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Although increased rates of solid organ cancers have been reported following liver transplantation (LT), the impact of quantitative exposure to calcineurin inhibitors (CNI) remains unclear. We have therefore probed the relationship between the development of solid organ cancers following LT and the level of CNI exposure. This prospective single-center study was conducted between 1995 and 2008 and is based on 247 tacrolimus-treated liver transplant recipients who survived at least 1 year following surgery. The incidence of cancer was recorded, and the mean blood concentration of tacrolimus (TC) was determined at 1 and 3 years following LT. The study results indicate that 43 (17.4%) patients developed de novo solid cancers. Mean TC during the first year after LT was significantly higher in patients who developed solid organ tumors (10.3 ± 2.1 vs. 7.9 ± 1.9 ng/mL, p < 0.0001). Independent risks factors in multivariate analysis were tobacco consumption before LT (OR = 5.42; 95% CI [1.93-15.2], p = 0.0014) and mean annual TC during the first year after LT (p < 0.0001; OR = 2.01; 95% CI [1.57-2.59], p < 0.0001). Similar effects were observed in 216 patients who received tacrolimus continuously for ≥3 years. It appears therefore that CNI should be used with caution after LT, and that new immunosuppressive therapies could deliver significant clinical benefits in this regard.

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This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.

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The main accusation against package inserts is that they are not understood by the patients: the vocabulary used is uncommon and the information is not always relevant. A recent European directive on package inserts for drugs concerning human use specifies the items that must be mentioned. Following this directive and regarding patient interest, a presentation for notices is proposed in which the subject headings are presented as questions and the text is a guide to drug practical use to provide the elements of surveillance. A summarized version added to this detailed notice for the convenience of the patient is also proposed, which should be translated into the language of each European Community's member state.

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Despite the great number of methods proposed, assessing the causal role of a drug in the occurrence of an adverse medical event remains one of the most controversial issues. Qualifying terms for criteria, such as "compatible", "suggestive" of "inconclusive", have never been strictly defined, leading to low reproducibility. Weights of the criteria are usually not adapted to the injured organ, decreasing the specificity of the method. In this paper, a new method for drug causality assessment is described. Contents and limits of the criteria have been defined by experts convened to organ-oriented international consensus meetings. Additional criteria have been introduced and weights attributed. The method was applied to reports of acute liver injuries. The reproducibility was tested by an independent team. The validity of this novel method is studied in the following paper, based on an original approach using reports with positive rechallenge as external standard.

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Standards are lacking for validation of drug causality assessment methods. An original model is proposed using a positive rechallenge as an external standard. This model was used to validate the novel causality assessment method (RUCAM) described in the previous article (Part I; J Clin Epidemiol 1993; 46: 1323). Seventy seven reports of drug-induced acute liver injuries with positive rechallenge were collected from the medical literature and divided into 49 cases and 28 controls. The RUCAM was applied to information obtained prior to readministration. The score was significantly higher (p < 10(-4)) in cases than in controls with high levels of sensitivity, specificity and predictive values. It is concluded that (1) adverse drug reaction reports with a positive rechallenge can provide a standard for validation of causality assessment methods, (2) RUCAM applied to drug-induced liver injuries has been validated.

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Since 1984, the use of the official method for determining the responsibility of drugs in side-effects has been compulsory in France. This method offers, but does not define, different qualificatives for chronological and semeiological criteria. Consensus workshops have been set up to define the undesirable side-effects themselves and the different qualificatives in each of the principal fields of pathology. As regards drug-induced interstitial pneumonia, chest specialists from university hospitals, members of the national system of pharmacovigilance and representatives of the Roussel-Uclaf central department of pharmaco-vigilance have determined: the limits of time elapsed between the beginning and end of drug administration and the occurrence of the adverse reaction; how to interpret various courses of the side-effect with and without temporary discontinuation of the drug, and how to interpret a possible readministration. A list of investigations aimed at excluding the main possible causes of interstitial pneumonia has been drawn up.

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In France, the use of an official drug adverse reaction assessment method is mandatory since 1984. The method proposes various qualifications for chronologic and semiologic criteria without clear limits. The definitions could vary with the nature of the side-effect. We report here the results of a consensus meeting on drug-induced photosensitivity. Dermatologists and experts in pharmacovigilance studied together how the "French method" could apply to the two variances of drug-induced photosensitivity: phototoxicity and photoallergy.

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We report the conclusions of consensus meetings organized by the "Direction de la Pharmacovigilance" of Roussel Uclaf, and attended by University Hospital Nephrologists, members of the National Network of Pharmacovigilance and representatives of Roussel Uclaf Drug Monitoring Department, in order to define more accurately, as regards drug-induced renal failure, the criteria and the terminology proposed by the French method of causality assessment of adverse drug reactions.

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None of the various methods for drug reaction assessment has been adapted to the well-defined damage of a specific organ. There are disagreements between the parties involved in this issue: practitioners, and experts in drug surveillance either in regulatory agencies or in the pharmaceutical industry. Consensus Meetings were therefore organized in order to answer the three basic questions related to the diagnosis of drug-induced liver injury: (a) is the liver involved? (b) what chronological and clinical criteria suggest a drug-induced reaction? (c) can non-drug-related causes be excluded? On the basis of the method for drug reaction assessment used in France, we describe criteria adapted to the case of acute cytolytic hepatitis, which constitutes only one aspect of the task of the Hepatology Working Group.

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