**4. Regulatory health authority perspectives**

While the epicenter of the burden of Chagas disease continues to be Latin America, migration and other factors have made the disease a global health concern. As such an international regulatory approach to drug approval is required. Early engagement with regulatory authorities in endemic regions of Central and South America is essential when designing a development program to address Chagas disease. Indeed, there is a compelling case for a single pan-Latin American approach to the evaluation and approval to accelerate patient access to new anti-*T. cruz*i therapeutics.

Outside Latin America, the US FDA has played an important role in stimulating research and development for neglected tropical diseases through several mechanisms, most notably the award of transferable priority review vouchers to eligible products and the use of expedited approval programs [79, 80]. While available in


#### **Table 5.**

*Considerations for clinical programs to support drug approval in chronic indeterminate Chagas disease.*

Latin America for decades, benznidazole and nifurtimox were only approved in the United States (for the treatment of children with Chagas disease) in 2017 and 2020, respectively. These drugs were assigned US FDA Orphan Drug status, and both were granted an accelerated approval based upon randomized clinical trials in children with primarily indeterminate disease using serology as the primary endpoint. Postapproval requirements (PMR) included phase IV studies to confirm activity and complete missing data gaps. As these drugs may serve as the SoC comparator in pivotal trials of a new therapy, review of the FDA assessment reports [72–74] provides useful insights into how a rigorous health authority viewed the challenges of developing a drug to treat Chagas disease.

Similar to the US FDA, the European Medicines Agency (EMA) can also grant Orphan Drug designation [81]. Furthermore, the EMA can support faster approval in certain non-European lower-income countries by providing a thorough scientific assessment and the facilitating WHO prequalification under their EU-4Mall (formerly called "Article 58") program [82]. Medicines reviewed under this provision benefit from scientific advice, EMA's PRIME (PRIority MEdicines) scheme [83], and accelerated review [84].

The authors did not find any regulatory assessment documents for indications of congenital and acute Chagas disease in the public domain. A summary of regulatory considerations linked with a clinical development program for an antitrypanosomal drug for use in chronic indeterminate Chagas disease is given in **Table 5**.
