The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance.

Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154

A method for estimating the probability of adverse drug reactions

Randomised controlled trials (RCTs) alone are unlikely to provide reliable estimates of the incidence of rare events because of their limited size. Cohort, case control, and other observational studies have large numbers but are vulnerable to various kinds of bias. Wanting to estimate the risk of death from bleeding or perforated gastroduodenal ulcers with chronic usage of non-steroidal anti-inflammatory drugs (NSAIDs) with greater precision, we developed a model to quantify the frequency of rare adverse events which follow a biological progression. The model combined data from both RCTs and observational studies. We searched systematically for any report of chronic (>/=2 months) use of NSAIDs which gave information on gastroduodenal ulcer, bleed or perforation, death due to these complications, or progression from one level of harm to the next. Fifteen RCTs (19364 patients exposed to NSAIDs for 2-60 months), three cohort studies (215076 patients redeeming a NSAID prescription over a 3-12 month period), six case-control studies (2957 cases) and 20 case series (7406), and case reports (4447) were analysed. In RCTs the incidence of bleeding or perforation in 6822 patients exposed to NSAIDs was 0.69%; two deaths occurred. Of 11040 patients with bleeding or perforation with or without NSAID exposure across all reports, 6-16% (average 12%) died; the risk was lowest in RCTs and highest in case reports. Death from bleeding or perforation in all controls not exposed to NSAIDs occurred in 18 out of 849489 (0.002%). From these numbers we calculated the number-needed-to-treat for one patient to die due to gastroduodenal complications with chronic (>/=2 months) NSAIDs as 1/((0.69x?6-16%, average 12%?)-0.002%))=909-2500 (average 1220). On average 1 in 1200 patients taking NSAIDs for at least 2 months will die from gastroduodenal complications who would not have died had they not taken NSAIDs. This extrapolates to about 2000 deaths each year in the UK.

Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use

Pharmacovigilance, defined by the World Health Organisation as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem’ plays a key role in ensuring that patients receive safe drugs. Our knowledge of a drug’s adverse reactions can be increased by various means, including spontaneous reporting, intensive monitoring and database studies. New processes, both at a regulatory and a scientific level, are being developed with the aim of strengthening pharmacovigilance. On a regulatory level, these include conditional approval and risk management plans; on a scientific level, transparency and increased patient involvement are two important elements. To review and discuss various aspects of pharmacovigilance, including new methodolgical developments.

Pharmacovigilance: methods, recent developments and future perspectives.

Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment.

http://www.jle.com/fr/revues/epd/e-docs/antiepileptic_drugs_indications_other_than_epilepsy__263021/article.phtml?tab=download&pj_key=doc_attach_16612

Antiepileptic drugs: indications other than epilepsy

The U.S. Food and Drug Administration (FDA) has long been conducting a program to monitor reported adverse drug reactions to approved drugs. The purpose of this paper is to review the rationale for monitoring adverse drug reactions, to describe the current program, and to encourage physician participation in the program. The program began in the late 1950s, after the registration by the American Medical Association of cases of aplastic anemia due to chloramphenicol.1 It expanded greatly when the 1962 revision of the Food and Drug Act required the pharmaceutical industry to report adverse drug reactions to the FDA. Since 1969, . . .

Adverse-Drug-Reaction Monitoring

P REMARKETINQ clinical evaluation of a new drug, even if thorough and well conducted, still leaves some important questions about that drug unanswered. Studies carried out during the premarketing phase are restricted to limited numbers of patients and are usually of short duration. Conclusions derived from such studies may therefore be of limited generalizability to the use of the drug in actual practice.

https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/j.1552-4604.1979.tb02464.x

Postmarketing Surveillance of New Drugs: I. Review of Objectives and Methodology

Our original goal was to analyze the experimental designs, results, and costs of all the studies that have been required and actually implemented as part of the conditions for new drug application (NBA) approval in the United States up to 1976. Six such examples were known to us at the beginning of the study. As the data were sought, however, it became clear that the scope of the study would have to be expanded. This was necessary primarily because some of the United States examples had not been im-

https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/j.1552-4604.1979.tb01649.x

Henry T. Davis

Papers

Postmarketing Surveillance of New Drugs: I. Review of Objectives and Methodology

Postmarketing Surveillance of New Drugs: II. Case Studies

Graphical analysis of multivariate pain data in analgesic trials