Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study

Abstract

Background: An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)compliant clinical trials. Methods: We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi. Results: Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low-and middle-income countries, specifically in sub-Saharan Africa. Conclusion: This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations.

Opportunities and Challenges in Developing a Cryptosporidium Controlled Human Infection Model for Testing Antiparasitic Agents

“…However, a recent controlled clinical trial to assess the safety and efficacy of clofazimine for the treatment of cryptosporidiosis in this population highlighted the significant challenges with this approach. 23 In addition to the operational complexity of conducting early phase clinical trials in resource-poor settings, 37 safety and efficacy evaluation in the HIV/AIDS cryptosporidiosis patient population is highly confounded by the severe immunocompromised state, presence of multiple diarrheal pathogens, other opportunistic coinfections, concurrent medications, failure of antiretroviral therapy, and high mortality. 38 As a potential alternative to investigating NCEs in HIV/AIDS cryptosporidiosis coinfected patients, a Cryptosporidium CHIM in adult healthy volunteers is considered herein as it offers a scientifically robust path to PoC for novel antiparasitic agents.…”

Defining clinical trial quality from the perspective of resource-limited settings: A qualitative study based on interviews with investigators, sponsors, and monitors conducting clinical trials in sub-Saharan Africa

“…These themes reflect aspects frequently discussed in the literature. However, existing literature addressed these aspects mainly from the perspective of ethics [ 24 , 25 ], ICH-GCP applicability [ 2 , 26 , 27 ], or lessons learned when implementing specific studies in specific regions in SSA [ 28 – 30 ]. In contrast, our study was transnational and strictly oriented towards associations with CT quality, which could but did not necessarily have to overlap with these perspectives.…”

Emerging treatment options for cryptosporidiosis

“…This phase 2a randomized, double-blind, placebo-controlled study had two parts: part A had primary outcomes of safety, pharmacokinetics, and reduction in Cryptosporidium oocyst shedding; part B was an open-labeled study comparing the pharmacokinetics of matched HIV-positive individuals without cryptosporidiosis (or diarrhea). The study faced many unexpected challenges with study initiation, population, implementation, and cultural issues [ 39 ▪▪ ], though the sponsors were able to find solutions to successfully reach the endpoint. The study found treatment with CFZ had no significant impact on Cryptosporidium oocyst shedding, diarrheal episodes, stool weight, or consistency scores.…”