Methodological quality of the review: Low confidence
Author: Kappagoda S, Ioannidis JP
Geographical coverage: Africa and South East Asia
Sector: Neglected tropical diseases
Equity focus: None specified
Review type: Effectiveness review
Quantitative synthesis method: Systematic review and network analysis
Qualitative synthesis method: Not applicable
Neglected tropical diseases (NTDs) comprise parasitic, viral and bacterial infections that cause substantial morbidity among the world’s poorest people, but have historically not been targeted for intensive drug development because of limited financial incentives in the private sector. These diseases are both a cause and effect of poverty. Although there are affordable and effective treatments for some NTDs, many require treatments that are expensive, toxic and difficult to administer – while some treatments are under threat from emerging drug resistance.
To assess the quantity and distribution of evidence from randomised controlled trials (RCTs) for the treatment of the major NTDs and to identify gaps in the evidence with network analysis.
In total, authors included 971 RCTs in the review. The most common study sites were Africa (27.6%) and South East Asia (26.9%). Only 26 (2.7%) of the trials were multi-centre.
Some diseases were much less studied than others. Direct inverse correlation between the amount of evidence and the need for a new drug development was not available.
Leishmaniasis (184 trials, 23,039 participants) and geohelminth infections (160 trials, 46,887 participants) were the most studied, while dracunculiasis (nine trials, 798 participants) and buruli ulcer (five trials, 337 participants) were the least studied. Relative to its global burden of disease, lymphatic filariasis had the fewest trials and participants. Only 11% of trials were industry funded.
Either a single trial or trials with fewer than 100 participants comprised the randomised evidence for first or second-line treatments for buruli ulcer, human African trypanosomiasis, American trypanosomiasis, cysticercosis, rabies, echinococcosis, New World cutaneous leishmaniasis and each of the foodborne trematode infections. Among the ten disease categories with more than 40 trials, five lacked sufficient head-to-head comparisons between first or second-line treatments.
Authors concluded that there is considerable variation in the amount of evidence from RCTs for each of the 16 major NTDs. Even in diseases with substantial evidence, such as leishmaniasis and geohelminth infections, some recommended treatments have limited supporting data and lack head-to-head comparisons. For several NTDs, evidence for at least one first or second-line treatment was scarce and head-to-head comparisons were uncommon.
Authors searched PUBMED and Cochrane Central Register of Controlled Trials for RCTs published up to 31st August 2011 that examined the treatment of 16 NTDs: American trypanosomiasis (chagas), buruli ulcer, cysticercosis, dengue fever, dracunculiasis (Guinea worm), echinococcosis (hydatid cyst disease), foodborne trematode infections, geohelminth infections, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies (prophylaxis after exposure), schistosomiasis and trachoma.
Authors did not report if the screening of studies and data extraction were conducted by two reviewers independently. In addition, authors did not report assessing the risk of bias of included studies.
Authors described the statistics for eligible trials and showed the cumulative sample size and number of trials over time. To provide an estimate of how the evidence from RCTs has changed over time for different diseases, authors divided the trials into those published before 2000 (n=609) and those published in 2000-12 (n=362). Authors chose 2000 as a watershed date as several initiatives to promote drug development for the NTDs were started after 2000. For each disease, authors separated trials targeting the primary infection from trials examining disease complications.
Authors note in the review that reasons that could explain the lack of randomised evidence for some recommended treatments might be due to a location being an endemic area – for example, the schistosomiasis drug oxamniquine is mainly used and available in Brazil. Oxamniquine is effective only against S mansoni, which limits its utility in areas of Africa where more than one species of Schistosoma co-occur.
Authors also noted that the relative lack of evidence from RCTs for certain diseases might also reflect the geographical distribution of the disease and whether there is capacity for clinical trial research in endemic sites, for example through links with institutions in developed countries. In addition, authors excluded unpublished studies which could underestimate the amount of evidence available and also affect treatment effects.
The authors did not restrict the search to a specific income setting. However, studies included were from Africa and South East Asia.
Summary of quality assessment:
Overall, there is low confidence in the conclusions about the effects of this study. Authors used a narrative approach to synthesise evidence, which seemed appropriate due to the diversity of included studies. Authors acknowledged the exclusion of unpublished trials which may underestimate the amount of randomised evidence, and notes the existence of publication bias within the review. Authors noted both the limitations of included studies and that findings of the review should be interpreted with caution.
This review has important limitations. Authors did not conduct a thorough search of the literature to ensure that all relevant studies were not omitted, and did not avoid language and publication bias. It’s not clear if authors used appropriate methods to screen studies for inclusion and extract data of included studies, avoiding bias. In addition, authors did not appraise included studies, therefore it’s not clear which evidence is subject to high or low risk of bias.