West Africa Lassa fever Consortium (WALC)
What is WALC?
The West Africa Lassa fever Consortium (WALC) was established in 2021 to develop an end-to-end framework for Lassa fever treatment, extending from clinical development to product availability, incorporating a flexible, multi-drug trial platform, that is regionally driven and owned.
Why this initiative?
To date, no treatment has been specifically developed and none is registered for Lassa Fever, a viral haemorrhagic fever present exclusively in few countries in West Africa. There is therefore no set path and no classical financial motive to develop treatments for Lassa Fever.
While Lassa fever is a public health priority in parts of West Africa, where it is endemic, the caseload is concentrated in countries where patients or health systems do not have sufficient purchasing power to be an attractive investment case for classic pharmaceutical business to develop therapies.
Apart from supportive care, only one drug – ribavirin – is available to treat it, but the evidence-base for its effectiveness is weak. There are potential candidate treatments to test clinically, but the path to registration and the methodologies for use have not been developed.
A coordinated approach using a portfolio of treatments within platform trials is therefore crucial to improve efficiencies and maximise chances of having effective, affordable treatments available for Lassa fever.
How will this be achieved?
We believe this can be achieved by building an end-to-end framework extending from clinical development to product availability, incorporating a flexible, multi-drug trial platform, that is regionally driven and owned.
The outputs of the project will be developed with, and agreed upon by regional and international stakeholders, including those conducting research (researchers, developers), beneficiaries (health practitioners, patients, communities), and norm-makers (policy makers, regulators).
We have formed a consortium including ISARIC (International Severe Acute Respiratory and emerging Infection Consortium), NCDC (Nigeria Centre for Disease Control), Alima (Alliance for International Medical Action), WaCa (Médecins Sans Frontières West and Central Africa Operational Directorate), and Kineta Inc. Our work is supported by a grant from Wellcome for one year.
Location of WALC partners and collaborators in West Africa
What will WALC deliver?
- The essential elements of a Clinical Development Plan (CDP) – the roadmap to support registration, to serve as a benchmark for the clinical development of Lassa fever therapeutics.
- Pre-positioned Phase II-III clinical trial protocols, which allow for comparable assessment of treatment effects through a platform study approach.
- Capacity strengthening plan for the delivery of clinical trials – identifying existing capacities and capacity strengthening needs and quantifying investments to reach the required standards that will be necessary ahead of the initiation of clinical trials.
- Preferred Product Characteristics (PPC) and Target Product Profile (TPP) following the WHO principles to “support an end-to-end perspective, linking product development, regulatory, policy and financing perspectives.”
- A range of ‘value propositions’ for Lassa fever product development, availability and access; identify partners and stakeholders interested to support the development, availability, and access of Lassa fever therapies; identify promising drug candidates and potential development partners and promote a portfolio approach.
Each of the products will be generic for any Lassa fever treatment. They will also be specifically applied to Kineta’s LHF-535, a compound nearing Phase II clinical development.
WALC is also monitoring the drug development pipeline and liaising with other developers to build a truly portfolio approach.
Who can use the project outputs?
Anyone – all products emerging from this programme (protocols, reviews, and other documents) will be published as open source and will be freely accessible to the community.
WALC work packages
Clinical Development Plan
The clinical development plan (CDP) describes and guides the clinical development strategy of a medicinal product and is central to the successful completion of a product’s evaluation so that it can be registered, adopted and used. It also specifies the documentation needed throughout the clinical development.
The CDP is informed both by medical needs and regulatory requirement, as well as a product’s characteristics.
While the process is well known and widely applied in pharmaceutical development, LF poses special challenges as benchmarks are lacking:
- There is no prior experience of building a CDP since no drug has as yet been developed specifically for LF, requiring, for instance, that regulatory pathways and rulings, both internationally and in the disease-endemic countries, should be identified.
- There is no agreed methodology as to how to test and assess the efficacy and safety of a LF treatment – see WP2.
- The settings where the clinical evaluation can take place are limited in number, are in LF-endemic countries, and may require investments for clinical research capacity strengthening – see WP3.
- There is no reference product profiling to identify the characteristics a medicinal product should meet to satisfy the medical needs – see WP4.
We are addressing these challenges through a collaborative approach, engaging a range of key stakeholders in discussions on the acceptability of prepositioned protocols, trial methodologies, acceptable endpoints, and approaches as to when to include children and pregnant women in clinical testing.
- Endemic-country regulators and ethics board, and international regulatory bodies (US FDA, EMA)
- Country programmes and MoH, WHO, WHO/AFRO
- Clinicians treating LF in dedicated facilities in the endemic countries, and international disease experts
This will ensure the clinical development will satisfy regulatory requirements and the product will meet end-users’ expectations.
The CDP will identify the studies to be conducted, including Phase II and Phase III clinical trials, additional non-clinical studies to be conducted (e.g. reproductive toxicology, as women of reproductive age are particularly exposed to the infection, and pregnant women are at high risk of foetal loss and death), and documentation to be prepared and updated (e.g. Investigators’ Brochure, PIP (paediatric investigational plan), as children are another target population).
Through this approach we will develop a generic LF CDP to be used as a benchmark for future LF clinical development, using a ‘portfolio approach’ with a prepositioned protocol such that products can enter clinical phases of development as they become available.
Developing protocols for Phase II-III clinical trials
This WP builds upon ongoing work by this group, including a systematic review of the clinical characterisation of LFand the delineation of core elements of a Phase III clinical trial framework for LF through a Delphi-type process.
The primary output of the WP will be a pre-positioned clinical trial protocol for pivotal Phase II/III platform trials, which will be developed through consultation with a range of experts and stakeholders.
Key areas of work within this WP involve progressing towards standardising ribavirin regimens and supportive care for trials; identifying optimal primary and secondary outcome measures; trial design; obtaining feedback from survivors and clinicians delineating the patient pathway.
It is critical that this work package identifies a primary outcome measure for a pivotal Phase II/III clinical trial that is acceptable to regional and international regulatory bodies. With this in mind, we have initiated a systematic process to identify an optimal primary outcome measure that will not only be applicable to Lassa fever but also to other difficult-to-study infectious diseases. This work involves collaboration with clinicians and researchers covering a range of difficult-to-study infectious diseases as well as regulators in West Africa and elsewhere.
We also recognise the importance of ensuring buy-in from clinicians and researchers active in Lassa fever research and patient management across West Africa. Within the social science work planned for the WALC project (described in the consultation protocol), we have made provision for qualitative interviews with Lassa fever survivors to understand the patient experience and relevant patient outcomes. Within our workplan we have also included a broad consultation with regional clinicians to understand the acceptability of the trial protocol in a clinical setting. This will also allow for us to identify potential challenges and deploy mitigation strategies when implementing the protocol across a range of different health contexts.
Strengthening trial site capacity
LF patients and treatment expertise are currently concentrated in a limited number of sites, mostly in Nigeria (Irrua Specialist Teaching Hospital, Federal Medical Centre Owo and Alex Ekwueme Federal Teaching Hospital Abakaliki) and Sierra Leone (Kenema).
Meeting GCP and GCLP standards will be a prerequisite to participate in regulatory trials. Improved practices will also benefit patients. While these facilities host significant medical expertise, they will also need investments to upgrade.
Within the scope of this project, we will identify existing capacities and capacity needs in a range of sites in Nigeria, Sierra Leone, Guinea, Benin and Liberia to reach the required standards that will be necessary ahead of the initiation of clinical trials.
Optimising resources is critical also in view of potential competition between different clinical research projects, and is part of the CDP discussion (WP1), with a view to developing collaboration between different stakeholders with a ‘portfolio approach’ to optimise use of resources and identify the best available therapy for LF.
Identifying a LF medication preferred product characteristics (PPC) and target product profile (TPP)
The CDP should also be informed by the medical need and how it will be addressed by the medicinal product. As per the WHO definition, the PPC describes the strategic public health goals of the product, its indications and target groups, as well as the main product attributes and their preferential characteristics. The TPP defines minimally acceptable and preferred criteria, whereas PPC contain only preferences.
We are conducting a broad consultation process with LF experts, response clinicians, survivors and communities, using Delphi process and qualitative interviews to develop generic PPC and TPP for LF therapies, following the WHO approaches and principles to “support an end-to-end perspective, linking product development, regulatory, policy and financing perspectives.”
Developing a value proposition for sustainable R&D and availability of LF therapeutics in West Africa
Given the relatively modest caseload – despite its epidemic potential – concentrated in countries where patients or health systems do not have sufficient purchasing power to be an attractive investment case for classic pharmaceutical business, LF treatments or vaccines are considered a typical case of neglected disease ‘market failure’.
Unless donors are prepared to fully finance both product R&D and production, and also subsidise procurement and access, no amount of market pushing and pulling can make this a viable business case in the traditional sense. At the same time, the human and socio-economic cost of not treating LF is huge, infecting in the first-place women and children while at the same time causing high fatality among an already scarce health workforce. Given the growing expression of regional agency, autonomy and resilience around pharmaceutical supplies to address their population’s health needs, reinforced recently through COVID-19, we believe it is possible to construct an alternative value proposition for the development of LF treatments that is rooted in West-African business, scientific and philanthropist networks.
Based on initial conversations and public discourse and commitments, we are consulting widely with key regional and international players to contribute to identifying alternative value propositions, including African science and health organizations (e.g. academies of sciences, West African Health Organization (WAHO), WHO/AFR), relevant ministries (e.g. ministry of health, NCDC, ministry of industry, trade and investment, ministry of finance), regional charities, foundations and philanthropists, NGOs (e.g. MSF/WACA, ALIMA), and civil society (e.g. Nigeria Health Watch). Alternative value propositions that we are exploring build on drivers such as Public Private Partnerships for health, Impact Investment, Mission driven investment and charity. Engaging relevant scientific, political and business leaders in the region, this value proposition will reflect the aspiration of not just being at the receiving end of the pharmaceutical pipeline, but be actively involved in, and driving, the chain of activities from product development and evaluation, to production, to access, and their financing.