Adverse drug event definition

Fig. 7.1 Relationship between Drug-related Problems (DRP), Adverse Drug Reaction (ADR), and Adverse Drug Event (ADE). The definitions of extrinsic and intrinsic DRPs have been adapted from van den Bent (2002)... 

American Society of Health-System Pharmacists. Suggested definitions and relationships among medication misadventures, medication errors, adverse drug events, and adverse drug reactions. Am J Health-Syst Pharm 1998 55 165-6. 

American Society of Health-System Pharmacists. Suggested Definitions and Relationships Among Medication Misadventures, Medication Errors, Adverse Drug Events and Adverse Drug Reactions. Am. J. Health-Syst. Pharm. 1998, 55, 165-166. 

Drug-related problems can be defined as Any undesirable event experienced by the patient that involves or is suspected to involve drug therapy and that actually or potentially interferes with a desired patient outcome (Strand et al. 1990). This is a vital component of Pharmaceutical Care and Clinical Pharmacy and will be described more in detail in another chapter. It should however be noted that there are several definitions and classification systems for DRPs. A literature review (van Mil et al. 2004) identified fourteen classifications and their critical elements. In the presented definition a potential problem is a DRP but this is not the case in all definitions and classifications. This is also the case for unavoidable adverse drug reactions (e.g. with cytotoxic agents). 

Synonyms of adverse reactions generally include adverse medical effects, untoward effects, side effects, adverse drug experiences, and adverse drug reactions. Specific distinctions among some of these terms may be defined operationally. For example, the term adverse reaction is used to denote those signs and symptoms at least possibly related to a medicine, whereas the term adverse experience is used to include nonmedicine-related medical problems in a trial such as those emanating from trauma or concurrent illness. Distinctions among side effects, adverse events, and adverse reactions are illustrated in the definitions of the two former terms. 

In order to study the possible association antidepressant drugs and adverse suicidal events in adult patients, FDA planned and conducted a meta-analysis study of randomized trials of antidepressants. The meta-analysis had several key features that supported its quality and utility for regulatory actions (1) hypotheses generated from previous and independent evidence provided the meta-analysis objectives (2) the meta-analysis was based on well-defined inclusion criteria and an exhaustive set of trials with patient-level data available (3) the meta-analysis employed rigorous and consistent outcome definitions across trials and patients and (4) the meta-analysis was based on prespecified statistical analysis plan. 

An evaluation of the rifaximin tolerability profile observed in almost 1,000 patients from 30 clinical trials was unable to identify a definite pattern of intolerance [33]. Very few adverse events have been reported during short-tem treatment with the drug, the most frequently reported being gastrointestinal in nature (e.g. flatulence, nausea, abdominal pain and vomiting). It is worthwhile to emphasize that the detection of GI adverse reactions could have been difficult in rifaximin trials since the symptoms of the underlying diseases were often similar to the GI complaints observed after drug treatment. 

All unexpected, serious and drug-related adverse events should be reported to MHLW, the investigators and study sites. The requirement to report to the MHLW is identical to ICH guidelines with an additional definition that adverse events include any suspicious infection related to a study drug. This addition reflects the bitter experience of spread of AIDS among haemophilia patients due to HIV-contaminated non-heat-treated human plasma products. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

Karl E. Peace (1987), Director, Research Statistics, SmithKline and French Laboratories, pointed out that it is frequently impossible to design trials to provide definitive information about safety—particularly about adverse events. He described occasions when it has been possible to design adequate safety studies, but concluded, However, for most new drugs in clinical development it is not possible. ... 

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