Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs in rheumatoid arthritis.

Safety, cost, and eVectiveness studies are critically important for definitive assessment of disease modifying drugs (DMARDs), particularly when new mechanisms of drug action are likely to be present. This requires post-marketing surveillance, as these dimensions cannot be adequately assessed in pre-marketing studies. “Post-marketing surveillance”, in our definition, is “the asking and answering of important questions the answers to which cannot be ascertained from premarketing trials”. Such questions include assessing the long term toxicity of the new drugs, comparison of the toxicity of the new drugs with alternative treatments, assessment of toxicity in elderly populations and persons with comorbid diseases, noting the characteristics of patients likely to experience toxicity, exploring the eVects of drug combinations on eYcacy and toxicity, and evaluating the long term net cost of treatment. For each of these questions, long term data are required. Such studies may require 1000 to 10 000 patient years of experience for each drug treatment arm. Randomised trials of this scope are not practical. Adverse event reporting systems lack accurate numerators and denominators and cannot validly compare different agents. Hence, prospective, protocol driven, large scale, observational studies are required. These should be started as early in the drug development sequence as possible. Data analysis must be sophisticated and must go far beyond purely descriptive studies without controls. Often, enrollment of early patients in phase 2 and 3 may shorten the time required for adequate follow up.