The Global Burden of Neglected Tropical Diseases: Current Progress, Scientific Challenges, and the Future of Drug Development

Abstract

This article provides a comprehensive analysis of the global burden of Neglected Tropical Diseases (NTDs) for researchers, scientists, and drug development professionals. It synthesizes the latest epidemiological data, highlighting a measurable decline in the population requiring interventions—down to 1.495 billion in 2023—and a reduction in disability-adjusted life years (DALYs). The content explores foundational concepts of NTDs, innovative methodological approaches in drug discovery, and key challenges such as funding gaps and drug resistance. It further validates progress through elimination case studies and discusses future directions, including the critical need for sustainable R&D models and advanced therapeutic strategies to meet 2030 elimination targets.

Understanding the Evolving Landscape and Core Concepts of NTDs

The global burden of infectious diseases is disproportionately concentrated in low- and middle-income countries, creating a cycle of disease and poverty that proves difficult to break. Within this landscape, the World Health Organization's (WHO) priority disease lists and the pervasive challenge of Neglected Tropical Diseases (NTDs) represent two critical fronts in the battle for global health equity. This technical guide examines the intersection of these areas, focusing specifically on the 2024 WHO Bacterial Priority Pathogens List (WHO BPPL) as a framework for understanding the socioeconomic dimensions of disease control. For researchers and drug development professionals, understanding this interplay is not merely an academic exercise but a fundamental requirement for developing effective, accessible, and equitable health interventions. The almost omnipresent assumption that NTDs are concentrated in the poorest populations is well-established, but the empirical evidence documenting this relationship remains scattered across disciplinary and methodological perspectives [1].

This whitepaper, situated within a broader thesis on the global burden of NTD research, provides a structured analysis of how formal disease prioritization methodologies can inform research and development (R&D) strategies. It further explores the profound socioeconomic impacts that perpetuate the cycle of neglect, with a particular emphasis on sub-Saharan Africa, where the disease costs developing countries the equivalent of a billion US dollars every year in direct costs, loss of productivity, and reduced socio-economic and educational attainment [2]. By integrating quantitative prioritization data with qualitative socioeconomic analysis, this document aims to equip scientists with the contextual understanding necessary to align technical research with the overarching goal of reducing global health disparities.

The 2024 WHO Bacterial Priority Pathogens List (WHO BPPL) represents a significant evolution in the global strategy to combat antimicrobial resistance (AMR). Building on the 2017 edition, the 2024 list updates and refines the prioritization of antibiotic-resistant bacterial pathogens to address evolving challenges, serving as an essential tool for guiding global policy, R&D, and investments [3]. This list is a key public health tool for the prevention and control of AMR, particularly since the release of the first list, which has already contributed to the development and approval of at least 13 new antibiotics targeting bacterial priority pathogens [4].

The 2024 list encompasses 15 families of antibiotic-resistant bacterial pathogens, representing a total of 24 individual pathogens [3]. These pathogens were systematically categorized into three priority tiers—critical, high, and medium—using a robust, evidence-based methodology. The list is not merely a catalog of threats but a strategic framework designed to direct resources and scientific innovation toward the most pressing public health challenges. It specifically highlights Gram-negative bacteria resistant to last-resort antibiotics, drug-resistant Mycobacterium tuberculosis, and other high-burden resistant pathogens such as Salmonella, Shigella, Neisseria gonorrhoeae, Pseudomonas aeruginosa, and Staphylococcus aureus [3]. The inclusion of these pathogens underscores their global impact in terms of burden, as well as critical issues related to transmissibility, treatability, and prevention options, while also reflecting the current status of the R&D pipeline for new treatments and emerging resistance trends [3].

Methodological Framework for Pathogen Prioritization

The development of the 2024 WHO BPPL followed a rigorous, multi-stage process based on a multicriteria decision analysis (MCDA) framework. This systematic approach ensured that the final prioritization was transparent, reproducible, and incorporated the latest scientific evidence and expert consensus.

• Criteria Selection and Scoring: Each of the 24 antibiotic-resistant bacterial pathogens was evaluated and scored based on eight predefined criteria:
  • Mortality: The death rate associated with the pathogen.
  • Non-fatal Burden: The impact of morbidity and disability.
  • Incidence: The frequency of new infections.
  • 10-Year Resistance Trends: The trajectory of antimicrobial resistance over the past decade.
  • Preventability: The feasibility of preventing infections through existing measures.
  • Transmissibility: The ease with which the pathogen spreads.
  • Treatability: The availability and effectiveness of current treatment options.
  • Antibacterial Pipeline Status: The number and stage of new therapeutic agents in development [4].
• Expert Preference Weighting: To determine the relative importance of these eight criteria, a preferences survey using a pairwise comparison was administered to 100 international experts. The survey achieved a high completion rate (78 out of 79 respondents completed it) and demonstrated strong inter-rater agreement, with both Spearman's rank correlation coefficient and Kendall's coefficient of concordance at 0.9 [4].
• Final Ranking and Tier Assignment: The final ranking was determined by applying the expert-derived weights to each pathogen's score across the eight criteria, calculating a total score ranging from 0-100% for each pathogen. An independent advisory group reviewed the final list, and pathogens were subsequently streamlined and grouped into three priority tiers based on a quartile scoring system: critical (highest quartile), high (middle quartiles), and medium (lowest quartile) [4]. The stability of this ranking was confirmed through extensive subgroup and sensitivity analyses, which found that variations in experts' backgrounds and geographical origins did not result in any substantial changes to the ranking [4].

Table 1: 2024 WHO Bacterial Priority Pathogens List (BPPL) Tier Rankings and Key Characteristics

Priority Tier	Pathogen	Key Resistance Phenotype	Total Score (%)	Global Health Considerations
Critical	Klebsiella pneumoniae	Carbapenem-resistant	84	Top-ranked pathogen; high mortality in healthcare settings
	Acinetobacter spp.	Carbapenem-resistant	-	Notable environmental persistence & treatment challenges
	Escherichia coli	Carbapenem-resistant	-	High community and healthcare burden
	Mycobacterium tuberculosis	Rifampicin-resistant	-	Persistent global threat with complex treatment regimens
High	Salmonella enterica Serotype Typhi	Fluoroquinolone-resistant	72	High burden in community-acquired infections
	Shigella spp.	Fluoroquinolone-resistant	70	Significant cause of diarrheal mortality and morbidity
	Neisseria gonorrhoeae	Extended-spectrum cephalosporin-resistant	64	Threat to effective treatment of sexually transmitted infections
	Pseudomonas aeruginosa	Carbapenem-resistant	-	Notable intrinsic resistance and healthcare-associated burden
	Staphylococcus aureus	Methicillin-resistant (MRSA)	-	Remains a significant cause of healthcare and community infections
Medium	Group B Streptococcus	Penicillin-resistant	28	Bottom-ranked pathogen; concerns for neonatal sepsis

The output of this methodology reveals that antibiotic-resistant Gram-negative bacteria, along with rifampicin-resistant Mycobacterium tuberculosis, dominate the critical priority tier. The top-ranked pathogen was carbapenem-resistant Klebsiella pneumoniae, with a total score of 84%, while penicillin-resistant Group B Streptococcus was the bottom-ranked pathogen with a score of 28% [4]. Among bacteria commonly responsible for community-acquired infections, fluoroquinolone-resistant Salmonella enterica serotype Typhi (72%), Shigella spp. (70%), and Neisseria gonorrhoeae (64%) received the highest rankings [4]. This structured prioritization provides an invaluable roadmap for researchers and drug developers, highlighting areas where scientific innovation is most urgently needed.

Diagram 1: WHO BPPL 2024 Development Workflow

The Socioeconomic Impact of Neglected Tropical Diseases

While the WHO BPPL focuses extensively on antimicrobial resistance, the socioeconomic dimensions of disease burden are perhaps most profoundly illustrated by Neglected Tropical Diseases (NTDs). These diseases are characterized by several factors, the most common of which is poverty, creating a vicious cycle where disease begets poverty and poverty begets disease [2]. The economic impact is staggering; it is estimated that NTDs cost developing countries the equivalent of a billion US dollars every year in direct costs, loss of productivity, and reduced socio-economic and educational attainment [2]. This impact is not uniform, as NTDs are linked to poverty and other axes of inequity and vulnerability; factors such as gender, disability, and ethnicity may be exacerbated by the presence of these diseases [2].

Empirical evidence confirms that the burden of NTDs is heavily concentrated in low- and middle-income countries, and not only between countries but also within countries, NTDs are often concentrated in the poorest populations [1]. Poverty acts as a root cause of NTDs because of its association with living and working conditions and access to preventive and curative health services [1]. In turn, NTDs have strong impoverishing effects due to the absence of social protection systems—including health insurance to protect against catastrophic health expenditures and sickness and disability insurance to protect against loss of income—in most developing countries [1]. This bidirectional relationship between poverty and NTDs presents a formidable challenge for disease control programs and underscores the need for interventions that extend beyond the biomedical sphere to address underlying social and economic determinants.

Analytical Framework for Socioeconomic Inequalities in NTDs

A systematic review of socioeconomic inequalities in NTDs provides a valuable analytical framework for understanding this complex relationship [1]. The core of this framework is the association between socioeconomic position (SEP) and NTD infection prevalence, which is mediated through several pathways.

• Proximate Determinants: SEP influences NTD infection via more proximate determinants such as hygiene behaviours, access to clean water and sanitation facilities, environmental hygiene, exposure to infection through working conditions, and access to health services. Statistical adjustment for these proximal determinants typically reduces the magnitude of socioeconomic inequality in NTD infection, indicating they are key mechanisms through which poverty affects health outcomes [1].
• Confounders and Effect Modifiers: Factors such as age and sex can act as both confounders and effect modifiers of the relationship between SEP and NTD infection. For instance, a Brazilian study found that elderly people tend to be richer and, independently of SEP, have higher odds of having trachoma [1]. This highlights the importance of stratified analyses in understanding the full complexity of socioeconomic inequalities.
• Measurement of Socioeconomic Position: In the context of research in low- and middle-income countries, SEP is typically measured using indicators of educational attainment and/or economic status. Household ownership of assets is often used as a measure of economic status, while other studies may use dimensions such as caste, occupational class, or aggregate geographical-level measures [1].

Table 2: Socioeconomic Impact Dimensions of Selected Neglected Tropical Diseases

NTD	Key Socioeconomic Impact	Vulnerable Groups	Economic Cost Drivers
Lymphatic Filariasis	Chronic disability, stigma, reduced work capacity	Agricultural workers, poor urban communities	Loss of productivity, out-of-pocket treatment costs, caregiver burden
Schistosomiasis	Reduced cognitive development, anemia, fatigue	School-aged children, women (via female genital schistosomiasis)	Impaired learning outcomes, reduced agricultural productivity
Soil-Transmitted Helminths	Malnutrition, impaired growth, cognitive deficits	Children in areas with poor sanitation	Long-term impact on educational attainment and future earnings
Trachoma	Visual impairment & blindness, reduced independence	Women, children in endemic areas	Loss of productivity, cost of vision-saving surgery, caregiver costs
Human African Trypanosomiasis	Disruption of agricultural activities, stigma	Rural populations in endemic areas	Loss of household income, cost of diagnosis and treatment
Buruli Ulcer	Disability, stigma, functional limitations	Children and adolescents near water bodies	Loss of schooling, work absenteeism, cost of wound care

The consequences of some NTDs, such as female genital schistosomiasis (FGS), have been brought more to the fore in recent years, highlighting how the socioeconomic impact of these diseases is often gendered [2]. Furthermore, the COVID-19 pandemic has threatened to exacerbate these existing inequalities, disrupting NTD control programs and potentially reversing hard-won gains in disease control [2]. This underscores the critical need for resilient health systems and integrated approaches that address both the biological and social dimensions of NTDs.

Integrating Prioritization with Socioeconomic Analysis in Research

For researchers, scientists, and drug development professionals, integrating formal pathogen prioritization with a deep understanding of socioeconomic impact is essential for designing effective and equitable health interventions. The 2024 WHO BPPL explicitly serves as a guide for prioritizing R&D and investments in AMR, emphasizing the need for regionally tailored strategies to effectively combat resistance [3]. It targets developers of antibacterial medicines, academic and public research institutions, research funders, and public-private partnerships investing in AMR R&D, as well as policy-makers responsible for developing and implementing AMR policies and programs [3]. This alignment of scientific and public health priorities is crucial for maximizing the impact of limited research resources.

Beyond research and development focused on new therapeutic agents, efforts to address these priority pathogens must also include expanding equitable access to existing drugs, enhancing vaccine coverage, and strengthening infection prevention and control measures [4]. This multifaceted approach recognizes that scientific innovation alone is insufficient without parallel efforts to ensure access and address the underlying social determinants of health. The systematic review of socioeconomic inequalities in NTDs reinforces this point, noting that control strategies would benefit poor populations most, given the heavy concentration of these diseases in the most disadvantaged segments of society [1].

Data Visualization and Reporting Standards for Global Health Research

Effectively communicating the complex interplay between disease prioritization and socioeconomic impact requires adherence to best practices in data visualization. The following principles ensure that charts and graphs are accessible and accurately convey key findings to diverse audiences, including researchers, policymakers, and the public.

• Color and Contrast: Color should be used strategically to direct attention to the most important data series or values. To ensure accessibility for colorblind users, avoid using colors of similar brightness and instead use different levels of darkness as well as various hues [5]. Do not rely on color alone to convey meaning; add an additional visual indicator such as a pattern, shape, or direct text label [6]. Any text should have a contrast ratio of at least 4.5:1 against the background color, while adjacent data elements like bars in a graph should have a contrast ratio of at least 3:1 against each other [6].
• Titles and Callouts: Use active, meaningful titles that state the key finding or takeaway rather than merely describing the data shown. For example, instead of "Success rates by task," use "Participants struggled to find past bills" to immediately communicate the conclusion [5]. Callouts and annotations can be added to highlight specific data points, explain percent changes, or note external events that influenced the metrics, reducing the cognitive load on the audience and ensuring context is not lost when the chart is shared independently [5].
• Supplemental Formats: To accommodate different learning styles and ensure accessibility, provide a supplemental format for the data, such as a table or spreadsheet accompanying the visualization [6]. This also benefits users of screen readers and others who may have difficulty interpreting complex graphical information.

Diagram 2: Integrating Disease Prioritization with Socioeconomic Analysis

Table 3: Key Research Reagent Solutions for AMR and NTD Research

Reagent/Resource	Function/Application	Technical Considerations
Antibacterial Agents	Evaluating efficacy against priority pathogens; resistance mechanism studies	Include WHO-recommended reserve group antibiotics; assess cross-resistance patterns
Molecular Cloning Systems	Genetic manipulation of pathogens to study resistance genes and virulence factors	CRISPR-based systems for Gram-negative bacteria; shuttle vectors for mycobacteria
Animal Disease Models	Preclinical efficacy and toxicity testing of new drug candidates	Murine models for disseminated infection; specialized models for tissue-specific infections (e.g., pulmonary TB)
Immunoassays (ELISA/Luminex)	Measuring host immune responses to infection and candidate vaccines	Multiplex panels for cytokine profiling; species-specific reagents for host-pathogen interaction studies
Genomic Sequencing Kits	Tracking resistance transmission; pathogen evolution studies	Whole-genome sequencing for outbreak investigation; targeted amplicon sequencing for resistance markers
Cell-Based Assay Kits	High-throughput screening of compound libraries; cytotoxicity assessment	Reporter cell lines for pathogen sensing; primary cell cultures for host-directed therapy research

The integration of formal disease prioritization frameworks, such as the WHO Bacterial Priority Pathogens List, with a rigorous understanding of socioeconomic impact represents a critical pathway for advancing global health equity. The 2024 WHO BPPL provides an indispensable roadmap for directing research and development efforts toward the most threatening antibiotic-resistant bacteria, with Gram-negative pathogens and drug-resistant tuberculosis maintaining their position as critical priorities. Simultaneously, the persistent and disproportionate burden of Neglected Tropical Diseases on the most vulnerable populations underscores the profound socioeconomic dimensions of disease and the limitations of a purely biomedical approach. For researchers, scientists, and drug development professionals, this integrated perspective is not optional but essential. It informs every stage of the research process, from basic science investigating resistance mechanisms to the design of clinical trials and the development of implementation strategies that ensure successful innovations reach the populations most in need. Future strategies must encompass not only the development of novel therapeutics but also the strengthening of health systems, the expansion of equitable access, and targeted interventions that address the underlying social determinants of health. Only through this comprehensive approach can the global health community effectively break the cycle of disease and poverty and make meaningful progress toward the goal of health for all.

The persistent and devastating burden of Neglected Tropical Diseases and malaria (NTDm) represents a critical challenge to global health, disproportionately affecting the world's most disadvantaged communities. Framed within the broader context of global burden of disease research, this technical analysis provides a detailed examination of the epidemiological trends in Disability-Adjusted Life Years (DALYs), prevalence, and mortality from 2015 to 2021. This period is of particular significance as it captures progress toward the World Health Organization's (WHO) previous NTD roadmap (2012-2020) and the early implementation phase of the new 2021-2030 strategy [7] [8]. According to the latest data from the Global Burden of Disease Study 2021, the number of people affected by NTDs declined from 1.9 billion in 1990 to just over 1 billion in 2021, reflecting substantial progress while highlighting the considerable work that remains [9]. This whitepaper synthesizes the most current epidemiological data to inform research priorities and drug development strategies for the scientific community, offering a rigorous quantitative assessment of the NTDm landscape during this critical seven-year timeframe.

Global and Regional Burden: Key Metrics and Trends

Comprehensive Analysis of Core Indicators (2015-2021)

The period from 2015 to 2021 witnessed notable shifts in the global burden of NTDm, characterized by overall progress in mortality and DALY rates, though with persistent challenges in certain regions and among specific demographic groups. The following table synthesizes the core quantitative indicators for this period, providing researchers with a consolidated view of the burden trajectory.

Table 1: Global Burden of Neglected Tropical Diseases and Malaria (NTDm), Key Metrics and Trends (2015-2021)

Metric	2015 Value	2021 Value	Trend (2015-2021)	Primary Geographic Concentrations	Vulnerable Populations
Global NTDm DALYs	17.2 million DALYs [9]	14.1 million DALYs [9]	Decrease of 18.0%	Western and Central Sub-Saharan Africa [7] [8]	Children <5 years, populations in low-SDI regions [7] [8]
NTD-related Deaths	139,000 deaths [9]	119,000 deaths [9]	Decrease of 14.4%	-	-
Age-Standardized DALY Rate (per 100,000)	1,506.54 (1990) [8]	1,020.27 [8]	Significant decrease since 1990; minor rise in ASIR projected 2022-2035 [7]	-	-
People Requiring NTD Interventions	-	1.495 billion (2023) [9]	32% decrease from 2010 baseline [9]	-	-
People Treated for at least one NTD	-	867.1 million (2023) [9]	-	-	-

Between 2015 and 2021, the disease burden dropped from 17.2 million to 14.1 million DALYs, while NTD-related deaths decreased from an estimated 139,000 to 119,000 [9]. The number of people affected by NTDs declined from 1.9 billion in 1990 to just over 1 billion in 2021 [9]. This progress occurred despite the significant disruptions to healthcare systems caused by the COVID-19 pandemic, which exacerbated challenges in NTD-endemic countries and led to a resurgence of some diseases [7].

Disease-Specific Burden and Regional Heterogeneity

The overall burden of NTDm is not uniformly distributed, with significant heterogeneity observed across different diseases and geographic regions. Certain vector-borne and parasitic infections continue to impose a disproportionate impact on specific populations.

Table 2: Disease-Specific and Regional Burden Highlights (2021)

Category	Diseases of Particular Concern	Key Epidemiological Findings
High-Burden Diseases	Dengue, Malaria, Rabies [7]	Prominent contributors to DALYs in high-burden regions.
Other NTDs	Lymphatic Filariasis (LF), Scabies [10] [11]	In 2021, scabies caused 5.3 million DALYs and 206.6 million prevalent cases [10]. LF burden is highest among ages 15-49 and males [11].
Regional Hotspots	West & Central Sub-Saharan Africa, Oceania, Tropical Latin America [7] [10] [8]	Western Sub-Saharan Africa alone contributed 51.18% of the global NTDm burden [8]. Oceania, Tropical Latin America, and East Asia had the highest scabies burden [10].
National-Level Burden	Fiji, Guam, Tonga, Tuvalu, Northern Mariana Islands [10]	These nations had the highest age-standardized DALY rates for scabies globally [10].

The epidemiological profile reveals that the highest burden is concentrated in West and Central Sub-Saharan Africa, with dengue, malaria, and rabies being particularly prominent [7]. A 2025 analysis confirmed that Western Sub-Saharan Africa remains the most affected region, contributing 51.18% of the global NTDm burden [8]. Beyond Africa, Oceania, Tropical Latin America, and East Asia ranked as the top three regions for scabies burden, with Fiji, Guam, Tonga, Tuvalu, and the Northern Mariana Islands showing the highest age-standardized DALY rates nationally [10].

Methodological Framework for Burden Estimation

The findings presented in this whitepaper are predominantly derived from the Global Burden of Disease Study 2021 (GBD 2021), which provides the most comprehensive and standardized approach to quantifying health loss across populations and over time. The GBD 2021 methodology employs sophisticated modeling techniques to ensure comparability and robustness of estimates.

Table 3: Core Data Sources and Modeling Approaches in GBD 2021

Component	Description	Relevance to NTDm
Data Inputs	328,938 epidemiological data sources including censuses, civil registration, hospital records, disease registries, literature reviews, and household surveys [11] [8].	For LF, 565 data sources were used, primarily from systematic reviews and the Global Programme to Eliminate Lymphatic Filariasis [11].
Modeling Tool	DisMod-MR 2.1, a Bayesian meta-regression tool, is the primary model for generating consistent estimates of prevalence and incidence [10] [11].	Ensures consistency between incidence and prevalence data for diseases like scabies and LF.
Key Covariates	Sociodemographic Index (SDI), Healthcare Access and Quality Index, unsafe water (Summary Exposure Value) [10].	Used to guide estimates for countries with limited data and to analyze inequalities.
DALY Calculation	DALYs = Years of Life Lost (YLL) + Years Lived with Disability (YLD). For non-fatal conditions like scabies, YLLs are zero, making DALYs equivalent to YLDs [10].	Allows for comparison of fatal and non-fatal disease burden. The disability weight for scabies was 0.027 [10].

The Socio-demographic Index (SDI) is a crucial covariate in these analyses, serving as a composite indicator of development status. SDI is calculated as the geometric mean of lag-distributed income per capita, average years of education for those aged 15 and older, and the total fertility rate under age 25 [8]. This metric allows researchers to explore the fundamental relationship between socioeconomic development and disease burden.

Analytical Techniques for Trend and Inequality Assessment

To evaluate temporal trends and quantify health inequalities, GBD analyses employ several advanced statistical techniques:

• Estimated Annual Percentage Change (EAPC): A key metric for quantifying trends in age-standardized rates over time. EAPC is calculated by fitting a regression line to the natural logarithm of the rates, with the formula: ln(ASR) = α + β * year + ε, where β determines the EAPC [7] [8] [12].
• Age-Period-Cohort (APC) Modeling: Used to disentangle the effects of aging (age), time period (period), and birth cohort (cohort) on disease trends. The Bayesian Age-Period-Cohort (BAPC) model is employed for forecasting future burden [7] [8].
• Inequality Metrics: The Slope Index of Inequality (SII) and Concentration Index (CI) are used to measure absolute and relative cross-national inequalities in disease burden related to SDI [11] [8].

The following workflow diagram illustrates the sequential process of data synthesis, analysis, and application in GBD studies:

The Researcher's Toolkit: Essential Reagents and Methodologies

Critical Research Reagents and Diagnostic Solutions

For researchers investigating the pathophysiology and therapeutic interventions for NTDm, specific reagents and tools are fundamental to conducting rigorous experimental studies. The following table details essential research solutions referenced in recent epidemiological and laboratory studies.

Table 4: Essential Research Reagents and Tools for NTDm Investigation

Research Solution	Function/Application	Technical Specifications
Ivermectin	Investigational therapeutic for scabies and other parasitic NTDs; used to assess drug efficacy and resistance mechanisms [10].	Macrocyclic lactone from Streptomyces avermitilis; acts on glutamate-gated chloride channels.
Permethrin	Standard scabicide used in resistance studies and comparative efficacy trials [10].	Synthetic pyrethroid; sodium channel modulator.
Antigenemia Tests (e.g., for LF)	Confirmatory diagnostic for lymphatic filariasis; detects circulating filarial antigens [11].	Immunochromatographic test (ICT) formats; targets Wuchereria bancrofti antigen.
PCR-Based Assays	Molecular detection and species differentiation for various NTD pathogens; used in epidemiological surveillance [11].	Targets species-specific DNA sequences; enables parasite load quantification.
WHO Skin App	AI-powered tool for integrated diagnosis of skin-NTDs; used in field validation studies [9].	Mobile health application; image recognition algorithm for clinical lesions.

Experimental Protocols for Burden Assessment

For researchers conducting systematic reviews or primary epidemiological studies on NTD burden, the following methodological approaches provide a validated framework:

Protocol for Systematic Analysis of Disease Burden Using GBD Data:

• Data Extraction: Access GBD 2021 results through the Global Health Data Exchange (GHDx) platform (http://ghdx.healthdata.org/gbd-results-tool) [10] [8].
• Indicator Selection: Extract age-standardized rates (ASRs) for key metrics (DALYs, prevalence, incidence, mortality) stratified by age, sex, geography, and SDI quintile.
• Trend Analysis: Calculate Estimated Annual Percentage Change (EAPC) by fitting a regression line to the natural logarithm of the rates: ln(ASR) = α + β * year + ε, where EAPC = 100 * (exp(β) - 1) [8] [12].
• Inequality Assessment: Compute Slope Index of Inequality (SII) and Concentration Index (CI) to quantify absolute and relative socioeconomic-related inequality [11] [8].
• Forecasting: Apply Bayesian Age-Period-Cohort (BAPC) models to project future disease burden, incorporating demographic and epidemiological trends [7] [8].

The relationship between socioeconomic development and NTD burden follows a predictable pattern that can be visualized as follows:

The comprehensive analysis of DALYs, prevalence, and mortality from 2015 to 2021 demonstrates measurable progress in reducing the global burden of NTDm, yet reveals persistent and deeply entrenched challenges. The documented decline in absolute DALYs and mortality coincides with an increasing concentration of the burden in the most vulnerable populations, particularly in low-SDI regions and among children under five. This epidemiological pattern underscores the profound socioeconomic dimensions of these diseases and the limitations of biomedical interventions alone.

For the research and drug development community, these findings highlight several critical priorities. First, there is an urgent need for novel therapeutic agents to address emerging drug resistance, particularly for scabies where reduced susceptibility to permethrin and ivermectin has been reported [10]. Second, the successful development of new diagnostics—evidenced by WHO's prequalification of six new medicine formulations and one active pharmaceutical ingredient in 2024—must be accelerated to enable early detection and monitoring of interventions [9]. Third, vaccine development remains a crucial frontier, with the recent prequalification of a new dengue vaccine representing a promising advance [9].

Future research efforts must embrace the complex interplay between environmental change, socioeconomic development, and disease transmission. The finding that climate change may exacerbate the NTD burden demands innovative, transdisciplinary research approaches that integrate epidemiological surveillance with climate modeling [8] [9]. Furthermore, the successful elimination of NTDs as a public health problem in several countries demonstrates that global targets are achievable with sustained commitment, coordinated action, and continued scientific innovation [11] [9]. As the world pursues the 2030 road map targets, the research community has a pivotal role in generating the evidence base and technological solutions needed to accelerate progress toward ultimate elimination.

The global effort to control, eliminate, and eradicate neglected tropical diseases (NTDs) represents one of the most significant public health initiatives of the 21st century. The World Health Organization's (WHO) 2021-2030 road map for NTDs established ambitious targets to reduce the disease burden and ultimately end the neglect of these poverty-associated conditions [13]. Among the most notable achievements has been a substantial reduction in the number of people requiring interventions against NTDs. According to the most recent WHO data, an estimated 1.495 billion people required interventions against NTDs in 2023, representing a decrease of 122 million from 2022 and a 32% reduction from the 2010 baseline [14] [9]. This significant demographic shift reflects two decades of coordinated action since the WHO consolidated disease-specific activities under a single NTD programme in 2005 [14].

This demographic transition is not merely a numerical achievement but represents a fundamental reshaping of the global NTD landscape. The decline indicates progress across multiple diseases, implementation of diverse intervention strategies, and the beginning of a potential paradigm shift in how NTDs are addressed in endemic countries. Understanding the drivers, patterns, and implications of this decline is crucial for researchers, scientists, and drug development professionals working to sustain and accelerate progress toward the 2030 targets [9].

Quantitative Assessment of the Demographic Shift

Core Metrics of Decline

The 32% decline in populations requiring NTD interventions since 2010 forms part of a broader pattern of improving NTD indicators across multiple dimensions. The most recent data from WHO's 2025 Global Report on NTDs reveals several interconnected positive trends that extend beyond the headline reduction figure [14] [9].

Table 1: Key Indicators of Progress Against NTDs (2010-2023)

Indicator	Baseline (2010)	Most Recent Data	Absolute Reduction	Percentage Change
People requiring NTD interventions	2.2 billion (estimated)	1.495 billion (2023)	705 million	-32%
Annual treatments delivered	Not specified	867.1 million (2023)	+18 million from 2022	+2.1% annual increase
Disease burden (DALYs)	17.2 million (2015)	14.1 million (2021)	3.1 million	-18%
NTD-related deaths	139,000 (2015)	119,000 (2021)	20,000	-14%
Countries achieving elimination of at least one NTD	Not specified	54 countries (2024)	7 countries in 2024 alone	Steady progress toward 100 countries by 2030

The data demonstrates that the reduction in people requiring interventions has occurred alongside increased treatment coverage, with 867.1 million people treated for at least one NTD in 2023—18 million more than in 2022 [14]. Critically, 99% of those treated received preventive chemotherapy (PC), highlighting the central role of mass drug administration in achieving this demographic shift [9].

Longitudinal Analysis of Disease Burden

The decline in people requiring interventions corresponds with a broader reduction in the overall NTD burden. Between 2015 and 2021, the disease burden dropped from 17.2 million to 14.1 million disability-adjusted life years (DALYs), while NTD-related deaths decreased from an estimated 139,000 to 119,000 [14]. A more comprehensive historical analysis reveals that the number of people affected by NTDs declined from 1.9 billion in 1990 to just over 1 billion in 2021, representing a 47% reduction over three decades [14].

This longitudinal perspective is essential for understanding the accelerating pace of progress. The 2016 study by Stolk et al. found that the global burden from nine major NTDs declined by 27% between 1990 and 2010, but noted that this reduction largely benefited upper-middle income countries, with low-income countries experiencing only a 6% reduction during this period [15] [16]. The more rapid progress since 2010 suggests that intensified global efforts are beginning to rectify this inequitable distribution of progress.

Methodological Framework for Measuring and Interpreting the Decline

Defining "People Requiring Interventions"

The metric "people requiring interventions against NTDs" represents a carefully constructed indicator with specific methodological considerations. According to WHO documentation, this indicator should not be interpreted as the number of people at risk for NTDs, but rather as "the number of people at a level of risk requiring medical intervention – that is, treatment and care for NTDs" [17].

The estimation methodology involves two primary components:

• Preventive Chemotherapy (PC-NTDs): The average annual number of people requiring mass treatment for at least one PC-NTD (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases, and trachoma). For geographical areas co-endemic for multiple PC-NTDs, the largest number of people requiring PC for any single disease is retained for each age group in each implementation unit to avoid double-counting [17].

• Case Management (Other NTDs): The number of new cases requiring individual treatment and care for other NTDs including Buruli ulcer, dengue, dracunculiasis, echinococcosis, human African trypanosomiasis, leprosy, leishmaniases, rabies, and yaws. This also includes people requiring surgery for PC-NTD complications and those needing rehabilitation [17].

To prevent overestimation from potential overlap between these two populations, the maximum of either the PC-requiring population or case management population is retained at the lowest common implementation unit and summed to create conservative country, regional, and global aggregates [17].

Methodological Evolution and Refinement

The methodology for estimating people requiring interventions has evolved significantly since its inception. The current approach uses an established methodology that has been tested and represents an agreed international standard [17]. As NTD programmes advance, improved co-endemicity data and validated models are expected to further refine these estimates by 2030.

Recent analytical updates in the 2025 Global Report include more sophisticated assessment of disease burden in terms of DALYs, prevalence and mortality; new perspectives on the financial risk associated with NTDs; and a detailed review of four thematic areas enabled by the Gap Assessment Tool [9]. These methodological advances provide greater precision in tracking the demographic shifts in NTD distribution.

Diagram 1: Methodological Framework for Estimating Populations Requiring NTD Interventions. This workflow illustrates the WHO's standardized approach for calculating the number of people requiring interventions, highlighting key steps to prevent double-counting in co-endemic areas through the maximum selection method [17].

Drivers of the Demographic Shift

Programmatic and Technical Innovations

The observed 32% decline in populations requiring NTD interventions since 2010 stems from multiple interconnected drivers spanning technical innovations, strengthened implementation frameworks, and strategic partnerships.

• Scale-up of Preventive Chemotherapy: The massive expansion of mass drug administration programmes has been the cornerstone of NTD control, with 99% of the 867.1 million people treated in 2023 receiving preventive chemotherapy [9]. Between 2011 and 2024, nearly 30 billion tablets and vials were delivered to countries, with 1.8 billion for treatments in 2024 alone [14] [18]. This represents one of the largest medicine donation programmes globally, currently involving 19 different types of NTD medicines donated by 12 manufacturers [14].

• Diagnostic and Technical Advancements: WHO prequalified six new medicine formulations, one active pharmaceutical ingredient, and a new dengue vaccine in 2024 [14]. The organization also launched a process to define research and development priorities for NTDs and facilitated the procurement of over 1 million diagnostic tests for five NTDs in 2024 [9]. These advancements have improved both the precision and scope of interventions.

• Integrated and Cross-Cutting Approaches: Progress has been accelerated through enhanced integration in the implementation of preventive chemotherapy, broader adoption of integrated strategies for skin-NTDs, and increased inclusion of NTDs in national health strategies, plans, and essential service packages [14]. The adoption of integrated approaches has enabled more efficient use of resources and expanded coverage.

Structural and Strategic Enablers

Beyond technical innovations, structural and strategic factors have played a crucial role in driving the demographic shift.

• Global Partnership Models: The coordinated effort involving pharmaceutical manufacturers, development partners, philanthropic organizations, national health authorities, and WHO has created an effective partnership model that has contributed significantly to the measurable decline in the global burden of NTDs [14]. This year marks 20 years since WHO consolidated disease-specific activities under a single programme dedicated to all NTDs, fostering collaboration that has proven highly effective [14].

• Country Ownership and Sustainability: As of 2024, 14 African countries had developed national plans to strengthen sustainability of NTD service delivery, reflecting growing country ownership and commitment [14]. This shift toward domestic resource mobilization and prioritization is critical for long-term sustainability.

• Mainstreaming and Global Advocacy: NTDs have maintained visibility in global forums such as the United Nations General Assembly, the United Nations Human Rights Council, and the G7 and G20 [14]. Partnerships were established or renewed with Gavi (on rabies vaccine) and with the Global Health Innovative Technology Fund (on access to medicines, vaccines, and diagnostics), expanding the reach and resources available for NTD control [9].

Research Implications and Future Directions

Evolving Research Priorities

The significant decline in populations requiring NTD interventions has profound implications for research priorities and drug development strategies. As programmes advance toward elimination goals, the research landscape must adapt to new challenges and opportunities.

Table 2: Essential Research Reagents and Tools for NTD Monitoring and Evaluation

Research Reagent/Tool Category	Specific Examples	Primary Function/Application	Development Status
Diagnostic Assays	Rapid diagnostic tests for LF, schistosomiasis; Molecular tests for HAT	Confirmation of elimination, surveillance in post-MDA settings	Variable; ongoing refinement needed
Medicinal Compounds	New chemical entities for leishmaniasis; Improved benznidazole formulations	Address drug resistance, expand therapeutic options	Six new medicine formulations prequalified in 2024
Monitoring & Evaluation Frameworks	WHO Gap Assessment Tool; Integrated survey methodologies	Track progress toward 2030 targets; Identify programmatic gaps	50+ WHO publications released in 2024
Data Integration Platforms	National health management information systems; Gender-disaggregated data collection	Mainstream NTD data into national health systems; Equity analysis	Gaps remain in complete data reporting
Vector Control Products	Novel insecticides for blackflies; Environmental management tools	Target vector-borne NTDs; Adapt to climate change	Climate change adaptation strategies emerging

The shifting demographics necessitate a parallel shift in research priorities toward more sensitive diagnostics for verification of elimination, tools for managing persistent hotspots, and strategies for integrating NTD surveillance into broader health systems [9]. The WHO's process to define R&D priorities for NTDs, launched in 2024, represents a strategic response to these evolving needs [14].

Addressing Persistent Challenges

Despite the significant progress, several challenges threaten the sustainability of the demographic gains and the achievement of the 2030 targets.

• Funding Constraints: Official development assistance for NTDs decreased by 41% between 2018 and 2023, creating severe disruptions to programmes and underscoring the need for prioritization, domestic resource mobilization, and strategic focus on high-impact interventions [14] [9]. This funding decline occurs despite evidence that investing in NTDs represents good value for money and serves as a pro-poor policy [15] [19].

• Cross-Cutting Gaps: Progress has been slow in reducing deaths from vector-borne diseases, expanding access to water, sanitation and hygiene (WASH), and protecting populations from catastrophic out-of-pocket expenditures [14]. Significant gaps also remain in ensuring complete data reporting on all NTDs and in collecting gender-disaggregated information [9].

• Emerging Threats: Climate change has emerged as a significant threat, particularly for vector-borne NTDs, potentially altering disease distribution and transmission dynamics [18] [8]. Recent research indicates that the NTD and malaria burden is projected to increase over the next 20 years, particularly in Middle and Low-middle Socio-Demographic Index regions, potentially reversing current gains [8].

Diagram 2: Strategic Framework for Accelerating NTD Progress. This diagram outlines the three interconnected pillars of the WHO's 2030 road map, highlighting how research and implementation strategies must align with programmatic actions, cross-cutting approaches, and transformed operating models to sustain demographic gains [13].

The 32% decline in populations requiring NTD interventions since 2010 represents a transformative demographic shift in the global landscape of neglected tropical diseases. This achievement demonstrates the cumulative impact of scaled preventive chemotherapy, technical innovations, strengthened partnership models, and increasingly integrated approaches to disease control [14] [9]. The progress is particularly remarkable given the multiple challenges faced, including the COVID-19 pandemic, funding constraints, and emerging threats such as climate change [18] [8].

For researchers, scientists, and drug development professionals, this demographic transition signals both achievement and imperative. It validates two decades of research and development investments while highlighting the need for adapted approaches suited to the changing epidemiology of NTDs. As programmes advance toward elimination goals, the demand will increase for more sensitive diagnostics, novel therapeutic options for persistent disease foci, and sophisticated tools for monitoring and evaluation in low-transmission settings [9]. The research community must also address ongoing challenges including inequitable progress across regions and diseases, funding instability, and data gaps that hinder precise measurement of advancements [14] [15].

The continued reduction of populations requiring NTD interventions remains achievable but will require sustained commitment, strategic resource allocation, and innovative approaches tailored to the evolving epidemiology of these diseases. By building on current momentum while addressing persistent barriers, the global community can maintain this positive demographic trajectory and achieve the ambitious targets set forth in the WHO 2030 road map [13].

Background: Neglected Tropical Diseases (NTDs) remain a significant global health challenge, affecting over 1.5 billion people worldwide. However, substantial progress has been made through coordinated elimination efforts. This review analyzes the successful strategies employed by 50 countries that eliminated at least one NTD by March 2024, providing a blueprint for future elimination programs.

Methodology: We conducted a systematic review of published literature and gray literature, extracting data on elimination program features, durations, interventions, strategies, partnerships, and historical failures. Data were synthesized to identify common success factors and challenges across different geographical and epidemiological contexts.

Results: Analysis revealed that elimination requires sustained, long-term efforts averaging two decades, with success hinging on country ownership, dedicated elimination programs, and multi-stakeholder partnerships. Eight NTDs have been eliminated in at least one country: Guinea worm disease, human African trypanosomiasis, lymphatic filariasis, onchocerciasis, rabies, trachoma, visceral leishmaniasis, and yaws. Togo achieved the most significant milestone, having eliminated four NTDs.

Conclusions: Accelerating NTD elimination requires intensified cross-sectoral approaches, including mainstreaming within health systems, improved Water, Sanitation, and Hygiene (WASH) infrastructure, and sustainable financing. This analysis provides a framework for researchers and program implementers to optimize future elimination strategies.

Neglected Tropical Diseases represent a group of 21 preventable and treatable conditions that disproportionately affect impoverished communities in tropical and subtropical regions [20]. These diseases impose a substantial health and economic burden, causing an estimated 14.1 million disability-adjusted life years (DALYs) lost annually and significant productivity losses estimated at $33 billion in household wages and income [20] [14]. The World Health Organization's (WHO) 2021-2030 road map for NTDs established ambitious targets, including having 100 countries eliminate at least one NTD by 2030 [20].

By March 2024, significant progress had been made toward these targets, with 50 countries having eliminated at least one NTD, reaching the halfway mark of the WHO's goal ahead of schedule [20] [21]. This milestone provides a unique opportunity to analyze the strategies and factors contributing to these success stories. Understanding these elements is crucial for accelerating progress in countries where NTDs remain endemic and for achieving the ultimate goal of reducing the global NTD burden.

This technical review synthesizes evidence from elimination programs across these 50 countries, with particular focus on the methodological approaches, quantitative outcomes, and implementation frameworks that have proven effective. The analysis aims to provide researchers, scientists, and drug development professionals with a comprehensive evidence base to inform future research priorities and elimination strategy design.

Methodology of the Systematic Review

Literature Search Strategy and Selection Criteria

The analysis of NTD elimination efforts was conducted through a comprehensive review of published and gray literature focusing on the 50 countries that had eliminated at least one NTD by March 2024 [20]. The methodological approach was systematic and structured to ensure complete coverage of relevant evidence.

Search Databases and Timeframe: Literature searches were conducted primarily on PubMed and secondarily on infoNTD databases between February 5 and May 22, 2024 [20]. The search strategy was initially piloted using lymphatic filariasis as a test case to assess the relevancy of retrieved results before being applied to all eight NTDs eliminated in at least one country.

Inclusion and Exclusion Criteria:

• Inclusion Criteria: Publications were included if they contained information on: (1) the elimination of one of the eight NTDs; (2) focus on countries or regions where elimination has been achieved; and (3) details of elimination efforts leading to validated or verified elimination [20].
• Exclusion Criteria: Publications were excluded if they were not available in English, Spanish, or French, or if the information provided had already been covered in other included sources [20].

Data Extraction and Synthesis

Data were extracted and recorded on various features of the elimination programmes, including:

• Durations and organizers of elimination efforts
• Interventions and strategies, including mainstreaming into other health services
• Partnerships involved
• Details of historical failed control efforts

These data were synthesized to generate a blueprint for NTD elimination, identifying common patterns and distinguishing factors between successful and unsuccessful efforts [20].

Quantitative Analysis of Global NTD Elimination Progress

Current Global Status of NTD Elimination

Table 1: Global Progress in NTD Elimination as of 2025

Indicator	2010 Baseline	2023/2024 Status	Change	2030 Target
People requiring NTD interventions	2.2 billion [14]	1.495 billion [14]	-32% [14]	Not specified
Countries eliminating ≥1 NTD	Not specified	50 (by March 2024) [20]	Not specified	100 [20]
Global disease burden (DALYs)	Not specified	14.1 million (2021) [14]	Reduced from 17.2M in 2015 [14]	Not specified
People treated for ≥1 NTD	Not specified	867.1 million (2023) [14]	Increased by 18M from 2022 [14]	Not specified
NTD-related deaths	Not specified	119,000 (2021) [14]	Reduced from 139,000 in 2015 [14]	Not specified

Table 2: NTDs Eliminated in at Least One Country (as of March 2024)

NTD	Number of Countries Achieving Elimination	Elimination Definitions	Key Interventions
Lymphatic filariasis	Multiple countries [20]	Elimination as a public health problem: reducing prevalence below target thresholds [20]	Mass drug administration (ivermectin + albendazole or DEC + albendazole) [22]
Trachoma	Multiple countries [20]	Elimination as a public health problem: prevalence of trachomatous trichiasis <0.2% in adults ≥15y [20]	SAFE strategy (Surgery, Antibiotics, Facial cleanliness, Environmental improvement)
Human African trypanosomiasis	Multiple countries [20]	Elimination as a public health problem: <1 case per 10,000 people in all sub-national areas; Zero transmission: no reported cases for 3 consecutive years [20]	Active screening, tiny targets for tsetse control, enhanced passive detection [23]
Guinea worm disease	Multiple countries [20]	Interruption of transmission: zero human cases and animal infections [20]	Health education, water filtration, case containment, vector control
Onchocerciasis	Multiple countries [20]	Elimination as a public health problem: <0.1% microfilarial prevalence in children; Interruption of transmission: no evidence of recrudescence for 5 years post-treatment [20]	Mass drug administration (ivermectin)
Rabies	Multiple countries [20]	Zero human deaths from dog-mediated rabies [20]	Mass dog vaccination, post-exposure prophylaxis
Visceral leishmaniasis	Multiple countries [20]	Elimination as a public health problem: <1 case per 10,000 people annually at sub-national level [20]	Active case detection, indoor residual spraying, treatment of PKDL cases [23]
Yaws	Multiple countries [20]	Elimination as a public health problem: <0.1% seroprevalence in children 1-5y; Interruption of transmission: no confirmed cases for 3 years [20]	Mass drug administration (azithromycin)

Geographical Distribution of Success

The 50 countries that have eliminated at least one NTD are distributed across all WHO regions, with notable concentrations in certain areas. Among these countries, 13 have eliminated at least two NTDs, with Togo achieving the highest milestone by eliminating four different NTDs [20]. Of the 50 countries, 46 had achieved NTD elimination specifically as a public health problem for one or more NTDs, while 22 countries had eliminated one or more NTDs with interruption of transmission [20].

The African Region, endemic for 20 of the 21 priority NTDs and comprising 35% of the global disease burden, has made significant strides despite facing substantial challenges [24]. Recent progress continues, with the number of countries having eliminated at least one NTD rising to 56 by June 2025, including Chad, Jordan, Brazil, Timor-Leste, Guinea, and Papua New Guinea [20].

Success Factors in NTD Elimination: A Systematic Analysis

Core Components of Successful Elimination Programs

Analysis of the 50 country success stories revealed several consistent factors that contributed to successful elimination outcomes:

Country Ownership and Leadership: Successful elimination programs were characterized by strong national ownership, with governments taking leadership in planning, implementation, and resource mobilization [20] [24]. This finding is supported by recent African Union initiatives, where 50 member states endorsed a groundbreaking digital micro-planning portal co-created by Africa CDC to accelerate NTD elimination, demonstrating regional commitment to home-grown solutions [24].

Sustained Long-Term Commitment: Elimination required at least two decades of sustained efforts in most cases, highlighting the necessity of long-term political and financial commitment beyond typical project cycles [20]. Programs that maintained consistent intervention intensity despite changing political landscapes were significantly more likely to achieve elimination targets.

Strategic Partnership Models: Successful programs leveraged partnerships between endemic countries and international stakeholders, including pharmaceutical companies, development agencies, and technical organizations [20]. These partnerships facilitated access to essential medicines, technical expertise, and supplementary funding. Notably, by the end of 2024, 19 different types of NTD medicines were donated by 12 manufacturers, with 1.8 billion tablets and vials delivered in 2024 alone [14].

Combination Intervention Strategies: Programs that deployed integrated combinations of interventions—including mass drug administration, vector control, surveillance, and case management—outperformed those relying on single interventions [20]. The most successful programs tailored these combinations to local epidemiological contexts and transmission dynamics.

Implementation Strategies and Intervention Approaches

Table 3: Analysis of Elimination Program Strategies and Timeframes

Program Characteristic	Prevalence in Successful Programs	Impact on Elimination Timeline	Key Considerations
Single-disease vertical approach	Most programs [20]	Standard timeline (≈20 years)	Allows focused resources but may miss integration opportunities
Integrated multi-disease approach	Fewer programs [20]	Potentially accelerated timeline	Increases program complexity but improves cost-effectiveness
Mass drug administration (MDA)	Universal in preventive chemotherapy NTDs [22]	5+ years typically required [22]	Coverage thresholds critical (typically ≥65%) [22]
Active case detection and management	Essential for IDM NTDs [23]	Varies by disease transmission intensity	Requires strong surveillance systems and community engagement
Vector control	Critical for vector-borne NTDs [23]	Can accelerate interruption of transmission	Must be tailored to local vector ecology and behavior
WASH interventions	Cross-cutting [20]	Long-term sustainability	Requires multi-sectoral coordination

The choice between vertical single-disease approaches and integrated multi-disease approaches represented a key strategic consideration. Most elimination programs targeted one NTD at a time, while fewer utilized integrated approaches [20]. However, recent trends show increased emphasis on integration, with advances including "enhanced integration in the implementation of preventive chemotherapy, broader adoption of integrated strategies for skin-NTDs, [and] increased inclusion of NTDs in national health strategies, plans and essential service packages" [14].

The research also highlighted the importance of adapting strategies to local epidemiological contexts. For lymphatic filariasis elimination, modeling studies recommended twice-yearly MDA at 65% coverage as the most effective strategy for achieving elimination within five years [22]. Similarly, for visceral leishmaniasis in the Indian subcontinent, the optimal duration of the attack phase needed adjustment according to pre-control endemicity levels [23].

Research and Diagnostic Innovation in Support of Elimination

The Evolving Role of Diagnostics in Elimination Campaigns

Diagnostics have played an increasingly critical role in NTD elimination efforts, with their importance growing as programs advance toward elimination goals [25]. The exigencies of elimination have reframed whom diagnosis is for and the myriad roles diagnostics can play beyond individual patient management.

Functions of Diagnostics in Elimination Settings:

• Mapping and Initial Assessment: Determining geographical distribution and prevalence before program initiation
• Intervention Monitoring: Tracking the impact of mass drug administration or other interventions
• Stopping Decisions: Providing evidence to determine when interventions can be safely interrupted
• Surveillance: Detecting resurgence after intervention cessation

The evolution of diagnostic approaches has been particularly notable. Early NTD campaigns were largely focused on "attack phase planning, whereby a similar set of interventions could be transplanted anywhere" [25]. In contrast, current approaches with elimination goals in sight require strategies to be tailored to local settings, with diagnostic data essential for local adaptation and programmatic decision-making.

Research Reagents and Technical Tools for Elimination Programs

Table 4: Essential Research Reagent Solutions for NTD Elimination Research

Reagent/Tool Category	Specific Examples	Research and Program Applications	Technical Considerations
Molecular diagnostics	PCR assays, LAMP tests	Confirmation of elimination, detection of low-level transmission	Specificity and sensitivity requirements increase near elimination
Serological assays	ELISA, RDTs for antigen/antibody detection	Mapping, monitoring transmission interruption, assessing intervention impact	Differentiation between current and past infection challenging
Point-of-care tests	Rapid diagnostic tests (RDTs)	Field-based surveillance, treatment decisions in remote settings	Stability in tropical conditions, minimal training requirements
Geographic information systems	ESPEN Collect, Tropical Data	Spatial mapping, hotspot identification, resource targeting	Data quality, completeness, and timeliness critical for elimination
Mathematical modeling tools	NTD Modelling Consortium frameworks	Program strategy optimization, resource allocation, forecasting	Must be calibrated to local transmission dynamics

The NTD Modelling Consortium, established to address the need for quantitative analysis to support elimination, developed models for nine NTDs [22] [23]. This consortium was unusual among modeling consortia because it crossed "a number of epidemiologically distinct infections, with different types of etiological agents and modes of transmission," allowing researchers to "exploit similarities between diseases, such as vector-borne dynamics or the impact of mass drug administration" [22].

The research identified key areas where diagnostic innovation remains crucial. For diseases targeted for elimination as a public health problem, diagnostics that can measure progress toward this specific target are essential. The limitations of current diagnostic tools become particularly apparent in the end stages of elimination programs, where the ability to detect very low levels of infection or transmission becomes paramount [25].

Conceptual Framework for NTD Elimination

The analysis of successful elimination programs reveals a consistent conceptual framework that integrates core components, implementation strategies, and enabling factors. The following diagram illustrates the logical relationships and workflow between these critical elements:

Challenges and Future Directions

Implementation Barriers and Setbacks

Despite the impressive progress documented in this review, significant challenges threaten further advancement toward NTD elimination goals. Analysis of both successful and failed elimination attempts identified several recurring barriers:

Funding Instability: Recent reductions in official development assistance (ODA) for global health, particularly for NTD programs, present serious threats to continued progress. Official development assistance decreased by 41% between 2018 and 2023, creating severe disruptions in treatment campaigns and impact surveys [14] [26]. The immediate impact of funding withdrawals has delayed 47 mass treatment campaigns intended to reach 143 million people, potentially postponing elimination targets in at least 10 additional countries [26].

Sociopolitical Instability: Historical analysis reveals that failed elimination efforts were frequently associated with sociopolitical instability, which disrupts program continuity and implementation quality [20]. Programs in conflict-affected or fragile regions face particular challenges in maintaining the consistent intervention coverage necessary for elimination.

Health System Limitations: Weak health systems struggle to deliver the targeted interventions required for elimination, particularly in the "last mile" of reaching the most remote or marginalized communities [20]. Limitations in infrastructure, human resources, and supply chain management can undermine even well-designed elimination programs.

Research Gaps and Innovation Priorities

Future progress in NTD elimination will require addressing several critical research gaps:

Improved Diagnostic Tools: As programs approach elimination, the limitations of current diagnostics become more apparent. There is an urgent need for tools that can detect ultra-low levels of infection, distinguish between current and past infections, and be deployed effectively at the point of care in remote settings [25].

Therapeutic Innovations: While existing medications have been instrumental in current successes, challenges remain with treatment regimens, safety profiles, and potential resistance. Novel therapeutic approaches are needed, particularly for NTDs where current options are suboptimal.

Implementation Research: More evidence is needed on effective strategies for reaching the most marginalized populations, integrating NTD services into strengthened health systems, and optimizing intervention mixes for different epidemiological contexts.

The analysis of 50 countries that have successfully eliminated at least one NTD provides valuable insights for the global research and public health communities. The evidence demonstrates that elimination is an achievable goal, but requires sustained, long-term commitment averaging two decades, combined with strategic approaches tailored to local contexts.

Core success factors include strong country ownership, dedicated elimination programs, multi-stakeholder partnerships, and combination intervention strategies. The evolving role of diagnostics and modeling has become increasingly important for guiding program decisions and measuring progress toward elimination goals.

Despite impressive progress, significant challenges remain, including funding instability, sociopolitical barriers, and health system limitations. Addressing these challenges will require renewed commitment to sustainable financing, strengthened health systems, and continued research innovation.

For researchers, scientists, and drug development professionals, this review highlights several priority areas: (1) development of next-generation diagnostics suitable for elimination settings; (2) optimization of intervention strategies through modeling and field research; and (3) implementation science to improve program delivery in challenging contexts. By building on the lessons from successful elimination programs and addressing remaining research gaps, the global community can accelerate progress toward the goal of eliminating NTDs as public health problems worldwide.

Innovative Strategies and Collaborative Models in NTD Drug Discovery and Development

Neglected Tropical Diseases (NTDs) represent a group of chronic, debilitating infections that affect over 1.4 billion people globally, primarily impoverished populations in developing regions [27] [28]. Despite causing approximately 14.1 million disability-adjusted life years (DALYs) lost annually and significant mortality, NTDs have historically experienced profound neglect in research and development investment [27] [29]. This whitepaper analyzes the structural, economic, and political factors driving innovation gaps in NTD research, examines historical funding patterns through quantitative analysis, and proposes integrated strategies to stimulate sustainable R&D ecosystems. The analysis is situated within the broader context of global disease burden, revealing that NTDs collectively cause disease burdens comparable to HIV/AIDS, tuberculosis, and malaria in sub-Saharan Africa, yet receive disproportionately minimal investment [29] [28].

The World Health Organization prioritizes twenty diseases as NTDs, caused by diverse pathogens including viruses, bacteria, parasites, fungi, and toxins [27] [28]. These conditions share fundamental characteristics: they predominantly affect impoverished populations, cause chronic disability and stigmatization rather than high mortality, and persist in areas with inadequate sanitation and limited healthcare infrastructure [29]. The conceptual framework of NTDs emerged in the years following the 2000 Millennium Declaration, which largely overlooked "other diseases" beyond HIV/AIDS, tuberculosis, and malaria in MDG 6 [29]. This initial exclusion from global health priorities created structural disadvantages in research investment that persist despite increased recognition.

The epidemiology of NTDs is complex, often involving environmental factors, animal reservoirs, and intricate transmission cycles that complicate public health control measures [27]. Approximately 1.495 billion people require preventive or curative interventions for NTDs annually, representing one of the most significant disease burdens concentrated exclusively among the world's most vulnerable populations [27]. The diseases perpetuate poverty through multiple pathways: impairing child growth and cognitive development, reducing school attendance, decreasing worker productivity, and exacerbating social inequality through stigma and discrimination [29].

Quantitative Analysis of R&D Investment Disparities

Historical Funding Patterns

Research investment in NTDs has consistently lagged behind other disease categories despite their significant collective burden. A comprehensive analysis of global health R&D investments revealed that approximately 80% of the US\$2.5 billion invested annually into diseases of poverty was allocated to HIV/AIDS, tuberculosis, and malaria, with NTDs receiving a minimal fraction [30]. This disparity exists despite evidence that NTDs collectively cause disease burdens comparable to the "big three" diseases in endemic regions [28].

Table 1: Comparative Analysis of NTD Burden and Investment

Disease Category	Global Prevalence (million)	DALYs (million)	Annual Deaths	Relative R&D Investment
All NTDs (collective)	1,400+ [28]	14.1 [27]	142,000 [28]	Low
Malaria	-	-	-	High
HIV/AIDS	-	-	-	High
Tuberculosis	-	-	-	High
Soil-transmitted helminths	807-1,200 [29] [28]	22.1 (hookworm) [28]	65,000 (hookworm) [28]	Minimal
Schistosomiasis	207 [28]	4.5 [28]	280,000 [28]	Minimal
Dengue & Chikungunya	-	-	-	Moderate

Case study analysis of the Bill & Melinda Gates Foundation's funding portfolio between 1998-2008 revealed that of US\$697 million allocated to NTD projects, only 35% (US\$241 million) supported social science research, with the remainder dedicated to basic science and translational research [30]. While this appears substantial, it represents a tiny fraction of global health R&D investment and is insufficient to address the vast tool gaps for NTD control and elimination.

Economic Drivers of Investment Neglect

The private pharmaceutical sector has historically underinvested in NTD R&D due to perceived commercial non-viability. Economic modeling analyses demonstrate that development of novel NTD treatments generates negative returns on investment when accounting for capitalized costs and failure risk, even with incentive programs like Priority Review Vouchers [31]. One study calculated that private returns would be negative for novel drugs like Fexinidazole and Acoziborole for Human African Trypanosomiasis, with the PRV proving insufficient to generate positive returns [31].

Table 2: Economic Analysis of NTD Drug Development Returns

Drug	Disease Target	Development Model	Private ROI without PPP	Key Economic Barriers
Fexinidazole	Human African Trypanosomiasis	PPP-led	Negative [31]	High development costs, limited market, regulatory hurdles
Acoziborole	Human African Trypanosomiasis	PPP-led	Negative [31]	High development costs, limited market, regulatory hurdles
Benznidazole	Chagas disease	Repurposed existing compound	Positive [31]	Lower development costs, existing safety data
Typical commercial drug	Non-communicable diseases	Private sector	Substantially positive [28]	Large patient populations, ability to recoup R&D costs

This market failure stems from fundamental economic realities: NTDs primarily affect populations with minimal purchasing power, potential treatment courses are typically short-term or single-dose, and endemic regions often lack robust healthcare delivery systems [31] [28]. Between 1975-1999, only 16 of 1,393 new chemical entities marketed were for tropical diseases or tuberculosis, demonstrating a 13-fold greater probability of new drugs targeting central nervous system disorders or cancer [28].

Experimental Analysis of R&D Models and Methodologies

Public-Private Partnership Case Studies

Recent successes in NTD drug development have predominantly emerged from public-private partnerships (PPPs) that strategically mitigate private sector risk. Qualitative case studies of successful PPPs supporting HAT and Chagas disease pipelines reveal four critical success factors: (1) pre-existing philanthropic infrastructure for target diseases, (2) alignment with corporate social responsibility objectives, (3) PPP coordination to reduce private-sector risk, and (4) complementary non-profit stewardship throughout development [31].

Experimental Protocol: Evaluating PPP Effectiveness in NTD R&D

Objective: To assess the impact of PPP structures on drug development outcomes for neglected tropical diseases.

Methodology:

• Case Selection: Identify PPP-led drug development projects for NTDs (e.g., Fexinidazole for HAT, Benznidazole for Chagas disease)
• Stakeholder Mapping: Conduct semi-structured interviews with 21+ key informants from industry, academia, non-profits, and regulatory agencies [31]
• Economic Modeling: Calculate net present value of R&D costs for average NTD drug development
• Comparative Analysis: Estimate private return on investment had projects been executed solely by for-profit entities
• Sensitivity Analysis: Model impact of key variables (PRV value, approval probabilities, development costs) on ROI [31]

Data Collection Instruments:

• Structured interview protocols assessing risk distribution, funding mechanisms, decision-making processes
• Financial modeling templates incorporating capitalized costs, failure risk adjustments, and revenue projections
• Partnership effectiveness metrics including timeline efficiency, resource mobilization, and regulatory success

Analysis Framework:

• Thematic analysis of qualitative interview data
• Net present value calculations with risk adjustment
• Counterfactual scenario development for private-sector-only development

Research Reagent Solutions for NTD Laboratories

Advancing NTD R&D requires specialized research tools and reagents adapted to resource-limited settings and unique pathogen biology. The following table outlines essential research reagents and their applications in NTD drug discovery and development.

Table 3: Essential Research Reagent Solutions for NTD R&D

Research Reagent	Function/Application	NTD Specific Considerations
Compound Libraries	Screening for novel therapeutic candidates	Focus on cost-effective, stable compounds suitable for tropical conditions [31]
Pathogen-Specific Cell Cultures	In vitro drug screening	Require biosafety level 2-3 facilities for parasite cultures (HAT, Leishmania) [31]
Species-Specific Antibodies	Detection, quantification, and cellular localization of pathogen antigens	Limited commercial availability for neglected pathogens [32]
Molecular Diagnostic Primers/Probes	Pathogen detection and differentiation	Must accommodate genetic diversity of field isolates [32]
Animal Model Systems	In vivo efficacy and toxicity testing	Limited models for chronic pathology manifestations [31]
Field-Stable Assay Components	Diagnostic development for low-resource settings	Temperature-stable reagents, minimal equipment requirements [32]

Structural Barriers and Policy Frameworks

Market Failure Mechanisms

The insufficient investment in NTD R&D represents a classic market failure where commercial incentives do not align with public health needs. This failure operates through multiple interconnected mechanisms:

Limited Market Size and Purchasing Power: NTDs predominantly affect the "bottom billion" living on less than US\$1.25 per day, creating minimal commercial markets for therapies [29]. Unlike chronic diseases in wealthy countries requiring long-term treatment, NTD therapies often involve single-dose or short-course regimens, further reducing revenue potential [31].

High Development Costs and Risk: Drug development remains expensive and high-risk, with failure rates exceeding 90% in some stages. For diseases with complex biology like HAT and Chagas disease, basic research gaps increase technical uncertainty and development costs [31]. Regulatory pathways for NTD drugs may be unclear, creating additional development barriers.

Intellectual Property Challenges: While patent protection typically drives pharmaceutical innovation, its value diminishes for markets with minimal purchasing power. Additionally, existing knowledge and compound libraries for NTDs are often fragmented across academic and government institutions without clear commercialization pathways [31] [32].

Policy Interventions and Their Efficacy

Several policy mechanisms have been implemented to stimulate NTD R&D investment, with varying degrees of success:

Priority Review Voucher (PRV) Program: This U.S. FDA program awards transferable vouchers for priority review of any other drug application to sponsors receiving approval for eligible neglected disease treatments [31]. Economic modeling indicates that while PRVs provide valuable incentives (worth approximately US\$100 million), they are insufficient alone to generate positive returns on novel NTD drug development when accounting for capitalized costs and failure risk [31].

Product Development Partnerships (PDPs): These entities strategically integrate capabilities from public, private, academic, and philanthropic sectors to advance neglected disease product development. The Drugs for Neglected Diseases Initiative (DNDi) has successfully developed seven new treatments for NTDs through this model by leveraging compound donations, public funding, and shared intellectual property management [31] [32].

Public Sector Funding Increases: The BMGF has emerged as a major funder of NTD research, accounting for approximately 21% of global neglected disease R&D investment [30]. However, funding distribution remains skewed toward basic research and product development rather than implementation research or social science, with only 39% of BMGF NTD projects supporting social science research [30].

Integrated Strategies for Sustainable R&D Ecosystems

Portfolio Management Approaches

Bridging the NTD innovation gap requires strategic portfolio management that balances high-risk novel research with incremental improvements to existing tools. Economic analyses suggest distinct strategies based on development pathway:

Repurposing Existing Compounds: Development of pre-existing compounds (e.g., Benznidazole for Chagas disease) demonstrates positive returns in the current environment and should be prioritized for near-term impact [31]. This approach leverages existing safety data and manufacturing experience, substantially reducing development costs and timelines.

Novel Chemical Entities: Development of truly novel therapeutics (e.g., Acoziborole for HAT) requires substantial public subsidy and non-profit stewardship throughout the pipeline [31]. Portfolio management should explicitly acknowledge the negative commercial returns and structure funding accordingly through blended finance models incorporating public, philanthropic, and private capital.

Diagnostic and Delivery Innovation: Beyond drug development, significant innovation gaps exist in NTD diagnostics and delivery technologies. Platform technologies received less than 0.4% of total R&D spending for diseases of poverty, representing a critical opportunity area [30].

Research Infrastructure Strengthening

Sustainable NTD R&D requires coordinated investment in fundamental research infrastructure beyond individual product development:

Pathogen Biology and Basic Science: Understanding fundamental disease mechanisms remains fragmented for many NTDs, impeding target-based drug discovery. Strategic investment in basic pathogen biology, host-pathogen interactions, and disease pathogenesis models would de-risk early-stage drug discovery [31].

Clinical Trial Capacity in Endemic Regions: Conducting clinical trials in NTD-endemic regions requires significant capacity building in research ethics, regulatory oversight, good clinical practice, and data management [32]. Strengthening these capabilities generates positive externalities for overall health system development.

Data Sharing and Collaboration Platforms: Pre-competitive collaboration platforms that enable data and compound sharing accelerate research progress. Initiatives like the NTD Compound Library have facilitated screening of pharmaceutical company compounds against neglected pathogens [31] [32].

The innovation gap in NTD R&D stems from complex structural and economic factors rather than scientific feasibility alone. Historical underinvestment has created a tool-deficient environment where current control strategies rely heavily on a limited number of donated drugs and decades-old technologies. Economic analyses demonstrate that market forces alone cannot address these gaps due to fundamental misalignment between commercial incentives and public health needs.

Successful models for advancing NTD R&D involve strategically designed public-private partnerships that redistribute risk, integrate capabilities across sectors, and incorporate non-profit stewardship throughout the development pipeline. The WHO's 2021-2030 NTD road map provides a framework for transitioning from vertical disease programs to integrated approaches, with targets including a 90% reduction in people requiring NTD interventions and elimination of at least one NTD in 100 countries [27].

Future progress requires sustained commitment to both basic research and translational development, recognizing that the innovation timeline for novel NTD tools typically exceeds commercial development horizons. Blended finance models that strategically combine public, philanthropic, and private capital can create sustainable funding streams aligned with the distinct economics of neglected disease R&D. Additionally, greater investment in implementation research and social science is needed to ensure successful adoption and scale-up of new technologies in resource-limited settings [30].

Bridging the NTD innovation gap represents both a moral imperative and a strategic investment in global health security. As the world faces increasing challenges from emerging infectious diseases and climate-sensitive pathogens, the research capabilities and development models pioneered for NTDs may prove increasingly relevant for broader global health priorities.

Product Development Partnerships (PDPs) are strategic alliances that use public and philanthropic funds to engage pharmaceutical companies and academic institutions in research and development (R&D) for diseases of the developing world that they would normally be unable or unwilling to pursue independently due to a lack of commercial incentive [33]. This whitepaper examines the core structure, operational mechanisms, and measurable impact of PDPs within the context of combating Neglected Tropical Diseases (NTDs), a group of infections affecting over one billion people globally and costing developing economies billions of dollars annually [27] [28]. By leveraging defined governance mechanisms, disciplined communication, and balanced intellectual property (IP) policies, PDPs have emerged as a critical non-profit R&D model for de-risking product development and accelerating the delivery of health solutions for the world's most vulnerable populations.

The Global Burden of Neglected Tropical Diseases

Epidemiology and Scope

Neglected Tropical Diseases (NTDs) are a diverse group of communicable diseases prevalent in tropical and subtropical conditions across 149 countries, primarily affecting populations living in poverty [28]. The World Health Organization (WHO) prioritizes 20 NTDs, including lymphatic filariasis, schistosomiasis, and dengue fever, which are caused by pathogens ranging from viruses and bacteria to protozoa and parasitic worms [27]. The epidemiology of NTDs is complex, often related to environmental conditions, with many being vector-borne and involving animal reservoirs [27].

Socioeconomic Impact

The impact of NTDs extends beyond devastating health consequences to include significant social and economic burdens. WHO estimates that more than 1.495 billion people require interventions for NTDs annually, with these diseases causing approximately 120,000 deaths and 14.1 million disability-adjusted life years (DALYs) lost each year [27]. The socioeconomic burden includes direct healthcare costs, loss of productivity, and reduced educational attainment, which collectively cost developing communities billions of dollars annually [27]. These diseases also cause stigmatization, social exclusion, and discrimination, placing considerable financial strain on patients and their families [27].

Table 1: Major Neglected Tropical Diseases and Their Global Burden

Disease	Global Prevalence (Million)	Population at Risk (Million)	DALYs (Million)	Primary Intervention
Schistosomiasis	207	780	4.5	Preventive Chemotherapy
Hookworm	576	3,200	22.1	Preventive Chemotherapy
Ascariasis	807	4,200	10.5	Preventive Chemotherapy
Leishmaniasis	12	350	2.1	Innovative Disease Management
African Trypanosomiasis	0.3	60	1.5	Innovative Disease Management
Chagas Disease	Information Missing	Information Missing	0.7	Innovative Disease Management

Source: [28] [34]

The Product Development Partnership Model

Evolution and Core Principles

The traditional definition of PDPs describes them as entities that "use public and philanthropic funds to engage the pharmaceutical industry and academic research institutions in undertaking R&D for diseases of the developing world that they would normally be unable or unwilling to pursue independently, without additional incentives" [33]. However, the landscape of partnership models has expanded dramatically beyond this original concept [33].

The proliferation of innovative partnership models has been driven by several factors across different sectors:

• Industry: Rising costs and risks in drug development coupled with thinning pipelines
• Governments: Unsustainable healthcare costs and increased global competition
• Academia: Constrained funding and shifting focus toward translational science
• Not-for-profits: Growing demands for accountability and transparency [33]

PDPs across this continuum yield shared benefits that no single partner can achieve independently, including combining expertise and resources, spreading funding and risk across multiple players, and efficiently allocating resources through stringent project vetting [33].

Key Operational Elements

Successful PDPs exhibit three common elements that enable their effectiveness:

1. Defined Governance Mechanisms Effective governance ensures appropriate participation in decision-making through four key components: transparency, accountability, oversight, and focus [33]. Various governance structures are implemented to manage complex relationships, such as Executive Committees with equal voting members, Scientific Committees of regional thought leaders, and Independent Boards that guide strategy while limiting potential conflicts of interest [33].

2. Disciplined Communication Approach PDPs must pursue consensus-based communication plans to ensure efficient operations, align stakeholder expectations, and maximize potential for sustainability [33]. This includes addressing the distinct needs of partners, the scientific community, funders, and the public [33]. Successful examples include multi-pronged outreach strategies targeting diverse stakeholders and publication of results in open-access journals [33].

3. Balanced Intellectual Property Policies IP policies must negotiate the often competing priorities of various partners, balancing the need for affordable products in developing countries with industry's need for reasonable return on investment in selected markets [33]. These policies are adaptable, with some partnerships negotiating exclusive global licenses with royalty-free provisions in endemic countries, while others adopt "open innovation" models with more flexible IP arrangements [33].

Diagram 1: PDP Operational Framework illustrating core inputs, processes, and outputs

Evaluating PDP Success: Quantitative Outcomes and Impact

Disease-Specific Milestones and Progress

PDPs have contributed to significant progress against high-priority NTDs through coordinated global efforts. The evidence of success is demonstrated by these measurable outcomes:

• Guinea Worm Disease: Near eradication achieved, with only 13 human cases reported globally in 2024, down from millions in the 1980s [35]
• Trachoma: Twenty-five countries validated by WHO as having eliminated trachoma as a public health problem since 2011 [35]
• Lymphatic Filariasis: 74% reduction globally between 2000 and 2018, with over 935 million people receiving treatment since 2000 [35]
• River Blindness: Eliminated in four South American countries and Niger, the first African country to achieve elimination, with 249.5 million people requiring preventive treatment in 2023 [35]

The London Declaration on NTDs in 2012 and subsequent Kigali Declaration in 2022 have galvanized political and financial commitments, with 62 signatories helping to achieve the goals in WHO's 2021-2030 NTD roadmap [35]. To date, 57 countries have eliminated at least one NTD, and pharmaceutical companies have donated 18 billion treatments to prevent and treat NTDs [35].

Table 2: Strategic Approaches for Different NTD Categories

Disease Category	Control Strategy	Primary Tools	Key PDP Examples
Lymphatic Filariasis, Onchocerciasis, Schistosomiasis, Soil-transmitted Helminths, Trachoma	Preventive Chemotherapy & Transmission Control (PCT)	Mass Drug Administration	Mectizan Donation Program
Buruli Ulcer, Chagas Disease, Human African Trypanosomiasis, Leishmaniasis	Innovative & Intensified Disease Management (IDM)	Improved Diagnostics, Case Detection & Treatment	DNDi, FIND
Vector-borne NTDs	Cross-Cutting	Integrated Vector Management	Innovative Vector Control Consortium
All NTDs	Surveillance & Data	Disease Mapping, Monitoring & Evaluation	WHO Global NTD Program

Source: [35] [34]

PDP Case Studies and Governance Structures

Different PDPs have implemented varied governance structures to achieve their objectives:

• Pox-Protein Public-Private Partnership (P5): Established an Executive Committee where each partner is an equal voting-member, providing strategic leadership and overseeing specific committees/working groups established on an as-needed basis [33]
• Structural Genomics Consortium: Utilizes independent boards that advise on and guide strategy, charged with proposal review and funding, while limiting industry's involvement to maintain objectivity [33]
• Sabin PDP (formerly Human Hookworm Vaccine Initiative): Implemented multi-pronged outreach strategies targeting patient groups, schools, media, and policymakers, while publishing over 100 peer-reviewed articles since 2000 [33]

Diagram 2: PDP Governance Structure showing key committees and functions

Research Protocols and Methodologies in PDPs

Integrated Development Approaches

PDPs employ comprehensive strategies to address multiple infectious diseases simultaneously through three main approaches:

1. Mass Drug Administration (MDA) Supported in regions with a prevalence of several diseases that can be treated with the same drugs or similar treatment schedules [35]. This approach leverages pharmaceutical donations for large-scale programs that target multiple NTDs concurrently, achieving significant efficiencies in resource utilization and population coverage [35]. Five target NTDs are particularly amenable to this approach: river blindness, lymphatic filariasis, soil-transmitted helminthiases, snail fever, and trachoma [35].

2. Public Health Surveillance Development of shared approaches to sample collection, processing, and data aggregation is critical for disease monitoring [35]. PDPs support the design of surveillance systems and precision mapping to pinpoint at-risk populations, which is particularly important for diseases like sleeping sickness and black fever that can be controlled through screening at-risk populations and treating infected individuals [35].

3. Vector Control Most NTDs are caused or spread by insects or worms, which are costly and difficult to control individually [35]. PDPs support the development of frameworks for cross-disease coordination, including integrating NTD and non-NTD tools [35]. For instance, the same diagnostic test could potentially be used for both sleeping sickness and malaria, creating efficiencies in healthcare delivery [35].

The Scientist's Toolkit: Essential Research Reagents

Table 3: Key Research Reagent Solutions for NTD Drug Discovery

Research Reagent	Function/Application	Example Use Case
Cell-Based Assay Systems	High-throughput screening of compound libraries against target pathogens	Screening 700+ tumor cell lines for sensitivity to growth inhibition, as done in crizotinib development [36]
Preclinical Tumor Models	In vivo evaluation of drug efficacy and toxicity	Regression studies of tumor cell lines implanted as xenografts in mice [36]
Functional Genomics Tools	Identification and validation of novel drug targets	Functional genomics screens to demonstrate relevance of ALK in NSCLC [36]
Global Phosphorylation Assays	Understanding signaling pathways and mechanism of action	Confirming drug target relevance through phosphoproteomic analysis [36]
Companion Diagnostic Kits	Patient stratification for targeted therapies	FDA-approved FISH test for ALK rearrangements in NSCLC [36]
Pharmacokinetic/Pharmacodynamic (PK/PD) Models	Quantitative relationship between drug exposure and response	Model-based drug development for optimizing dosing regimens [37]

Product Development Partnerships represent a transformative model that has successfully addressed the market failures in drug development for neglected tropical diseases. By combining expertise and resources from multiple sectors, implementing defined governance structures, and balancing the competing priorities of various stakeholders through innovative IP frameworks, PDPs have demonstrated measurable success in controlling, eliminating, and eradicating devastating diseases that disproportionately affect the world's poorest populations.

The continued evolution of PDP models—including experimentation with flexible partnership structures and "open innovation" approaches—will be essential for addressing the ongoing challenges in global health R&D [33]. As constrained resources necessitate more efficient approaches, the PDP model offers a proven framework for accelerating the development and delivery of health solutions to those most in need, ultimately breaking the cycle of poverty perpetuated by neglected tropical diseases and contributing to the achievement of broader global health equity goals.

Neglected Tropical Diseases (NTDs) remain a significant global health challenge, primarily affecting populations in low- and middle-income countries. The World Health Organization (WHO) estimates that 1.495 billion people required interventions against NTDs in 2023, representing a 32% decrease from the 2010 baseline yet still reflecting a substantial disease burden [9] [14]. Between 2015 and 2021, the NTD burden decreased from 17.2 million to 14.1 million disability-adjusted life years (DALYs), while NTD-related deaths fell from 139,000 to 119,000 [9] [14]. These 21 diverse diseases, including Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis, share a common neglect in therapeutic development due to limited commercial incentives, complex biological mechanisms, and constrained research funding in endemic regions [38] [39].

The 2021-2030 WHO Roadmap on NTDs sets ambitious targets for control and elimination by 2030, achieving this requires innovative approaches to overcome historical challenges in NTD drug discovery [38] [9]. Fortunately, the field has begun shifting from traditional methods to modern strategies that integrate phenotypic screening, artificial intelligence, and multi-target agents [38]. These approaches offer promising avenues for identifying novel therapeutic candidates with enhanced efficacy against complex disease pathways. This review examines these transformative methodologies, their integration into the NTD drug discovery pipeline, and their potential to accelerate the development of more effective treatments for these devastating diseases.

Phenotypic Screening in NTD Drug Discovery

Conceptual Framework and Advantages

Phenotypic screening is a drug discovery approach that identifies bioactive compounds based on their ability to alter observable characteristics (phenotypes) in cells, tissues, or whole organisms without requiring prior knowledge of specific molecular targets [40]. This method has re-emerged as a powerful strategy after decades of target-based dominance, particularly valuable for NTDs where molecular understanding remains incomplete. Alexander Fleming's discovery of penicillin through observation of bacterial death around mold represents an early example of phenotypic screening [40].

This approach offers several distinct advantages for NTD research:

• Unbiased Discovery: Identifies novel mechanisms of action not limited to known biological pathways [40]
• Biologically Relevant Outcomes: Captures complex biological interactions within intact cellular environments, improving translational predictability [41] [40]
• First-in-Class Potential: Historically responsible for a disproportionate share of first-in-class therapeutics, including antibiotics and early antiparasitics [40]

Experimental Models and Methodologies

Phenotypic screening employs tiered experimental models of increasing physiological relevance:

Table 1: Experimental Models for Phenotypic Screening in NTD Research

Model Type	Examples	Applications in NTD Research	Throughput
2D Monolayer Cultures	Immortalized cell lines	Primary cytotoxicity screening, basic functional assays	High
3D Organoids/Spheroids	Patient-derived tissue models	Liver stage parasites (e.g., Opisthorchis viverrini), tissue-specific infection models	Medium
iPSC-Derived Models	Patient-specific differentiated cells	Disease modeling, personalized therapeutic screening	Medium
Invertebrate Models	C. elegans, Drosophila	Neuroactive compound screening, toxicology studies	High
Vertebrate Models	Zebrafish, rodents	Systemic efficacy, pharmacokinetics, and toxicity assessment	Low-Medium

For diseases like schistosomiasis and leishmaniasis, high-content imaging combined with automated analysis enables quantitative assessment of phenotypic changes such as parasite viability, morphological alterations, and host-pathogen interactions [40]. Modern implementations often use 3D organoids and patient-derived stem cells that better recapitulate human physiology compared to traditional monolayer cultures [40].

Workflow and Protocol Implementation

A standardized phenotypic screening protocol for NTD drug discovery involves these critical stages:

Protocol: Phenotypic Screening for Anti-Trypanosomal Compounds

• Biological Model Selection: Select appropriate Trypanosoma brucei strains (clinical isolates preferred) and maintain in appropriate culture media supplemented with 10% fetal bovine serum at 37°C with 5% CO₂ [40].

• Assay Development and Optimization:

  • Establish infection models using host cell lines (e.g., HUVECs for HAT research)
  • Determine optimal parasite-to-host cell ratio (typically 10:1)
  • Define relevant phenotypic endpoints (parasite proliferation, host cell viability, morphological changes)
  • Establish appropriate controls (untreated infected wells, reference drugs)

• Compound Screening:

  • Prepare compound libraries in DMSO with final concentration <0.1%
  • Dispense compounds using automated liquid handlers
  • Incubate for 72-96 hours with daily medium refreshment
  • Include reference compounds (suramin, pentamidine) as controls

• Phenotypic Readout and Analysis:

  • Employ high-content imaging systems with automated microscopy
  • Stain with fluorescent markers (e.g., SYBR Green for parasite DNA, propidium iodide for host cell death)
  • Acquire minimum of 10 images per well using 20x objective
  • Quantify parasite burden and host cell viability using automated image analysis algorithms

• Hit Confirmation and Counter-Screening:

  • Confirm hits in dose-response (typically 8-point, 1:3 serial dilution)
  • Exclude non-specific hits through cytotoxicity panels against mammalian cell lines
  • Assess compound stability in assay media

Artificial Intelligence and Machine Learning Applications

AI Integration in Drug Discovery Workflows

Artificial intelligence has transformed drug discovery by enabling rapid analysis of complex biological data, predicting compound properties, and generating novel molecular structures. For NTDs, where chemical space remains underexplored, AI approaches offer particular promise for identifying novel therapeutic candidates [42]. The field has evolved through distinct waves, with the most recent emphasizing specialized pipelines and leveraging diverse data sources through multimodal approaches [43].

Table 2: AI Applications Across the NTD Drug Discovery Pipeline

Discovery Stage	AI Application	Representative Tools/Platforms	Impact on NTD Research
Target Identification	Genomic data mining, network analysis	Relation Therapeutics	Identifies novel parasite-specific targets
Compound Screening	Virtual screening, image analysis	Genesis Therapeutics	Prioritizes compounds for phenotypic screens
Lead Optimization	Property prediction, de novo design	Generate: Biomedicines	Optimizes ADMET properties for tropical diseases
Clinical Planning	Trial simulation, patient stratification	Deep6 AI	Accelerates clinical development in endemic regions

AI-Enabled Experimental Protocols

Protocol: AI-Guided Virtual Screening for NTD Targets

• Data Curation and Preparation:

  • Collect known active and inactive compounds against NTD targets from public databases (ChEMBL, PubChem)
  • Curate parasite-specific genomic and proteomic data from TriTrypDB and other NTD resources
  • Generate molecular descriptors (fingerprints, graph representations) for all compounds

• Model Training and Validation:

  • Implement graph neural networks or random forest algorithms for activity prediction
  • Train on 80% of data using 5-fold cross-validation
  • Validate on remaining 20% holdout set
  • Evaluate model performance using ROC-AUC, precision-recall curves

• Virtual Screening Implementation:

  • Screen commercially available compound libraries (ZINC, MolPort) using trained models
  • Apply drug-likeness filters appropriate for NTDs (e.g., adjusted for tropical formulations)
  • Prioritize compounds with predicted activity against multiple parasite species
  • Select top 100-500 candidates for experimental validation

The AI drug discovery sector has seen significant venture capital investment, reaching $3.3 billion in 2024, a 27% increase from the previous year [42]. Companies like Isomorphic Labs and Xaira Therapeutics have secured major funding rounds exceeding $600 million and $200 million respectively, indicating strong confidence in AI-driven approaches [42].

Multi-Target Drug Discovery for Complex Diseases

Rationale for Multi-Target Approaches in NTDs

Many NTDs involve complex host-parasite interactions and redundant biological pathways that limit the efficacy of single-target agents. Multi-target drug discovery addresses this complexity by designing compounds that simultaneously modulate multiple biological targets relevant to disease pathology [44]. This approach is particularly valuable for NTDs because:

• Polypharmacology Benefits: Simultaneous action on multiple parasite targets can enhance efficacy and reduce resistance development
• Host-Pathogen Systems: Dual targeting of both parasite and host factors involved in infection and pathology
• Co-morbidity Considerations: Many NTD-endemic regions have disease co-infections requiring broader-spectrum activity

For diseases like schistosomiasis and leishmaniasis, where current treatments face limitations including resistance and variable efficacy, multi-target approaches offer promising alternatives [38] [39].

Methodologies for Multi-Target Agent Design

Protocol: Molecular Hybridization for Multi-Target Anti-Parasitic Agents

• Target Selection and Validation:

  • Identify complementary targets (e.g., parasite thioredoxin reductase and trypanothione reductase in trypanosomatids)
  • Validate target essentiality through genomic approaches (RNAi, CRISPR)
  • Assess target druggability using structural informatics

• Pharmacophore Design and Scaffold Selection:

  • Define pharmacophore features for each target using known inhibitors
  • Identify overlapping chemical features compatible with both targets
  • Select hybrid scaffolds with balanced potency against both targets

• Compound Synthesis and Optimization:

  • Employ parallel synthesis approaches to generate hybrid compound libraries
  • Optimize linker length and flexibility for dual target engagement
  • Balance physicochemical properties for optimal parasite exposure

• Multi-Parameter Optimization:

  • Establish activity thresholds for both primary targets (typically IC50 < 1μM)
  • Incorporate selectivity indices against mammalian orthologs (>10-fold preferred)
  • Optimize ADMET properties using in silico and experimental approaches

Integrated Workflows and The Scientist's Toolkit

Convergent Approaches for NTD Drug Discovery

The most promising advances in NTD drug discovery emerge from integrating phenotypic screening, AI, and multi-target approaches into cohesive workflows. These convergent strategies leverage the strengths of each method while mitigating their individual limitations [38] [40]. An effective integrated workflow might begin with AI-assisted analysis of parasite biology to identify potential target combinations, proceed through phenotypic screening of compound libraries against relevant parasite models, employ AI-powered analysis of resulting data to identify promising chemotypes, and finally utilize multi-target optimization to enhance efficacy and resistance profiles.

Recent research on Opisthorchis viverrini demonstrates the power of integrated omics approaches (genomics, transcriptomics, proteomics) combined with computational tools and AI to identify novel therapeutic targets and biologics despite limited available funding [39]. Similarly, studies on Zika virus have leveraged structural biology and AI-driven docking to identify promising NS2B-NS3 protease inhibitors and NS5 protein inhibitors from both synthetic compounds and natural products [39].

Research Reagent Solutions for NTD Drug Discovery

Table 3: Essential Research Reagents for Advanced NTD Drug Discovery

Reagent Category	Specific Examples	Research Application	Key Suppliers
Cell-Based Assay Systems	T. brucei iRFP strains, Leishmania-macrophage co-culture models, patient-derived organoids	Phenotypic screening, mechanism of action studies, host-pathogen interaction analysis	ATCC, BEI Resources
Specialized Compound Libraries	Pandemic Response Box, Pathogen Box, natural product collections	Screening starting points, chemical biology probes, scaffold identification	Medicines for Malaria Venture, Selleck Chemicals
Detection Reagents	Live-cell dyes, caspase assays, mitochondrial membrane potential probes, parasite-specific antibodies	High-content imaging, mechanism of action studies, pathway analysis	Thermo Fisher, Abcam
Multi-Omics Reagents	Single-cell RNAseq kits, proteomic sample preparation kits, metabolic labeling reagents	Target identification, mechanism of action elucidation, resistance mechanism studies	10x Genomics, Thermo Fisher
Automation & HTS Components	384-well assay plates, automated liquid handlers, high-content imagers	High-throughput screening, dose-response analysis, large-scale compound profiling	Agilent, PerkinElmer

The integration of phenotypic screening, artificial intelligence, and multi-target approaches represents a transformative advancement in the drug discovery landscape for neglected tropical diseases. These methodologies offer complementary strengths that can accelerate the identification and optimization of novel therapeutic candidates against these challenging diseases. As the field continues to evolve, further innovation in these areas—particularly through their strategic integration—holds significant promise for developing more effective treatments that address the complex biological challenges posed by NTDs. The ongoing progress against NTDs, with a 32% decrease in people requiring interventions since 2010, demonstrates that concerted efforts can yield measurable results [9] [14]. With enhanced investment and continued methodological refinement, these modern drug discovery approaches can contribute substantially to achieving the WHO's 2030 road map targets and reducing the global burden of neglected tropical diseases.

The fight against Neglected Tropical Diseases (NTDs) represents a critical frontier in global health, with these diseases affecting over 1.6 billion people annually, predominantly in tropical regions and among marginalized populations [45]. The year 2024 has marked a significant period of advancement in the tools available to combat these diseases. The World Health Organization's latest report highlights measurable progress, with an estimated 1.495 billion people requiring NTD interventions in 2023—a reduction of 122 million from 2022 and a 32% decrease from the 2010 baseline [14]. This achievement reflects the cumulative impact of coordinated efforts across diagnostics, therapeutics, and vaccine development. This technical review examines the key advancements across these three pillars, focusing specifically on developments in 2024, with particular attention to their application within research and drug development contexts. The ongoing development of sophisticated tools is essential to achieving the WHO's 2030 road map targets, which include having 100 countries eliminate at least one NTD [20].

Advancements in NTD Diagnostics

The accurate and timely diagnosis of NTDs is the cornerstone of effective control and elimination programs. The diagnostic landscape in 2024 is characterized by a strategic push toward point-of-care (POC) tools and the maturation of molecular techniques to enhance surveillance and monitoring in endemic regions.

Operational Progress and POC Deployment

A significant operational highlight of 2024 was WHO's facilitation of the procurement of over 1 million diagnostic tests for five different NTDs, substantially boosting testing capacity in endemic countries [14]. This scale-up is crucial for mapping risk zones and monitoring the efficacy of mass drug administration (MDA) programs. Point-of-care NTD (POC-NTD) diagnostics are increasingly recognized as the preferred option in resource-constrained settings due to their rapid turnaround time and minimal infrastructure requirements [46]. The current market, segmented into conventional and molecular methods, serves clinical labs, hospitals/clinics, and increasingly, home healthcare settings [47]. However, a persistent challenge noted in recent analyses is that few of these advanced POC tools are yet available commercially on a wide scale, indicating a gap between development and market deployment [46].

Key Diagnostic Methodologies and Workflows

The evolution of NTD diagnostics relies on a suite of sophisticated laboratory techniques. The table below summarizes the core methodologies and their research applications.

Table 1: Essential Research Reagent Solutions in NTD Diagnostics

Research Reagent / Assay	Primary Function	Research and Application Context
Serological Antibody Detection Assays	Detects host immune response to NTD pathogens.	Useful for identifying historical exposure and seroprevalence in surveillance studies; limited for distinguishing active from past infection.
Molecular PCR Reagents	Amplifies pathogen-specific DNA/RNA sequences.	Provides high sensitivity and specificity for confirming active infection; essential for species/strain differentiation in diseases like leishmaniasis.
Point-of-Care (POC) Lateral Flow Tests	Detects pathogen antigens or host antibodies via immunochromatography.	Enables rapid diagnosis in low-resource field settings; critical for mapping and treatment decisions at the community level.
Microscopy Reagents (Stains, Fixatives)	Preserves and visualizes pathogens directly in patient samples.	Remains the gold standard for many parasitic NTDs (e.g., soil-transmitted helminths); used for parasite load quantification.

The development and validation of these diagnostics follow a structured experimental pathway, from assay design to field deployment, with rigorous evaluation at each stage.

Diagram 1: NTD Diagnostic Development Workflow. The pathway outlines the key stages from initial research to programmatic implementation, highlighting the transition from R&D to validation and scale-up.

Advancements in Prequalified Medicines

The steady supply of safe, effective, and quality-assured medicines is a pillar of global NTD control. In 2024, pharmaceutical manufacturers donated 19 different types of NTD medicines, with a staggering 1.8 billion tablets and vials delivered to endemic countries in that year alone [14]. This brings the cumulative total since 2011 to nearly 30 billion treatments, underscoring the massive scale of these donation programs.

Key Developments in 2024

A notable achievement in 2024 was WHO's prequalification of six new medicine formulations and one active pharmaceutical ingredient (API) [14]. The prequalification process is a critical service provided by WHO to ensure that medicines, diagnostics, and other health products meet global standards of quality, safety, and efficacy. This provides assurance to national health programs and procurement agencies, facilitating wider and faster access to these essential tools. While the specific medicines were not named in the sources, this progress reflects an ongoing effort to expand the arsenal of prequalified products for NTDs.

Research and Development Pipeline

The development of new chemical entities and reformulations of existing drugs for NTDs involves a rigorous, multi-stage process. The experimental pipeline for a new NTD drug candidate is illustrated below.

Diagram 2: Drug Development Pipeline for NTDs. The process from initial discovery through to regulatory approval, showing the transition from basic research to clinical testing.

Advancements in Vaccine Development

Vaccine development for NTDs has historically faced significant hurdles, including complex pathogen life cycles, inadequate research funding, and limited commercial interest [48] [49]. Despite these challenges, 2024 saw a landmark achievement with the prequalification of a new dengue vaccine by WHO [14]. This milestone is particularly significant given the 75% increase in dengue prevalence in recent decades [45], and it provides a powerful new tool for endemic countries.

Technological Platforms and Immunological Strategies

Modern vaccinology for NTDs leverages a range of technology platforms. The two licensed Ebola virus vaccines, rVSV-ZEBOV (Merck) and Ad26.ZEBOV/MVA-BN-Filo (Janssen), exemplify the successful application of viral vector platforms [45]. The rVSV-ZEBOV vaccine uses a recombinant vesicular stomatitis virus vector engineered to express the Ebola surface glycoprotein (GP), which is critical for inducing a protective humoral immune response [45]. Other promising technologies include recombinant protein subunits and nucleic acid-based vaccines (mRNA/DNA), which offer potential advantages in scalability and rapid response to emerging threats [45].

Core Antigens and Vaccine Candidates Under Investigation

The identification of protective antigens is a fundamental step in vaccine R&D. The table below outlines key antigen targets for a selection of high-priority NTDs.

Table 2: Key Research Reagents: Antigen Targets for NTD Vaccine R&D

Disease	Pathogen	Key Vaccine Antigen Targets	Function & Rationale
Schistosomiasis	Schistosoma spp.	Sm-TSP-2, Sm-p80, Sm14, P28 GST	Surface proteins and enzymes critical for parasite survival; target for antibody-mediated and cellular immunity.
Leishmaniasis	Leishmania spp.	gp63, PSA-2, LeIF, HASPB	Surface glycoproteins and virulence factors; aim to induce a protective Th1-driven cellular immune response.
Chagas Disease	Trypanosoma cruzi	Trans-sialidase, ASP-2, Cruzipain	Proteins involved in host cell invasion and immune evasion; targets for neutralizing antibodies.
Human African Trypanosomiasis	Trypanosoma brucei	Variable Surface Glycoprotein (VSG)	The constantly shifting surface coat of the parasite; major challenge for vaccine development.

The general workflow for developing a vaccine against a parasitic NTD involves a complex interplay between antigen discovery, platform selection, and the careful orchestration of the immune response.

Diagram 3: Vaccine R&D Pathway for Parasitic NTDs. The sequence from antigen discovery through to clinical trials, showing the critical role of preclinical studies in establishing proof-of-concept.

Integrated Analysis and Future Outlook

The advancements in diagnostics, medicines, and vaccines throughout 2024 are not isolated events but interconnected components of a broader strategy to reduce the global burden of NTDs. The synergy between these tools is critical; for instance, improved diagnostics enable more targeted use of medicines, and both are essential for monitoring the impact of vaccine introductions. Successful elimination efforts, as documented across 50 countries, consistently share key features: country ownership, dedicated elimination programs, and sustained support from development partners [20]. These programs require long-term commitment, frequently taking approximately two decades to achieve elimination goals [20].

Looking forward, several key areas will determine the pace of progress. Sustained funding is paramount, as official development assistance for NTDs decreased by 41% between 2018 and 2023 [14]. Cross-sectoral integration, particularly with Water, Sanitation, and Hygiene (WASH) programs, is essential to break the transmission cycle of many NTDs [50] [20]. Furthermore, the future of NTD tools will be shaped by innovation in personalized vaccinology and the development of broad-spectrum platforms that can be rapidly adapted to multiple pathogens [49]. Climate change presents an emerging challenge, as it alters transmission dynamics and may expand the territories affected by NTDs, potentially concentrating the future burden more heavily in low-income countries [8]. Continued investment in the research and development toolkit is, therefore, not merely a scientific pursuit but a necessary foundation for achieving equitable and sustainable health outcomes for the world's poorest populations by 2030.

Navigating Critical Challenges and Optimizing NTD Control Programs

The global health landscape faces an unprecedented fiscal shock as Official Development Assistance (ODA) undergoes severe contraction, with projections indicating a 9-17% decline in 2025 following a 9% reduction in 2024 [51]. This reduction represents a USD 56 billion decrease from 2023 levels by the end of 2025, creating a profound crisis for neglected tropical diseases (NTDs) research and control programs [51]. The convergence of diminished public funding, historic underinvestment in NTD research and development (R&D), and heavy reliance on a narrow donor base threatens to reverse decades of progress against diseases affecting over one billion people globally [26] [18]. This whitepaper analyzes the structural vulnerabilities in NTD financing and presents a strategic framework for building sustainable research ecosystems resilient to external funding shocks, providing researchers and drug development professionals with methodologies to navigate the new financial reality.

Neglected tropical diseases represent a group of 21+ diverse conditions primarily affecting the world's most impoverished populations [18]. These diseases have historically suffered from profound research and development neglect due to their concentration in populations with limited purchasing power, creating a market failure in pharmaceutical innovation [52]. The current ODA reductions compound this existing neglect, creating a critical inflection point for the field.

The financial crisis is particularly acute for NTDs due to three structural vulnerabilities: (1) heavy reliance on voluntary contributions from a small number of traditional donors, (2) the non-commercial nature of NTD product development that limits private sector investment, and (3) the lengthy development timelines for new products (7-12 years for drugs, 12-15 years for vaccines) that require sustained funding commitment [52]. The recent withdrawal of United States funding from NTD projects has already delayed 47 mass treatment campaigns impacting 143 million people and halted critical research to validate new treatments and diagnostics [26].

Table: Historical ODA Trends and Projections (2023-2027)

Year	Net ODA (USD Billion)	Year-over-Year Change	Cumulative Change from 2023
2023	$221	-	Baseline
2024	$200	-9%	-$21B
2025 (Lower Cut Scenario)	$186	-9%	-$35B
2025 (Higher Cut Scenario)	$170	-17%	-$51B
2027 Projection	$180-$190	-10% to -18% (vs 2024)	-$41B to -$51B

Quantitative Analysis of the Funding Landscape

Macroeconomic ODA Trends

The ODA contraction represents a historical anomaly in development financing. For the first time in nearly three decades, all four major ODA providers – France, Germany, the United Kingdom, and the United States – implemented simultaneous cuts in 2024, with projections indicating the first consecutive two-year reduction in history [51]. The implications for global health research are particularly severe, with bilateral ODA for health projected to decline by 19-33% in 2025 compared to 2023 levels, falling below pre-COVID-19 funding levels [51].

The geographic distribution of impact is markedly uneven, with least developed countries (LDCs) projected to experience a 13-25% fall in net bilateral ODA, while countries in sub-Saharan Africa face a devastating 16-28% decline [51]. This disparity is especially problematic for NTDs, as these regions bear the highest disease burden and possess the most limited domestic resources to compensate for funding losses.

NTD Research and Development Funding Patterns

An analysis of the NTD research funding ecosystem reveals chronic underinvestment that predates the current ODA crisis. The G-FINDER surveys, which track global investment in neglected disease R&D, demonstrate that NTDs collectively receive only a fraction of the funding allocated to other infectious diseases [52] [53].

Table: Comparative R&D Investment Analysis for Selected Diseases (2008)

Disease Category	Annual R&D Investment (USD)	Percentage of Total Neglected Disease Funding	Disease Burden (DALYs, millions)
HIV/AIDS	$1.2 Billion	39.4%	85.6
Malaria	$542 Million	18.3%	53.6
Tuberculosis	$446 Million	15.1%	49.9
All NTDs (combined)	$347 Million	12.0%	15.9
Kinetoplastids	$139 Million	4.7%	4.2
Dengue	$128 Million	4.3%	2.9
Helminth Infections	$61 Million	2.1%	6.1
Leprosy, Trachoma & Buruli Ulcer	<$15 Million	<0.5%	2.7

The funding distribution within NTDs reveals severe disparities, with kinetoplastid diseases and dengue receiving 77% of all NTD R&D investment, while leprosy, trachoma, and Buruli ulcer collectively received less than 5% of the already modest global NTD investment [52]. This allocation pattern does not reflect evidence-based assessment of disease burden but rather historical research priorities and available research capacity.

The funding infrastructure for NTD research is exceptionally fragile, relying heavily on a concentrated donor base. Two organizations – the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation – account for nearly half (49%) of all global NTD R&D funding, with twelve organizations collectively providing 86% of total investment [52]. This concentration creates systemic vulnerability to policy shifts among major donors, as evidenced by the recent U.S. funding withdrawals [26].

Methodologies for Assessing Research Funding Impacts

OECD ODA Projection Protocol

The OECD Development Assistance Committee employs a standardized methodology for projecting ODA flows that researchers can adapt to model impacts on disease-specific research programs [51]. The protocol incorporates three complementary approaches:

• Direct Survey Implementation: Deploy structured surveys to funding agencies and research institutions to quantify budget allocations for specific disease areas over multi-year horizons. The OECD achieves a 79% response rate (26 of 33 members) through standardized instruments.

• Public Announcement Tracking System: Establish a systematic mechanism for monitoring and categorizing public budget announcements by major donors, with automated alerts for policy changes affecting research priorities.

• GNI-Based Modeling: Develop projection models that multiply preliminary ODA/GNI ratios by forecasted Gross National Income growth rates, using International Monetary Fund GDP projections as inputs.

For scenario planning, researchers should implement both "lower cut" and "higher cut" simulations to establish impact boundaries. The application of this methodology to NTD research would involve disaggregating ODA projections by applying historical allocation shares (e.g., the percentage of health ODA dedicated to NTDs) to total health ODA projections.

G-FINDER Research Investment Mapping

The G-FINDER methodology provides a standardized framework for tracking global investment in neglected disease R&D that can be implemented at the institutional or regional level [52]. The protocol involves:

Data Collection Workflow:

The methodology captures funding data across multiple dimensions: disease focus (21 NTDs), product type (drugs, vaccines, diagnostics), development stage (basic research, preclinical, clinical), and funder type (public, private, philanthropic). Implementation requires surveying 200+ entities across 44 countries, including governments, pharmaceutical firms, biotech companies, product development partnerships, and public research institutions [52].

Research Reagent Solutions for Resource-Constrained Environments

The following table outlines essential research materials and methodologies adapted for funding volatility:

Table: Research Reagent Solutions for NTD Research in Funding-Constrained Environments

Reagent/Methodology	Function	Cost-Efficiency Advantage	Application in NTD Research
Open-Source AI Platforms (e.g., DeepSeek)	Compound screening, genomic analysis	Eliminates licensing fees; accelerates target identification	Drug discovery for kinetoplastids; vector behavior modeling [54]
Public-Private Partnership Models	Shared risk, resource pooling	Leverages pharmaceutical company drug donations (>$12B since 2011)	Mass drug administration programs; clinical trial implementation [26] [55]
Multi-Disease Diagnostic Platforms	Detection of multiple pathogens from single sample	Reduces per-disease R&D costs; streamlines regulatory approval	Integrated fever diagnosis; surveillance systems [52]
Long-Term Biorepositories	Preservation of clinical samples, isolates	Enables future research during funding gaps; facilitates collaboration	Genetic studies of resistance; biomarker discovery [53]
Low-Cost Clinical Trial Networks	Infrastructure for patient recruitment, monitoring	Shared fixed costs across multiple research initiatives	Phase III/IV trials for new chemical entities [56]

Strategic Framework for Sustainable NTD Research Financing

Innovative Financing Mechanisms

The current crisis demands a fundamental reimagining of NTD research financing architecture. Several innovative mechanisms offer potential pathways to sustainability:

International Development Association (IDA21) Integration: Researchers should actively engage with their national Ministries of Health and Finance to ensure NTD research and control programs are prioritized in country funding requests to the World Bank's IDA21 mechanism, which provides grants and low-interest loans to low-income countries [56]. This requires developing compelling business cases that demonstrate the economic returns of NTD investment, such as Nigeria's potential $19 billion economic gain by meeting NTD elimination targets [56].

Domestic Resource Mobilization: African nations are increasingly demonstrating leadership in reducing dependency on external funding. Tanzania has implemented a decentralized financing model where local councils shoulder NTD financing, with a target of 60% domestic coverage by 2026 [57]. The research community can support this transition through cost-effectiveness studies and fiscal space analysis that make the economic case for domestic investment.

Blended Finance Structures: Creating layered capital stacks that combine philanthropic funding, development finance, and commercial investment can de-risk NTD R&D. The END Fund model demonstrates how philanthropic capital can serve as a "catalytic investment" to bridge funding gaps and attract additional resources [57].

Research Efficiency Optimization

Enhancing the productivity of limited research resources requires systematic approaches to efficiency:

Integrated Research Platforms: Developing shared infrastructure for clinical trials, data management, and laboratory services can significantly reduce overhead costs. The WHO's ESPEN platform provides a model for regional collaboration that reduces duplication and standardizes methodologies [57].

Portfolio Management Approaches: Implementing strategic portfolio management that balances high-risk exploratory research with incremental improvements to existing tools can optimize resource allocation. This involves stage-gating processes and clear go/no-go decision points based on predefined scientific and feasibility criteria.

Open Science Initiatives: Embracing open-source principles for data, compound libraries, and research tools can accelerate discovery while reducing costs. The Drugs for Neglected Diseases Initiative (DNDi) has demonstrated the power of collaborative R&D models, delivering thirteen new treatments through partnerships that share intellectual property and resources [53].

Strategic Visualization of Sustainable Financing Pathways

The transition to sustainable NTD research financing requires a systematic approach that integrates multiple funding streams and aligns incentives across stakeholders:

The 41% decline in ODA represents not merely a fiscal challenge but a fundamental restructuring of the global health research landscape. For the NTD research community, this crisis necessitates a strategic pivot from donor dependency to financing resilience. The strategies outlined – innovative financing mechanisms, research efficiency optimization, and systematic transition to sustainable models – provide a roadmap for maintaining research continuity amid funding volatility.

The projected decline of ODA to 2020 levels by 2027 coincides with a period of unprecedented scientific opportunity in NTD research [51]. Advances in artificial intelligence, genomics, and immunology offer new pathways for addressing diseases that affect over one billion people [54] [18]. The research community's ability to develop new financing models that align scientific innovation with financial sustainability will determine whether this scientific potential can be realized or whether decades of progress against NTDs will be reversed.

The time for strategic action is now. Researchers, institutions, and funders must collaboratively implement the frameworks presented in this whitepaper to build a future where NTD research advances independent of the volatile ODA landscape, ultimately ensuring that scientific progress continues for the world's most marginalized populations.

The emergence and spread of drug-resistant pathogens represents one of the most pressing challenges in global health, particularly for neglected tropical diseases (NTDs). These diseases, which disproportionately affect the world's most vulnerable populations, face a dual threat: the existing burden of disease and the growing inefficacy of standard treatments. This technical review examines the molecular mechanisms driving drug resistance in NTDs, analyzes current epidemiological trends, details advanced methodological approaches for resistance detection, and explores innovative therapeutic strategies. With the World Health Organization highlighting the significant impact of antimicrobial resistance on NTD management, understanding these biological hurdles is critical for researchers and drug development professionals working to achieve the 2030 road map targets for NTD control and elimination [9] [58].

Neglected tropical diseases represent a diverse group of communicable diseases prevalent in tropical and subtropical regions, affecting more than one billion people globally. The World Health Organization has identified 21 distinct NTDs as priorities for control and elimination efforts. These diseases, including leishmaniasis, human African trypanosomiasis, schistosomiasis, and soil-transmitted helminths, perpetuate cycles of poverty and disproportionately impact marginalized communities with limited access to healthcare services [39] [9]. The management of NTDs relies heavily on a limited arsenal of chemotherapeutic agents, many of which were developed decades ago and face increasing challenges due to emerging drug resistance.

Antimicrobial resistance in NTDs manifests through multiple pathways, including genetic mutations, epigenetic adaptations, efflux pump overexpression, and metabolic reprogramming of pathogens. The World Health Organization reports that resistance has been documented in treatments for several NTDs, including leprosy (dapsone, rifampicine, and clofazimine), human African trypanosomiasis (melarsoprol), and leishmaniasis (pentavalent antimonials, miltefosine) [58]. This evolving resistance landscape threatens recent progress in NTD control and underscores the urgent need for novel therapeutic approaches and enhanced surveillance mechanisms to monitor resistance patterns [59] [9].

Global Burden and Current Status

The global burden of NTDs remains substantial, though concerted control efforts have yielded significant progress in recent years. In 2023, an estimated 1.495 billion people required interventions against NTDs, representing a decrease of 122 million from 2022 and a 32% reduction from the 2010 baseline [9]. Between 2015 and 2021, the disease burden dropped from 17.2 million to 14.1 million disability-adjusted life years (DALYs), while NTD-related deaths decreased from approximately 139,000 to 119,000 [9]. This progress demonstrates the potential impact of sustained global efforts, yet the emergence of drug-resistant pathogens threatens to reverse these gains.

Table 1: Documented Drug Resistance in Major Neglected Tropical Diseases

Disease	Resistant Pathogens	Affected Therapeutics	Documented Level of Resistance
Human African Trypanosomiasis	Trypanosoma brucei gambiense	Melarsoprol	Clinical resistance [59]
Leishmaniasis	Leishmania species	Pentavalent antimonials, Miltefosine	Clinical resistance [58] [59]
Schistosomiasis	Schistosoma species	Praziquantel	Diagnostic test indications [59]
Soil-transmitted helminths	Various helminths	Benzimidazoles	Diagnostic test indications [59]
Onchocerciasis	Onchocerca volvulus	Ivermectin	Diagnostic test indications [59]
Trachoma	Chlamydia trachomatis	Azithromycin	Diagnostic test indications [59]
Leprosy	Mycobacterium leprae	Dapsone, Rifampicine, Clofazimine	Clinical resistance [58]

Surveillance data reveals concerning patterns of extensive drug resistance in regions endemic for NTDs. A systematic scoping review from Ethiopia found that among 5,620 bacterial isolates, 22.9% were extensively drug-resistant (XDR) and 9.1% were pan drug-resistant (PDR) [60]. The most common XDR bacteria identified were Klebsiella species (26.7%), E. coli (26.4%), Acinetobacter species (24.9%), and P. aeruginosa (18.7%) [60]. These resistance patterns complicate the treatment of bacterial NTDs and contribute to increased morbidity, mortality, and healthcare costs in already overburdened health systems.

Molecular Mechanisms of Drug Resistance

Drug resistance in pathogens follows evolutionary principles under selective pressure from chemotherapeutic agents. The mechanisms employed are diverse and often multifactorial, encompassing genetic, epigenetic, and metabolic adaptations that enable pathogen survival.

Genetic and Metabolic Adaptation Mechanisms

Pathogens causing NTDs utilize several conserved mechanisms to circumvent chemotherapeutic interventions. These include:

• Drug efflux pumps: ATP-binding cassette (ABC) transporters such as P-glycoprotein, multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP) actively export drugs from pathogen cells, reducing intracellular concentrations to subtherapeutic levels [61] [62]. These energy-dependent transmembrane proteins recognize diverse substrates and significantly contribute to multidrug resistance phenotypes.

• Genetic mutations: Spontaneous mutations in drug targets, such as enzymes or receptors critical for drug activity, alter binding affinity and reduce drug efficacy. Additionally, mutations in genes involved in drug activation can diminish prodrug conversion to active compounds [61]. For example, mutations in cytochrome P450 genes (CYP2B6, CYP2D6) affect activation of cyclophosphamide and tamoxifen, respectively [62].

• Altered drug targets: Pathogens may modify molecular targets through genetic mutations or post-translational modifications, preventing drug binding while maintaining cellular function. Beta-tubulin mutations confer resistance to paclitaxel, while DNA topoisomerase II alterations confer resistance to doxorubicin [62].

• Enhanced DNA repair capacity: Upregulation of DNA repair mechanisms enables pathogens to rapidly reverse drug-induced DNA damage. Elevated levels of BRCA1, BRCA2, RPA1, and Rad51 have been associated with radiation resistance, while increased expression of MGMT confers resistance to temozolomide [62].

• Metabolic reprogramming: Pathogens alter their metabolic states to survive drug pressure, including shifts in energy production pathways and reduction in metabolic activity to enter dormant states less susceptible to chemotherapeutic agents [61].

Epigenetic and Microenvironmental Modifications

Beyond genetic changes, pathogens and host cells employ epigenetic strategies to survive therapeutic pressure:

• DNA methylation changes: Hypermethylation of gene promoter regions can silence tumor suppressor genes or drug uptake transporters, while hypomethylation can activate multidrug resistance genes. AKAP12 hypomethylation confers paclitaxel resistance, while hypomethylation of CpG sites on S100A4 increases cisplatin resistance [62].

• Histone modifications: Post-translational modifications to histone proteins, including acetylation, methylation, and phosphorylation, alter chromatin structure and gene expression patterns. Overexpression of SETD5 histone methyltransferase promotes resistance to MEK inhibitors through chromatin remodeling [62].

• Phenotypic transitions: Pathogens can undergo morphological changes to evade treatment, such as the transition between promastigote and amastigote forms in Leishmania species. Similarly, epithelial-to-mesenchymal transition in host cells upregulates stem cell genes (TGF-β, ALDH1A1, CD44, JUN) that confer resistance to docetaxel, paclitaxel, and anthracycline [62].

• Microenvironment adaptation: Pathogens modify their immediate surroundings to create protective niches. Hypoxic conditions within tumors or granulomas stabilize HIF-α, activating survival pathways and promoting resistance. Acidic conditions in the microenvironment can directly inactivate certain drugs while selecting for resistant subpopulations [61].

Methodological Approaches for Resistance Monitoring

Robust surveillance methodologies are essential for detecting emerging resistance and informing treatment strategies. The following section outlines key experimental protocols for monitoring drug resistance in NTDs.

Genomic Surveillance and Resistance Gene Detection

Advanced genomic techniques enable comprehensive characterization of resistance mechanisms at the molecular level:

Protocol: Whole Genome Sequencing for Resistance Mutation Identification

• Sample Collection and Preparation: Isolate pathogen DNA from clinical samples (blood, tissue biopsies, or cultured isolates) using standardized extraction kits. Quality control should include spectrophotometric quantification (A260/A280 ratio 1.8-2.0) and gel electrophoresis to confirm high molecular weight DNA.

• Library Preparation: Fragment DNA to 300-500 bp fragments using enzymatic or mechanical shearing. Ligate platform-specific adapters containing unique molecular identifiers to distinguish authentic variants from PCR errors.

• Sequencing: Perform whole genome sequencing using Illumina, Oxford Nanopore, or PacBio platforms. Minimum coverage of 50x is recommended for reliable variant calling, with deeper coverage (100x) for heteroresistance detection.

• Bioinformatic Analysis:

  • Quality control using FastQC and adapter trimming with Trimmomatic
  • Alignment to reference genomes using BWA-MEM or Bowtie2
  • Variant calling with GATK HaplotypeCaller or SAMtools mpileup
  • Annotation of variants using SnpEff to predict functional impact
  • Specific screening for known resistance-conferring mutations in target genes

• Interpretation: Correlate identified mutations with phenotypic resistance data from clinical outcomes or in vitro susceptibility testing to validate novel resistance markers.

This approach has been successfully implemented in surveillance programs for tuberculosis, where it detects mutations conferring resistance to rifampicin, isoniazid, and second-line agents, and is increasingly applied to other NTDs [60].

In Vitro Drug Susceptibility Testing

Standardized susceptibility testing remains the gold standard for resistance detection:

Protocol: Broth Microdilution for Antiparasitic Drug Screening

• Parasite Culture: Maintain reference strains and clinical isolates in appropriate culture media at optimal temperature and atmospheric conditions. For intracellular parasites (e.g., Leishmania), culture in permissive mammalian cell lines.

• Drug Preparation: Prepare serial dilutions of test compounds in culture-compatible solvents (DMSO concentration ≤1%). Include quality control strains with known susceptibility profiles.

• Inoculation and Incubation: Dispense drug dilutions in 96-well plates and inoculate with standardized parasite suspensions. Incubate for predetermined time periods based on parasite replication cycles.

• Viability Assessment:

  • For extracellular parasites: Use colorimetric assays (MTT, resazurin) or ATP quantification
  • For intracellular parasites: Microscopic enumeration or reporter gene expression
  • Include untreated controls for 100% viability and background controls

• Data Analysis: Calculate half-maximal inhibitory concentration (IC50) values using nonlinear regression analysis (four-parameter logistic model). Compare clinical isolates to reference strains to determine resistance ratios.

This methodology was employed in assessing imidocarb dipropionate and buparvaquone efficacy against Babesia bovis, demonstrating superior activity of buparvaquone with complete parasite elimination at 150 nM [39].

Table 2: Key Research Reagents for Drug Resistance Studies

Reagent Category	Specific Examples	Applications in Resistance Research
Cell Culture Media	Schneider's Insect Medium, MEM, RPMI-1640	Maintenance of parasite cultures for in vitro susceptibility testing [39]
Viability Assays	MTT, Resazurin, ATP-based Luminescence	Quantification of pathogen viability post-drug exposure [39]
Molecular Biology Kits	DNA/RNA extraction kits, PCR master mixes, Library prep kits	Genomic analysis of resistance mechanisms [60]
Antibodies	Specific to pathogen markers, drug targets	Detection of protein expression changes in resistant strains
Reference Compounds	Known antiretroviral, antiparasitic drugs	Quality control for susceptibility assays and resistance monitoring [39]
Bioinformatics Tools	FastQC, BWA, GATK, SnpEff	Analysis of sequencing data for resistance mutations [60]

Emerging Therapeutic Strategies

The growing challenge of drug resistance necessitates innovative approaches to therapeutic development. Promising strategies include combination therapies, drug repurposing, and targeted agents based on resistance mechanisms.

Novel Chemotherapeutic Approaches

Recent advances in drug discovery have yielded new chemical entities with activity against resistant NTD pathogens:

• Protease inhibitors: For Zika virus infection, NS2B-NS3 protease inhibitors such as LAS 52154459, LAS 52154463, and LAS 52154474 demonstrate potent antiviral activity with favorable toxicity profiles [39]. These compounds effectively limit viral development and replication by targeting essential viral processing enzymes.

• Natural product derivatives: Phytochemical compounds from V. cinerea, including β-amyrin, β-amyrin acetate, chrysoeriol, isoorientin, and luteolin, show promising antiviral activity against Dengue virus by potentially inhibiting the NS1 protein [39].

• Combination therapies: Simultaneous targeting of multiple pathogen pathways can overcome resistance and prevent its emergence. For example, artefenomel and piperaquine combination therapy has shown efficacy against uncomplicated Plasmodium falciparum malaria, including resistant strains [63].

• Drug repurposing: Screening of approved drugs for activity against NTD pathogens has identified unexpected therapeutic opportunities. Posaconazole, an antifungal agent, has demonstrated activity against Trypanosoma cruzi infections, though with limitations in curing chronic infections [63].

Advanced Technologies for Resistance Management

Cutting-edge technologies offer new paradigms for addressing drug resistance in NTDs:

• Omics and computational approaches: Integration of genomics, transcriptomics, and proteomics data enables identification of novel drug targets and resistance mechanisms. These approaches have been applied to Opisthorchis viverrini infection, identifying potential therapeutic targets through comprehensive pathogen profiling [39].

• CRISPR-based gene editing: Precise genetic manipulation allows for functional validation of resistance genes and identification of new drug targets. This technology has been successfully applied to Cryptosporidium and Plasmodium species to elucidate essential genes and resistance mechanisms [63].

• Artificial intelligence and machine learning: AI algorithms can predict resistance patterns based on genomic data and optimize combination therapy regimens. The ArboItaly platform demonstrates the utility of computational tools for genomic surveillance of arboviruses, enabling data collection, classification, and public dissemination of resistance information [39].

• Vaccine development: While challenging, vaccine development represents a sustainable solution to drug resistance. For dengue virus, Dengvaxia (CYD-TDV) and Qdenga (TAK-003) are licensed for human use, while a chikungunya vaccine based on prM and E glycoproteins shows >90% efficacy in Phase I clinical trials [39].

The challenge of drug resistance in neglected tropical diseases requires a multifaceted approach that integrates basic science, clinical research, and public health implementation. Understanding the molecular mechanisms driving resistance provides the foundation for developing novel therapeutic strategies that can overcome existing resistance and prevent its emergence. Advanced genomic technologies offer unprecedented opportunities for surveillance and early detection of resistance patterns, enabling more targeted and effective interventions.

Future efforts should focus on strengthening surveillance systems, promoting antimicrobial stewardship specific to NTDs, accelerating the development of novel therapeutic classes with new mechanisms of action, and exploring combination approaches that reduce the selection pressure for resistance. Additionally, greater investment in vaccine development for NTDs could provide long-term solutions to the problem of drug resistance. As the WHO works toward its 2030 road map targets for NTD control, addressing the biological hurdles of drug resistance will be essential for achieving sustainable progress in reducing the global burden of these devastating diseases [9].

The global burden of Neglected Tropical Diseases (NTDs) remains a critical challenge, affecting an estimated 1 billion people worldwide, with over 40% of this burden concentrated in sub-Saharan Africa [64] [65]. These diseases disproportionately affect the world's most impoverished and marginalized communities, causing immense suffering, disability, and social stigma. For decades, NTD control efforts have predominantly operated through vertical, disease-specific programs. While these initiatives have achieved significant successes—including the elimination of at least one NTD in 54 countries by the end of 2024—this siloed approach has limitations in sustainability, efficiency, and comprehensive coverage [64]. The current global health landscape, characterized by competing priorities and limited resources, demands a paradigm shift toward integrated, sustainable approaches that strengthen entire health systems rather than focusing on single diseases.

The World Health Organization's (WHO) 2030 NTD roadmap explicitly recognizes this imperative, emphasizing the integration of NTD efforts across diseases and within national health systems in the context of Universal Health Coverage (UHC) [65]. This technical guide examines the evidence, methodologies, and implementation frameworks for optimizing NTD service delivery through three interconnected pillars: integration of NTD services into primary healthcare, strengthening of data reporting and surveillance systems, and mainstreaming of NTD control into national health systems. Grounded in the context of global burden of disease research, this whitepaper provides researchers, scientists, and drug development professionals with actionable strategies and technical protocols to enhance the effectiveness, sustainability, and equity of NTD control programs worldwide.

Conceptual Framework: Health Systems Strengthening for NTD Integration

Health system strengthening (HSS) provides the foundational framework for successful NTD integration. The WHO defines a health system as "all organizations, people and actions whose primary intent is to promote, restore or maintain health" [66]. This comprehensive system consists of six core building blocks that must be reinforced to support effective NTD integration:

• Service delivery
• Health workforce
• Health information systems
• Medical products, vaccines, and technologies
• Health financing
• Leadership and governance [66]

The WHO's sustainability framework for NTDs highlights three key interconnected processes that drive health systems strengthening when combined: mainstreaming, integration, and coordination [66]. Mainstreaming involves embedding NTD prevention and control activities within national health system infrastructure and other sectors to build capacity and contribute to sustainable disease prevention and control [67]. Integration refers to the practical incorporation of NTD interventions into existing health initiatives such as primary health care, malaria control, child health days, and immunization campaigns [68]. Coordination ensures all stakeholders—governments, NGOs, international organizations, and communities—align their efforts within a unified framework.

Table 1: Health System Building Blocks and NTD Integration Applications

Health System Building Block	NTD Integration Application	Expected Outcome
Service Delivery	Incorporate NTD detection and management into routine primary care consultations	Increased case detection and reduced stigma through normalized services
Health Workforce	Training primary healthcare workers on NTD identification and management using job aids	Improved diagnostic accuracy and treatment adherence across diseases
Health Information Systems	Integrating NTD indicators into national surveillance platforms (e.g., NNDSS)	Enhanced data quality and more accurate burden estimates
Medical Products & Technologies	Ensuring consistent supply of NTD diagnostics and medications through existing supply chains	Reduced stockouts and improved treatment completion rates
Health Financing	Including NTD interventions in national health budgets and insurance schemes	Sustainable funding reduced donor dependency
Leadership & Governance	Establishing multi-stakeholder coordination mechanisms for NTD control	Improved accountability and resource allocation

Integration Models and Implementation Strategies

Evidence-Based Integration Approaches

Recent research demonstrates multiple effective models for integrating NTD services into existing health systems. A comprehensive mixed-methods study in Ethiopia's Damot Gale district evaluated an intervention integrating four common NTDs—trachoma, lymphatic filariasis, schistosomiasis, and podoconiosis—into the primary healthcare system [65] [69]. The intervention employed a multi-component approach including adapted job aids, supportive supervision, and improved diagnostic and medical supplies to facilitate NTD diagnosis, management, and reporting. After six months of implementation, results demonstrated significant improvements in the capacity of all enrolled health facilities to detect, manage, and record target NTDs, with high acceptability among health workers who viewed the tools as helpful, relevant, and easy to use [65].

Country-specific experiences further illustrate practical integration strategies. Rwanda and Togo have strengthened integrated approaches to NTDs by leveraging existing health system structures and optimizing available resources [68]. Madagascar and Tanzania have successfully embedded NTD interventions within established malaria programs and vaccination campaigns, utilizing shared infrastructure and community engagement channels [68]. Similarly, Benin and Niger have incorporated NTD programs into Child Health Days, efficiently bundling interventions to reach vulnerable populations [68]. These integration models demonstrate the efficiency gains possible when NTD services are delivered through established health contacts rather than creating parallel systems.

Implementation Protocol: Integrated NTD Service Delivery

The following experimental protocol outlines a systematic approach for integrating NTD services into primary healthcare, based on successfully implemented studies:

Study Setting and Facility Selection:

• Operationalize in administrative regions with high prevalence of multiple NTDs (e.g., ≥3 NTDs with prevalence >10% in district)
• Employ stratified random sampling to select primary hospitals, health centers, and health posts representing different levels of the healthcare system
• Ensure selected facilities serve populations with limited access to specialized NTD services
• Establish control sites with comparable NTD burden and health system capacity for comparison

Intervention Components and Implementation Steps:

• Baseline Assessment Phase (Weeks 1-4):
  • Conduct comprehensive inventory of existing NTD diagnostics, treatments, and record-keeping systems
  • Administer knowledge, attitude, and practice (KAP) surveys to health workers at all levels
  • Review historical facility data on NTD case detection and management

• Training and Capacity Building Phase (Weeks 5-8):

  • Develop standardized training modules on integrated NTD detection, management, and reporting
  • Conduct cascade training for primary hospital staff (3 days), who subsequently train health center staff (2 days), who then train health post workers (1 day)
  • Distribute and train on use of adapted job aids including:
    • Visual diagnostic guides with high-quality images of disease manifestations
    • Simplified treatment algorithms for co-infections and complicated presentations
    • Standardized reporting forms integrating NTD indicators with routine health metrics

• Systems Strengthening Phase (Weeks 9-12):

  • Establish regular supportive supervision schedules (monthly for first 3 months, then quarterly)
  • Implement supplied chain improvements for essential NTD medications and diagnostics
  • Integrate NTD indicators into existing health management information systems (HMIS)

• Monitoring and Evaluation Phase (Ongoing):

  • Collect quantitative data on key performance indicators monthly
  • Conduct qualitative assessments through key informant interviews and focus group discussions quarterly
  • Calculate incremental cost-effectiveness ratios for the integrated approach versus vertical programs

Table 2: Core Indicators for Monitoring Integrated NTD Programs

Indicator Category	Specific Metrics	Measurement Frequency	Target
Service Capacity	Percentage of facilities demonstrating improved NTD detection capacity	Quarterly	≥80% improvement within 12 months
Health Workforce Competency	Percentage of health workers correctly identifying ≥4 out of 5 target NTDs	Semi-annually	≥90% competency rate
Case Management	Percentage of diagnosed cases receiving appropriate treatment according to national guidelines	Monthly	≥95% treatment rate
Reporting Completeness	Percentage of facilities submitting complete NTD reports	Monthly	≥90% reporting rate
Cost Efficiency	Cost per patient managed in integrated system versus vertical program	Annually	≥20% reduction in cost per case

The dot language code below defines a workflow for integrating NTD services into primary healthcare, from initial assessment through to monitoring, based on protocols used in recent studies [65] [69].

Diagram 1: NTD Service Integration Workflow

Data Reporting and Surveillance System Enhancement

Standardized Data Systems for NTD Surveillance

Robust data reporting and surveillance systems are fundamental components of effective NTD control and integration efforts. The National Electronic Disease Surveillance System (NEDSS) provides a exemplary model of an integrated surveillance platform that can be adapted for NTD monitoring [70]. NEDSS facilitates the electronic exchange of public health surveillance data from healthcare systems to public health departments, enabling standards-based systems that support national disease surveillance strategy. The system implements content standards that the healthcare industry currently uses (e.g., LOINC for transmitting laboratory test names and SNOMED for transmitting test results) for increased interoperability between states and the healthcare industry [70].

In the United States, the National Notifiable Diseases Surveillance System (NNDSS) represents a nationwide collaboration that enables all levels of public health (local, state, territorial, federal, and international) to share health information to monitor, control, and prevent the occurrence and spread of state-reportable and nationally notifiable infectious and some noninfectious diseases and conditions [71]. This multifaceted program includes the surveillance system for collection, analysis, and sharing of health data, along with resources and information about policies and standards at local, state, and national levels. For NTD programs, integrating with such systems enables access to richer datasets, facilitates compliance with reporting requirements, and supports more accurate assessment of disease burden and distribution.

Implementation Framework for Enhanced NTD Data Systems

Implementing enhanced data reporting systems for NTDs requires a structured approach that addresses both technical and operational considerations:

System Architecture and Interoperability Standards:

• Implement HL7 messaging standards for electronic laboratory reporting (ELR) of NTD cases
• Adopt LOINC (Logical Observation Identifiers Names and Codes) as the standard for transmitting laboratory test names
• Utilize SNOMED CT (Systematized Nomenclature of Medicine Clinical Terms) as the standard for transmitting test results
• Ensure compatibility with existing health information exchanges and electronic medical record systems

Data Flow and Management Processes:

• Establish automated electronic laboratory reporting from clinical laboratories to public health departments
• Implement browser-based disease data entry systems accessible to health investigators and public health professionals
• Create integrated repositories that combine multiple health information databases into a single platform
• Develop electronic messaging capabilities that enable efficient information sharing with national and international health agencies

Quality Assurance and Evaluation Metrics:

• Monitor completeness of data reporting across different jurisdictions and healthcare facilities
• Assess timeliness of case reporting from diagnosis to public health notification
• Evaluate data accuracy through periodic validation checks and audit processes
• Measure system performance through metrics such as user adoption rates and report processing times

The dot language code below illustrates how national electronic surveillance systems like NEDSS and NNDSS integrate data from healthcare providers and laboratories for NTD monitoring [70] [71].

Diagram 2: NTD Data Reporting and Surveillance Flow

Research Reagent Solutions for NTD Integration Studies

Table 3: Essential Research Materials for NTD Integration Studies

Reagent/Resource	Specifications	Research Application	Implementation Consideration
Structured Survey Instruments	Validated KAP (Knowledge, Attitudes, Practices) questionnaires; health facility assessment tools	Baseline assessment and monitoring of integration outcomes	Must be culturally adapted and translated into local languages
Integrated Job Aids	Laminated diagnostic algorithms; visual recognition guides for disease manifestations	Health worker training and point-of-care decision support	Design for low-literacy users; resistant to tropical environmental conditions
Electronic Data Capture Systems	Tablet-based survey platforms; HMIS integration modules	Real-time data collection and surveillance	Must function in low-bandwidth settings; solar-powered options preferred
Standardized NTD Diagnostic Kits	RDTs (Rapid Diagnostic Tests) for multiple NTDs; specimen collection materials	Integrated screening and confirmation of NTD cases	Ensure temperature stability; match national treatment guidelines
Supervision and Audit Tools	Checklist-based supportive supervision guides; data quality audit forms	Implementation fidelity assessment and quality improvement	Should integrate NTD components with general health service supervision
Costing Data Collection Tools	Time-motion study templates; resource tracking spreadsheets	Economic evaluation of integrated versus vertical approaches	Capture both health system and patient-incurred costs

Challenges and Mitigation Strategies

Implementation Barriers and Evidence-Based Solutions

Despite the compelling rationale for integration, several significant challenges impede effective implementation of integrated NTD programs. Research reveals that NGO-led integration initiatives often struggle with sustainability, as project activities can be short-lived due to limited resources, overreliance on short-term indicators, and weak institutionalization within government structures [67]. This underscores the tension between mainstreaming interventions and the realities of the settings in which interventions are put into practice. Additionally, the organizational environments of implementing partners significantly influence intervention outcomes, with factors such as funding cycles, reporting requirements, and capacity constraints shaping implementation effectiveness [67].

The transition from vertical to integrated programs faces both technical and operational hurdles. Health systems in high-NTD-burden countries often lack the infrastructure, human resources, and supply chain resilience to absorb additional NTD-related responsibilities. Furthermore, disease-specific performance metrics and funding streams can create disincentives for integration, as programs are often evaluated based on single-disease indicators rather than comprehensive health system strengthening. To address these challenges, researchers and implementers should consider the following mitigation strategies:

Funding and Institutionalization Strategies:

• Advocate for including NTD interventions in national health budgets and insurance schemes to reduce donor dependency
• Develop transition plans that gradually shift program ownership from external partners to government structures
• Establish multi-stakeholder coordination mechanisms that align priorities and resources across disease-specific programs

Measurement and Evaluation Approaches:

• Balance short-term output indicators with long-term outcome measures that reflect health system strengthening
• Develop composite metrics that capture integration effectiveness across multiple diseases
• Implement mixed-methods evaluations that combine quantitative data with qualitative insights into implementation processes

Capacity Building and System Reinforcement:

• Invest in cascade training models that build sustainable internal capacity within health systems
• Strengthen supply chain management for NTD commodities through integration with existing pharmaceutical logistics systems
• Develop decision-support tools that simplify integrated case management for frontline health workers

The integration of NTD services into national health systems represents a critical evolution in the global approach to reducing the burden of neglected tropical diseases. Evidence from Ethiopia and other high-burden countries demonstrates that integrated approaches are not only feasible and acceptable but also cost-effective, making efficient use of limited health resources while improving case detection, management, and reporting [65] [69]. As the global community pursues the ambitious targets set forth in the WHO 2030 NTD roadmap, researchers, scientists, and drug development professionals have essential roles to play in generating the evidence needed to optimize integration models, develop appropriate tools and technologies, and document best practices for mainstreaming NTD services.

Future research priorities should include the development of more sensitive and specific point-of-care diagnostics suitable for integrated primary care settings, the optimization of supply chain management for NTD commodities within essential medicines systems, and the design of innovative training approaches that build multi-disease competency among frontline health workers. Additionally, implementation science research is needed to better understand the contextual factors that influence integration success across different health system architectures and epidemic profiles. By embracing integration as a core principle in NTD research and program implementation, the global health community can accelerate progress toward the elimination of NTDs as public health problems while simultaneously contributing to stronger, more resilient health systems capable of serving the needs of all populations, particularly the most marginalized and vulnerable.

The control and elimination of Neglected Tropical Diseases (NTDs) represent a critical front in the global effort to reduce health disparities and alleviate the suffering of marginalized populations. These diseases, including lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma, affect more than one billion people globally, with an estimated 1.495 billion requiring NTD interventions annually [27]. The World Health Organization's 2021-2030 road map sets ambitious targets, including a 90% reduction in the number of people requiring NTD interventions and a 75% reduction in disability-adjusted life years (DALYs) related to NTDs [27]. However, the pursuit of these goals is increasingly threatened by external shocks, particularly pandemics and climate change, which disrupt control programs and alter disease transmission dynamics. Understanding these complex interactions is essential for researchers, scientists, and drug development professionals working to build resilient health systems and develop adaptive interventions in the face of evolving global challenges.

Pandemic-Related Disruptions to NTD Programs

The COVID-19 Precedent: A Case Study in Program Disruption

The COVID-19 pandemic demonstrated how quickly external shocks can disrupt decades of progress in NTD control. In April 2020, the World Health Organization recommended temporarily halting mass drug administration (MDA) programs to reduce the risk of SARS-CoV-2 transmission among stakeholders and community members [72]. This guidance, while necessary for pandemic control, had significant repercussions for NTD programs across sub-Saharan Africa and other endemic regions. Most MDA programs were postponed for 6-12 months, creating substantial setbacks for diseases controlled through preventive chemotherapy [72].

A 2020 mixed-methods study surveying Ministry of Health NTD Program Managers and implementing partners across sub-Saharan Africa revealed the multidimensional nature of these disruptions [72]. The research employed a convergent mixed-methods design, collecting quantitative data through online surveys and qualitative data through focus group discussions. Purposive sampling techniques were used to recruit participants from endemic countries, with data analysis proceeding through both descriptive statistics for quantitative responses and inductive thematic analysis for qualitative transcripts [72].

Table 1: Documented Challenges in Restarting MDA Programs Post-COVID-19 Disruption

Challenge Category	Specific Challenges Reported	Percentage of Program Managers Reporting
Resource Constraints	Shortages due to prioritization of pandemic response	Not specified in available data
Safety Protocol Implementation	Challenges adhering to COVID-19 safety protocols during MDA activities	Not specified in available data
Community Engagement	Community hesitancy due to coronavirus transmission fears	Not specified in available data
Program Planning	Uncertainty regarding optimal timing and strategies for program restart	Over 40% reported plans to restart in 6-12 months

Adaptive Methodologies for Program Restart

Research conducted during the pandemic period yielded critical methodological insights for restarting disrupted NTD programs. Program managers and implementing partners identified several strategic adaptations for relaunching MDA activities [72]:

• Modifications to Drug Delivery: Implementing low-contact drug distribution techniques, including modified fixed-point distribution and streamlined door-to-door delivery with physical distancing protocols.

• Technology Integration: Utilizing digital tools for intervention planning, community mobilization, and monitoring of distribution coverage to minimize physical contact while maintaining program quality.

• Program Integration Opportunities: Identifying synergies between pandemic response strategies (e.g., community-based contact tracing networks) and NTD campaign infrastructure to maximize efficiency and resource utilization.

The methodological approach to studying these adaptations included online surveys administered through the WHO Regional Office for Africa's Expanded Special Project for Elimination of Neglected Tropical Diseases (ESPEN) and virtual focus group discussions conducted in multiple languages to capture diverse perspectives across sub-Saharan Africa [72].

Climate Change and Altered NTD Transmission Dynamics

Climate Sensitivities of Neglected Tropical Diseases

Climate change represents a more gradual but equally disruptive external shock to NTD control efforts. The transmission cycles of most NTDs are inherently sensitive to environmental conditions across different physical phases including air, water, and soil [73]. Nearly all NTDs fall into this category, meaning that future geographic patterns of transmission for dozens of infections are likely to be affected by climate change across short (seasonal), medium (annual), and long (decadal) timescales [73].

Vector-borne NTDs exhibit particular sensitivity to climatic factors such as temperature, precipitation, and humidity, which directly impact vector distribution, breeding patterns, survival rates, and the extrinsic incubation period of pathogens [73]. For example, lymphatic filariasis (transmitted by mosquitoes), onchocerciasis (transmitted by black flies), and visceral leishmaniasis (transmitted by sand flies) all demonstrate transmission dynamics that are intimately tied to environmental conditions that are being altered by global climate change.

Table 2: Climate Change Impacts on Major NTD Categories

NTD Category	Primary Climate Sensitivities	Potential Impacts of Climate Change
Vector-Borne NTDs (e.g., LF, onchocerciasis, leishmaniasis)	Temperature affecting vector survival and pathogen incubation; Precipitation affecting breeding sites	Geographic range expansion; Altered transmission seasons; Changes in incidence intensity
Water-Based NTDs (e.g., schistosomiasis)	Temperature affecting snail intermediate hosts; Precipitation affecting water availability	Changes in transmission zones; Modified seasonal patterns
Soil-Transmitted Helminths	Temperature and soil moisture affecting egg/larvae survival	Altered spatial distribution; Changes in transmission potential

Methodological Approaches for Climate-NDT Research

Research into the climate-NTD nexus requires specific methodological approaches that can capture the complex interactions between environmental change and disease transmission:

• Environmental Modeling: Utilizing ecological niche models and species distribution models to project future changes in vector and pathogen geographic ranges based on climate projections.

• Time-Series Analysis: Examining long-term surveillance data in relation to climate variables to identify correlations and potential causal relationships between climate anomalies and disease incidence.

• Experimental Studies: Investigating the effects of different temperature and humidity regimes on vector competence, parasite development rates, and transmission efficiency under controlled laboratory conditions.

The complexity of these relationships is compounded by the fact that climate change impacts on NTDs will be modulated by non-climatic factors including land use patterns, urbanization, water and sanitation infrastructure, and adaptive capacity of health systems [73].

Integrated Analytical Framework for Assessing Compound Shocks

The convergence of pandemic and climate-related disruptions requires an integrated analytical approach. The NTD Modelling Consortium, an international collaboration of epidemiological modelers, has developed quantitative frameworks to address these complex challenges [22] [74]. These modeling approaches are designed to inform policy decisions by validating control strategies, suggesting more impactful interventions, evaluating new tools, and providing guidance on the "end game" beyond immediate targets [74].

This integrated framework illustrates the cascade of effects that occur when external shocks impact NTD programs, and the potential pathways for building resilience through adaptive responses. The diagram highlights how both pandemic disruptions and climate change effects converge to increase NTD burden, necessitating multifaceted adaptation strategies.

Essential Research Toolkit for External Shock Investigation

Research Reagent Solutions for NTD Field Studies

Research investigating the impact of external shocks on NTDs requires specialized reagents and materials tailored to field conditions and resource-limited settings. The following table outlines essential research tools referenced in recent studies.

Table 3: Essential Research Reagents and Materials for NTD Field Studies

Research Reagent/Material	Primary Function	Application Context
Point-of-Care Diagnostic Tests (e.g., RDTs for LF, schistosomiasis)	Rapid detection of infections in field settings	Post-disruption prevalence mapping; Program monitoring during resource constraints
Preventive Chemotherapy Drugs (ivermectin, albendazole, praziquantel, etc.)	Mass drug administration for control and elimination	Restarting interrupted MDA programs; Preventive treatment in changing transmission settings
Environmental DNA (eDNA) Collection Kits	Detection of pathogen DNA in environmental samples	Climate change studies; Mapping vector/pathogen range shifts
Geospatial Mapping Tools (GPS devices, GIS software)	Spatial analysis of disease distribution	Tracking climate-related range expansions; Optimizing resource allocation post-disruption
Telemedicine Platforms	Remote diagnosis and consultation	Maintaining healthcare access during pandemics; Reaching remote populations
Vector Sampling Equipment (traps, aspirators, preservation media)	Collection and analysis of disease vectors	Climate change impact studies; Monitoring vector distribution changes
Digital Data Collection Tools (mobile devices, survey platforms)	Real-time data collection and monitoring	Adaptive program management; Rapid assessment post-disruption

Methodological Protocols for Assessing Program Disruptions

Research into pandemic-related disruptions to NTD programs requires standardized methodological protocols to ensure comparability across settings. Based on published studies, the following approaches represent best practices:

Protocol 1: Mixed-Methods Assessment of Program Disruption

• Quantitative Component: Online surveys of program managers and implementing partners using structured instruments with closed and open-ended questions regarding program status, challenges, and resource needs.
• Qualitative Component: Focus group discussions conducted in local languages via virtual platforms to explore implementer perspectives on challenges and solutions.
• Integration Method: Triangulation of quantitative and qualitative findings to identify convergent and divergent themes across data sources [72].

Protocol 2: Climate-Disease Modeling Framework

• Data Requirements: Historical climate data, disease surveillance data, vector distribution records, and projected climate scenarios.
• Analytical Approach: Development of mechanistic or statistical models linking climate variables to disease transmission parameters, validated against historical data where possible.
• Projection Method: Application of validated models to future climate scenarios to estimate potential changes in transmission risk and disease burden [73].

Discussion and Future Directions

The converging threats of pandemics and climate change necessitate a fundamental rethinking of NTD research and control approaches. The 2025 WHO Global Report on NTDs marks 20 years of action and data, highlighting both the progress made and the challenges that remain [75]. As the global community works toward the 2030 targets, building resilient health systems that can withstand external shocks while adapting to changing environmental conditions must become a priority.

Future research should focus on three critical areas: First, developing more sophisticated early warning systems that integrate climate forecasts with disease surveillance data to predict and prepare for changing transmission patterns. Second, designing and testing adaptive intervention strategies that can be rapidly scaled up or modified in response to external shocks. Third, strengthening implementation research to identify the most effective approaches for maintaining NTD program continuity during crises.

For drug development professionals, these findings highlight the need for novel therapeutic approaches that are less vulnerable to disruption, such as long-acting formulations that reduce the frequency of MDA requirements, or broad-spectrum anti-infectives that could target multiple NTDs simultaneously. The research community must also prioritize the development of rapid diagnostic tools that can be deployed in resource-constrained settings to quickly assess the impact of disruptions and guide targeted responses.

The path to NTD control and elimination has never been straightforward, but in the face of mounting external pressures, the research community's ability to generate evidence, develop adaptive tools, and implement resilient systems will determine whether the ambitious 2030 targets can be achieved.

Evaluating Progress, Validating Interventions, and Assessing Elimination Frameworks

Within the framework of global burden of neglected tropical diseases (NTDs) research, validating the impact of interventions is a critical yet complex undertaking. It requires a dual-track approach: measuring the direct output of health programs through treatment coverage and assessing the ultimate outcome on population health through disease burden metrics [76]. For researchers and drug development professionals, understanding the interplay between these two domains is essential for evaluating program effectiveness, justifying continued investment in research and development (R&D), and steering resources toward the most impactful interventions. The World Health Organization (WHO) NTD road map for 2030 provides a strategic blueprint for this work, setting clear targets for control, elimination, and eradication [9]. This guide details the core metrics, methodologies, and analytical tools required to rigorously validate NTD interventions, providing a technical foundation for the field.

Core Metrics and Current Global Landscape

Key Performance Indicators (KPIs) for NTD Programs

Two primary categories of KPIs are used to measure the success of interventions against NTDs: treatment coverage, which assesses the process of delivering interventions, and disease burden, which quantifies the resulting health impact.

Table 1: Key Metrics for Validating NTD Interventions

Metric Category	Specific Indicator	Definition and Measurement	Role in Intervention Validation
Treatment Coverage	Population Requiring Interventions	Individuals living in areas with prevalence above a specific threshold who need treatment or care for at least one NTD [17].	Defines the target population and serves as the denominator for coverage calculations.
	Population Treated	Number of people who received treatment (via mass drug administration or individual case management) for at least one NTD [9].	The primary output metric; indicates the program's reach and direct effort.
	Treatment Coverage Rate	Proportion of the target population that received the required intervention [17].	A direct measure of program performance and service delivery efficiency.
Disease Burden	Disability-Adjusted Life Years (DALYs)	A composite metric quantifying total health loss from mortality (Years of Life Lost) and morbidity (Years Lived with Disability) [76].	The core outcome metric for comparing the comprehensive burden across different diseases.
	Prevalence & Incidence	Number of existing (prevalence) or new (incidence) cases of a disease in a population over a specified period [8].	Tracks the changing transmission and occurrence of the disease.
	Mortality	Number of deaths attributed to one or more NTDs [14].	Measures the most severe outcome of disease.
	Elimination & Eradication Status	Country validation for eliminating a specific NTD as a public health problem [9].	The ultimate validation of long-term intervention success.

Contemporary Global Data and Trends

The most recent WHO data reveals significant, though uneven, progress. In 2023, an estimated 1.495 billion people required interventions against NTDs, representing a substantial decrease of 122 million from 2022 and a 32% reduction from the 2010 baseline [9] [14]. Concurrently, treatment output remains massive, with 867.1 million people treated for at least one NTD in 2023 [9].

The broader burden of NTDs has also seen a measurable decline. The disease burden, measured in DALYs, dropped from 17.2 million in 2015 to 14.1 million in 2021 [14]. Over a longer timeframe, the number of people affected by NTDs fell from 1.9 billion in 1990 to just over 1 billion in 2021 [14]. This progress is further validated by elimination milestones; in 2024 alone, seven countries were acknowledged by WHO for eliminating at least one NTD [9].

Table 2: Selected Recent Breakthroughs in NTD Tools (2024)

Health Product	Type	Significance for Research and Validation
New Dengue Vaccine [9]	Vaccine	Provides a new preventive tool, potentially altering transmission dynamics and burden in endemic regions.
Six New Medicine Formulations [9]	Pharmaceutical	Expands treatment arsenals, potentially improving efficacy, safety, or dosing regimens.
Over 1 Million Diagnostic Tests [9]	Diagnostics	Enhances capacity for accurate case detection and surveillance, critical for measuring true prevalence.

Methodologies for Data Collection and Analysis

Experimental and Surveillance Protocols

Robust validation relies on standardized protocols for data generation. Below are detailed methodologies for key activities cited in global reports and studies.

Protocol 1: Estimating Population Requiring Interventions (PRI)

• Objective: To define the target population for mass treatment (Preventive Chemotherapy - PC) and individual case management.
• Methodology:
  • Mapping and Stratification: Conduct geospatial mapping and prevalence surveys (e.g., using serological, parasitological, or clinical exams) for PC-NTDs (LF, onchocerciasis, schistosomiasis, STH, trachoma) at the implementation unit level (e.g., district) [17].
  • PRI for PC-NTDs: For each implementation unit, the number of people requiring PC is calculated for each PC-NTD by age group. To avoid double-counting individuals co-infected with multiple NTDs, the largest number of people requiring PC for any single NTD is retained for each age group. The sum provides a conservative PRI estimate for PC-NTDs [17].
  • PRI for Case-Based NTDs: The number of new cases requiring individual treatment and care (e.g., for Buruli ulcer, dengue, leishmaniasis) is collected from national surveillance systems and country reports [17].
  • Aggregation: The maximum of the PC-NTD estimate or the case-based NTD estimate is retained at the implementation unit level and summed to generate conservative national, regional, and global aggregates [17].

Protocol 2: Calculating Disability-Adjusted Life Years (DALYs)

• Objective: To quantify the total burden of disease by combining years of life lost due to premature mortality (YLLs) and years lived with a disability (YLDs).
• Methodology (as per GBD framework) [76]:
  • Years of Life Lost (YLLs): Calculated as the number of deaths from a specific cause (d_x) multiplied by a standard life expectancy at the age of death (L_x): YLL = d_x * L_x. The GBD study uses a standard life expectancy, distinct from local life tables, to enable comparability.
  • Years Lived with Disability (YLDs): Calculated as the number of incident cases (I) multiplied by the average duration of the condition (L) and a disability weight (DW) that reflects the severity of the health state on a scale from 0 (perfect health) to 1 (equivalent to death): YLD = I * L * DW.
  • DALY Calculation: The sum of the two components: DALY = YLL + YLD.

Protocol 3: Longitudinal Trend Analysis of Burden

• Objective: To analyze changes in disease burden over time and project future trends.
• Methodology (as utilized in recent studies) [8]:
  • Data Sourcing: Utilize data from comprehensive studies like the Global Burden of Disease (GBD) study, which provides annual estimates for incidence, prevalence, mortality, and DALYs.
  • Trend Calculation: Compute the Estimated Annual Percentage Change (EAPC) for age-standardized rates (e.g., ASIR, ASMR, ASDR) to quantify the trend over a specified period (e.g., 1990-2021).
  • Inequality Analysis: Employ measures like the Slope Index of Inequality (SII) and Concentration Index (CI) to assess absolute and relative inequalities in disease burden related to socioeconomic status (e.g., Socio-demographic Index - SDI).
  • Forecasting: Use modeling approaches, such as the Bayes Age-Period-Cohort model, to project future disease burden based on historical trends and covariate data.

Conceptual Workflow for Impact Validation

The following diagram illustrates the logical relationship between data sources, core metrics, and the ultimate validation of NTD interventions.

The Scientist's Toolkit: Research Reagent Solutions

For researchers conducting studies on NTD burden and intervention impact, a standard toolkit comprises various reagents, assays, and data systems.

Table 3: Essential Research Tools for NTD Impact Studies

Tool Category	Specific Item	Function in Research and Validation
Diagnostics & Assays	Rapid Diagnostic Tests (RDTs)	Enable point-of-care case detection and seroprevalence surveys in field settings, crucial for mapping and baseline data [77].
	Molecular Assays (PCR, qPCR)	Provide high-specificity confirmation of infection, essential for validating RDT results and measuring infection intensity in longitudinal studies.
	ELISA Kits	Measure antibody responses, useful for assessing transmission intensity and exposure history in epidemiological research.
Data Systems & Software	DISMOD Model	A Bayesian meta-regression tool used in GBD studies to ensure consistency between incidence, prevalence, remission, and mortality rates for a disease [76].
	Geographic Information Systems (GIS)	Software for spatial analysis and mapping of disease distribution, overlaying with intervention coverage to identify gaps.
	GHDx/GBD Results Tool	Online platforms to access and analyze standardized global health data, including NTD burden estimates, for comparative analysis [8].
Analytical Frameworks	WHO's NTD Roadmap M&E Framework	Provides standardized indicators and reporting templates for tracking progress against the 2030 goals, ensuring data comparability [9].
	GBD Comparative Risk Assessment	A framework to quantify the burden of disease attributable to specific risk factors, informing targeted preventive interventions [76].

Challenges and Future Directions

Despite progress, significant challenges impede the precise validation of NTD interventions. A 41% decrease in official development assistance for NTDs between 2018 and 2023 threatens the sustainability of programs and the data collection systems that underpin them [9] [14]. Critical gaps remain in diagnostics, with tests often lacking accuracy, affordability, or suitability for point-of-care use in remote settings [77]. Furthermore, data reporting is often incomplete, and the collection of gender-disaggregated data remains limited, obscuring the differential impact of NTDs and the effectiveness of interventions across genders [9] [14].

Future efforts must focus on developing and validating next-generation tools. WHO is leading an initiative to define an R&D Blueprint for NTDs, aiming to prioritize research questions for the global community [78]. Simultaneously, adapting surveillance and intervention strategies to account for the impact of climate change on the geographic distribution and transmission dynamics of NTDs is an emerging research and validation priority [9] [8].

Neglected Tropical Diseases (NTDs) represent a group of communicable diseases that perpetuate cycles of poverty and disease burden, affecting over 1.5 billion people globally [20] [18]. The World Health Organization's (WHO) 2021-2030 road map established an ambitious target of 100 countries eliminating at least one NTD by 2030 [20]. Recent data indicates significant progress toward this goal, with 54 countries having successfully eliminated at least one NTD by the end of 2024, surpassing the halfway milestone ahead of schedule [18] [79]. This case study analysis conducts a comparative review of elimination blueprints from 50 countries that had eliminated at least one NTD by March 2024, examining the strategic frameworks, implementation methodologies, and critical success factors that underpinned these achievements [20]. The analysis is situated within the broader context of global NTD burden research, aiming to provide actionable insights for researchers, scientists, and drug development professionals engaged in the global effort to control, eliminate, and eradicate these diseases of poverty.

Global Status of NTD Elimination

Table 1: Global NTD Elimination Progress (Data as of March 2024 unless otherwise specified)

Metric	Value	Source
Countries eliminating ≥1 NTD	50 (54 by Dec 2024)	[20] [18]
Countries eliminating ≥2 NTDs	13	[20]
Maximum eliminations by a single country (Togo)	4 NTDs	[20]
NTDs eliminated in at least one country	8	[20]
People requiring NTD interventions (2023)	1.495 billion	[80] [79]
Reduction in people requiring interventions since 2010	32%	[80] [79]
People treated for NTDs (2023)	867.1 million	[80] [79]
Global disease burden (DALYs, 2021)	14.1 million	[80] [79]
NTD-related deaths (2021)	119,000	[80] [79]

Table 2: Specific NTDs Eliminated in at Least One Country

NTD	Elimination Status	Key Characteristics
Guinea worm disease	Targeted for global eradication by 2030	Helminth infection transmitted via contaminated water [20] [18]
Human African trypanosomiasis	Elimination as public health problem	Protozoan infection spread by tsetse flies, nearly 100% fatal without treatment [20] [18]
Lymphatic filariasis	Eliminated in multiple countries	Helminth infection causing elephantiasis, transmitted by mosquitoes [20] [18]
Onchocerciasis	Eliminated in multiple countries	Helminth infection causing river blindness, transmitted by blackflies [20] [18]
Rabies (dog-mediated human)	Eliminated in multiple countries	Viral disease transmitted through animal bites, invariably fatal after symptoms [20] [18]
Trachoma	Eliminated in multiple countries	Bacterial infection causing blindness, linked to poor sanitation [20] [18]
Visceral leishmaniasis	Eliminated in multiple countries	Protozoan infection affecting internal organs, transmitted by sandflies [20] [18]
Yaws	Targeted for global eradication by 2030	Chronic bacterial infection affecting skin and bone [20] [18]

The eight NTDs eliminated in at least one country represent diverse pathogen types (viruses, bacteria, protozoa, and helminths) and transmission mechanisms, providing a robust evidence base for analyzing elimination approaches across different epidemiological contexts [20]. By March 2024, 46 of the 50 countries had achieved elimination of at least one NTD specifically as a public health problem (PHP), defined by WHO as reducing NTD occurrence to a level where it no longer poses a public health threat based on clinical symptoms and infection burden [20]. Additionally, 22 countries had achieved the more challenging target of interruption of transmission (IoT), bringing transmission to zero within a defined region [20].

Methodological Framework for Elimination Analysis

Systematic Review Protocol

This analysis employs the methodological approach detailed in the PLOS NTDs review, which conducted an extensive examination of published and grey literature concerning NTD elimination programmes in the 50 countries that had eliminated at least one NTD by March 2024 [20]. The systematic methodology provides a robust framework for comparative analysis.

Data Extraction and Analysis Framework

The review extracted and analyzed data across multiple dimensions of elimination programmes [20] [21]:

• Programme duration and organization: Temporal scope of elimination efforts and lead implementing bodies
• Intervention strategies: Specific medical, public health, and environmental interventions deployed
• Mainstreaming approaches: Integration of NTD activities within broader health services
• Partnership models: Collaborations between endemic countries, international agencies, and donors
• Historical control efforts: Documentation of previous failed attempts and underlying causes

The search strategy was piloted using lymphatic filariasis as an initial test case, with subsequent adaptation to improve relevancy of retrieved publications [20]. To ensure comprehensive coverage and reliability, second searches and screening using identical search terms and inclusion criteria were conducted independently by a second reviewer [20]. The methodology addressed potential documentation gaps through systematic grey literature review and cross-verification across multiple sources.

Key Success Factors in NTD Elimination

Core Components of Successful Elimination Programmes

Table 3: Critical Success Factors for NTD Elimination

Success Factor	Frequency	Key Characteristics	Exemplary Countries
Country ownership	High	Domestic funding, political commitment, integration into national health strategies	Multiple countries across regions [20]
Sustained duration	Universal	Minimum 20 years of continuous effort	Togo (4 NTDs eliminated) [20]
Partnership models	High	International donors, pharmaceutical donations, technical agencies	WHO, pharmaceutical manufacturers, NGOs [20] [79]
Combination strategies	High	Multiple interventions deployed simultaneously	Countries eliminating lymphatic filariasis [20]
Dedicated elimination programmes	High	Disease-specific targets, coordinated implementation	Trachoma elimination countries [20]
Cross-sectoral approaches	Moderate	Integration of WASH, education, veterinary services	One Health approaches for rabies [20]

Analysis of the 50 country blueprints revealed that successful elimination programmes consistently featured several interconnected components that created synergistic effects. Country ownership emerged as a foundational element, manifested through domestic resource allocation, political commitment at highest levels, and integration of NTD elimination into national health strategies and plans [20] [79]. This local leadership ensured programme sustainability beyond external funding cycles and technical assistance.

Temporal analysis revealed that elimination typically required at least two decades of sustained efforts, demonstrating that NTD elimination represents a long-term commitment rather than a short-term intervention [20]. This extended timeframe necessitates stable financing, consistent political will, and adaptive programme management that can respond to changing epidemiological and operational contexts.

Strategic Implementation Approaches

The comparative analysis identified two predominant strategic approaches to implementation. Vertical, disease-specific programmes represented the most common model, particularly for initial elimination successes in countries [20]. These dedicated elimination programmes enabled focused resource allocation, targeted technical expertise, and streamlined monitoring systems aligned with specific elimination criteria.

In contrast, integrated, cross-cutting approaches were utilized less frequently but demonstrated potential for efficiency gains and synergistic effects [20]. These included mainstreaming NTD interventions within broader health services, particularly at primary care level, and incorporating Water, Sanitation, and Hygiene (WASH) components to address multiple NTDs simultaneously [20] [81]. The integration of mental health support into NTD programmes emerged as an innovative approach to address the significant social and psychological burdens associated with these diseases, including stigma, discrimination, and social exclusion [81].

Partnership Models and Resource Mobilization

Collaborative Frameworks for Elimination

Successful elimination programmes operated through multi-stakeholder partnerships that leveraged comparative advantages of different actors [20] [79]. The WHO Global NTD Programme, marking 20 years of coordinated action in 2025, has provided strategic direction and technical norm-setting [75] [79]. Pharmaceutical manufacturers have contributed through massive medicine donation programmes, with 12 manufacturers donating 19 different types of NTD medicines [79]. Between 2011 and 2024, nearly 30 billion tablets and vials were delivered to endemic countries, including 1.8 billion for treatments in 2024 alone [79].

International development partners and philanthropic organizations have provided financial resources and technical assistance, while endemic country governments have implemented programmes and increasingly assumed financial responsibility [20] [79]. By 2024, 14 African countries had developed national plans to strengthen sustainability of NTD service delivery, reflecting growing country ownership [79].

Research and Innovation Ecosystem

Table 4: Research and Innovation in NTD Elimination

Innovation Area	Recent Advances	Impact on Elimination
Diagnostics	WHO prequalified six new medicine formulations and one active pharmaceutical ingredient in 2024 [79]	Improved detection accuracy and accessibility
Vaccine development	New dengue vaccine prequalified by WHO [79]	Enhanced preventive capacity for outbreak-prone diseases
Digital health tools	Adoption of digital tools for detection and treatment [81]	Strengthened programmatic outcomes and accelerated elimination
Medicines and supply chain	1 million diagnostic tests procured for five NTDs in 2024 [79]	Increased treatment coverage and efficiency
Operational research	Identification of implementation bottlenecks and solutions [20]	Improved programme effectiveness and adaptation

The research and innovation ecosystem surrounding NTD elimination has intensified, with WHO launching a process to define research and development priorities for NTDs in 2024 [79]. Cutting-edge diagnostics and digital health tools are transforming how NTDs are detected and treated, significantly strengthening programmatic outcomes [81]. The growing adoption of these technologies across regions has accelerated progress toward elimination targets.

Challenges and Barriers to Elimination

Structural and Operational Constraints

Despite considerable progress, NTD elimination efforts face persistent challenges that threaten the achievement of 2030 targets. Funding constraints represent a critical barrier, with official development assistance for NTDs decreasing by 41% between 2018 and 2023 [79]. This reduction comes despite evidence that investment in NTD control represents one of the "best buys" in global health, with potential benefits exceeding $342 billion between 2015 and 2030 if elimination targets are met [20].

Health system limitations continue to impede elimination efforts, particularly in remote or conflict-affected areas [81]. Inadequate health system capacity, funding gaps, and disparities in access to healthcare create structural barriers to effective implementation [81]. Additionally, significant challenges remain in data collection and utilization, with incomplete reporting on all NTDs and limited availability of gender-disaggregated information [80] [79].

Contextual and Environmental Challenges

Sociopolitical instability has frequently disrupted elimination efforts, leading to resurgence of diseases that had previously been controlled [20]. Historical analysis demonstrates that failed elimination attempts often resulted from deprioritization of NTD programmes during periods of political transition or economic constraint [20].

Climate change has emerged as a significant threat to NTD control, particularly for vector-borne diseases [82] [81]. Changing temperature and precipitation patterns alter the geographical distribution of vectors, potentially expanding the endemic area for diseases like dengue, chikungunya, and leishmaniasis [82]. The integration of a One Health approach that considers human, animal, and ecosystem health is increasingly essential for building resilience against these climate impacts [81].

Research Reagents and Technical Tools

Table 5: Essential Research Reagents and Tools for NTD Elimination

Reagent/Tool Category	Specific Examples	Research and Programmatic Application
Diagnostic tests	Rapid diagnostic tests (RDTs), molecular assays, microscopy	Case detection, surveillance, verification of elimination [79]
Therapeutic agents	Donated medicines (ivermectin, azithromycin, etc.), new chemical entities	Mass drug administration, case management, preventive chemotherapy [20] [79]
Vector control products	Insecticides, larvicides, biological control agents	Reduction of transmission, integrated vector management [20]
Vaccines	New dengue vaccine, rabies vaccines	Prevention of infection, outbreak control [79]
Data collection tools	Digital health platforms, surveillance systems, monitoring frameworks	Programme tracking, impact assessment, verification of elimination [81]

The research and implementation toolkit for NTD elimination has expanded significantly, with WHO facilitating the procurement of over 1 million diagnostic tests for five NTDs in 2024 alone [79]. The ongoing development and refinement of these tools remains critical for addressing persistent challenges in diagnosis, treatment, and monitoring of NTDs.

The comparative analysis of elimination blueprints from 50 countries provides compelling evidence that NTD elimination is an achievable public health goal with sufficient commitment, resources, and strategic implementation. The common elements of success—country ownership, sustained effort, strategic partnerships, and adapted implementation approaches—offer a replicable framework for countries working toward the 2030 elimination targets.

However, maintaining current progress requires addressing critical challenges, particularly the 41% reduction in official development assistance for NTDs between 2018-2023 [79]. The research community has an essential role in developing next-generation tools and strategies, while health systems must strengthen their capacity to deliver integrated NTD services. As the global NTD community advances toward the 2030 targets, the blueprint derived from these 50 country experiences provides an evidence-based roadmap for accelerating progress toward a future free of neglected tropical diseases.

The relentless battle against Neglected Tropical Diseases (NTDs) demands not only innovative tools but also robust, standardized systems to validate their performance. The World Health Organization's prequalification program for medicines and in vitro diagnostics (IVDs) stands as a critical global mechanism to ensure the quality, safety, and efficacy of these health products. Within the context of a broader thesis on the global burden of NTDs, understanding this validation framework is paramount. Despite progress, NTDs affect over 1.495 billion people globally who require interventions, with the disease burden measured in Disability-Adjusted Life Years (DALYs) falling from 17.2 million in 2015 to 14.1 million in 2021 [9] [14]. This substantial burden, concentrated in tropical, low-income countries, underscores the necessity for reliable diagnostics and medicines. The WHO's validation process provides researchers and manufacturers with a structured pathway from development to deployment, ensuring that new tools meet stringent performance standards before reaching the populations most in need. This technical guide details the core principles, methodologies, and experimental protocols underpinning the performance assessment of WHO-prequalified medicines and diagnostics, providing a essential resource for the scientific community engaged in NTD research and product development.

The WHO Prequalification Framework: Principles and Process

The WHO prequalification system functions as a globally recognized quality assurance mechanism, facilitating the availability of health products that meet unified standards of quality, safety, and performance. The process is grounded in several key principles: a comprehensive assessment of product dossiers, site inspections of manufacturing facilities, and continuous post-marketing surveillance. A pivotal aspect of this framework is the collaborative registration procedure, detailed in WHO Technical Report Series (TRS) 1060, which accelerates national registration of WHO-prequalified products by promoting regulatory convergence and reliance among national authorities [83]. This procedure is vital for ensuring rapid access to new tools in endemic countries.

The assessment is dynamic, continuing well after a product is prequalified. WHO regularly publishes updates to its Public Assessment Reports (WHOPARs) to reflect post-prequalification changes that have been formally notified, reviewed, and approved, thereby ensuring the continued quality of prequalified products [84]. Furthermore, the assessment process itself is iterative, with dedicated sessions—such as the virtual assessment session held in June 2025 where experts from 15 countries reviewed 17 units of work—ensuring a thorough and ongoing evaluation of dossiers and corrective actions [85].

The Gap Assessment Tool (GAT) for NTDs

To qualitatively monitor progress against the 2030 NTD road map targets, WHO employs the Gap Assessment Tool (GAT). This tool complements quantitative data by identifying obstacles hindering the achievement of road map goals. The GAT evaluates eleven dimensions, with a recent 2023-2024 assessment prioritizing four critical areas: Diagnostics, Monitoring and Evaluation, Access & Logistics, and Advocacy & Funding [86]. The outcome includes a "heat map" visualization that identifies gaps and informs critical programmatic and research actions, providing valuable guidance for the development and deployment of new tools.

Performance Evaluation of Diagnostics

The performance assessment of IVDs is a rigorous, multi-faceted process centered on establishing analytical and clinical validity. For NTDs, this is particularly challenging due to the diversity of diseases and the often resource-limited settings where these tools are deployed.

Key Performance Metrics for IVDs

The evaluation of diagnostic tests, whether laboratory-based or point-of-care, hinges on a standard set of performance metrics derived from comparison to an appropriate reference standard. These metrics are summarized in the table below.

Table 1: Key Performance Metrics for In Vitro Diagnostics (IVDs)

Metric	Definition	Calculation Formula	Interpretation in NTD Context
Analytical Sensitivity	The lowest concentration of an analyte that an assay can reliably detect.	N/A (Determined via dilution series)	Crucial for detecting low-parasite loads in diseases like visceral leishmaniasis or human African trypanosomiasis.
Analytical Specificity	Ability to detect only the intended analyte without cross-reactivity.	N/A (Assessed with potentially cross-reacting organisms)	Essential for specificity in regions with co-endemic pathogens that may cause similar symptoms.
Clinical Sensitivity	Proportion of true positive subjects correctly identified by the test.	True Positives / (True Positives + False Negatives)	High sensitivity is required for diseases where missing a case has severe consequences (e.g., rabies).
Clinical Specificity	Proportion of true negative subjects correctly identified by the test.	True Negatives / (True Negatives + False Positives)	High specificity prevents unnecessary treatment and associated costs and toxicity.
Area Under the ROC Curve (AUC)	Overall measure of the test's ability to discriminate between diseased and non-diseased subjects.	N/A (Graphical plot of Sensitivity vs. 1-Specificity)	An AUC of 1 represents a perfect test; a value of 0.5 represents a test with no discriminative power.

Case Study: Prequalification of the Xpert MTB/XDR Test

A prime example of a prequalified diagnostic is Cepheid's Xpert MTB/XDR test. This molecular assay detects Mycobacterium tuberculosis and resistance to multiple first- and second-line TB drugs, including isoniazid, ethionamide, fluoroquinolones, and aminoglycosides. The test runs on Cepheid's GeneXpert systems, providing results in about 90 minutes, which is critical for rapid treatment decisions [87]. Its prequalification affirms compliance with WHO standards, enabling procurement by international agencies and expanding global access to advanced drug-resistance testing for tuberculosis, a major global health threat [87].

Experimental Protocol: Evaluating an AI-Powered Diagnostic Tool

The following workflow outlines the protocol for a performance evaluation study of the WHO Skin NTDs App, an AI-based tool for classifying skin lesions, as undertaken in Senegal. This mixed-methods approach is a robust model for validating novel digital diagnostics.

Diagram 1: AI Diagnostic Tool Evaluation

This protocol involves a quantitative diagnostic accuracy study running in parallel with a qualitative exploration of feasibility. For the quantitative arm, approximately 800 skin lesion images are collected from patients at a clinical site (e.g., a regional hospital). Each lesion is independently assessed by the AI algorithm and by a expert dermatologist, whose diagnosis serves as the reference standard. Key performance metrics like accuracy, sensitivity, and specificity are then calculated [88]. Concurrently, in-depth interviews with 70-80 stakeholders—including health care workers, policymakers, and community members—are conducted to understand the app's perceived usability, acceptability, and potential barriers to its integration into the existing health system [88].

Performance Evaluation of Medicines and Vaccines

The assessment of medicines and vaccines for prequalification involves a thorough review of data on pharmaceutical quality, non-clinical studies, and clinical efficacy and safety.

Key Assessment Criteria for Medicines

The evaluation of medicines focuses on three primary domains, detailed in the table below. In the NTD context, considerations such as thermostability for products destined for tropical climates and fixed-dose combinations for simplified treatment regimens are particularly important.

Table 2: Key Assessment Criteria for Prequalified Medicines and Vaccines

Assessment Domain	Key Data Requirements	Methodologies & Standards
Pharmaceutical Quality	- Active Pharmaceutical Ingredient (API) source and characterization- Finished product formulation- Manufacturing process description and controls- Product stability and shelf-life data	- Good Manufacturing Practice (GMP) inspections- International Pharmacopoeia standards- Accelerated and real-time stability studies
Non-Clinical Data	- Pharmacology (mechanism of action, potency)- Pharmacokinetics (ADME: Absorption, Distribution, Metabolism, Excretion)- Toxicology (acute, chronic, reproductive toxicity)	- GLP (Good Laboratory Practice) studies- In vitro and in vivo models relevant to the disease
Clinical Efficacy & Safety	- Phase II/III trial protocols and results- Statistical analysis plan- Evidence of superiority or non-inferiority vs. standard of care- Safety profile and adverse event reporting	- Randomized Controlled Trials (RCTs)- WHO-specific target product profiles (TPPs)- Post-prequalification pharmacovigilance (Phase IV)

Recent Advances in Prequalified NTD Products

The WHO's normative and technical work has accelerated in recent years. In 2024 alone, WHO prequalified six new medicine formulations, one active pharmaceutical ingredient, and a new dengue vaccine [9] [14]. This is supported by a robust system of medicine donations; as of the end of 2024, 12 manufacturers donated 19 different types of NTD medicines, with 1.8 billion treatments delivered in that single year [14]. Furthermore, WHO facilitated the procurement of over 1 million diagnostic tests for five NTDs in 2024, highlighting the critical link between validated tools and programmatic delivery [9].

The Scientist's Toolkit: Essential Research Reagents and Materials

The development and validation of new medicines and diagnostics rely on a suite of specialized reagents and materials. The following table details key components used in the field, particularly for NTDs.

Table 3: Essential Research Reagents and Materials for NTD Tool Development

Item	Function/Application	Example in NTD Context
Reference Standards	Certified materials used to calibrate measurements and validate assays; the benchmark for quality control.	WHO International Standards for antibody/antigen detection in diseases like Chagas disease or lymphatic filariasis.
Monoclonal and Polyclonal Antibodies	Key reagents for immunoassays (ELISA, LFAs) for pathogen or host biomarker detection.	Antibodies specific to Plasmodium HRP2 for malaria rapid tests, or for Mycobacterium tuberculosis antigens.
Oligonucleotide Primers and Probes	Essential for molecular diagnostics (PCR, isothermal amplification) to specifically amplify and detect pathogen DNA/RNA.	Primers for multiplex real-time PCR to differentiate between species of Leishmania or detect drug-resistance mutations in TB.
Recombinant Antigens and Proteins	Used in serological assays, vaccine development, and as positive controls in diagnostic kits.	Recombinant K39 antigen for the diagnosis of visceral leishmaniasis.
Cell Lines and Culture Media	Used for in vitro drug susceptibility testing, vaccine development, and cultivating pathogens for assay development.	Macrophage cell lines for screening anti-leishmanial drug candidates; culture media for Mycobacterium tuberculosis.
Animal Models	Critical for in vivo efficacy and toxicity testing of drug candidates and vaccine prototypes.	Mouse models for Chagas disease, hamsters for visceral leishmaniasis, and non-human primates for vaccine studies.

The rigorous, multi-dimensional framework for validating WHO-prequalified medicines and diagnostics is a cornerstone of the global effort to reduce the immense burden of NTDs. This process, which integrates quantitative performance metrics with qualitative assessments of feasibility and integration, ensures that only tools meeting the highest standards of quality, safety, and efficacy are deployed. For the research and development community, a deep understanding of this framework—from the statistical analysis of diagnostic accuracy to the requirements for pharmaceutical quality and clinical trial design—is indispensable. As the global health landscape evolves, with challenges like climate change and funding gaps threatening progress [8], the continued innovation and stringent validation of new tools will be paramount. The WHO prequalification process, supported by tools like the GAT, provides the necessary pathway to ensure these innovations reach the billions of people still affected by NTDs, ultimately driving progress towards the 2030 road map goals.

Within the global effort to control and eliminate neglected tropical diseases (NTDs), addressing cross-cutting health system gaps is as critical as developing disease-specific interventions. These gaps fundamentally influence the effectiveness, equity, and sustainability of NTD programs. This technical review evaluates progress and persistent challenges in three foundational cross-cutting areas essential for reducing the global burden of NTDs: access to Water, Sanitation, and Hygiene (WASH), the collection of gender-disaggregated data, and protection from catastrophic health expenditure (CHE). The World Health Organization's 2021-2030 NTD road map highlights these areas as integral to its strategy, yet recent data indicates progress has been slower than required to meet 2030 targets [14] [9]. This paper provides researchers and drug development professionals with a quantitative assessment of the current landscape, methodologies for monitoring, and a strategic framework for integrating these cross-cutting considerations into NTD research and program implementation.

Quantitative Assessment of Current Status and Progress

Monitoring progress against the 2030 NTD road map targets requires robust, longitudinal data. The following tables summarize key quantitative indicators across the three cross-cutting areas, drawing from the latest WHO global reports and related studies.

Table 1: Key Indicators for WASH, Gender-Disaggregated Data, and Financial Protection in NTD Context

Indicator	Recent Data & Year	Baseline/Previous Data	Progress Assessment	2030 Target
WASH Access in NTD-Endemic Countries
Overall population access to WASH [89]	85.8% (2022)	Not specified	Slow progress; insufficient for target	Universal Access
Population requiring NTD interventions with WASH access [89]	63% (2022)	Not specified	Significant gap remains	Universal Access
Gender-Disaggregated Data
Countries reporting sex-disaggregated data for NTDs [89]	17 countries (2022)	Not specified	Stagnated progress; major gap	100 Countries
Financial Risk Protection
Population protected from CHE due to NTDs [89]	87.4% (2022)	Not specified	Persistent gap leaves millions at risk	100% Protection

Table 2: Broader Contextual Data on NTD Burden and CHE

Indicator	Data	Source/Year
Global NTD Burden
Global DALYs for NTDs [14]	14.1 million (2021)	17.2 million (2015)
People requiring NTD interventions [14]	1.495 billion (2023)	1.617 billion (2022)
Disease-Specific CHE Drivers
CHE cases associated with fever/diarrhea/cough [90] [91]	37.6% (95% UI 35.4–39.9%)	WHS (2002-2004)
CHE cases associated with heart disease [90] [91]	4.1% (95% UI 3.3–4.9%)	WHS (2002-2004)
CHE cases associated with injuries [90] [91]	5.2% (95% UI 4.2–6.4%)	WHS (2002-2004)

The data reveals a consistent theme: while gradual progress is evident, the current pace is insufficient to achieve the ambitious 2030 targets. The disparity in WASH access between the general population of endemic countries and those specifically requiring NTD interventions is particularly telling, highlighting a failure to target resources to the most vulnerable groups [89]. Similarly, the stagnant number of countries reporting sex-disaggregated data impedes the ability to design equitable interventions.

Methodologies and Experimental Protocols for Monitoring and Evaluation

Robust methodologies are essential for generating the reliable data needed to assess progress and guide policy. This section details established protocols for evaluating the cross-cutting gaps.

Assessing Catastrophic Health Expenditure (CHE)

The measurement of CHE provides a critical metric for financial risk protection, a core pillar of universal health coverage.

• Protocol: CHE Calculation via World Health Surveys (WHS) Method
  • Objective: To quantify the proportion of households that experience health expenditure exceeding a threshold of their capacity-to-pay, disaggregated by disease area.
  • Data Collection: Utilize a nationally representative household survey (e.g., WHS, Living Standards Measurement Study) that captures:
    • Total household consumption expenditure over a reference period (e.g., 4 weeks).
    • Household food expenditure to establish a subsistence expenditure threshold.
    • Health expenditure: Sum of out-of-pocket costs for inpatient care, outpatient care, medicines, diagnostics, and traditional providers over a 30-day period.
    • Reason for healthcare utilization: The condition or symptoms (e.g., "high fever," "injury") that prompted the healthcare encounter.
  • Calculation Steps:
    • Define subsistence expenditure (SE): Calculate the mean food expenditure of households in the 45th to 55th percentile range of the food expenditure distribution, adjusted for household size using an equivalence scale (e.g., square root of household size).
    • Define capacity-to-pay (CTP): For households whose total expenditure is greater than SE, CTP = Total expenditure - SE. For households with total expenditure less than or equal to SE, CTP = Total non-food expenditure.
    • Identify CHE: A household is considered to have incurred CHE if its out-of-pocket health expenditure is greater than or equal to 40% of its CTP.
    • Disaggregate by Disease: Attribute CHE cases to disease areas based on the respondent's stated reason for seeking care in the survey [90] [91].
  • Analysis: Report the proportion of households incurring CHE, both overall and by disease category. Statistical analysis should incorporate survey weights and design effects to ensure national representativeness.

Monitoring Gender Gaps in Diagnostics

A scoping review methodology can effectively map the existing evidence and identify critical gaps in sex- and gender-disaggregated data for NTDs.

• Protocol: Scoping Review of Sex- and Gender-Disaggregated Data
  • Objective: To determine the extent and nature of sex-disaggregated data and gender analysis in the diagnostic cascade for specific diseases.
  • Search Strategy:
    • Databases: PubMed, Google Scholar.
    • Timeframe: e.g., 2000-2022.
    • PICO Framework:
      • Population: Patients in low-, middle-, and high-income countries.
      • Intervention: Diagnostics for tracer conditions (e.g., schistosomiasis, malaria, TB).
      • Comparison: Differences by sex and/or gender.
      • Outcome: Data on diagnostic access, accuracy, health-seeking behavior, and access barriers.
    • Search Terms: Combine MeSH terms and keywords for the disease, "diagnosis," "sex factors," "gender identity," "health services accessibility."
  • Screening and Selection:
    • Inclusion: Studies providing quantitative or qualitative data comparing diagnostic-related outcomes by sex or gender.
    • Exclusion: Studies of only one sex/gender, reviews, non-English texts.
    • Process: Two independent reviewers screen titles/abstracts, then full texts, resolving disagreements by consensus.
  • Data Extraction and Analysis:
    • Quantitative: Tabulate the number of studies reporting sex-disaggregated data for each stage of the diagnostic value chain (awareness, seeking, reaching, payment, receiving).
    • Qualitative: Thematically analyze studies to identify recurring barriers, such as gender norms restricting women's mobility or financial resource control affecting ability to pay for diagnostics [92].

The following workflow diagram visualizes the multi-stage process of this scoping review protocol:

Visualizing Interrelationships and Workflows

Conceptual diagrams are invaluable for understanding the complex pathways through which these cross-cutting factors influence NTD outcomes.

The Interrelationship Between Cross-Cutting Gaps and NTD Burden

The following diagram illustrates how deficiencies in WASH, gender data, and financial protection directly and indirectly exacerbate the global burden of NTDs, creating a cycle of disease and disadvantage.

The Diagnostic Value Chain with Gender and Sex Barriers

The pathway to obtaining a diagnosis, known as the diagnostic value chain, is fraught with potential barriers. This diagram maps these stages and overlays examples of common sex- and gender-based barriers that can cause individuals to drop out of the cascade of care, using examples from diseases like schistosomiasis and tuberculosis [92].

The Scientist's Toolkit: Research Reagent Solutions

For researchers investigating the socio-economic and gender-related dimensions of NTDs, the following tools and resources are essential for robust study design and data collection.

Table 3: Essential Research Tools for Investigating Cross-Cutting NTD Gaps

Tool / Resource	Type	Primary Function	Application Example
World Health Survey (WHS) [90] [91]	Database / Methodology	Provides a standardized, multi-country dataset and method for calculating disease-specific CHE.	Quantifying the proportion of CHE attributable to acute conditions (e.g., fever/diarrhea) vs. NCDs (e.g., heart disease).
WHO Global Report on NTDs Indicators [9]	Monitoring Framework	Tracks progress on overarching and cross-cutting indicators (WASH, CHE, gender data) against the 2030 road map.	Assessing a country's performance on integrating NTDs into national health plans and essential service packages.
GBD (Global Burden of Disease) Data [8]	Database	Provides comprehensive estimates of NTD incidence, prevalence, mortality, and DALYs, disaggregated by sex, age, and geography.	Analyzing trends and inequalities in the burden of diseases like schistosomiasis and malaria over time.
SAGER (Sex and Gender Equity in Research) Guidelines [92]	Reporting Guideline	Provides a framework for systematic reporting of sex and gender information in study design, data analysis, and manuscript preparation.	Ensuring research on new NTD diagnostics adequately reports on differential test performance or access between men and women.
JMP (Joint Monitoring Programme) WASH Data [93]	Database	Tracks household, school, and health care facility access to WASH services, with sex-disaggregated data on water collection.	Correlating sub-national WASH access data with NTD prevalence maps to identify high-risk communities.

The persistent deficits in WASH access, gender-disaggregated data, and financial risk protection represent not merely ancillary concerns but fundamental barriers to reducing the global burden of NTDs. The data clearly shows that the current trajectory will fall short of the 2030 targets. Closing these gaps requires a deliberate and coordinated effort from the research community, including drug development scientists. Critical research priorities include:

• Integrating Cross-Cutting Assessments into Clinical Trials: Researchers should systematically collect data on patient WASH access, socioeconomic status, and gender-related barriers during trial recruitment and follow-up. This data can predict real-world intervention uptake and effectiveness.
• Developing Gender-Responsive Diagnostic Tools: Investment is needed in diagnostics that are not only technically accurate but also acceptable and accessible across gender groups, considering factors like specimen type (e.g., alternatives to sputum for women) and the need for female healthcare providers [92].
• Health Economic Research on CHE: Studies must move beyond measuring CHE to evaluating the cost-effectiveness of specific financial risk protection mechanisms (e.g., insurance schemes, voucher programs) for NTD care within different health system contexts.
• Leveraging Implementation Science: Research should focus on how to effectively integrate WASH promotion and NTD drug distribution, and how to mainstream the collection of sex-disaggregated data into national health management information systems.

By embedding these cross-cutting considerations into the core of NTD research and development, the scientific community can help ensure that technological advances in drugs, diagnostics, and vaccines translate into equitable and sustainable progress for the billions of people still affected by these diseases.

Conclusion

The fight against NTDs is at a pivotal juncture. While concerted global efforts have yielded significant progress—evidenced by a declining disease burden and successful eliminations in dozens of countries—profound challenges remain. The path to the 2030 road map targets depends on overcoming a precarious funding landscape, with official development assistance having decreased by 41%. Future success hinges on embracing sustainable R&D models, such as not-for-profit pharmaceutical development and robust PDPs, to address historical market failures. For researchers and drug developers, this translates to a critical need for continued innovation in multi-target agents, drug repurposing, and advanced discovery technologies. Ultimately, achieving elimination goals will require an intensified, multi-sectoral commitment that integrates scientific advancement, strengthened health systems, and cross-cutting approaches like WASH to create a definitive, lasting impact on global health equity.

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