Response from the Drugs for Neglected Diseases Initiative (DNDi)

to the UK International Development Committee Parliamentary inquiry

on the immediate and future impact of the COVID-10 Pandemic

 

Introduction

The Drugs for Neglected Diseases Initiative (DNDi) is a public-private partnership developing and ensuring equitable access to new drugs or new treatments for people living with neglected diseases. Acting in the public interest, DNDi bridges gaps in essential drugs for these diseases by initiating and coordinating drug research and development (R&D) projects in collaboration with the international research community, the public sector, the pharmaceutical industry, and other relevant partners. Experts credit DNDi for the significant progress on R&D for neglected tropical diseases[1], for its attention to neglected patients such as children with HIV and those faced with unaffordable hepatitis C treatment, and for its open science model.

DFID funding has enabled DNDi to deliver 8 new treatments for five diseases in 15 years, building on global collaborations with the public and private sectors worldwide and ample collaborations with UK scientists. Core funding from DFID enables DNDi to approach drug development in a results-oriented and cost-effective manner, which results in significantly lower costs for drug development than seen in the private sector, and for treatments which are adapted for the needs of patients in resource-limited settings.

As COVID-19 hit, DNDi had 20 active clinical trials for neglected diseases, at different stages, being conducted in 18 countries, mostly low- and middle-income countries.  DNDi’s immediate focus has been to protect the health, safety, and well-being of the patients in its clinical trials and of health personnel involved. DNDi is working to ensure continuity in its research and development (R&D) activities wherever possible and to avoid disruptions in care. However, the pandemic has had significant impact on DNDi’s work worldwide, both operationally and financially.

With its network of partners, DNDi also immediately sought to leverage its expertise and reach within the world’s scientific community to mobilize for the COVID-19 response in resource-constrained settings at a time when most research projects were initiated in high-income countries.  Together with its partners, it identified the specific challenge ahead in low income countries and launched two initiatives:

We thank the International Development Committee for the opportunity to contribute to this Inquiry and will focus on the direct and indirect impacts on developing countries and the implications for UK policy, in 6 areas:

 

 

 

 


1. Specific challenges with COVID-19 in Africa

DNDi has 15 years of experience of scientific innovation with African partners, including, most recently, for Fexinidazole, the first 10-days  all-oral treatment, and the first novel treatment for sleeping sickness in decades, developed in collaboration with global scientists and local clinicians in the Democratic Republic of Congo, where the trials took place, mostly in remote communities where the disease is prevalent: Fexinidazole was approved by the European Medicines Agency in November, and promptly adopted into guidelines in endemic countries.

While it is fully appreciated that Africa is a very diverse continent, with a very wide variety of populations and health situations, within a given country and between countries, the following broad challenges are expected in relation to COVID-19:

Scientists in Africa, and their colleagues worldwide, are racing against the clock to prepare for the pandemic’s rise in low-resources settings, where the number of hospital beds per 1,000 people is a fraction of the hospitalization capacity in high-income countries, and the number of doctors per 1,000 people is on average 20 times less than in Europe. The standard of care as it is defined in well-resourced  settings will be very difficult, if not impossible to implement, in many resource-limited settings, with limited capacity to manage a surge of severe pneumonia and a very limited number of intensive care beds[3]. With less than an average of 100 ventilators per country, the mortality impact would be high.

Figure 1. Hospital beds capacity across Africa: 1.8 average hospital beds per 1,000 people

In addition to the limited capacity of health systems to manage a surge of severe pneumonia, the low availability of appropriate personal protective equipment (PPE) and other protective gear for front-line health care staff means that these key staff are likely to be disproportionately affected by COVID-19. Disruption or complete breakdown of health care systems would result in high direct and indirect mortality since care of all illness would be affected.

The response from the research community to the COVID-19 pandemic has been vigorous. To date, the distribution of clinical trials is centred in the countries most affected by COVID-19, particularly China and South Korea, and high-income countries in Europe and North America.

However, very few trials are planned in Africa, south and southeast Asia, and central and South America. A review of clinical trial registries, as of March 24, 2020, identified 555 relevant registered clinical trials[4]. Of the 332 COVID-19 related clinical trials, 188 are open for recruitment and 146 trials are preparing to recruit[5]. A more recent figure from the COVID-19 trials tracker shows that almost 1,500 clinical trials on COVID-19 have been registered as of April 19th, 2020, with only a handful based in sub-Saharan Africa such as Ghana, Nigeria and South Africa[6].

Gaps in research mean that there is a high risk that current research develops products that do not respond to the needs of resource limited African countries settings. For example, Remdesivir is a drug that is being widely tried in high income countries. However, this drug needs to be administrated through daily infusion for 10 days, which is far from being ideal in resource limited settings. Priority should be given to research into interventions that reflect the specific needs of countries and are readily implementable. For resource-poor settings, that means interventions need to be adaptable to the health care systems and the populations they serve.

Few trials have so far been large enough to be decisive in terms of policy guidance. COVID-19 trials should be adequately powered to generate evidence. Large, well conducted clinical trials are needed urgently to support guidelines on prevention and clinical management. There is also much that might be improved in supportive care and organization in resource limited settings that could reduce direct and indirect COVID-19 morbidity and mortality. Research is needed now to guide the increasingly difficult choices that resource-limited health-care systems will face.

Some of the treatments under development for COVID-19 are products already registered for other indications such as malaria and HIV. In the context of global demand for COVID-19 treatments, some countries have imposed export bans or sought to stockpile these products while waiting for clinical data, disrupting the supply chain and raising concerns about price increases. Once new health tools are developed, they will need to be affordable and equitably allocated, both between wealthier and poorer countries, and within countries. This means the most vulnerable and those at highest risk must be prioritized. The results of research need to be affordable and equitably allocated.

Testing is a challenge in a number of low- and middle-income countries. While new tests have been developed using existing technologies, most tests for COVID-19 are still slow to implement and are resource intensive (e.g. PCR and GenXpert require laboratory infrastructure). To screen patients and provide clinical care, quality assured, true point-of-care (rapid) tests are critically needed, especially in resource-limited settings with increasingly overwhelmed health systems. In addition, adequate supply and distribution of these tests at an affordable price need to be ensured for, especially in a context where most manufacturers first serve their domestic or regional demand. Once a drug that reduces severity of COVID-19 is authorised, the goal should be for patients to be rapidly screened, diagnosed and treated, adopting a test and treat strategy

 

 

In terms of manufacturing, preparation of clinical trial medicines and vaccines might require new doses or formulations and placebos. Many LMIC settings will not have ready access to suitable Good Manufacturing Practice (GMP) manufacturers, and those that do have access may need support in ensuring quality assurance and obtaining regulatory approvals. This also applies to validated diagnostics. 

 

Related to manufacturing, the broader issue of supply volumes and market dynamics will be at the core of the challenge as already illustrated in trade tensions among affected high-income countries. As evidenced with preliminary results on hydroxychloroquine, should a particular commodity appear promising, issues of timely volumes of available active pharmaceutical ingredients (API), timely qualification of additional GMP manufacturing capacity, and priorities for needs-based distribution schemes will likely arise

 

2. The need for support for research to inform policy in resource-constrained settings of LMICs.

With leaders from the Wellcome Trust South-East Asian Research Units and the Infectious Diseases Data Observatory, DNDi co-founded --and is now hosting-- the COVID-19 Clinical Research Coalition[7] which aims to fast-track research that will provide evidence on COVID-19 prevention, diagnosis and case management in resource-limited settings to guide policies and practices.

While the section above focuses on COVID-19 risks in Africa, a similar assessment was made with regards to all resource-constrained settings worldwide, which led to a call, published in the Lancet in early March 2020, for a mobilization of scientists worldwide to address these challenges, and join a Coalition to accelerate research.  The Coalition now gathers over 150 members from 40 countries, with close to one-third of the members based in Africa, and with a significant number of partners in the UK, bringing together an unprecedented array of health experts, including public-sector research institutes, ministries of health, academia, not-for-profit research and development organizations, NGOs, international organisations, and funders all committed to finding COVID-19 solutions for resource-poor settings.

The COVID-19 Clinical Research Coalition Members commit to

  1.   accelerate COVID-19 research in areas where the virus could wreak havoc on already-fragile health systems and cause the greatest health impact on vulnerable populations
  2.   leverage each other’s expertise to fast-track research that will provide evidence needed to guide policies and practices on COVID-19 prevention, diagnosis, and case management in resource-limited settings.
  3.   Promote and implement open sharing of research knowledge and data
  4.   Champion equitable and affordable access to the proposed interventions.

A dearth of funding for clinical trials in LMICs. 

While there has been great interest in the coalition, it is worth noting that for several months most funding instruments launched by government donors supported research in high-income countries. Most did not exclude LMICs projects, but by not earmarking for LMICs research, these research calls for proposals de facto reduced most if not all prospects for research in low-income settings.

Given the urgent need for such research, DNDi would urge the Committee, as part of its Inquiry, to recommend the development of funding streams aimed at accelerating research in low-resource settings in LMICs.

 

3. Why specific studies for resource constrained settings in LMICs? The ANTICOV trials perspective.

There is a need for therapies in community settings where health systems are particularly fragile, to prevent evolution from mild to severe cases, to reduce the number of hospitalizations, considering very limited hospitalization capacity in many settings.

Priority should be given to interventions that reflect the specific needs of countries and are readily implementable. For resource-poor settings, that means interventions need to be affordable and available, and adaptable to the health-care systems and the populations they serve, with a focus on those who are most at risk.

DNDi, with partners, is currently designing specific studies   for resourced constrained settings  as part of the ANTICOV consortium.

The ANTICOV Consortium aims to generate data on new treatment strategies for mild SARS-CoV-2 patients in resource-limited settings, to reduce the number progressing to severe forms requiring hospitalization, thereby relieving the burden on health care systems and contributing to “flattening the curve” in contexts where systematic measures like quarantine or use of personal protective equipment are very difficult to implement.

To avoid small, fragmented studies with limited support, and to provide timely evidence-based policy, the multicentric Platform clinical trial (ANTICOV) will mobilize a wide network of countries (approx. 15) across the African continent, recruit between 2,000 and 3,000 patients in at least 20 clinical sites, and conduct an open-label, randomized, comparative, adaptive, multi-country study to test the safety and efficacy of new therapeutic strategies against the standard of care in mild SARS-CoV-2 patients in resource-limited settings.

The overall goal is to provide equitable and affordable access to new and adapted testing and treatment strategies for COVID-19 in LMICs, limiting the number of hospitalisations due to COVID-19 in low resource settings. The programme aims to deliver 1-2 treatment(s) that prevent the progress to the severity of COVID-19 and that are adapted to LMIC settings. The consortium members will monitor the available data on other repurposed molecules to select the best products to be tested.

The most vulnerable populations who will benefit from the programme are 1) older people – who are at risk of more severe COVID-19 disease and thus death; 2) those with chronic illness and populations with high levels of infectious disease co-morbidities (e.g. HIV/AIDS, Leishmaniasis, malaria and tuberculosis); 3) women – who are disproportionately likely to be healthcare workers, and who are exposed to the COVID-19 risk at work, with a direct impact on their family. Furthermore, availability of treatment will mitigate the isolation and social burden on care givers, especially mothers with young children.

The data resulting from the ANTICOV study will complement the anticipated outcomes of clinical trials being led by the World Health Organization (WHO) and others. New knowledge provided will support standardised, best evidence-based approaches for clinical management and better health outcomes for mild SARS-CoV-2 patients, to lessen the burden on health care systems in resource-limited settings.

Overall, this programme fosters collaboration among global health actors to find COVID-19 solutions that work in places with weak health systems, as recommended by the Access to COVID-19 Tools (ACT) Accelerator.

 

4.. Effect of COVID-19 on DFID leadership and programs in neglected diseases overall

AS DFID itself has noted, its support for tackling neglected diseases is a critical part of its commitment to the 2030 Sustainable Development Agenda. “Motivated by the need to tackle the impacts that neglected diseases, including neglected tropical diseases, have on the poor in the developing world, the UK has had a long history of support, using its funding and influence to champion and help catalyse the academic, public and private sector to take action. As neglected primarily occur in rural and poor urban areas of low-income and middle-income countries, NTDs not only provide an important marker for global progress towards achieving universal access to health, but also towards the leave no-one behind agenda, and the commitment that development should seek to improve the lives of the poorest and most vulnerable in the world.”[8]

The race to control and eliminate Neglected Tropical Diseases (NTDs) as public health threats has been significantly slowed down by the emergence of COVID-19, thus slowing the potential to get millions out of the cycle of poverty and disease. Both country-level implementation of NTD control programs, and global policy momentum have been affected.

For country- and community-level operations, on April 1, 2020, WHO recommended that community-based surveys, active case-finding activities and mass drug administration campaigns for NTDs be postponed until further notice, adding that “support for prompt diagnosis, treatment and care of neglected tropical diseases for patients presenting to healthcare facilities should continue wherever possible”. WHO also encouraged local health authorities to use existing NTD platforms and surveillance mechanisms to support implementation of COVID-19-related measures. In practice, many NTD national control programs are being affected by the crisis, including through critical staff reassignment.

At the policy level, it had been planned to achieve great momentum in 2020, with the launch of the WHO Neglected Tropical Diseases Roadmap, and with the first Global Summit on Malaria and NTDs scheduled to be held concurrently with the Commonwealth Heads of Government Meeting in Kigali in June 2020, where the impetus given through the launch in London in 2010 (with the London Declaration on NTDs ) was to be renewed. While key events will not go ahead as planned in 2020, it is important that DFID, and UK leadership at large, seek to accelerate the global momentum after the publication of the new WHO Roadmap on Neglected Tropical Diseases in 2020.

On the research agenda, several Product Development Partnerships (PDPs) have been enabled by DFID to develop new tools for neglected diseases, and all of them are encountering challenges in the context of the pandemic. For all PDPs, including DNDi, the COVID-19 pandemic presents a multi-dimensional set of new challenges -- which we illustrate below -- with different impacts in different regions, owing both to the differential impact of the pandemic in various countries and to different measures being taken by countries to contain its progression.

DFID support is essential to brace for the impact of COVID -19 on PDP operations, and their ability to effectively deliver on the promise of public-private partnerships for innovation to stall neglected disease

 

5. Effect of COVID-19 on DFID funded key programs: the example of DNDi

DNDi undertakes R&D from end-to-end, that is from early-stage discovery of promising molecules, through the entire translation and development process to registration and access. The COVID-19 has impacted every stage:

Slowed early stage drug discovery and translational work

DNDi early drug discovery work, which identifies and refines promising molecules that are active against disease-causing microbes, includes laboratory chemistry, driven with partners primarily in Wuhan and Kolkata, and parasitology, with partners labs in Seoul, Dundee, Antwerp, and Brisbane. All these locations have been heavily affected, in rapid sequence, by the progression of the pandemic from the Asia-Pacific to Europe. Most sites were closed for extended periods, and while they are now coming slowly back online, the immediate impact has been putting all DNDi’s work on hold for the first four months of 2020. We expect delayed or only partial uptake of work for the remainder of the year, while DNDi and partners have to bear most of the ongoing costs of these programs.

DNDi’s Open Innovation Network projects, which integrate undergraduate and graduate students at universities in the UK, India and North America, have stopped all work, as universities remain either closed or only open to undertake COVID-19 research.

Challenges with research, clinical trials and capacity strengthening:

As COVID-19 hit, DNDi had 20 active clinical trials at different stages, being conducted in 18 countries. DNDi’s immediate focus has been to protect the health, safety, and well-being of the patients in our clinical trials, of our partners, and of our team. We work to ensure continuity in our research and development (R&D) activities wherever possible, to avoid disruptions in care for the neglected communities we serve, and to ensure we deliver on our commitments to them.

We have developed guidance for all clinical R&D teams on care of patients and safety of staff and instituted an internal task force to provide continual support to the teams. Of great concern is increased risk of loss to follow-up of patients, and of lack of access to care due to worsening health conditions. The limitation of movement also has impact on our capacity to conduct monitoring of projects and training activities for capacity strengthening. Some specific examples of effects include:

 

Financial impact of the pandemic on the DFID-funded programme

As a result of the issues outlined above, DNDi also anticipates a significant financial impact both in 2020 and beyond. Part of the challenge is linked to milestone-based funding anticipated for 2020, which is unlikely to materialize due to delays imposed by the pandemic, yet the organization continues to bear the costs of these programmes and for the significant staff time applied to coping with the pandemic to design and implement an optimal approach.

A detailed assessment is underway, but a preliminary projection[1] leads DNDi to anticipate  a reduction of research activity of 20% in 2020, which translates into a reduction of approximately 15% of our overall budget, owing to work being delayed or put on hold, and a net deficit in 2020, owing to the cumulative effects of these delays. In addition, our capacities to engage with funders has been limited and all are focused on COVID response, affecting our financing prospects for 2020 and 2021 for non-COVID activities.

As a result, we have enacted measures to reduce our operational costs but remain concerned about the impact of the crisis on the financial health of the organization.

Our experience both in our programmes, and of the financial impacts, is but one example of similar challenges faced by all working in this field.

 

Impact on efforts to strengthen health systems, including with new tools.

Weak health systems constitute the highest risk factor in the COVID-19 response. Before the novel coronavirus emerged, there was growing consensus that NTDs were a “litmus test” of universal health coverage. There was also an effective understanding that the missing tools (diagnostics, drugs, and vaccines) for neglected diseases are required to realize Universal Health Coverage (UHC) and Sustainable Development Goal 3 (SDG3). New tools that can be used at the primary care level limit the requirement for hospitalization; several of these tools have the potential to eliminate the requirement for costly vertical programs, and some of these tools are critical to the sustainable elimination of diseases. Without them, health systems remain labile. If gains made to date against neglected diseases are to be maintained, it is therefore essential that the UK historical investment accelerating R&D for neglected diseases be sustained. DNDI would ask the Inquiry to include a recommendation requesting the continued support for biomedical R&D for infectious diseases, in addition to new support for COVID-19

 

6. Policy considerations for UK Funding.

 

DNDI welcomes the UK’s leadership in co-convening, and the commitments made at the recent pledging event on 4th May for development and testing of COVID-19 diagnostics, medicines, and vaccines, and the consensus by governments that the fruits of health research and development should be accessible and affordable to all. Putting life-saving health technologies into the hands of clinicians and patients worldwide, irrespective of the relative ability to pay, will be decisive for our collective ability to stem the pandemic. However, the success of the global response will depend on tying this funding to a series of collective actions to speed R&D and ensure accessibility and affordability. In doing so it can both improve the immediate outcomes for new tools for COVID-19, and also potentially set the foundations for a more sustainable and equitable approach for all areas of public health importance. We urge the Inquiry to consider as part of its recommendation on UK Aid the following 5 actions:

A global endeavour: A small group of countries cannot take on the role of finding and deciding on the tests, drugs and vaccines that work for the world. We need to identify the tools and interventions that are the most appropriate and effective for widely different settings and in different countries. We also need to harness the multiplicity of solutions and contributions. We need to ensure that researchers and public health leaders from low- and middle-income countries are included in decision making on how and where funds are spent, as they are both the most legitimate and the most likely to identify what works best for their populations.

Open Science: We urge the UK to support a global commitment to open sharing of research knowledge and data. R&D is often done behind closed doors, whether due to commercial confidentiality or because companies do not wish to disclose negative results. But we know from experience that open science – publishing results and data in the open, in real-time – improves efficiency and accelerates scientific progress by sharing research knowledge. Funding should be made conditional to results and data -- including genetic data on the virus, promising compounds, clinical trial protocols and results -- being put in the public domain.

Free of intellectual property restrictions: Making new health tools free of intellectual property restrictions will be essential. Legal rights to control knowledge can act as a barrier, both to research itself and to large-scale production of affordable health technologies. Funding should require that no new legal rights be sought, and technology owners should commit to either not enforce their existing intellectual property, or to share knowledge by licensing it on a non-exclusive basis globally.

Sufficient production, equitable allocation, and affordable pricing: Ensuring enough quality-assured tests, treatments, vaccines, and other essential equipment are manufactured may be the greatest challenge of all. Increasing existing production capacity will not be enough. Additional sources will need to be created, including through transfer of technology. Once new health tools are developed, they will need to be equitably allocated both between wealthier and poorer countries, and within countries. This means the most vulnerable and those at highest risk must be prioritized. The pricing of these tools must be as close as possible to what it costs to make them, so that they are affordable for health systems, and free to those most in need.

Transparency on R&D funding:  The volume of public funds invested in the discovery and development of health technologies to address COVID-19 is historical. Taxpayers have a right to see a public return on these public investments in R&D. Transparency will be key to securing public trust and support and to demonstrate that both governments and funding recipients are accountable for these investments and how they are used.

 

Conclusion: DFID’s leadership is needed now more than ever.

DFID’s strategic approach has made a lasting impact in global health and has helped cement the UK’s role as a key champion of global health and development. Its continued leadership in advocating for the need to tackle extreme poverty, help the world’s most vulnerable and provide direct support for the development of new health tools and more resilient health systems is needed now more than ever.

 

Drugs for Neglected Diseases

May 6, 2020.

 

[1]For example, a 10 year analysis by the Access to Medicine Foundation attributed the increase in R&D for Neglected Tropical Diseases (NTDs) to “efforts led by the World Health Organization (WHO) and product development partnerships (PDPs), such as the Drugs for Neglected Diseases initiative (DNDi), which have coordinated and driven attention for pharmaceutical R&D targeting  NTDs”  https://accesstomedicinefoundation.org/media/uploads/downloads/5d93329e141cb_Access-to-Medicine-Index-10-Year-Analysis.pdf

[2] COVID-19 Clinical Research Coalition. Accelerating research on COVID-19 in resource-limited settings [Internet]. 2020 [cited April 15, 2020]. Available from: https://covid19crc.org/

[3] Finnan D. Lack of Covid-19 treatment and critical care could be catastrophic for Africa [Internet]. 2020 [cited April 17, 2020]. Available from: http://www.rfi.fr/en/africa/20200403-lack-of-covid-19-treatment-andcritical-care-could-be-catastrophic-for-africa

[4]  Maguire BJ, Guérin PJ. A living systematic review protocol for COVID-19 clinical trial registrations. Wellcome Open Res. 2020; (published online April 2.) https://doi.org/10.12688/wellcomeopenres.15821.1

[5] Infectious Diseases Data Observatory (IDDO), University of Oxford, UK. Living systematic review COVID19. Coronavirus disease 2019 registered clinical trials. https://www.iddo.org/research-themes/covid19/live-systematic-clinical-trial-review. Date:2020, Date accessed: March 31, 2020.

[6] University of Oxford. Covid-19 Trials Tracker [Internet]. 2020 [cited April 17, 2020]. Available from: http://covid19.trialstracker.net/index.html

[7] COVID-19 Clinical Research Coalition. Accelerating research on COVID-19 in resource-limited settings [Internet]. 2020 [cited April 15, 2020]. Available from: https://covid19crc.org/

[8] Watts C (2017) Neglected tropical diseases: A DFID perspective. PLoS Negl Trop Dis 11(4): e0005492. https://doi.org/10.1371/journal.pntd.0005492