Investing in late-stage clinical trials and manufacturing of product candidates for five major infectious diseases: a modelling study of the benefits and costs of investment in three middle-income countries.

BACKGROUND: Investing in late-stage clinical trials, trial sites, and production capacity for new health products could improve access to vaccines, therapeutics, and infectious disease diagnostics in middle-income countries. This study assesses the case for such investment in three of these countries: India, Kenya, and South Africa. METHODS: We applied investment case modelling and assessed how many cases, deaths, and disability-adjusted life years (DALYs) could be averted from the development and manufacturing of new technologies (therapeutics and vaccines) in these countries from 2021 to 2036, for five diseases-HIV, tuberculosis, malaria, pneumonia, and diarrhoeal diseases. We also estimated the economic benefits that might accrue from making these investments and we developed benefit-cost ratios for each of the three middle-income countries. Our modelling applies two investment case perspectives: a societal perspective with all costs and benefits measured at the societal level, and a country perspective to estimate how much health and economic benefit accrues to each middle-income country for every dollar invested in clinical trials and manufacturing by the middle-income country government. For each perspective, we modelled two scenarios: one that considers only domestic health and economic benefits; and one that includes regional health and economic benefits. In the regional scenarios, we assumed that new products developed and manufactured in India would benefit eight countries in south Asia, whereas new products developed and manufactured in Kenya would benefit all 21 countries in the Common Market for Eastern and Southern Africa (COMESA). We also assumed that all 16 countries in the Southern African Development Community (SADC) would benefit from products developed and manufactured in South Africa. FINDINGS: From 2021 to 2036, product development and manufacturing in Kenya could avert 4·44 million deaths and 206·27 million DALYs in the COMESA region. In South Africa, it could prevent 5·19 million deaths and 253·83 million DALYs in the SADC region. In India, it could avert 9·76 million deaths and 374·42 million DALYs in south Asia. Economic returns would be especially high if new tools were produced for regional markets rather than for domestic markets only. Under a societal perspective, regional returns outweigh investments by a factor of 20·51 in Kenya, 33·27 in South Africa, and 66·56 in India. Under a country perspective, the regional benefit-cost ratios amount to 60·71 in India, 8·78 in Kenya, and 11·88 in South Africa. INTERPRETATION: Our study supports the creation of regional hubs for clinical trials and product manufacturing compared with narrow national efforts. FUNDING: Bill & Melinda Gates Foundation.

Analysis of the health product pipeline for poverty-related and neglected diseases using the Portfolio-to-Impact (P2I) modeling tool.

Background: To estimate how much additional funding is needed for poverty-related and neglected disease (PRND) product development and to target new resources effectively, policymakers need updated information on the development pipeline and estimated costs to fill pipeline gaps. Methods: We previously conducted a pipeline review to identify candidates for 35 neglected diseases as of August 31, 2017 ("2017 pipeline"). We used the Portfolio-to-Impact (P2I) tool to estimate costs to move these candidates through the pipeline, likely launches, and additional costs to develop "missing products." We repeated this analysis, reviewing the pipeline to August 31, 2019 to get a time trend. We made a direct comparison based on the same 35 diseases ("2019 direct comparison pipeline"), then a comparison based on an expanded list of 45 diseases ("2019 complete pipeline"). Results: In the 2017 pipeline, 538 product candidates met inclusion criteria for input into the model; it would cost $16.3 billion (B) to move these through the pipeline, yielding 128 launches. In the 2019 direct comparison pipeline, we identified 690 candidates, an increase of 152 candidates from 2017; the largest increase was for Ebola.  The direct comparison 2019 pipeline yields 196 launches, costing $19.9B. In the 2019 complete pipeline, there were 754 candidates, an increase of 216 candidates from 2017, of which 152 reflected pipeline changes and 64 reflected changes in scope. The complete pipeline 2019 yields 207 launches, costing $21.0B. There would still be 16 "missing products" based on the complete 2019 pipeline; it would cost $5.5B-$14.2B (depending on product complexity) to develop these products. Conclusion: The PRNDs product development pipeline has grown by over a quarter in two years. The number of expected new product launches based on the 2019 pipeline increased by half compared to 2017; the cost of advancing the pipeline increased by a quarter.

Developing new health technologies for neglected diseases: a pipeline portfolio review and cost model.

Background: Funding for neglected disease product development fell from 2009-2015, other than a brief injection of Ebola funding. One impediment to mobilizing resources is a lack of information on product candidates, the estimated costs to move them through the pipeline, and the likelihood of specific launches. This study aimed to help fill these information gaps. Methods: We conducted a pipeline portfolio review to identify current candidates for 35 neglected diseases. Using an adapted version of the Portfolio to Impact financial modelling tool, we estimated the costs to move these candidates through the pipeline over the next decade and the likely launches. Since the current pipeline is unlikely to yield several critical products, we estimated the costs to develop a set of priority "missing" products. Results: We found 685 neglected disease product candidates as of August 31, 2017; 538 candidates met inclusion criteria for input into the model. It would cost about $16.3 billion (range $13.4-19.8B) to move these candidates through the pipeline, with three-quarters of the costs incurred in the first 5 years, resulting in about 128 (89-160) expected product launches.  Based on the current pipeline, there would be few launches of complex new chemical entities; launches of highly efficacious HIV, tuberculosis, or malaria vaccines would be unlikely. Estimated additional costs to launch one of each of 18 key missing products are $13.6B assuming lowest product complexity or $21.8B assuming highest complexity ($8.1B-36.6B). Over the next 5 years, total estimated costs to move current candidates through the pipeline and develop these 18 missing products would be around $4.5B (low complexity missing products) or $5.8B/year (high complexity missing products). Conclusions: Since current annual global spending on product development is about $3B, this study suggests the annual funding gap over the next 5 years is at least $1.5-2.8B.

Phylogenetic and ecologic perspectives of a monkeypox outbreak, southern Sudan, 2005.

Identification of human monkeypox cases during 2005 in southern Sudan (now South Sudan) raised several questions about the natural history of monkeypox virus (MPXV) in Africa. The outbreak area, characterized by seasonally dry riverine grasslands, is not identified as environmentally suitable for MPXV transmission. We examined possible origins of this outbreak by performing phylogenetic analysis of genome sequences of MPXV isolates from the outbreak in Sudan and from differing localities. We also compared the environmental suitability of study localities for monkeypox transmission. Phylogenetically, the viruses isolated from Sudan outbreak specimens belong to a clade identified in the Congo Basin. This finding, added to the political instability of the area during the time of the outbreak, supports the hypothesis of importation by infected animals or humans entering Sudan from the Congo Basin, and person-to-person transmission of virus, rather than transmission of indigenous virus from infected animals to humans.

Human monkeypox outbreak caused by novel virus belonging to Congo Basin clade, Sudan, 2005.

To determine the outbreak source of monkeypox virus (MPXV) infections in Unity State, Sudan, in November 2005, we conducted a retrospective investigation. MPXV was identified in a sub-Sahelian savannah environment. Three case notification categories were used: suspected, probable, and confirmed. Molecular, virologic, and serologic assays were used to test blood specimens, vesicular swabs, and crust specimens obtained from symptomatic and recovering persons. Ten laboratory-confirmed cases and 9 probable cases of MPXV were reported during September-December 2005; no deaths occurred. Human-to-human transmission up to 5 generations was described. Our investigation could not fully determine the source of the outbreak. Preliminary data indicate that the MPXV strain isolated during this outbreak was a novel virus belonging to the Congo Basin clade. Our results indicate that MPXV should be considered endemic to the wetland areas of Unity State. This finding will enhance understanding of the ecologic niche for this virus.