Reporting of safety data from randomised trials.

Randomised trials estimate the efficacy and toxicity of interventions. While the quality of efficacy reporting in such trials has drawn a lot of attention, the reporting of safety data has not. We evaluated systematically the quality and extent of information on drug toxicity in reports of randomised trials. We selected treatments for HIV-1 infection, where drug toxicity is common and drugs are mostly new, and so safety should be a priority. All published randomised trials, 1987–97, with sample size of 100 patients or more (n=60; enrolment 36 280) were assessed with prespecified quality measures. Although most trials (81·7%) reported how many patients discontinued study treatment, reasons were given in only 38·3%. The severity of adverse events and abnormal laboratory tests was adequately defined only in 33·3% and 61·7% of reports, and partially defined in a further 20% and 13·3%. Estimates were closely replicated by a second independent rater (kappa coefficients 0·72 and 0·85 for clinical and laboratory measures, respectively). Adequate definition was specified as detailed description of severity; or reference to known toxicity scales with reporting of severe and higher-grade event frequencies per arm for at least two side-effects. Partial definition meant that the report did not separate moderate from severe or higher toxicity; or, severe and higher grade event frequencies were given only for one of many reported side-effects. Protocols with inadequate definitions lumped numbers for all grades; did not split numbers per arm; gave no numbers for any specific events; provided only generic statements (“the medication was overall quite well tolerated”); or did not report on safety. Nine trials gave no frequencies for any clinical adverse events and 11 trials gave no frequencies for any laboratory toxicity. No table was used for safety data in 19 reports (31·3%), while there was no figure with such data in 52 (86·3%). Considering text, tables, and figures together, the median percentage of space allocated to safety information in the results section was 13% (interquartile range, 7–19%). The median space allocated to safety results was 0·5 page (mean 0·54 page), marginally smaller (p=0·056) than the space (45 breaths/min), tachycardic (>140 beats/min), and cyanosed; his jugular venous pressure was not raised. He was able to talk in full sentences and gave a history of having taken two Ecstasy tablets with little effect, so he took a further half tablet, after which he began to feel shaky (estimated total dose 180 mg MDMA, calculated from the MDMA content of the remaining half tablet). Within 25 min of the first assessment he had an apparent tonic-clonic convulsion, but was able to respond to questions. He became increasingly tachypnoeic, and his carotid pulse rate was about 200 per min. A few minutes later he vomited and had a cardiorespiratory arrest. Attempts at resuscitation were unsuccessful. At necropsy, the lungs were strikingly oedematous and congested, the liver showed some pallor and had a slightly fatty appearance, but there were no other significantly abnormal features. No tissue samples were retained for possible pharmacogenetic studies. Toxicology showed blood concentrations of MDMA 4·56 mg/L, 3,4methylenedioxyamphetamine 0·36 mg/L, and ethanol of 0·24 g/L. No other illicit drugs were detected. Ritonavir concentrations were not measured. MDMA has been previously associated with death, most commonly through excessive exertion leading to hyperthermia. Cases of overdose have been described, with ingestion of 42 tablets leading to an MDMA concentration of 7·72 mg/L, which caused mild systemic effects; in another case, overdose of 18 tablets led to an MDMA concentration of 4·05 mg/L and life-threatening illness, with symptoms similar to our patient. The protease inhibitor, ritonavir, is a potential inhibitor of CYP2D6, an isozyme responsible for demethylenation, the principal pathway by which MDMA is metabolised. Thus, ingestion of MDMA in recreational amounts by a person taking ritonavir could lead to toxic effects due to a high plasma concentration of MDMA, which the results suggested had happened in our patient. A plasma concentration of about 0·5 mg/L of MDMA would be expected after ingestion of 180 mg, but the actual concentration was almost ten times that anticipated. In addition to a possible drug interaction, the patient’s metabolism of MDMA may have been poor; 3–10% of white people are deficient in CYP2D6. Impaired hepatic function may have decreased the biotransformation of MDMA. Death was consistent with a severe serotoninergic reaction to MDMA. Severe reactions to MDMA need, therefore, to be identified immediately and urgent transfer to hospital arranged. Samples should be taken for possible pharmacogenetic analysis. Ritonavir could interact with many drugs that are metabolised by CYP2D6, including amphetamine derivatives. The potential for interactions of prescribed medications with MDMA should be highlighted. Manufacturers’ instructions should contain the appropriate warnings of the danger of interactions with illicit drugs.