Spontaneous event reporting

Despite the anecdotal nature and sometimes poor documentation, publication of case reports in journals remains one of the most useful primary sources of information on ADRs. ADR reports in the literature can be identified in several different ways. Prepublication manuscripts describing a spontaneous case report or an event from a clinical trial are sometimes provided by authors to the manufacturer of the drug and the regulatory authority in that country. Pharmaceutical companies are required to be aware of the literature as to the safety of their approved therapeutic products, and are assumed (by law) to be cognizant of such. 

Published case reports on alprazolam show a slightly different profile (266, 267, 268 and 269). Four patients had taken the drug for 4.5 months or less one had also taken chlorpromazine and trazodone and a fifth patient had taken alprazolam (3 mg/day for 26 weeks) and phenelzine (45 mg/day for 13 weeks), abruptly stopping both. According to the FDA s Spontaneous Adverse Event Reporting System, more seizures have been reported with alprazolam than with all other BZDs combined (270). The next highest incidence was reported for lorazepam. The FDA report stated the following ... 

DSHEA severely limited when the FDA could take action to protect the public and what actions could be taken. The burden of proof to show harm is now placed on the FDA. Moreover, dietary supplement manufacturers are not required to report adverse dietary supplement events. In fact, between 1994 and 1999 fewer than 10 of the 2500 adverse events associated with dietary supplements and reported to the FDA were reported by the manufacturer (53). The Office of Inspector General concluded the spontaneous adverse event reporting system has difficulty generating signals of possible public health concern due to limited medical information, product information, manufacturer information, consumer information, and ability to analyze trends (57). One weight loss supplement manufacturer is reported to have withheld from the FDA 14,684 complaints of adverse events regarding ephedra, which included heart attacks, strokes, seizures, and deaths (53). 

In an observational study of spontaneous adverse events reports gatifloxacin was associated with much higher rates of hypoglycemia and hyperglycemia (477 reports per 107 retail prescriptions) compared with ciprofloxacin (4 reports), levofloxacin (11 reports), and moxi-floxacin (36 reports) (437). 

In a retrospective analysis of spontaneous adverse event reports encompassing more than 430, 000 patients who had received zoledronic acid between August 2001 and March 2003, only 72 cases of renal failure were identified by the US Food and Drug Administrahon [78, 79]. It should be noted, however, that patients with risk factors for renal deterioration, including advanced cancer, previous bisphosphonate exposure, and use of nonsteroidal anti-inflammatory medications, may have contributed to the progression of renal failure [79]. Because of the potentially serious nature of this adverse event, it is recommended to monitor renal funchon in patients with cancer before each infusion of zoledronic acid, provide adequate hydration, and modify or discontinue treatment if renal complications occur [30, 78, 79]. 

Fung MC, Hsiao-hui Wu H, Kwong K, Hornbuckle K, Muniz E. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades—1969-98. Pharmacoepidemiol Drug Saf 2000 9 (Suppl 1) S24. 

The dossier contains data from case report forms collected from hospitals. The number of cases is around 3000-4000 observations, reporting prescriptions on a routine basis (survey of use). Safety information comes from this particular survey and from spontaneous ADR reporting (serious events reports and the synthesis of the periodic safety update reports). Of course, information on measures taken during the period should be added (modification of the data sheet, etc.), as well as updated information regarding approval of the drug in foreign countries. 

Spontaneous adverse event reporting may be defined as any system of safety data collection which relies upon physicians, other healthcare workers and sometimes patients to report adverse clinical events which, they suspect, may be causally related to the administration of a drug or drugs. It is these systems which are sponsored by the governments of virtually all developed countries and, increasingly, by developing countries as well. For the physician in the pharmaceutical industry it is this method of safety evaluation that will most frequently be encountered and, in spite of its numerous defects and limitations, will take up much working time. 

Studied. Some of the information gathered on spontaneous adverse event reporting (ADRs) was made available to the ICH EC Working Party by Dr M. Papaluca. 

Spontaneous case reports can reassure a company if a report describes a large accidental overdose with no serious adverse effects. They can also provide reassurance, when reviewed as a whole set, that no reports for drug x causing event y have been received. Clusters of similar spontaneous reports should be meaningfully analyzed for consistency in time to onset, pattern of presentation and dechallenge, to identify a signal and to get a feel for its significance. 

The spontaneous case report database cannot be used to give an accurate incidence rate of even the Type B adverse reactions, as not all cases are reported, either because someone who should act as the reporter is not sufficiently motivated, or he/ she does not recognize the event as an adverse reaction in that patient (Kessler 1993 Fletcher... 

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