A New Era in Tuberculosis Prevention and Treatment: Breakthroughs in Drug Development and Future Prospects

Abstract

Tuberculosis (TB) remains a significant global public health challenge, despite recent advances in drug development. However, a comprehensive and systematic overview of the current clinical trial landscape in TB prevention and treatment is still lacking. This study aims to systematically review recent breakthroughs in TB drug development, assess their scientific value and global impact, and provide valuable insights for clinicians and policymakers involved in TB control efforts. We systematically searched the INFORMA pharmaceutical database to identify 1041 clinical trial projects related to TB. Two independent researchers screened and extracted the data, and discrepancies were resolved through consultation with a third researcher. Inclusion criteria were: (1) trials explicitly focused on TB drug development, (2) studies containing detailed descriptions of drug mechanisms or therapeutic targets, and (3) interventional studies. Exclusion criteria were the absence of key information, incomplete datasets, or non-interventional study designs. Descriptive statistical analyses were employed to systematically summarize trial characteristics, and data distribution features were visualized accordingly. Between 1990 and 2025, the number of TB-related clinical trials increased significantly, with a notable peak observed between 2018 and 2023. China and South Africa emerged as leading contributors to research activity, while the United States and the United Kingdom accounted for the majority of “Completed” trials. Despite the emergence of novel agents, traditional cornerstone drugs continued to dominate the development pipeline. Bedaquiline, in particular, demonstrated rapid, largely driven by supportive health policies. Academic institutions were the primary funding of TB trials, and regional analysis revealed heightened research activity in Asia and Africa. However, the global distribution of research resources remained uneven, highlighting the need for improved collaboration mechanisms to promote both health equity and innovation. This study systematically offers a comprehensive review of recent breakthroughs in TB drug development, revealing the current status and persistent challenges facing global clinical trials. Realizing the goal of ending TB will require sustained investment in scientific innovation, equitable resource allocation, and steadfast political commitment. Through coordinated global efforts, a new era in TB prevention and treatment is within reach.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-025-01221-3.

Key Summary Points

Why carry out this study?

Tuberculosis (TB) remains a critical global health threat. There is a rise in drug-resistant cases, such as multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), and persistent gaps in treatment efficacy and access.

Despite advances in novel drugs like bedaquiline and delamanid, there has been no review analyzing the global clinical trial landscape for TB prevention and treatment.

This study aimed to systematically evaluate 1041 clinical trials of TB from 1990 to 2025 to identify breakthroughs, recognize resource disparities, and assess the scientific and global impacts of new therapies.

What was learned from the study?

China (with 224 trials) and South Africa (with 216 trials) lead in the volume of trials. However, the United States and the United Kingdom dominate in completed studies. Traditional drugs like isoniazid and rifampicin remain widely used, while the number of trials on bedaquiline surged (78 trials) due to policy support.

Most trials were funded by academic institutions, with limited industry involvement. Vulnerable groups such as children and women are underrepresented. Policy shifts of the World Health Organization (WHO), for example, the 2018 guidelines for MDR-TB, have accelerated drug development.

Global resource allocation is uneven. Thus, enhanced collaboration, equitable financing, and inclusive trial designs are necessary to end TB.

Introduction

Tuberculosis (TB), an ancient infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a significant global public health challenge [1, 2]. According to the latest World Health Organization (WHO) data, 10.8 million new TB cases were reported globally in 2023, including 8.2 million newly diagnosed cases, the highest since 1995 [3]. Despite the widespread implementation of the 'directly observed treatment, short-course' (DOTS) strategy, which has achieved substantial success over the past two decades [4], the global TB control landscape remains complex. Key challenges include the rise of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), high rates of HIV co-infections, diagnostic imitations, and the prolonged duration of treatment. These obstacles have severely hindered the realization of WHO's strategic goal of “Ending the TB Epidemic” [5–10]. Since their introduction in the mid-20th century, traditional first-line anti-TB drugs (e.g., isoniazid, rifampicin) have established the cornerstone of TB chemotherapy. However, their long treatment durations (at least 6 months for drug-sensitive TB and up to 18–24 months for drug-resistant TB), notable toxicity, and the increasing rates of drug resistance have exposed critical limitations in the current drug development paradigm. For nearly half a century, innovation in TB therapeutics stalled, a period referred to as the “desert era”, leaving clinicians with outdated tools in the face of evolving drug resistance threats. In contrast, the second decade of the 21st century has witnessed a significant paradigm shift in anti-TB drug development, marking the dawn of a promising new era. This breakthrough has been driven by enhanced understanding of Mtb biology, advances in high-throughput screening technologies, strengthened public–private partnerships, and the creation of expedited regulatory pathways. A key milestone was the approval of bedaquiline, the first anti-TB drug with a novel mechanism of action (targeting mycobacterial ATP synthase) in nearly four decades. Approved by the Food and Drug Administration (FDA) in 2012 and subsequently endorsed by strong WHO guidelines signaled renewed momentum in TB drug innovation [11]. Subsequently, delamanid, another novel agent in the nitroimidazole class, expanded therapeutic options. The combination of pretomanid (PA-824), bedaquiline, and linezolid (BPaL regimen) demonstrated cure rates of up to 90% for XDR-TB and patients with complex MDR-TB in pivotal studies, such as Nix-TB and ZeNix, while shortening treatment duration to just 6 months [12–15]. Drug repurposing has also yielded substantial progress: linezolid, when optimized for dosing and toxicity management, has shown strong potential against drug-resistant TB [16–18]; next-generation fluoroquinolones such as moxifloxacin have become integral components of intensified regimens due to their superior anti-mycobacterial activity and improved safety profile [19, 20]. These innovations, both in new drugs and optimized combination regimens, have significantly improved treatment efficacy and patient adherence, while reducing the risk of resistance development and transmission due to treatment failure.

The current TB drug development pipeline is advancing with unprecedented breadth and depth, offering renewed hope for global TB control. However, despite these advances, no study to date has systematically organized the clinical trial landscape for TB prevention and treatment. Therefore, this study aims to systematically analyze the progress of global TB clinical trials from 1990 to 2025, with a particular focus on the application of novel drugs (such as bedaquiline) and their impact on the treatment of MDR-TB/ XDR-TB. Through a comprehensive analysis of clinical trial data, we aim to uncover the disparities in global resource allocation and propose optimization strategies to enhance international collaboration in TB prevention and treatment. Furthermore, this study explores the influence of policy adjustments on TB drug development, providing a scientific basis for the design and implementation of future clinical trials.

Methods

Data Screening and Extraction

This study conducted a comprehensive analysis of clinical trial activity related to TB using the INFORMA pharmaceutical database (https://pharma.id.informa.com/). The search was performed using the keyword: “Tuberculosis (TB)”. Two independent researchers screened and extracted data and any disagreements were resolved by consultation with a third researcher. A total of 1041 eligible clinical trial projects were identified, and relevant information was systematically extracted. Clinical trials were analyzed across multiple dimensions, including annual initiation trends, geographic distribution, sponsor types, drug types, mechanisms of action, and trial phases and statuses. Strict inclusion and exclusion criteria were applied. Inclusion criteria were: (1) trials explicitly focused on the development or application of anti-TB drugs; (2) trials providing a clear description of drug mechanisms or therapeutic target; (3) interventional study designs. Exclusion criteria included: (1) lack of key information (e.g., unspecified drug targets or mechanisms); (2) incomplete datasets; (3) non-interventional study designs (e.g., observational studies or patient registries). For trials with missing or ambiguous information on drug targets, additional verification was performed using relevant literature or external databases. If the target could not be reliably identified, the trial was excluded from final analysis. The final results of the included trials are presented in Supplementary File 1. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Statistical Analysis

Descriptive statistical methods were employed to systematically summarize and interpret the characteristics of the included trials. Data distribution features were visualized using box plots, histograms, and other graphical tools. Outliers were identified and handled to ensure robustness of the dataset. Categorical variables were presented as frequencies (counts) and percentages. Cross-tabulations were constructed to explore associations between categorical variables and to identify potential patterns in the trial landscape.

Results

Overview of Tuberculosis Clinical Trials

Figure 1A illustrates the temporal trends in TB clinical trials by phase from 1990 to 2025. A significant increase in early phase trials (phase I and phase II) occurred after 2000, peaking between 2018 and 2023. Phase IV trials experienced substantial growth after 2017. Transitional trial phases (I/II and II/III) remained comparatively underrepresented (Fig. 1B). As shown in Fig. 1C, trial activity was unevenly distributed globally. China (224 trials) and South Africa (216 trials) led in trial volume, reflecting their research intensity. China and India had a higher proportion of “Planned” trials, while the United States and the United Kingdom reported predominantly “Completed” trials. Uganda and Tanzania exhibited a disproportionate number of “Terminated” trials. Although “Completed” trials represented the majority globally, the notable number of “Terminated” (113) and “Closed” (67) trials points to inefficiencies in resource allocation (Fig. 1D). Figure 1E shows that traditional drugs such as isoniazid and rifampicin still dominate the pipeline, while bedaquiline has experienced rapid growth, reaching ethambutol in frequency, despite the latter’s half-century history of use. Academic institutions were the primary trial sponsors (499 trials), followed by governments (164 trials) and other pharmaceutical companies (161 trials). Major pharmaceutical corporations sponsored only 52 trials, likely due to a preference for high-return areas. Non-profit entities (47) and collaborative organizations (87) contributed significantly to filling research gaps, highlighting the importance of public-interest research (Fig. 1F). Regional analysis (Fig. 1G) showed the highest trial activity in Asia (478 trials) and Africa (311 trials), likely driven by disease burden and growing research capacity. The Americas (200 trials) and Europe (182 trials) followed, with North America (146 trials) and Western Europe (125 trials) leading. South America (68 trials) and Eastern Europe (61 trials) trailed behind. Research investment in the Caribbean/Central America (23 trials), West Asia/Middle East (17 trials), and Australia/Oceania (14 trials) remained lower, indicating insufficient regional capacity and policy engagement (Fig. 1G).

Fig. 1.

Overview of clinical trials for tuberculosis. A Annual distribution of clinical trials for tuberculosis. B Trial phase of different trial types. C Distribution of the top 20 countries conducting clinical trials for tuberculosis. D Trial status of different trial types. E Distribution of the top ten drugs of tuberculosis. F Distribution of the top ten funding organizations of tuberculosis. G Distribution of the top ten regions of tuberculosis

Mechanisms and Trends in Global Tuberculosis Clinical Trials

Table 1 systematically summarizes the primary mechanisms of action of anti-TB drugs and their respective corresponding numbers of clinical trials, providing insight into the evolving dynamics and strategic directions in TB treatment. Isoniazid (182 trials) and rifampicin (132 trials), as traditional drugs, significantly lead in development quantity, reflecting their foundational role in TB therapy and the continued clinical demand for their widespread application. Notably, the newer drugs bedaquiline (78 trials) and delamanid (42 trials), which act via inhibition of ATP synthase and cell wall synthesis, respectively, have shown marked growth in development activity. The trend is closely related to the global rise of MDR-TB and the corresponding intensification of international control efforts, as well as the role of pharmaceutical innovation in addressing drug resistance challenges. By contrast, other areas such as natural products (29 trials) and the BCG vaccine (28 trials) have seen fewer trials.

Table 1.

Distribution and trends of mechanisms of action in the tuberculosis drug development pipeline

Primary tested drug	Mechanism of action	Number
Isoniazid	Unidentified pharmacological activity	182
Rifampicin	RNA synthesis inhibitor	132
Tebrazid	Unidentified pharmacological activity	111
Myambutol	Unidentified pharmacological activity	79
Bedaquiline	Adenosinetriphosphate synthase inhibitor	78
Rifapentine	RNA polymerase inhibitor	67
	DNA-directed RNA polymerase inhibitor
Linezolid	Protein 50S ribosomal subunit inhibitor	56
	Protein synthesis inhibitor
Moxifloxacin	DNA topoisomerase II inhibitor	48
	DNA topoisomerase IV inhibitor
Delamanid	Cell wall synthesis inhibitor	42
Clofazimine	DNA inhibitor	41
Levofloxacin	DNA topoisomerase II inhibitor	40
	DNA topoisomerase IV inhibitor
Pretomanid	Adenosinetriphosphate synthase inhibitor	39
	Protein synthesis inhibitor
	Protein 23S ribosomal subunit inhibitor
	Cell wall synthesis inhibitor
Natural product	/	29
BCG vaccine, unspecified	Immunostimulant	28
Anti-tuberculosis treatment	Unidentified pharmacological activity	23
Vitamin B6	Unidentified pharmacological activity	23
Rifabutin	DNA-directed RNA polymerase inhibitor	22
Tuberculosis vaccine (ID), Emergent	Immunostimulant	22
Rifampicin/isoniazid/pyrazinamide/ethambutol	RNA synthesis inhibitor	19
	Cell wall synthesis inhibitor
Danish-SSI 1331 BCG vaccine	Immunostimulant	16

From a trend perspective, while traditional drugs still dominant development efforts, the emergence of novel compounds and immunomodulators points to a transition from a monotherapeutic to a more diversified therapeutic strategy. This shift is propelled not only by scientific advancements but also by public health priorities, policy reforms, resource distribution, and market forces. For instance, the relatively high number of trials involving RNA synthesis inhibitors (e.g., rifampicin, rifapentine) and protein synthesis inhibitors (e.g., linezolid) suggests sustained interest in targeting core bacterial metabolic pathways. In contrast, the lagging development of DNA synthesis inhibitors (e.g., clofazimine) and immunomodulators (e.g., BCG vaccine) suggests areas where greater investment is warranted to meet the multifaceted challenges of TB prevention and treatment.

In summary, the pharmacological diversity and innovation-driven development in the anti-TB drugs provide critical guidance for optimizing global control strategies. Future research should focus on the synergistic effects of novel drugs and immunotherapies, while strengthening resource integration and policy support to address key issues such as drug resistance and insufficient vaccine efficacy.

Trends in the Development of Three Novel Anti-tuberculosis Drugs: Dual Impact of Innovation-Driven and Policy Incentives

Figure 2 illustrates the development trends of bedaquiline, delamanid, and pretomanid since 2005. During the early stage (2005–2012), trail activity was relatively sparse, potentially due to insufficient investment in foundational research. After 2013, the development of bedaquiline and delamanid accelerated significantly, reflecting the influence of global TB policy shifts (e.g., WHO guidelines updates) and rising market demand. Notably, 2023 marked a peak in trial activity for both bedaquiline (14 trials) and delamanid (nine trials), possibly in response to the emergence of new drug-resistant TB strains. In contrast, the development of pretomanid has remained relatively stable, suggesting that its full therapeutic potential is not yet realized. Overall, these data reveal the dual driving forces of scientific innovation and policy intervention in shaping anti-TB drug development, providing critical insights into future directions for clinical research and resource allocation.

Fig. 2.

Research trends of bedaquiline, delamanid, and pretomanid (2005–2025)

Country and Institutional Distribution of Trials Related to Three Novel Anti-tuberculosis Drugs

An analysis of global development activity for bedaquiline, delamanid, and pretomanid reveals a significant increase in clinical trials, particularly after 2015. This trend is closely associated with enhanced international TB prevention and control policies and expanded funding initiatives.

Development of bedaquiline is concentrated in countries such as South Africa, China, and India, while delamanid and pretomanid exhibit higher activity in South Africa, Peru, and the United States (Fig. 3A–C). Notably, there has been a steady rise in participation by academic institutions, governments, and non-profit organizations, reflecting the growing significance of multi-stakeholder collaboration models in driving drug innovation (Fig. 3D–F). Furthermore, despite the disruptions caused by the global pandemic after 2020, research activities have maintained robust growth. A significant increase in clinical trials for bedaquiline and pretomanid during this period highlights the pressing need for new therapeutic options against drug-resistant TB.

Fig. 3.

Countries and funding agencies involved in the development of three novel anti-tuberculosis drugs. A Distribution of the top five countries conducting clinical trials for bedaquiline; B distribution of the top five countries conducting clinical trials for delamanid; C distribution of the top five countries conducting clinical trials for pretomanid; D distribution of the top five funding institutions supporting clinical trials for bedaquiline; E distribution of the top five funding institutions supporting clinical trials for delamanid; F distribution of the top five funding institutions supporting clinical trials for pretomanid

Phases and Completion Status of Trials Related to Three Novel Anti-tuberculosis Drugs

This study provides a detailed analysis of the clinical development dynamics of bedaquiline, delamanid, and pretomanid from 2005 to 2025, with a focus on trial phases (I to IV) and statuses (e.g., Closed to Terminated). The findings reveal core trends: clinical trial activity for all three drugs accelerated significantly after 2020, with phase II trials constituting the majority.

Bedaquiline has been actively investigated in phase II trials since 2009, reaching a peak of 7 phase II trials in 2023, indicating accelerated development likely driven by the global urgency for novel anti-TB drugs. Similarly, delamanid also experienced rapid growth in 2023, reaching seven phase II trials (Fig. 4A–C). Notably, delamanid recorded a sharp increase in completed trials, with the number of Completed trials reaching 16 by 2025, reflecting its efficiency in clinical translation.

Fig. 4.

Temporal evolution of clinical trial phases and progress for three novel anti-tuberculosis drugs. A Phases of clinical trials for bedaquiline; B phases of clinical trials for delamanid; C phases of clinical trials for pretomanid; D Progress of clinical trials for bedaquiline; E PROGRESS of clinical trials for delamanid; F Progress of clinical trials for pretomanid

In contrast, pretomanid has demonstrated a more stable development pattern. However, the number of Open status trials reached 3 in 2023, demonstrating sustained research interest and suggesting its potential as a key candidate in combination therapies (Fig. 4D–F).

Analysis of Participant Demographics in Trials Related to Three Novel Anti-tuberculosis Drugs

This study also examines the participant demographics of clinical trials involving bedaquiline, delamanid, and pretomanid over the 2005 to 2025 period, revealing notable disparities in gender and age representation. Cross-gender (both sexes) studies have continued to dominate. For instance, bedaquiline had 13 trials in 2023 enrolling both male and female participants (Fig. 5A–C). In contrast, gender-specific trials, particularly those focused on female participants, remain scarce, with no more than one female-specific trial per year across all three drugs. Age-related analysis shows a pronounced emphasis on adult populations. For example, delamanid reported nine adult-only trials in 2023, accounting for 56% of its total trials that year (Fig. 5D–F). However, the inclusion of women, children, and the elderly in clinical trials for these three drugs remains limited, underscoring the need for more inclusive research designs to address vulnerable and underrepresented populations.

Fig. 5.

Gender and age group distribution in clinical trials of three novel anti-tuberculosis drugs. A Gender distribution in clinical trials for bedaquiline; B gender distribution in clinical trials for delamanid; C gender distribution in clinical trials for pretomanid; D age distribution in clinical trials for bedaquiline; E age distribution in clinical trials for delamanid; F age distribution in clinical trials for pretomanid

Discussion

In recent years, the WHO’s strategic initiative to “Ending Tuberculosis” has significantly accelerated the global expansion of TB-related clinical trials, particularly in cutting-edge areas such as the development of novel anti-TB drugs, optimization of short-course therapies, and the advancement of new vaccines. However, despite the notable increase in related studies, current clinical trials continue to face several critical challenges, including the lack of reviews, fragmented research designs, and insufficient generalizability of findings. In light of these issues and the current research landscape, this study aims to systematically integrate and analyze the latest developments in global TB clinical trials. It provides a comprehensive evaluation of key trial characteristics, including countries, funding agencies, development trends, demographic representation by gender and age. By critically reviewing the progress and limitations of existing research, this study seeks to lay a solid scientific foundation for further optimizing TB prevention and treatment strategies. Furthermore, it aims to promote the transition of TB treatment to a precision medicine model, and offering both theoretical insights and practical guidance for achieving global TB control goals.

An overarching analysis of trial distributions and mechanisms reveals the complexity interplay of scientific, political, and strategic drivers shaping this field. The marked peak in trial activity between 2018 and 2023 closely aligns with the political impetus generated by the first United Nations High-Level Meeting (UNHLM) on TB in 2018. This milestone event established ambitious global prevention and treatment goals, directly catalyzing an influx of research investment worldwide [21, 22]. One striking trend is the surge in phase IV trials after 2017, reflecting an urgent global demand to assess the real-world effectiveness and safety of marketed drugs, particularly bedaquiline. This trend also signifies a broader shift in global TB strategies, away from an exclusive focus on new drugs discovery and toward the optimization of existing therapies, expanding of drug accessibility, and improvement in treatment management.

The “explosive growth” in bedaquiline-related trails (78 trials, comparable to ethambutol, a drug used for over half a century) exemplifies this transition. At a deeper level, this growth reflects a paradigmatic shift in global TB control policies. For instance, the WHO’s 2019 updated guidelines for drug-resistant TB and the End TB Strategy spurred investment in new drugs targeting resistant strains [23]. The rapid approval of bedaquiline and its swift inclusion in WHO treatment guidelines exemplify how urgent public health needs, driven by policy, can effectively steer research resources toward high-priority clinical challenges [24–26]. However, the persistent dominance of traditional cornerstone drugs such as isoniazid (182 trials) and rifampicin (132 trials) in the trial landscape underscores the ongoing relevance of established regimens. Their prominence reflects not only the stability and reliability of these agents but also the continuous need to enhance them, through strategies such as treatment shortening and side-effect reduction, to meet evolving clinical and public health demands.

From a geographical perspective, China and South Africa lead in the number of TB clinical trials, a reflection of their high disease burden, enhanced research capabilities, and supportive policy environments. China’s relatively high number of “Planned” trials signals continued investment and expansion in TB research, aligning with recent governmental policy shifts toward increased public health funding. In contrast, the United States and the United Kingdom are dominated characterized by a higher proportion of “Completed” trials, showcasing the maturity, efficiency, and resource integration capacity of their clinical research systems. The sustained prominence of bedaquiline in South Africa (seven trials in 2023), and its explosive growth in China (five trials) and India (two trials) in the same year, reflects the synergistic impact of WHO’s high-burden country strategy and localized innovation policies, such as China’s “Major New Drug Innovation” initiative. As core contributors to global TB research, the policy frameworks in China and South Africa play a decisive role in shaping the scale, efficiency, and innovation direction of clinical activities. China, through its “Healthy China 2030” strategy, promotes intersectoral integration, incorporates TB prevention and treatment into the national medical insurance system, and promotes the “TB-Free Community” model, efforts that collectively reduce patient financial burden and enhance diagnostic accessibility at the community level [27]. Further reinforcing this momentum, the National Health Commission, in partnership with agencies such as the National Development and Reform Commission, Ministry of Education, Ministry of Science and Technology, Ministry of Civil Affairs, Ministry of Finance, State Council Poverty Alleviation Office, and National Medical Security Administration, issued the “Action Plan to Stop TB (2019–2022)”. This top-level policy design is mirrored in China’s leading number of “Planned” trials, emphasizing forward-looking strategic planning. In parallel, AI-assisted diagnosis and tongue swab technologies have been deployed to enhance patient screening and improve trial enrollment efficiency [28–30]. In South Africa, TB control is integrated into the National Health Insurance (NHI) framework, with Clinical Practice Guidelines (CPGs) serving as a key mechanism for coordinating cross-sector and multi-level medical resources. The Ministry of Health-led CPGs prioritize high-burden infectious diseases, including TB, HIV/AIDS, and malaria), by promoting standardized, evidence-based treatment pathways. Meanwhile, other developers such as professional societies and clinical collaboration groups predominantly focus on non-communicable diseases, highlighting the strategic prioritization of TB within the national health agenda. These efforts aim to establish a unified and efficient coordination mechanism for the NHI implementation and universal healthcare system [31]. Moving forward, the “policy-technology-guarantee” triad model exemplified by China and South Africa should be transplanted to other high-burden regions. Such translation of best practices could help narrow global disparities in TB research efficiency, enabling more precise alignment between resource allocation and public health priorities.

The distribution of funding entities in TB clinical trials further reveals underlying financial flows and their driving factors. Academic institutions remain the predominant funders, underscoring the critical role of basic research in the development of TB therapeutics. However, the relatively limited involvement of major pharmaceutical companies suggests a focus on more lucrative therapeutic areas, suggesting the need to strengthen public–private partnerships to attract more industrial investment in TB research. The active participation of non-profit entities and collaborative organizations helps to bridge funding gaps, highlighting the importance of public-interest research in addressing global public health challenges. Notably, major global health actors such as the Global Fund and the Bill & Melinda Gates Foundation play a critical support in supporting innovation in TB drug, offering financial and strategic backing for high-impact initiatives [32, 33].

The demographic distribution of participants in clinical trials for novel anti-TB drugs serves as a critical lens through which to examine the evolution of global public health policies, shifting priorities in drug-resistant TB control, and advances in research ethics. Bedaquiline, delamanid, and pretomanid, as core drugs in drug-resistant TB treatment, exhibit imbalances in both gender and age representation across clinical trials, revealing structural tensions between research strategies and real-world population needs. Trial design data indicate a strong bias toward “all-population applicable” (Both category) with bedaquiline reporting 68 trials compared to only three gender-specific trials, delamanid 40 vs. 1; pretomanid 34 vs. 3. Gender-specific trials were largely absent before 2019 and only began to emerge sporadically thereafter. A turning point came with the 2018 WHO guideline update on multidrug-resistant TB, which explicitly called for the inclusion of special populations, such as individuals co-infected with HIV, children, and women of childbearing age [34]. This policy directive catalyzed a modest but important increase in gender-specific trials after 2021, including bedaquiline’s first female-specific trial. The influence of policy levers is further validated in the age distribution of trial participants. Before 2013, clinical trials were nearly absent, only 1 trial across all three drugs included children. This landscape began to shift following the launch of United Nations Children’s Fund (UNICEF) 2013 “Roadmap for Childhood TB: Toward Zero Deaths”, and particularly after the implementation of the 2018 “Roadmap towards ending TB in children and adolescents”. This initiative, coupled with Global Fund–targeted financing and administrative measures such as accelerated regulatory pathways for pediatric formulations, have systematically reduced research barriers and promoted a steady rise in pediatric trials [35]. Interestingly, trial coverage of the elderly population (≥ 65 years) shows drug-specific patterns. Bedaquiline showed elderly representation in 29% of its trials (34 out of 117), significantly higher than pretomanid’s 18% (18 out of 59). This discrepancy is closely related to bedaquiline’s known cardiotoxicity, particularly its QT interval, prolonging effect, which poses heightened risks is particularly prominent in elderly populations with cardiovascular diseases [36–38]. As a result, regulatory authorities have increasingly required pharmaceutical companies to supplement safety data in this demographic, reflecting a “risk-driven” allocation logic in clinical research planning.

In summary, the gender and age distribution of participants in trials of novel anti-TB drugs not only reflect clinical practices but also serve as barometers of policy effectiveness, research direction, and promotion barriers. Although WHO guidelines have significantly accelerated the adoption of new drugs, the legacy of gender underrepresentation persists, and pediatric drug data remain insufficient. At the same time, the rising inclusion of elderly patients underscores growing awareness of the complex safety considerations in this vulnerable group. The abnormal peaks in the data provide important signals for tracking emerging research priorities and evaluating the effects of global health interventions. In the future, efforts should focus on building an evidence-based drug for inclusive drug use that comprehensively addresses women, children, and elderly populations, and on advancing precision medicine approaches for complex elderly cases. Such strategies are essential to ensuring the equitable, safe, and efficient clinical application of next-generation anti-TB drugs.

Although this study has conducted an in-depth analysis of the field of tuberculosis clinical trials, there are still certain limitations. Firstly, the data mainly rely on a single database (INFORMA), which may lead to the omission of trials on unregistered or regional platforms, resulting in an underestimation of the research activity in low- and and middle-income countries. Secondly, the included trials have high heterogeneity (e.g., phase I and phase IV trials co-exist), and the statistical methods are limited to descriptive analysis, failing to deeply quantify the impact of confounding factors such as policy intensity and funding scale on the trial results. Moreover, the study has not fully explored the translation efficiency between clinical trial results and actual public health practices, especially the accessibility and affordability in resource-limited areas. To address these limitations, future research should integrate data from multiple databases and regional platforms, use stratified analysis and advanced statistical methods to quantify the impact of confounding factors, and strengthen the evaluation of the translation efficiency of clinical trial results, particularly for practical applications in resource-limited areas.

Conclusions

The analysis of TB-related clinical trial data presented in this study provides valuable insights into the evolving global landscape of TB research. Despite substantial progress having been made, persistent gaps in geographical representation, funding, and population inclusivity highlight the need for a more equitable and comprehensive approach to anti-TB drug development. Bridging these gaps will require sustained investment, enhanced multisectoral collaboration, and a strong commitment to translating research findings into measurable public health outcomes. As the global community advances toward the goal of TB elimination, the lessons derived from current clinical trial practices will play a pivotal role in shaping future strategies, ensuring that no population is overlooked and that innovations are deployed where they are needed most.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Chun-Yan Zhao: Formal analysis; resources; writing—original draft. Chang Song: Conceptualization; validation; writing—original draft. Yi-Bo Lu: Supervision; validation. Ai- Chun Huang: Methodology; software. Chun-Mei Zeng: Formal analysis; methodology. Ren-Hao Liu: Validation; writing—review & editing. Wei-Wen Li: Conceptualization; methodology; software; supervision. Zhou-Hua Xie and Qing Dong Zhu: Funding acquisition; project administration; validation; writing—review & editing.

Funding

The Guangxi Zhuang Autonomous Region Health Commission Self-Financed Scientific Research Project (Z-A20231211) and Guangxi Key Research and Development Projects (Guike AB25069097) funded this study and covered all costs associated with the development and publication of this manuscript, including the journal’s Rapid Service Fee.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of Interest

The authors (Chun-Yan Zhao, Chang Song, Yi-Bo Lu, Ai- Chun Huang, Chun-Mei Zeng, Ren-Hao Liu, Wei-Wen Li, Zhou-Hua Xie, Qing-Dong Zhu) have no conflicts of interest to declare.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.