Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda.
BACKGROUND
New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.


METHODS
Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.


RESULTS
Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.


CONCLUSIONS
Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.
Staedke
Sarah G
SG
London School of Hygiene & Tropical Medicine, London, UK. sarah.staedke@lshtm.ac.uk
Jagannathan
Prasanna
P
Yeka
Adoke
A
Bukirwa
Hasifa
H
Banek
Kristin
K
Maiteki-Sebuguzi
Catherine
C
Clark
Tamara D
TD
Nzarubara
Bridget
B
Njama-Meya
Denise
D
Mpimbaza
Arthur
A
Rosenthal
Philip J
PJ
Kamya
Moses R
MR
Wabwire-Mangen
Fred
F
Dorsey
Grant
G
Talisuna
Ambrose O
AO
D016907:Adverse Drug Reaction Reporting Systems / Q000592:standards* / Q000706:statistics & numerical data*; D000962:Antimalarials / Q000009:adverse effects* / Q000627:therapeutic use; D037621:Artemisinins / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D016896:Treatment Outcome; D014454:Uganda
D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin