Joint review for a phase 3 multicentre vaccine candidate against tuberculosis by the African Vaccine Regulatory Forum Secretariat

¹Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo, ²Regulatory Affairs, Coalition for Epidemic Preparedness Innovations, London, United Kingdom, ³Gates Foundation, Nairobi, Kenya

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

Essay    

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Although treatable and curable, it is one of the leading causes of death globally, coupled with huge economic implications on households [1]. As of 2021, 23% of TB cases globally occurred in the WHO African Region [1]. In 2022, TB continued to be the second leading cause of death worldwide from a single infectious agent, after COVID-19, and resulted in nearly twice as many deaths as HIV/AIDS [2]. In 2023, the WHO African and South-East Asia regions accounted for 80% of global TB deaths among HIV-negative individuals and 81% of total TB deaths, including those with HIV [3].

Although the Bacillus Calmette-Guerin (BCG) vaccine has been widely used and has a long history of protecting infants and young children from severe TB, it does not offer sufficient protection against pulmonary TB among adolescents and adults who carry the highest burden [4]. Therefore, developing new TB vaccines for these age groups is essential to hasten the eradication of the TB epidemic [5]. One of the commitments of the recent United Nations high-level meeting on TB in 2023 is to expedite the research, development, and deployment of safe, effective, affordable, and accessible TB vaccines within the next five years, utilizing global collaboration platforms and WHO initiatives [3].

It has been estimated that a vaccine developed for adolescents and adults that is 50% effective in preventing TB could potentially avoid a total of 37.2 to 76.0 million cases and save between 4.6 and 8.5 million lives between 2025 and 2050. While one with a 75% efficacy has the potential to prevent 54-110 million new cases of TB and 6.7-12.3 million deaths caused by TB within the same period [4]. Therefore, the timely availability of a safe and effective vaccine is urgently needed to reduce global incidence and mortality caused by TB in line with the global strategy for TB research and innovation [2]. As of 2023, there were about 16 TB vaccine candidates in the pipeline [2]. Six of them were in Phase III trials as of August 2024 [3].

Clinical trials can be conducted across multiple countries and various sites within countries for the same product. In a multi-center, multi-country clinical trial, it is necessary to submit clinical trial applications (CTAs) to individual national regulatory authorities (NRAs) and ethics committees (ECs), typically adhering to varying formats specified by each country. Individual reviews will be conducted at separate times before the communication of outcomes to the sponsor. Moreover, numerous questions submitted by countries are likely to exhibit similarities, making the process of raising and responding to queries a highly inefficient one for all parties. In 2006, the WHO introduced the concept of joint reviews within the context of the African Vaccine Regulatory Forum (AVAREF) to enhance the evaluation of multi-country clinical trial applications, facilitate the harmonization of regulatory requirements, practices, and processes across countries, and strengthen capacity for more efficient oversight [6-9]. In this paper, we describe the joint review procedure of a clinical trial protocol, known as the Gates Medical Research Institute (MRI) study aimed at assessing the “prophylactic efficacy, safety, and immunogenicity of the investigational M72/AS01E-4 Mtb vaccine when administered intramuscularly on a 0,1-month schedule to adolescents and adults (15 to 44 years of age)”. We also highlight the experiences of the reviewers who were part of this procedure.

AVAREF secretariat joint review procedure

The AVAREF Secretariat´s joint reviews aim to improve the quality of reviews for applications submitted across multiple countries, streamline review timelines, facilitate the exchange and validation of findings among regulators and ethics committees, and serve as a tool for capacity building. Three distinct options for joint reviews exist within the support framework offered by the AVAREF Secretariat to Member States and sponsors. Regular joint reviews occur within a 60-day timeline, expedited reviews within 30 days, and emergency reviews within 10 to 15 days [7]. Upon submission of an expression of interest by the applicant (product developer) to the AVAREF Secretariat, a preliminary meeting is arranged to discuss a joint review pathway and to establish subsequent steps for joint reviews. The NRAs, ECs, and relevant institutional review boards (IRBs) are invited to engage in a joint review procedure and establish timelines based on the specific joint review pathway types. The AVAREF Secretariat facilitates the coordination of joint reviews by organizing meetings and ensuring adherence to timelines.

The Gates-MRI clinical trial application expedited joint review

The AVAREF Secretariat facilitated the Joint Review of the Gates MRI study, involving four countries, namely Kenya, Malawi, Mozambique, and Zambia. This meeting started with a virtual pre-submission meeting on December 4, 2023, which was followed by the in-person joint review meeting held on January 24-25, 2024, in Addis Ababa, Ethiopia. Before this meeting, Gates MRI (the sponsor), submitted the clinical trial application. The submission was independently evaluated by focal points from the ECs and NRAs of the participating countries. Gates' MRI addressed the review queries from the participating countries through the AVAREF Secretariat.

During the two-day in-person joint review meeting, each country was represented by members of NRAs, ECs, and/or IRBs. This meeting´s objectives were to: i) engage with the sponsor regarding the queries raised by the reviewers and their responses, ii) discuss any outstanding queries that arose during the meeting, iii) collectively agree on a timeline for addressing the outstanding queries and completing the rest of the joint review procedure, and iv) come to a unified recommendation on the CTA. Following the joint review procedure, the AVAREF Secretariat sought feedback from the reviewers to gain insights into their experiences and identify potential areas for improvement. Reviewers were invited to share their perspectives on the strengths and challenges encountered during the joint review, as well as their suggestions for enhancing the process.

The overall experience with the AVAREF Secretariat´s facilitated joint review procedure for the Gates MRI TB vaccine candidate

The AVAREF Secretariat -facilitated joint review procedure has been widely recognized for its strengths, challenges, and opportunities for improvement. One of the key strengths highlighted is the platform´s ability to foster effective collaboration and knowledge sharing among regulators and assessors across multiple countries. The procedure has also been commended for its efficiency, particularly in reducing timelines for clinical trial approvals through streamlined interactions between ECs and NRAs. Additionally, the procedure was described as well-structured, professional, and organized, with many expressing appreciation for the AVAREF Secretariat´s responsiveness. Beyond the technical aspects, the platform provided meaningful opportunities for personal and professional growth.

Despite these strengths, some challenges were noted. A recurring issue was the late receipt of protocols from sponsors at the individual country level, which posed difficulties in ensuring timely reviews. This can be attributed to the lack of a centralized submission process, requiring sponsors to submit documents to each participating country separately. Consequently, the timeliness of document submission varied across countries, raising questions about the reasons behind these disparities. Furthermore, in some instances, reviews commenced without all the required documents being received, which occasionally hindered the review procedure. Logistical challenges, particularly those related to time zones and the hybrid meeting format, were also highlighted as barriers to seamless collaboration

Effectiveness and efficiency of AVAREF Secretariat in coordinating the review procedure

AVAREF Secretariat's role in coordinating and facilitating the review procedure was generally considered to be beneficial. A key strength noted was the Secretariat´s proactive and organized approach in more recent years, which ensured timely engagements, streamlined communication, and effective management of timelines for responses to queries. The AVAREF Secretariat was commended for the organized and structured approach to communication of timelines, which kept reviewers informed and engaged, leading to a smooth and productive review procedure. The online platform used by the Secretariat for storing documents, including protocols, reviewers´ comments, and responses from sponsors, was particularly highlighted as an enabler of efficiency, as it fast-tracked the review procedure and minimized delays. AVAREF's secretariat services and follow-up efforts were described as excellent, with several respondents emphasizing the secretariat's pivotal role in maintaining the quality and timeliness of the reviews.

Challenges encountered during the joint review procedure

A mixture of logical, procedural, and communication challenges was highlighted as contributing to challenges encountered during the procedure. One area of concern was document submission and updates. Updated documents, such as revised versions of the protocol, were shared during the review procedure, but some reviewers had difficulty in downloading the applicant´s documents for a myriad of reasons, including but not restricted to internet bandwidth and organizational anti-virus settings.

Travel and logistical arrangements also posed some challenges. For instance, air tickets were not issued from their location of residence, which resulted in additional travel and accommodation expenses. Furthermore, some reviewers noted a lack of meal arrangements upon arrival and during the review period, leaving them to navigate local towns in search of food. Visa processing issues were another barrier, with some reviewers experiencing difficulties due to inadequate prior communication about entry requirements. Issues related to communication further disrupted the procedure. it was noted that sponsors did not adequately respond to queries raised by reviewers, which hindered the review´s progress and effectiveness. Challenges with in-country processes and dynamics were also highlighted. Rigidity of in-country committees made it difficult to fully leverage the benefits of the joint review recommendations. Moreover, delays in sponsor payments to countries caused further setbacks, impacting the CTA approval.

Finally, operational issues created challenges in the review procedure. For example, differences in knowledge and representation among countries affected the level of participation and engagement during the reviews. Additionally, internet connectivity issues occasionally disrupted the procedure for some reviewers who participated during online meetings, further complicating the review experience.

Suggestions for improving AVAREF Secretariat´s facilitation of future joint reviews

A range of constructive suggestions to enhance the efficiency, effectiveness, and overall experience of AVAREF Secretariat´s joint review procedure was provided. One key area for improvement is document management and review timelines. The importance of sharing all relevant documents well in advance, allowing reviewers sufficient time for thorough review, was highlighted. They also emphasized the need to provide adequate time for countries to comprehensively review protocols before the joint review meetings. Communication and coordination between the AVAREF Secretariat and participating countries, and other stakeholders, were highlighted as another area for enhancement. Regular updates, clear communication channels, and status reports were recommended to maintain engagement and alignment.

Timeliness and resource management emerged as significant concerns. Reviewers suggested adhering to stricter timelines for responses and feedback, supported by automated reminders and deadlines to ensure commitments are met. Capacity building was seen as a vital component of improving the procedure. Training sessions and workshops were proposed to familiarize stakeholders with review tools, processes, and expectations. To build technical expertise, it was suggested that joint reviews include at least two NRA reviewers per country, with virtual attendance options for countries with limited resources or experience.

Given the logistical issues, particularly around visa and travel arrangements, were a significant challenge for some reviewers, suggestions included improving the flow of information regarding visa requirements and ensuring that visas are processed well in advance. Ensuring proper meal arrangements during meetings was another practical recommendation to enhance comfort. The preferred format of meetings was also discussed, which was face-to-face meetings. Such meetings allow for direct interaction between reviewers and sponsors, facilitating better communication and quicker resolutions. For online meetings, it was suggested that reviewers from the same country gather in a single location to minimize distractions and ensure smoother collaboration.

The need for greater support for local review committees was highlighted. Encouraging flexibility in local processes to align with AVAREF Secretariat´s streamlined timelines could help countries initiate studies faster and become more competitive globally. AVAREF Secretariat´s role in guiding and supporting these committees was seen as crucial to achieving this goal. Finally, there were calls for frequent reviews of the procedure to identify inefficiencies and implement improvements, coupled with stronger enforcement of standards to ensure that all stakeholders, including sponsors and investigators, adhere to the agreed protocols and timelines.

This paper focuses exclusively on the feedback from reviewers in participating countries and does not include feedback from trial sponsors. A similar report on the experiences of sponsors/applicants with the AVAREF Secretariat´s platform for joint reviews has been documented elsewhere [10]. Incorporating the viewpoints of sponsors in future post-joint review surveys will provide a more comprehensive understanding of the joint review procedure and its broader impact on stakeholders. Also, post-review feedback will subsequently be incorporated into the AVAREF Secretariat's joint review procedures as a quality improvement exercise to inform the refinement of the joint review procedure, enhance the overall experience for reviewers, and ensure a more efficient and collaborative procedure in subsequent reviews. The iterative approach to improving the Secretariat´s joint review platform will not only strengthen regulatory harmonization across Africa but also support the timely development and approval of critical vaccines, addressing the region´s most pressing public health challenges.

Conclusion     

The AVAREF Secretariat -facilitated joint review procedure for the Gates MRI TB vaccine candidate exemplifies the potential of collaborative and streamlined approaches to clinical trial application review in Africa. While the procedure was commended for its efficiency, professional structure, and ability to foster cross-country collaboration, it also highlights areas requiring refinement to enhance its overall impact. These insights provide a roadmap for strengthening future joint reviews. These include early document availability, enhanced stakeholder communication, capacity building through training, and logistical improvements. Ultimately, AVAREF Secretariat´s joint review procedure continues to prove its value as an effective platform for harmonizing regulatory efforts, expediting clinical trial approvals, and facilitating the timely development and approval of lifesaving vaccines for diseases affecting Africans.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

The manuscript was conceptualized by and Kwasi Nyarko. The first draft was written by Chinwe Iwu-Jaja and Jacqueline Rodgers. Chinwe Iwu-Jaja, Jacqueline Rodgers, Kwasi Nyarko, and Charles Shey Wiysonge contributed to different versions of the manuscript. All authors read and agreed to the final version of the manuscript.

Acknowledgments     

We acknowledge the focal persons from countries represented by the NRAs, ECs, and IRBs for being part of this joint review procedure and for providing insights on their experiences and suggestions to improve the procedure.

References