Secular changes in published clinical trials of second-line agents in rheumatoid arthritis

Treatment of rheumatoid arthritis (RA) was boosted in the 1950s by the discovery that injectable gold and antimalarial drugs were effective therapies. The effects of these medications were established by comparing them to placebo (inert) treatment, and they became the standard second-line therapy and were used after nonsteroidal anti-inflammatory drugs such as aspirin, until penicillamine was introduced in the 1970s. Other second-line agents have since become available, including methotrexate, sulfasalazine, and azathioprine. Their effects have been established using placebo controls and also in comparisons with the gold and antimalarial drugs, the ''old standards''. Other changes in the testing of antirheumatic drugs have occurred, including rising costs, which increased support from grant agencies or pharmaceutical companies, publication of standards, and the use of more complex methods in these studies. The changes that have occurred in 105 clinical trials of antirheumatic drugs, from 1945 to 1989, were evaluated. The use of placebos to evaluate drug effects decreased by 75 percent during this time period. The incidence of full funding of drug trials by drug companies increased from zero, in the initial time period, to 61 percent in the most recent decade. The average age of patients was significantly older in the later studies, and patients tended to have less severe disease in these later studies. The use of statistical methods changed somewhat during the study period, but most studies still fail to indicate the statistical power of their study design and type of analysis. This review indicates that the trends in studies of antirheumatic drugs should be considered when comparing results from research performed at different times. (Consumer Summary produced by Reliance Medical Information, Inc.)