public health priority, guidelines for review and processing of applications, joint review procedure of CTAs, and scientific advice to sponsors and PIs. This paper aims to comprehensively examine the AVAREF toolkit development process, document its adoption across African member states, and assess its impact on Clinical Trial regulation harmonization. Through this analysis, we provide evidence of the toolkit's role in strengthening Africa's Clinical Trial ecosystem and its contribution to accelerating access to safe and efficacious medical products.

Why a toolkit?

A toolkit is a set of resources available for performing the functions of an institution or programme [6]. Toolkits allow for better organization, clear steps in processes, predictability of outcomes, and efficient delivery of services. The AVAREF toolkit was therefore developed to ensure that all the member states have information, recommendations, and resources to enable them to receive CTAs submissions, schedule and conduct reviews, and provide decisions to sponsors and principal investigators within recommended timelines. Other regulatory networks, institutions, and programs have developed toolkits that have played a critical role in ensuring that reviews of documents have been conducted efficiently [6]. Toolkits are used for a variety of other public health programmes, including storage, handling, and use of vaccines (CDC). The WHO in 2011 developed the Global Vaccine Safety Blueprint (GVSB) [7] to allow countries and networks in LMICs to carefully monitor immunization programs and case management. To successfully implement the GVSB, a toolkit was developed and made accessible to all countries [8]. For ethics and regulatory harmonization in Africa, it is essential that the same submission guidelines for Clinical Trial applications, review procedures, timelines for responses, and other information, recommendations, and related resources are used consistently by all ethics committees (ECs) and regulatory authorities.

Unpacking the AVAREF toolkit

The AVAREF toolkit comprises templates, guidelines, checklists, and training materials for the provision of scientific advice to applicants, multi-country review of Clinical Trial applications, and inspection of Clinical Trial sites. The toolkit documents listed below are available on the AVAREF website [9]. The different elements of the AVAREF toolkit are outlined under this section. The open-access approach ensures that sponsors, investigators, regulators, and ethics committee members across Africa and globally can utilize these standardized resources to foster efficiency and harmonization.

AVAREF checklist and application form for submission of Clinical Trial applications

Principal among the resources required for the assessment of a Clinical Trial application by an NRA or EC is a common checklist for the requirements of a Clinical Trial application. Such a tool, if common to all NRAs and ECs of the different countries of the continent, will significantly benefit investigators and sponsors. Through AVAREF, there is a harmonized list of requirements for Clinical Trial applications applicable to all African countries. The checklist includes the title, a list of investigators, and all sections of a Clinical Trial application.

Timelines for review of Clinical Trial applications for investigational products addressing different diseases of public health priority

Essential for efficient processing of Clinical Trial applications is a predictable timeline that governs the process. Most regulatory authorities and ethics committees often provide a timeline for processing of applications, which enables sponsors and principal investigators to better plan for these expensive Clinical Trials. In Africa, timelines for processing applications are often ad hoc and dependent on the fees payable to the NRA or EC. The basis of the AVAREF timelines for processing of Clinical Trials is largely the public health impact of the target disease [10]. Having recognized the long delays in processing of Clinical Trial applications in Africa, WHO has supported the AVAREF secretariat to set timelines for different types of Clinical Trials on the African continent. This tool in the AVAREF toolkit established three key timelines. These different timelines cover Clinical Trials of vaccines and therapeutics for non-endemic diseases and conditions, denoted as the regular timeline. The second timeline for processing of Clinical Trial applications applies to products against diseases that are considered as public health priorities for the African continent. This timeline is shorter than the regular timeline. To address Public Health Emergencies of International Concern (PHEIC) and epidemics within the continent, a much shorter timeline referred to as an emergency timeline has also been established. This third timeline covers products under development against diseases classified by the WHO as PHEIC, or epidemics within the African continent. Further details of each of the three timelines are provided below.

Regular timeline: the first timeline to be established by AVAREF for the processing of Clinical Trial applications applies to all endemic diseases on the continent. The time taken from submission of an application, its verification, review, and final decision has been set at 60 working days. The timeline includes clock stops for investigators and sponsors to address incomplete application packages or to provide responses to queries raised by the NRA or ECs. AVAREF promotes simultaneous submissions of Clinical Trial applications to NRAs and ECs, thus ensuring that within 60 days, a sponsor would have received a decision on an application from the NRA. Examples of products successfully reviewed for Clinical Trials under this timeline include the meningococcal A conjugate vaccine, rotavirus vaccines, vaccines and therapeutics against malaria, TB, and HIV. This timeline applies to applications targeting the major endemic diseases of the continent.

Expedited timeline: the expedited timeline arose from the largest outbreak of Ebola virus disease, caused by Ebola Zaire. The Ebola outbreak was devastating and without reliable treatment, and no vaccine. Clinical Trials of therapeutic and candidate vaccines became a major priority. Additionally, shorter timelines for processing of CTAs became critical. During the outbreak of Ebola, which started in Guinea, Liberia, and Sierra Leone in 2014, AVAREF engaged scientists, developers, sponsors, NRAs, and ECs to agree on a shorter timeline of 30 working days for the complete processing of Clinical Trials applications for therapeutics and vaccines against the disease. The expedited timeline prioritizes R&D of products against the priority public health diseases of the African continent. The timeline is also applicable to any other diseases that the WHO considers a public health priority for the continent, and encourages developers as well as Product Development Partnerships (PDPs) to invest in R&D in Africa.

Emergency timeline: the establishment of the emergency timeline was intended to facilitate rapid product development during public health emergencies. The COVID-19 pandemic required that AVAREF build the capacity to review Clinical Trials applications for therapeutics and vaccines against the disease. This timeline covers two categories of therapeutics: those previously licensed and repurposed to address the disease and novel products, including vaccines. A timeline of 15 working days is applicable to novel investigational products/ candidate vaccines, while previously licensed and repurposed medicines attract a shorter 10 working days under the emergency timeline. AVAREF applied this timeline to licensed antivirals, vaccines, and other health products against COVID-19. The impacts of this tool on the pandemic were that treatments and vaccines were available for use on the continent within a year [11].

Guideline for Clinical Trial application processing

The AVAREF network recognized the need for a common procedure or process for the processing of Clinical Trials trial applications by NRAs and ECs as fundamental to regulatory harmonization. The AVAREF guideline for processing of applications was developed and quickly adopted by all the countries of the network and subsequently the continent. The guideline defines the steps for processing an application, beginning with the receipt and screening of the application for completeness. The AVAREF Clinical Trial application form is designed to collect comprehensive details related to Clinical Trials, making it uniquely identifiable. The form includes sections to capture essential data such as: trial information, regulatory details, sponsor investigator and trial site information, investigational medicinal product (IMP) details, trial scope, and recruitment details. It also provides information on how to convene the reviewers for an application, the use of experts, meetings with the sponsor, compilation of questions, and the communication of the final decision. The AVAREF Clinical Trials application processing supported harmonization of the processes by different countries and was the basis for joint review of multi-country Clinical Trial applications. The impact was a progressive increase in joint reviews of multi-country Clinical Trials and more health products against public health priorities on the continent. This steady increase in joint review began with RTSS in 2007, joint reviews of two candidate vaccines against Ebola in 2014 and 2015, and joint reviews of therapeutics against several COVID-19 therapeutics and the R21 malaria vaccine in 2020 [10].

Guideline for joint review procedure of Clinical Trials applications

The joint review procedure became necessary because of multi-national Clinical Trials, involving an application submitted to two or more countries on the continent. The first of these was the application for the trial of the meningococcal A conjugate vaccine in three countries in West Africa. The guideline enabled the three countries to apply a harmonized procedure to jointly review one Clinical Trials application. The procedure describes the submission of the application, the collation of all the questions from different reviewers, and a face-to-face meeting involving the applicant, the ECs, and NRAs of the participating countries to discuss and resolve the questions. A final set of recommendations agreed to by all the countries becomes the basis for a final decision by all the countries. The guideline also describes roles for the chair of the review committee, discussants, and rapporteurs for the procedure. The impact of joint reviews of Clinical Trial applications is reflected in the availability of vaccines, which include the meningococcal A conjugate vaccine, vaccines against malaria, Ebola, and other priority diseases now available on the continent [12-14].

Guideline for scientific advice to sponsors and PIs

During R&D, sponsors and product developers need to engage with regulators and ethics committees as early as possible to obtain advice and information. AVAREF scientific advice gives sponsors, developers, opportunity to obtain scientific advice from a panel of experts made up of the Clinical Trials target countries´ regulators and independent subject matter experts. For example, in 2022, the Secretariat organized a scientific advice session for Medicine for Malaria Ventures MMV in relation to a new combination against acute malaria [15]. The panelists discuss the candidate's therapeutic, the trial design, endpoint, and outcomes with the sponsor and investigators. The panelists provided written scientific advice to the sponsor. The potential impact of scientific advice is that it reduces delays in Clinical Trials and improves the chances of success.

Good clinical practice (GCP) inspection and oversight tools

Once the Clinical Trial is approved, the GCP Inspection Guide and the GCP Inspection Checklist provide a standardized framework for regulatory authorities to assess compliance with approved protocols, ensure integrity of the trial, and quality in implementation of the Clinical Trials. These tools ensure that trials adhere to WHO and other international ethical, scientific, and regulatory standards, strengthening oversight across Africa. The GCP Inspection Guide offers structured recommendations for preparing and conducting inspections at all trial phases. Subsequently, the GCP guide and the inspection process were transformed into an online course and are available to sponsors, NRAs, ECs, investigators, and academic and research institutions. The potential impact is a harmonized approach to ascertaining GCP readiness before and during the trial.

The guidance on emergency preparedness

Two AVAREF guidelines have been developed to support joint Clinical Trials evaluations and regulatory system preparedness in emergencies, reinforcing harmonized regulatory oversight across Africa. The Guidance on Emergency Preparedness equips regulators with strategies to respond rapidly and effectively during public health emergencies. It provides streamlined regulatory pathways, risk-based decision-making frameworks, and expedited approval mechanisms to accelerate access to critical medical interventions while maintaining safety, scientific integrity, and ethical standards. The implementation of these tools made an impact during the Ebola epidemic and the COVID-19 pandemic, ensuring that therapeutics and vaccines were made available in the shortest time possible.

Chronology of development of these tools

The formal development of these tools began in earnest with the establishment of AVAREF in 2006. Although these tools were not formally endorsed by all the country´s, some of the tools were nonetheless in use in several countries. Subsequently, formal endorsement took place at AVAREF assembly meetings. Efforts at tools development were accelerated when the Paul Ehrlich Institut's VaccTrain Team commenced providing technical support to the Clinical Trials Working Group under the framework of the German Global Health Protection Programme. This collaboration, specifically aligned with AVAREF's 2018-2020 strategic plan and recommendations from the International Conference of Drug Regulatory Authorities (ICDRA) 2016, facilitated the systematic compilation and review of templates used by reference African National Regulatory Authorities and international regulatory bodies. The ICDRA 2016 recommendations specifically encouraged low and medium-income countries to follow models used by well-established international NRAs for Phase I-III clinical trials, providing the methodological foundation for AVAREF's approach.

The Clinical Trials Working Group (CTWG), comprising experts from Burkina Faso, Ghana, Kenya, Malawi, Nigeria, Uganda, and Zimbabwe, undertook the comprehensive task of developing harmonized submission and assessment templates. In the initial stage, the CTWG systematically compiled and reviewed templates to assess Clinical Trials applications, including quality, non-clinical, and Clinical Trials application forms used by reference African NRAs and other international regulatory authorities. Parallel to the Clinical Trials toolkit development, the Good Clinical Practice inspections working group collaborated with WHO consultants to develop Clinical Trials inspection guides and checklists. Notably, the GCP inspection checklist, though developed in 2017, underwent pilot testing in 2019 to ensure practical applicability across diverse regulatory environments. The harmonized Clinical Trial application form and assessment templates were further revised by the Technical Coordinating Committee and endorsed by the Steering Committee at AVAREF's fifth meeting in September 2018, marking a crucial milestone in the toolkit's development journey. The tools underwent further refinement through 2019, culminating in their presentation to the Technical Coordinating Committee and Steering Committee during the July 2019 meetings in Brazzaville, Republic of Congo. The final endorsement occurred at the second biennial AVAREF Assembly held on October 2, 2019, in Victoria Falls, Zimbabwe, where member states unanimously adopted the comprehensive toolkit, fulfilling the strategic vision articulated in the 2018-2020 strategic plan.

Continental adoption and implementation

The adoption pattern of AVAREF tools demonstrates a strategic approach to continental harmonization, beginning with early adopter countries and expanding through regional economic communities for domestication. The initial implementation occurred through the Clinical Trials Working Group member countries, which served as testing grounds for the harmonized templates. Ghana, Kenya, Zambia, and Nigeria emerged as early leaders in introducing and disseminating the tools within their regulatory frameworks, demonstrating practical application of the standardized processes. The strategic vision, articulated before the 2019 Assembly, aimed to have all 55 African member states adopt and incorporate the tools into their battery of instruments for evaluating Clinical Trial applications, including emergency preparedness scenarios. This unanimous endorsement reflected the growing recognition of standardized tools' value in addressing the heterogeneous regulatory landscape that had previously presented regulatory challenges for sponsors across Africa's diverse regulatory environments.

The tools were subsequently piloted with representatives from major regional economic communities, including the Economic Community of West African States (ECOWAS), the East African Community (EAC), and the Southern African Development Community (SADC), ensuring regional representation and buy-in. The strategic approach emphasized sharing tools with regional economic communities specifically for domestication rather than mere implementation, recognizing the importance of local adaptation while maintaining harmonized standards. The commitment to publishing tools on the AVAREF website ensured broader accessibility and transparency across the network.

Demonstrable impact and outcomes

It is generally not easy to prove the impact of the use of a toolkit. The AVAREF toolkit's impact manifests through tangible improvements in Clinical Trials oversight and regulatory efficiency across multiple disease areas and emergency contexts, directly supporting the overarching goals of improving regulatory systems, accelerating development of safe and efficacious medical products in Africa, reducing mortality and the burden of epidemics, and improving quality of life. The joint review procedures, beginning with the groundbreaking meningococcal A conjugate vaccine trial across three West African countries, established a precedent for multi-country regulatory coordination that has since been replicated across numerous therapeutic areas. Under the regular timeline framework of 60 working days, the toolkit has facilitated successful reviews of critical public health interventions, including meningococcal A conjugate vaccine, rotavirus vaccines, and various vaccines and therapeutics targeting malaria, tuberculosis, and HIV. These achievements represent significant progress in addressing diseases that disproportionately affect African populations, demonstrating the toolkit's practical value in accelerating access to life-saving interventions while maintaining rigorous scientific standards.

The expedited timeline of 30 working days, established during the 2014 Ebola outbreak, proved instrumental in facilitating rapid therapeutic and vaccine development during public health emergencies. This framework enabled coordinated responses across Guinea, Liberia, and Sierra Leone, and demonstrated AVAREF's capacity to adapt regulatory processes to emergency contexts while maintaining scientific rigor. Perhaps most significantly, the emergency timeline framework developed during the COVID-19 pandemic showcased the toolkit's flexibility and responsiveness to global health crises. The strategic commitment to use the standardized templates for all future joint reviews of Clinical Trials applications coordinated by AVAREF has created consistency and predictability in multi-country regulatory processes. Beyond individual product approvals, the toolkit has strengthened regulatory capacity through joint Good Clinical Practice inspections, technical support provision to member countries, and the establishment of the African Advisory Committee on vaccine safety. These capacity-building initiatives have created a foundation for sustained regulatory excellence across the continent. However, implementation challenges remain evident, particularly in achieving consistent timeline adherence across all member states. Low data reporting rates and communication gaps between the Secretariat and member states underscore the ongoing need for enhanced coordination mechanisms and more effective information exchange systems. Looking forward, technological innovations represent the next evolution in toolkit sophistication.

Conclusion     

The AVAREF toolkit represents a transformative achievement in African regulatory harmonization. From its systematic development beginning with the establishment of AVAREF in 2006, the toolkit has demonstrated measurable impact through successful joint reviews, emergency response capabilities, and capacity building initiatives. Despite implementation challenges, the standardized tools have established a foundation for regulatory excellence, positioning Africa to accelerate access to safe and efficacious medical products while addressing the continent's disproportionate disease burden.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Bartholomew Dicky Akanmori developed the study concept and prepared the initial draft. All authors provided substantial input and revisions to later versions. They reviewed and approved the final version of this manuscript.

References