Adverse event definition

According to the researchers, nearly half of the adverse events definitely, probably, or possibly caused by ephedra were cardiovascular side effects. The most common cardiovascular side effect was hypertension, or high blood pressure. Other reported cardiovascular events were palpitations, tachycardia (an abnormally fast heartbeat), stroke, and seizures. The researchers stated that 10 of the adverse events definitely, probably, or possibly caused by ephedra resulted in death, and 13 of the events caused permanent disability. In one-fifth of the cases, there was not enough evidence or information about the incident, and the remaining complications were not related to ephedra. 

Please detail how safety data will be collected. Safety data should be collected according to the definitions of an adverse event and a serious adverse event as outlined in ICHE2A... 

In general, for smokers with cardiac disease, the benefits of nicotine replacement therapy outweigh the potential risks. In a safety and efficacy study that included veterans with cardiac disease, smoking concurrently with the nicotine patch was not associated with an increase in adverse events (Joseph et al. 1996). Although bupropion SR is generally well tolerated by smokers, it has not been adequately studied in persons with cardiac disease, and definitive conclusions regarding its safety in this patient population cannot currently be made (Society for Research on Nicotine and Tobacco 2003). 

Just as there is an adverse event form, there is usually a serious adverse event (SAE) form. Note here that serious as defined by the FDA is different from severe on the adverse event form. A patient can have a severe headache that may not be considered serious. The ICH guideline (also in ICH E3) entitled Clinical Safety Data Management Definitions and Standards for Expedited Reporting defines serious adverse events as follows ... 

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. 

Adverse event. Unwanted effects that occur and are detected in populations. The term is used whether there is or is not any attribution to a medicine or other cause. Adverse events may be known parts of a disease that are observed to occur within a period of observation, and they may be analyzed to test for their frequency in a given population or trial. This is done to determine if there is an unexpectedly increased frequency resulting from nondisease factors such as medicine treatment. The term adverse event or adverse experience is used to encompass adverse reactions plus any injury, toxicity, or hypersensitivity that may be medicine-related, as well as any medical events that are apparently unrelated to medicine that occur during the study (e.g., surgery, illness, and trauma). See definition of Adverse reaction. 

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. 

Because ARMS is a form of passive surveillance that is based on spontaneous reports, it has a number of limitations. Most importantly, it cannot establish a definitive, causal relationship between the ingestion of an incriminated substance and the occurrence of symptoms. Since people are exposed daily to a myriad of food ingredients, it is inherently difficult to attribute an adverse event to a specific food substance. Moreover, symptoms reported are often vague or general in nature. Other confounders, which were discussed by Bradstock et al. (1986), include ... 

Phase III Extended large-scale trials to obtain additional evidence of efficacy and safety, and definition of adverse effects. Humans exposed several hundred to several thousand Phase IV Post-marketing surveillance occurs after the chnical trials programme is complete. It is used to collect adverse event data from a large patient population. Humans exposed 10 000+... 

An adverse event or experience (as in the preceding section) is defined as any undesirable experience occurring to a subject whether or not considered related to the investigational product(s). Sponsors will have their own set of definitions and SOPs governing reporting of adverse events. The following account is generally applicable to most situations. 

The thalidomide traged) was a powerful stimulus for the setting up of an effective system of adverse event monitoring. An excellent early publication which set out many of the basic principles and definitions of terms and procedures is that of Finney. ... 

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. 

On the other hand, multiple fixed-dose designs have one definite drawback because the doses cannot be adjusted to the individual patients needs, the risk of patients dropping out of a study, due to insufficient efficacy or significant adverse events, particularly in the first few weeks of treatment, is relatively high. 

Of 206 postmenopausal women who took the oral combination of estradiol valerate plus norethisterone (5) eight withdrew because of bleeding during year 1 during years 2 and 3 there were no withdrawals because of bleeding. By the end of year 3, 133 patients had completed the study. There were serious adverse effects in 24, but there was no definite relation to therapy. The numbers of adverse events reported each year by the patients who completed the study are shown in Table 1. The authors concluded that this combination was effective in the majority of patients and was well tolerated. 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

Vascular tortuosity predicting adverse events following carotid stenting. (See text for definition.)... 

The phrase responses to a medicinal product in this definition means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. ... 

From a statistical point of view, compelling evidence of unexpected adverse events is the hardest to address satisfactorily. When unanticipated safety concerns arise, the fact that they are unanticipated means by definition that they would not have been addressed in the study protocol or statistical analysis plan and that no prespecified analytical strategy is in place. Additionally, file vast range of possible adverse events that might be anticipated means that controlling adequately for multiplicity problems is difficult (Ellenberg et al., 2003). 

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. ... 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

After detection of a possible ADE, causality assessment needs to be performed. It is important to be able to rank the likelihood of an ADR as unlikely, possible, probable, or definite. A major problem with determining causality is that confounding variables can contribute to the complexity of causality assessment. In order to determine causality, several important points of data are required. These include the nature of the adverse event, name of the putative drug, other potential causes, and the temporal relationship between the drug and adverse event. Potential causes are obtained by examining the medical history, physical examination findings, and directed diagnostic tests. 

---