Joint reviews and scientific advice: a deep dive into AVAREF´s signature services

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    

National Regulatory Authorities (NRAs) and Ethics Committees (ECs) provide essential regulatory decision-making and/or oversight for the development, evaluation, and use of health products in their national jurisdictions. These institutions, in carrying out their functions, provide certain services to their end users and stakeholders. In a recent article, we have argued that NRAs and ECs are not simply gatekeepers but important actors in ensuring that products are developed to meet public health requirements [1]. Thus, by offering such services that lead to access to safe and effective health products of assured quality, NRAs and ECs carry the weight of the responsibility to safeguard the health and well-being of communities. In recognition of its important role in public health, the African Vaccine Regulatory Forum (AVAREF) in its formative years, developed several services [2] which it makes available to clinical trial investigators, sponsors of clinical trials, product developers, and their partners to facilitate product development [3].

In the present article, we focused on the multi-country clinical trial application joint review procedure and the scientific advice, two signature services offered by AVAREF. The manuscript describes the need for these services, especially in low to middle-income countries (LMICs), and highlights situations in which these services have proven critical in supporting research and development. The article also captures timelines for these services using data compiled by the WHO AVAREF Secretariat.

As a service, the AVAREF joint review procedure is a unique process developed to facilitate the scientific and ethics review of a clinical trial application submitted by investigators or sponsors to two or more countries. It enables ECs and NRAs of different countries to nominate experts who would review a common application for a clinical trial, to collectively prepare a consolidated list of questions for the sponsor, and to discuss directly with the sponsor the candidate product, trial design, safety, and other aspects of the proposed trial. It lends itself to situations where investigators and sponsors seek a decision on a multi-country clinical trial application within a pre-specified timeline, much shorter than submitting their application country by country, while ensuring that the same parameters and standards are achieved across all the clinical trial sites. The AVAREF joint review procedure is particularly important for multi-country trials by ensuring that there is heterogeneity of study participants enrolled and that data obtained are representative of a sub-region or the continent at large [4]. This service has been offered in both routine clinical trials and public health emergencies, and it has shown great value in epidemics and pandemics, where there is limited efficacy or safety data for a product whose development has to be accelerated to help prevent deaths [5]. In short, AVAREF joint reviews are intended to enhance the quality of the reviews of an application submitted to multiple countries, optimize review timelines for such applications, serve as a platform to allow regulators and ECs to exchange and validate their findings with peers, and act as a capacity-building mechanism.

Each joint review is preceded by a request from the sponsor to the WHO AVAREF secretariat. Once the WHO has obtained written confirmation from the NRAs and ECs, the AVAREF secretariat convenes a pre-submission meeting, the purpose of which is to present the product, the clinical trial plan, and agree on all the terms and conditions of the joint review, including the proposed timelines. The next steps, after a decision is made to proceed with the joint review, are the setting up of a secure electronic submission and review platform by WHO, followed by electronic submission of applications at the national level by the sponsor. The AVAREF Secretariat then convenes the joint review meeting itself, but serves as a neutral broker with no influence over the review and its outcome. The secretariat also follows up with all participants (NRAs, ECs, sponsors, investigators, etc.) to ensure that they meet the agreed timelines for each stage until a final decision, which is the key outcome of the joint review procedure, is communicated to the sponsor by each participating country [6].

As a service, the AVAREF scientific advice procedure was introduced later. Before that, the AVAREF secretariat, with other experts, provided scientific and regulatory advice on an ad hoc basis to any sponsor who required this service. The scientific advice process enables NRAs, via the AVAREF Secretariat, to provide unbiased, up-to-date, and consistent regulatory and scientific feedback to sponsors. The feedback covers products under development, clinical trial design, safety considerations, and available regulatory pathways to take their products forward to marketing. The process brings sponsors together with subject matter experts, experts from ECs and NRAs from several countries, to answer a set of questions compiled by that sponsor on its product intended for clinical evaluation and subsequent marketing on the continent. This is exemplified by the collaboration put in place through the AVAREF network, which led to the development of vaccines against Ebola [5]. The service becomes very important when it precedes a joint review or during an epidemic or a pandemic involving a hitherto unknown pathogen.

A scientific advice session is triggered by an official request from the sponsor to the AVAREF secretariat. The secretariat assembles the experts who may be immunologists, pharmacologists, epidemiologists, pathologists, toxicologists, biostatisticians, and other disciplines with relevant experience in research and development (R&D). Having established confidentiality and a declaration of interest by the panel of experts, the secretariat convenes the scientific advice session. The panelists select their own chair and provide independent advice without any influence from the sponsor. The AVAREF secretariat is responsible for convening the meeting and following up to ensure that the experts complete their report, which is submitted to the sponsor who requested the service [3]. Our manuscript provides a brief historical context, describing in detail the services offered by AVAREF and timelines for service delivery. We also highlight feedback from stakeholders, identify challenges associated with the service delivery, and discuss how to improve performance. Furthermore, we point out the importance of these services and how they can become part of the work of the African Medicines Agency (AMA).

Description of the AVAREF joint review procedure as a service: the AVAREF joint review procedure has specific requirements. These requirements are: (i) Expression of interest or specific request from a sponsor, product development partners (PDPs), NRAs, and ECs of at least two countries, the WHO, or other international organization. (ii) The target product should be against a public health priority disease or condition in Africa. (iii) The intended clinical trials must be conducted in African countries. The joint review service is divided into specific steps that reflect the sequence of events. These steps are: (i) The official request through AFRO management (the regional director´s office). This step is handled by the AVAREF Secretariat at AFRO (avaref@who.int). (ii) After the regional director´s approval, the AVAREF Secretariat confirms the requirement and communicates officially with various entities to secure nominations. (iii) Pre-submission meeting organized by AVAREF Secretariat. The pre-submission meeting brings together ECs and NRAs of the participating countries, observers from additional countries where the sponsor has agreed to the joint review, including observers, sponsor(s), PIs, and AVAREF Secretariat. (iv) Training on the use of the WHO secure digital platforms. This is the responsibility of the AVAREF Secretariat. (v) Submissions of Clinical Trial Applications (CTAs) to ECs and NRAs directly and an upload onto the WHO digital platform. (vi) EC and NRA reviews and posting of queries onto the platform. Access to the platforms is provided through the AVAREF Secretariat. (vii) AVAREF Secretariat downloads of queries and responses by sponsors ahead of joint review meetings. (viii) Convening of the joint review meeting by AVAREF Secretariat. (ix) Follow up with all joint review participants to meet timelines on decisions. (x) Closure of joint reviews by AVAREF Secretariat. Depending on the type of joint review (regular 60 days, expedited 30 days, or emergency 10 and 14 days), each step is allocated a timeline that is closely monitored by the AVAREF Secretariat.

Compilation and analysis of data on specific steps of the joint review: data compiled by the AVAREF Secretariat on joint reviews was tabulated. The data was then analyzed to show timelines for each specific step and to highlight proportions of countries that met the approved timelines for the reviews. Where delays occurred, the secretariat identified the causes and documented them.

Round table discussion, exit interviews and surveys: for this manuscript, information from roundtable (focus group) discussions with ECs and NRAs who participated in joint reviews was summarized and included under the results section. In addition, post joint reviews or exit interviews were carried out with some of the focal points who participated in the joint reviews. The information obtained from the interviews was analyzed and presented as part of the results. Finally, we also did surveys which covered joint reviews. All the research methodologies were consistent with standard qualitative research [7].

Description of the AVAREF scientific advice process as a service: the scientific advice process also requires that some conditions be met. These conditions are: (i) Formal request to the WHO Secretariat. (ii) Linkage to a product of public health priority to the region. (iii) Clinical trials or R&D on the African continent. The specific steps for a scientific advice process are as follows: (i) Request from a sponsor, PDP, or principal investigator (PI). (ii) AVAREF Secretariat ascertainment of the requirements, identification of subject matter experts, and official communication with various entities. (iii) AVAREF Secretariat establishes declaration of interest (DOI) and confidentiality agreements with scientific advice panelists. (iv) AVAREF Secretariat compilation of questions from the sponsor/ PDPs/PIs and communication with panelists. (v) Convening of the scientific advice meeting. (vi) Follow up by AVAREF Secretariat for completion of the report of the scientific advice panelists and dissemination of reports.

Compilation and analysis of data on specific steps of the scientific advice process: data compiled by the AVAREF Secretariat on scientific advice were tabulated. The data were then analyzed to show timelines for each specific step and to highlight proportions of panelists who met the approved timelines for the scientific advice. Where delays occurred, the secretariat identified the causes and documented them.

Exit interviews and surveys: the Boston Consulting Group (BCG), on behalf of the AVAREF, conducted exit interviews with the sponsor/PDP/PI and panelists. The information was tabulated and analyzed as part of the results. The Secretariat also conducted surveys and compiled the data (Table 1, Table 2). All the research methodologies were consistent with standard qualitative research [7].

Stakeholders´ feedback on AVAREF joint reviews, the case of ANTICOV Consortium COVID-19 clinical trial application: this was the largest clinical trial in Africa to treat COVID-19 cases. It involved multiple sponsors (26 members of the consortium), 13 African countries, and was conducted across 19 clinical trial sites. Stakeholders highlighted some key successes during this joint review. The first success highlighted relates to the accelerated process and decision. The sponsor indicated that despite some delays, the emergency joint review resulted in faster decisions than would have otherwise been possible. Seventy percent of the authorities who participated in the joint review were able to deliver decisions within 25 days or fewer. The second strong point concerns improved review and outcomes. Through collaboration, countries were able to conduct a more thorough review, which improved the overall protocol and allowed countries to learn from one another. The third and final highlight is about the positive impact of the interventions. Introducing discussants and adding a meeting to resolve outstanding queries were beneficial, and progress management was improved by internal tracking tools.

Institutions and networks that succeed often have clearly defined services that they render. These services must be known to all their stakeholders and should have well-defined timelines, as part of a robust quality management system and in line with the service charter of the institution. It is important to have predictable timelines for product development, especially in the pharmaceutical industry. Funding for the discovery and development of new therapeutics and vaccines costs the industry a lot of money, and any delays in the process can escalate costs and may adversely affect their development [8]. It is also important to stress that global public health needs have grown, and shorter timelines are expected for products to meet public health expectations. The case of COVID-19 R&D for therapeutics and vaccines confirms this important assertion. Governments, philanthropists, and the WHO had high expectations of industry to come up with vaccines and therapeutics against SARS-CoV-2 within months rather than years. Consequently, by providing well-defined services with timelines, AVAREF seeks to support faster R&D and access to public health interventions.

The continent of Africa must address frequent epidemics of Lassa fever, Monkeypox, Ebola, and other diseases for which there were no vaccines and therapeutics for several decades. In addition, the region must be ready for other endemic diseases for which there are no effective vaccines or therapeutics. Therefore, ECs and regulators have a critical role in R&D on the continent. AVAREF, in recognizing this, together with evidence of prolonged timelines for processing of clinical trial applications, therefore considered it critical to clearly define its flagship services in support of clinical trials and product development in general. These timelines were linked to different categories of diseases, namely endemic diseases, which require priority interventions, frequent causes of epidemics, and pandemics.

The feedback from all stakeholders and users of these services is a critical part of the monitoring and evaluation of performance. Generally, stakeholders are satisfied with the services rendered by AVAREF. However, delays often occur, especially when it comes to making final decisions and communicating this to the sponsors. Occasionally, as the data shows, a few countries would not decide within the agreed timeline. The AVAREF Secretariat is working on new ways of ensuring that ECs and NRAs comply with their own decisions and recommendations to eliminate this problem. Although the AVAREF service offering delivery of outputs is a work in progress, the impact is already being felt, and AVAREF services are in the process of remarkably altering product development in Africa. This is expected to reflect an improvement in access to health products. The commitment of WHO management at the highest level, together with partner commitment, both technical and financial, would be critical going forward. Another dimension to the AVAREF services is that they apply to all countries, and this is often reinforced during the implementation by requesting that the countries sign an MoU to commit to the timelines. However, the recommendations from a joint review have been opened to individual country decisions.

It is important to note that the AVAREF joint review process has integrated within its capacity building for reviewers, developing a community of trust, and ultimately developing a basis for the application of reliance. The joint process enables less experienced reviewers to learn from others within the community, hence building trust, the basis for reliance policies. Similarly, the use of the platform and associated tools also enhances the adoption of the common tools developed by AVAREF, thereby increasing regulatory harmonization, convergence, and excellence within the community of reviewers. With the operationalization of the African Medicines Agency (AMA), the use of the platform becomes a means or model for the operationalization of AMA.

On the other hand, AVAREF is a facilitator with no power or authority to enforce, for example, the agreed timelines. In addition, AVAREF does not collect any fees for its coordinating and management role for the process. Thus, AVAREF relies on the goodwill and willingness of participating countries to fulfill the outcomes of joint reviews. These issues would need to be addressed for sustainability. Additional process improvements could be introduced, such as sponsors having to submit only one complete CTA, even if it implies that payments are made to the individual countries. An alternative should be one payment to the AVAREF Secretariat, which then will distribute these payments to the respective participating NRAs.

Conclusion     

While the timelines for AVAREF joint processes are significantly improved relative to working outside the AVAREF platform, additional improvements could be made. The non-tracking of the stop clocks within the joint reviews also needs to be addressed. The AVAREF joint review lends itself to further process improvements and has been tried and tested. Other regional and global networks may benefit by emulating what AVAREF has done by providing such services at a continental level.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Bartholomew Dicky Akanmori was responsible for the study conceptualization and writing the original draft. The manuscript underwent several rounds of critical revisions by Kwasi Nyarko, Diadié Maïga, Jacqueline Rogers, Charles Shey Wiysonge, and Chinwe Iwu-Jaja. Chinwe Iwu-Jaja prepared the final manuscript for submission and coordinated the submission process. All the authors have read and approved the final version of this manuscript.

Tables     

Table 1: types of joint reviews and timelines

Table 2: scientific advice process, steps, and timelines

References