Methodological and political issues in clinical pharmacology research by the year 2000

Parallel groups in a large, multicenter, phase III "pivotal" randomized cli nical trial (RCT) with clinically relevant end-points are seen by the medic al community as the "gold standard" of clinical research. However, there ar e limitations, some methodological and others political. The main one is th e external validity of the method because a treatment, as studied in RCTs, does not necessarily reflect how it is used in clinical practice. Also, the method, as it stands, is not really predictive of the success in a particu lar patient of a certain intervention studied in a trial. To overcome these methodological drawbacks, different options have been implemented. The mos t important ones are: (1) the performance of pragmatic RCTs intended to add ress effectiveness rather than efficacy; (2) meta-analysis; and (3) the use of observational studies, with or without a comparison group. Recent exper ience has shown that type-A adverse drug reactions (ADRs) related to a spec ific class of drugs have been successfully characterized throughout cohort- or population-based case-control studies, whereas the evidence linking a s pecific drug entity to a type-B ADR, apparently severe enough to withdraw t he drug from the market, has come mainly from case reports or case series. Other limitations of the RCT are more of a political nature. These large "p ivotal" trials are mostly sponsored by the pharmaceutical industry, and to guarantee the scientific and ethical integrity of data produced, they are p erformed following standard operating procedures (SOPs) and good clinical p ractice (GCP) guidelines. Sometimes industry is not interested in sponsorin g trials; thus, RCTs performed are in practice highly biased because of the ir potential economical profits. Furthermore, applying SOPs and GCPs is exp ensive and difficult to implement, and it is hard to find funding in public institutions. As a result, there is an urgent need to create a network of independent, skilled groups interested in sponsoring and performing institu tional RCTs following "user friendly" GCP when the profits are low, but sci entific interest high.