**1. Introduction**

Chagas disease is a largely vector-borne infection caused by *Trypanosoma cruzi*, a kinetoplastid protozoan parasite endemic to Latin America. It affects an estimated 6–7 million people globally, is associated with 1.2 million cases of cardiomyopathy, and causes 10–14,000 deaths annually [1, 2]. While most infections are transmitted by triatomine insects, infection can be acquired through oral routes, congenital infection, and organ transplantation. For many decades, Chagas disease was mainly seen in rural populations of Central and South America, but in recent years the number of cases diagnosed in urban endemic areas and outside Latin America has increased due to economic, cultural, and migratory patterns [3, 4]. Consequently, a drug development plan for Chagas disease must consider the international regulatory perspectives and different national healthcare systems to enable faster patient access to diagnosis and treatment.

Beyond the direct clinical impact of the disease on patients, the substantial economic impact of Chagas disease on society has been estimated by Lee et al. [5]. The annual societal cost (i.e., healthcare costs plus productivity loss) of Chagas disease globally was projected at more than over 800,000 life years lost to disability (DALYs) with a

financial burden exceeding USD \$600 million. When projected future costs (including cardiomyopathy and heart failure) are taken into account, the economic burden of this disease reaches a staggering USD \$7.19 billion per year. In contrast, global R&D funding for Chagas disease was reported as only USD \$37.12 million in 2019 (representing less than 1% of R&D funding for neglected diseases in developing countries), of which 35% came from private industry [6].

Against this economic background, the substantial resources needed to develop and approve a novel drug should be noted. Novel drug development is complex and multidisciplinary with a predicted success rate to bring a new drug to approval of less than 12% [7]. Estimated fully capitalized costs range from USD \$800 million to USD \$2.2 billion per compound approved. Clinical trial phases of drug development account for the majority of these investments and further costs are incurred postapproval for activities such as patient registries, follow-on studies, and drug safety monitoring.

We will discuss the various strategic and operational challenges facing physicians, scientists, and clinical researchers designing drug development programs for new antitrypanosomal agents for Chagas disease. Highlighting these issues allows researchers to explore solutions that generate sound scientific evidence for costeffective and timely drug development programs.
