Adr Reports Review Practices At The

Each serious unlabeled ADR report, every serious ADR report (labeled or unlabeled) submitted directly to the FDA by health professionals or consumers, and reports describing specific predetermined "important" medical events are electronically transferred to the computer "in-box" of one of approximately 20 safety evaluators, who review them on a daily basis. The safety evaluators are primarily trained clinical pharmacists who are assigned to cover specific groups or classes of drugs. Over time, they acquire in-depth familiarity with the products they monitor.

In reviewing these case reports the primary focus is placed on identifying previously unrecognized serious ADRs. When such a report is identified, a computer search is made of the entire AERS database for reports of similar cases with the drug in question. These cases are reviewed for clinical content and completeness. If important information is missing or supporting medical records are needed for some cases, the safety evaluator contacts the reporter, usually a health professional, to obtain the needed data. This is a time-consuming but essential process, especially when faced with a serious ADR associated with a widely used medicine. In parallel with these activities, a literature review is performed, national drug usage data is obtained and, frequently, an epidemiologist within the office conducts an investigation of background incidence rates and risk factors for the clinical event of interest. For example, a case series of pancreatitis in association with use of a particular drug product might be supplemented by incidence data from a population-based, randomized survey conducted by the US National Center for Health Statistics.

After a case series is assembled and follow-up completed, it is analyzed for drug-relatedness. Several factors are important to this assessment. Temporal association describes the relationship between drug exposure and event. If the adverse effect preceded the drug exposure, the drug cannot have caused the effect. If the reaction resolves with the withdrawal of the drug, the "dechallenge" is positive; if the reaction reoccurs with the re-initiation of the drug, the "rechallenge" is positive. Dechallenge is often cited as evidence of drug-relatedness. However, the lack of resolution (negative dechallenge) should not be viewed as evidence against an association. Many adverse effects, once initiated, follow a course of their own. This is especially apparent with certain blood dyscrasias, serious skin reactions and acute liver failure. Positive rechallenge has traditionally been cited as strong evidence of drug association. Our experience suggests that the absence of reoccurrence should not be taken as evidence against the association. For most recognized and serious ADRs, rechallenge is not intentionally performed.

The timing of onset of the ADR after the beginning of drug use may provide clues as to possible mechanisms (short latency: anaphylaxis; long latency: cirrhosis). It is also important to note if other explanations for the adverse effect are present such as underlying disease states or other medications. A profound hypotensive episode shortly prior to development of acute liver failure may be the causative factor rather than the drug the patient was taking. Alternatively, the natural course of the patient's medical condition(s) may be associated with the event of interest. Additionally, other medications taken by the patient may be linked to the ADR. Disease states and/or other drugs may therefore cloud or confound the relationship between a particular drug and event, complicating the assessment of case reports. Finally, clinical and laboratory features of the ADR and its progressive unfolding may also provide information that distinguishes it from underlying or other disease processes (Meyboom et al., 1997). For example, myopathy is a recognized consequence of HIV infection, but can also result from zidovudine, used in the treatment of HIV/AIDS. Zidovudine-induced myopathy was found to be due to damaged muscle mitochondria, distinguishable from HIV myopathy based on the presence of "ragged-red" fibers in biopsy specimens from affected patients (Dalakas et al, 1990).

The safety evaluator usually stratifies the cases into those with more complete information in which other potential explanations are absent or extremely remote, cases with incomplete information, and cases with other risk factors or potential explanations for the adverse event. The case material is evaluated in combination with drug usage data, epidemiologic information and the published literature. In general, a signal results if there are higher-quality, unconfounded cases plus supporting cases with less complete information or confounding factors present. There is no "threshold" number of cases required to indicate the significance of a potential signal; medical judgement is used in each situation. An analysis of the safety issue is presented to the medical reviewing division responsible for ongoing regulation of the drug. A decision is then made about whether the signal is strong enough to warrant a regulatory action such as changes in product labeling, further study, issuance of a public health advisory, restriction of use or market withdrawal.

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