Adverse event exposures

Electronic Data Analysis Training. Instructs reviewers on how to access NDA data in SAS Transport format via the EDR and to convert the files to formats that can be used with a variety of software packages. NDA Electronic Data Analysis Training (NEDAT) incorporates the use of the SAS System Viewer, Stat/Transfer, and JMP to convert the data and perform basic analysis. Additional introduction to JMP courses that discuss analysis of adverse events, exposure, efficacy, lab, and demographic data are also available. 

None of this is to say that safety is ultimately a matter of luck, but the random variability in adverse event frequency means that effective interventions should be triggered by exposures— which are far less subject to random variability— not just by serious adverse events. Even more than major adverse events, exposures signal the need for action, and major adverse events signal that many exposures have been discounted or overlooked. 

The first issue lies in the whole realm of the human disease process itself. Many adverse drug events mimic diseases and vice versa. Is an adverse event really an adverse event, or is it merely a natural occurrence of a disease process that is entirely independent of drug exposure The science of drug safety is often complicated by the lack of objective markers of drug toxicity that can systematically separate a disease process from an adverse drug event process [2]. Clinical trials, often viewed as the gold standard to assess efficacy, are simply too limited in scope to answer safety questions in a systematic way. 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

Limited Knowledge of Exposure and Reporting Rates in Postmarketing Data. Unlike clinical trials and electronic medical records in clinical practice, postmarketing voluntarily reported data contain limited information about the total number of patients exposed and the duration of exposure. This problem is compounded by the fact that adverse events are often underreported [2,9]. 

One of the major drawbacks of calcineurin inhibitors is their ability to cause acute and chronic nephrotoxicity. Acute nephrotoxicity has been correlated with high calcineurin inhibitor doses and usually is reversible. Chronic toxicity, however, typically is irreversible and is linked to chronic drug exposure. Table 52—4 expands on the more common calcineurin inhibitor-induced adverse events. 

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

Today, extensive regulatory guidelines shape the way new medicines or chemicals are developed but we remain heavily reliant on the ability of the rodent, dog, rabbit, and monkey to predict the outcome of human exposure. Many potentially useful drugs are rejected due to the adverse effects (often at high doses) outweighing the potential benefit but adverse events continue to be detected in marketed drugs. 

A number of variables influence the likelihood of an adverse event being reported. These include the length of time that a product has been marketed, the market share, experience and sophistication of the population using the product, and publicity about adverse events. Currently there is little incentive for health professional reporting of adverse events, which partially imderlies the problem with underreporting. Lack of exposure data and the issue of underreporting preclude estimation of incidence rates. Causality assessment is difficult or impossible because of the quality of the data received and the lack of a comparator (control) group. Finally, comparisons of product safety cannot be directly obtained from adverse event data. 

Large samples are also required for most studies of infrequent outcomes, such as stillbirth, specific congenital malformations and low birth weight small samples may lack the power to reveal a true association between the exposure and adverse event, if one exists. Registries can alleviate the problem if they are complete and well... 

Acute (toxicology) An adverse event that occurs following a one-time or short-time exposure to an agent (chemical or physical) over 24 hours. In some cases, urgent treatement may be required (compare with chronic). 

Catastrophic medication errors, particularly when someone dies, are a newsworthy event. Health care is not immune. Such errors are not likely to remain secret. As a result of the adverse public exposure, reputations will be diminished, with potentially significant consequences for individual practitioners and institutions. The only means available, at least initially, to rehabilitate individual and institutional reputations is an appropriate message and response through the media. 

Learned helplessness effective (EDS0) in 50% of the test population. Behavioural phenomenon consisting of passivity and withdrawal after exposure to an uncontrollable adverse event. 

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