Little work has been carried out on the epidemiology of the two serious skin reactions--toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). We collected details of all the hospitalized cases of TEN and SJS in the Federal Republic of Germany for the years 1981 through 1985 inclusive. Inquiries by telephone, letter, and personal visits produced an overall response of 91%; 259 cases of TEN and 315 cases of SJS were identified. From these data, we were able to calculate an overall annual risk of 0.93 and 1.1 per million for TEN and SJS, respectively. The average age group was higher for TEN (63 years) than for SJS (25 years). Women are markedly more at risk for TEN in the ratio of 2:1, these figures being reversed for SJS. The mortality was 34% (87/259) for TEN and only 1% (2/315) for SJS. An association with previous medication defined as "definite, probable, possible" could be established for 89% of cases of TEN and 54% of cases of SJS. The drugs most commonly involved were antibiotics (TEN, 40%; SJS, 34%), followed by the analgesics (TEN, 23%; SJS, 33%). As with the drug groups, the incidences being based on the defined daily doses, were high for sulfonamides, beta-lactam antibiotics, and some nonsteroidal anti-inflammatory drugs.
During a consensus conference in Lugano, Switzerland, 175 statements on controlled clinical trials were drafted by 47 representatives from academia, governmental registration agencies and industry in nine countries. Their opinion on these statements was similar to that of 47 'matched pairs' who did not attend the conference. Thus, the opinion of participants and non-participants appears to reflect the general opinion of those currently involved in designing, conducting and analysing controlled clinical trials. The Lugano statements give answers to the following questions: Is the controlled clinical trial in a crisis? What is the motivation to perform controlled clinical trials? Is it possible for a physician participating in a controlled clinical trial to act in the patient's best interest? Is it possible to obtain truly informed consent in a controlled clinical trial? When is it ethical to withhold active treatment in a controlled clinical trial? What are the controversial issues in the design of a good controlled clinical trial? Is there a double standard with respect to efficacy and adverse drug reactions in controlled clinical trials? What are the alternatives to controlled clinical trials and when should they be performed? How can sponsor bias be minimized? How should an ethics committee decide whether a controlled clinical trial is ethical? Should registration agencies become directly involved in the planning and conduct of controlled clinical trials? Do the declarations of Tokyo and Helsinki facilitate the conduct of ethically valid controlled clinical trials? Is it possible to create an international standard for the conduct and regulation of controlled clinical trials? Why do messages from controlled clinical trials filter into medicine so slowly? Is it possible to bridge the gap between controlled clinical trials and clinical reality? What are the costs of doing and not doing controlled clinical trials? When should drug companies decide to start a trial programme with a specific compound? Is there public hostility against controlled clinical trials? If so, how can it be reduced? The respondents almost unanimously felt that controlled clinical trials are a must: the public must be told that progress in medicine depends on controlled clinical trials, that patients often benefit from participating in them and that the alternative, practising in the face of constant uncertainty, is worse than the possible disadvantages related to the conduct of the trial.
Despite all its limitations, the spontaneous reporting system still forms the basis for drug safety assessments in the Federal Republic of Germany. Although there have been some promising attempts to standardise the methodology of detecting, analysing and evaluating adverse drug events (ADEs) in certain clinico-pharmacological institutes and psychiatric departments, the approaches have not been integrated and are used only locally. The only exception is the Freiburg Documentation Centre for Severe Skin Diseases, which is attempting comprehensive, country-wide documentation of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. We show that surveillance of 40% of all hospital beds would allow the acquisition of reliable data even on rare and serious AEs which could then be extrapolated in a statistically meaningful way. The medical societies in Germany have traditionally taken a leading role in establishing standards for the preclinical and clinical investigation of new drug compounds. We suggest that they also make it their task to define the framework for an intensified adverse events monitoring system, since it is the patient who ultimately benefits from a quantification of drug therapy risks.
A consensus conference was held in 1984 on controversial issues concerning controlled clinical trials. Thirty-six individuals working in academic institutions, forty-six in industry and twelve in regulatory authorities participated. Academics accepted and industrial representatives rejected the following: existing regulations cannot cope with the rate at which new treatments develop; drug companies may be reluctant to undertake surveillance programmes because sales will fall if adverse reactions are detected; novel remedies should not be promoted before extensive post-marketing surveillance; third parties should finance trials promising to reduce the costs of illness and trialists should be separated from sponsors in data analysis and interpretation, the investigator owning the data unless stated otherwise. Industrial representatives supported and academics rejected the following: government price control inhibits drug development and a multicentre trial can be justified simply by the wish to speed drug registration.
2Boehringer Ingelheim Kg, Binger Strasse, 0-55218; -"Hoechst AG, P. 0. Box 800320, 0-65926 Frankfurt am Main 80; 41nstitute fur Medizinische Biometrie, Universitat Heidelberg, Im Neuenheimer Feld 305, 0-69120 Heidelberg; 'Universitats -Hautklinik, Hauptstrasse 7, 0-79104 Freiburg i . Br.
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