Abstract: To effectively encourage competition and consumer choice, it is necessary to license and promote families of closely related pharmaceutical derivatives as long as neither efficacy nor safety are compromised when compared to the original drug. Licensing subclasses of authorised pharmaceutical compounds poses additional problems. In contrast to clinical evaluation of the principle compound, testing of closely related derivatives may appear unethical in placebo controlled trials where efficacy of the primary product has been proven. In addition, reduced efficacy of the primary compound in the specific trial setting and the need for large study populations are just some of the methodological problems associated with these type of comparative studies. Further, the benefits seen in daily clinical practice when multimorbid patients are treated and/or patients are less carefully selected and monitored may substantially differ from those seen in clinical trials. However, this issue is no different when considering derivative drugs than prototype medicaments. Proposal: A possible solution to the problem of testing closely related pharmaceutical derivatives is the performance by an independent institution of large, simple, randomized post-marketing trials that examine comparative effectiveness, safety and toleration of drugs within a sub-group. As at present, derivative drugs should receive market authorisation based on clinical outcome data on efficacy and safety available and in cases where this is not possible - for ethical or practical reasons - according to well validated surrogate outcome data. However, after receiving marketing authorisation, new derivative drugs should be comparatively evaluated in every day clinical practice for benefits, safety and effectiveness. As comparative treatments original drugs and derivatives should be included which requires a large study population. In some cases, the introduction of a no treatment group seems ethically justified as very uncommonly data on effectiveness for treatments - even for "well established" therapeutical approaches - are provided. The recruitment of a large study population should be possible as GPs, specialists, and outpatient wards should be involved in these multicentre studies. The frequency of scheduled follow-up visits should correlate with the frequency seen in daily practice. Hence, the workload for the investigators is only minimally increased resulting in a reduction of efforts and costs for such trials. Furthermore, the inclusion criteria must be as broad as possible meaning that the investigators should include all patients for which the specific treatment is intended. These strategies should help to attain the large numbers of patients that are needed to detect moderate differences in benefits that can be expected from similar compounds.