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3 Identification and Evaluation of the Evidence Base
Pages 57-90

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From page 57...
... , is presented along with the types of studies identified and considered. How these methodologic considerations were applied to interpret the evidence is presented in the specific antimalarial drug chapters.
From page 58...
... Therefore, the committee preferentially uses persistent to describe those adverse events that began during the period of drug use and that continued after drug cessation and beyond the period that the drug would still be present, which is defined as ≥28 days post-cessation. Adverse events that occur or change in their severity with prolonged use of an antimalarial drug are considered to be acute events because they occur while the drug is in use; if they do not persist once the use of the drug has ceased, they are outside the committee's charge of examining the evidence related to persistent health effects.
From page 59...
... , the article was included in the results of the search. Search terms included full and abbreviated chemical names, common and manufacturer trade names, and the chemical abstracts service numbers for each of the antimalarial drugs of interest.
From page 60...
... Most of TOXLINE's bibliographic citations contain abstracts or indexing terms and chemical abstract service registry numbers. Index Medicus, a second database produced by the National Library of Medicine, covers citations indexed in PubMed and Medline.
From page 61...
... Several types of publications were captured: epidemiologic studies, case reports and case series, clinical trials, laboratory animal studies, in vitro studies, reviews, meta-analyses, summaries of expert meetings, clinical and travel-based guidelines, conference abstracts, commentaries, and letters to the editor. Exact duplicate articles were deleted.
From page 62...
... Although the committee did not assess review articles exhaustively, it did consider them for specific topics, such as the known biologic mechanisms of action and the p ­ harmacokinetic and pharmacodynamic properties of the antimalarials of interest and their concurrent adverse events. Commentaries, opinions, letters to the editor, and author responses that referred to an included article were captured and considered along with the original article.
From page 63...
... In addition to presentations focused on the malaria prophylaxis policies of different government agencies, representatives from FDA gave an overview of the FDA's postmarketing pharmacovigilance system of adverse events and of how that information is used to monitor for signs of safety issues. A representative of CDC explained how the agency assembles and weighs data for making country-specific recommendations for malaria prophylaxis for U.S.
From page 64...
... It was this final set of studies that provided the basis for the committee's conclusions on the relationships between the use of an antimalarial drug and specific categories of adverse health effects. The quantitative and qualitative procedures underlying the committee's literature evaluation have been made as explicit as possible, but ultimately the conclusions about associations expressed in this report are based on the committee's collective judgment.
From page 65...
... Other areas were explored, although not exhaustively, using the human and animal literature. These areas included case reports of adverse events; studies of adherence to a drug of interest when used for malaria prophylaxis; the co-­ administration of an antimalarial for prophylaxis with sporozoite immunization; the co-administration of an antimalarial for prophylaxis with medications for other common conditions (e.g., antimalarial with warfarin, antihypertensives, insulin, etc.)
From page 66...
... These included studies of populations administered antimalarial drugs for a use other than malaria prophylaxis (e.g., for treatment of leishmaniasis, flukes, pneumonia, lupus, rheumatoid arthritis, cancer, or sexually transmitted infections) because studies of populations that use the antimalarial drugs of interest for reasons other than malaria prophylaxis were determined not to be comparable to or representative of the populations using the drugs for malaria prophylaxis; studies that exclusively examined antimalarial efficacy, effectiveness or sensitivity, or drug resistance without mentioning adverse effects (or the lack of them)
From page 67...
... Supplemental Evidence Spontaneous reports of adverse events and case studies provide the least rigorous evidence of an effect. MedWatch, FDA's program for postmarketing ­ surveillance, collects clinical information involving drugs from health care professionals and consumers through a variety of outlets, including mail, internet, and telephone, but the largest source of postmarketing information on adverse events is the drug companies themselves (IOM, 2007)
From page 68...
... Because these studies were considered to provide supportive evidence, their results would not be enough to change the level of evidence for an association. Primary Evidence Studies that compared different groups of human populations based on the exposure to antimalarial drugs can be broadly classified as either observational studies or trials.
From page 69...
... For example, several studies included only a brief statement that "no serious adverse events were reported" without further explanation of what adverse events were examined, how "serious" was defined, or what the timing of those events was. A total of 21 epidemiologic studies that reported on adverse events that were captured or persisted for more than 28 days are included in this report: Ackert et al., 2019; Andersen et al., 1998; DeSouza, 1983; Eick-Cost et al., 2017; Green et al., 2014; Laothavorn et al., 1992; Leary et al., 2009; Lee et al., 2013; LegeOguntoye et al., 1990; Meier et al., 2004; Miller et al., 2013; Nasveld et al., 2010; Rueangweerayut et al., 2017; Schlagenhauf et al., 1996; Schneider et al., 2013, 2014; Schneiderman et al., 2018; Schwartz and Regev-Yochay, 1999; Tan et al., 2017; Walsh et al., 2004; and Wells et al., 2006.
From page 70...
... The responsible committee members then presented the information from each relevant study to the full committee for discussion, including the methods used for selecting the study populations and conducting the research (i.e., design, population, length of follow-up, sources of measurement for exposure and adverse events or health outcomes [such as selfreported information, medical records, claims data, validated tests and tools, etc.] , the statistical analyses used, adjustment factors, etc.)
From page 71...
... In addition to the quality of individual studies, it is important to consider the number of such studies, which also tends to be quite limited, especially for certain antimalarial drugs. The need for replication is quite clear, and the evidence base should ideally consist of many studies with varying strengths and limitations to identify a pattern that can be discerned in a series of imperfect studies.
From page 72...
... Instead, for each study that met the inclusion criteria, the study methods are described, the implications of those methods on the results and inferences that can be made are discussed, and an assessment is presented of the contribution that the study makes individually and in the aggregate to the evidence base. The committee recognizes the challenges in traditional hypothesis testing and over-reliance on "statistically significant" p values that rely on arbitrary cutoffs.
From page 73...
... Observational studies have the advantage of using "real-world" populations, and often include larger numbers of exposed persons than clinical trials, but most lack a comparable nonexposed group. Observational studies of adverse events to a drug often compare users of one drug to those of another drug used for the same indication to help control for factors associated with receiving care for the specific indication and for being prescribed or filling a prescription for that indication.
From page 74...
... adverse events. Formally, statistical power refers to the probability that a particular statistical test (e.g., an effect estimate comparing outcomes between treatment and control groups in a randomized trial)
From page 75...
... As noted above, randomized controlled trials are considered the gold standard for internal validity due to their ability to provide unbiased effect estimates for the sample at hand. Many of the strongest study designs found in the reviewed literature involved the randomization of antimalarial drugs.
From page 76...
...  may help to reduce the misclassification of exposures. If studies of antimalarial drugs are to make meaningful contributions, there should be either documentation of drug prescriptions with a high likelihood -- if not certainty -- of adherence or else self-report based on carefully designed questionnaires.
From page 77...
... For example, whereas electrocardiograms are tests based on objective biologic indicators that can be used to diagnose certain cardiovascular conditions, structured clinical interviews are needed to diagnose psychiatric conditions. In part because some of these health outcomes do not have biologically based diagnostic tests, such as mental health diagnoses and symptoms and some neurologic symptoms such as cognitive impairment (e.g., problems with memory, attention, or concentration)
From page 78...
... Part of an assessment of the potential for confounding is to examine any steps taken by the investigators to mitigate the impact of potential confounders. Confounding could occur, for example, if the use of antimalarial drugs for prophylaxis is associated with personal or situational attributes that may also predict the adverse outcome
From page 79...
... The stressors associated with living and working outside of the country may themselves increase risk for adverse health outcomes, especially psychiatric outcomes. Exposure to combat areas is also likely to increase the risk of negative health outcomes.
From page 80...
... Biologic Plausibility In assessing biologic plausibility -- defined by the committee as the existence of mechanisms observed in studies of experimental animals, cell cultures, or pathophysiology assessments that could account for the various adverse events observed in humans using the various antimalarial drugs of interest for prophylaxis -- the committee required that published articles include objective tests of the impact of these drugs on endpoints relevant to potential pathologic processes. Outcomes were not limited to any specific organ or system, and reviewed studies included the exposure of experimental animals, cell lines, and, in some cases, human tissue or blood samples to antimalarial drugs.
From page 81...
... Instead, the use of a particular antimalarial and its dosage for prophylaxis is based on selfreport or, when observed by researchers or clinicians, as part of the study design. Often, full adherence to the drug regimen is assumed in estimating and quantifying the risk of specific adverse events and health outcomes related to the use of a particular drug, even though many studies have shown that individuals often fail to fully adhere to the regimen, especially when the drug is to be taken for long periods of time, introducing the potential for misclassification bias (Brisson and Brisson, 2012; Cunningham et al., 2014; Landman et al., 2014; Saunders et al., 2015)
From page 82...
... , travelers and expats, research volunteers, people with adverse events reported to national or ­ anufacturer registries, and people living in malaria-endemic areas. These m populations use antimalarial drugs but do not have some of the same potentially confounding stressors such as combat.
From page 83...
... The most commonly used experimental animal models for testing the potential toxicity of antimalarial drugs are mice, rats, dogs, and rhesus monkeys. Although animal and cell-culture studies provide important information for understanding the biochemical and molecular mechanisms associated with the toxicity induced by drugs and chemicals, many factors may lead to differences between the results of controlled animal studies and the effects observed in humans.
From page 84...
... Accordingly, committee members read each study critically and considered its relevance and quality. When drafting language for a conclusion, the committee considered the timing and duration of the exposures, the nature of the specific adverse events or health outcomes, the populations exposed, and the quality, precision, and consistency of the evidence examined.
From page 85...
... Each conclusion consists of two parts: the first sentence provides the category of association, and the second sentence offers a conclusion regarding whether further research in a particular area is merited based on any signals from all the currently available evidence reviewed for that outcome (assessed epidemiologic studies that reported outcomes at least 28 days post-drug-cessation, studies of concurrent adverse events, case reports, data from selected subpopulations, FDA labels, and biologic plausibility)
From page 86...
... Typically, at least one high-quality study indicates a positive association, but the results of other studies could be inconsistent. Because there are a number of agents of concern whose toxicity profiles are not expected to be uniform -- specifically, the antimalarial drugs of interest -- apparent inconsistencies can be expected among study populations that have experienced different exposures.
From page 87...
... Limited or Suggestive Evidence of No Association The category of "limited or suggestive evidence of no association" was originally defined for health outcomes for which several adequate studies covering the "full range of human exposure" were consistent in showing no association or reduced risk (not distinguished for the purposes of this evaluation, which was focused on the potential for adverse effects) with an exposure of interest at any concentration, with the studies having relatively narrow confidence intervals.
From page 88...
... Am J Trop Med Hyg 81:356-362.
From page 89...
... 2017. Long term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995-2014.


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