[The limits of controlled clinical studies: the case of rheumatology]

The double blind, placebo controlled, randomized clinical trial is the best tool for gathering evidence concerning the efficacy and safety of a drug. However, in some clinical situations--rheumatology is one--these trials have an intrinsic difficulty in representing the clinical reality: e.g., indicating how a drug influences course of a disease over the long-term. Beginning with the distinction between the "activity" of a drug as confirmed by randomized clinical trials, and its "efficacy" over time, as desired by the patient, we attempt to question why this difficulty arises. Several differentiating elements are involved. The objective of the randomized clinical trial design, that is, activity on acute parameters, may not coincide with the interests of the patient, i.e., efficacy in controlling disability or chronic pain. The duration of a randomized clinical trial is sufficient to measure drug activity but not to provide an indication of its effects on the course of the disease. In the randomized clinical trial, the size of the sample, generally from 10(2)-10(3) patients can, at the most, lead to the conclusion that a drug is "active" while the measurement of efficacy is based on a much greater number of observations. With regard to recruitment criteria, clinical trial patients are chosen on the basis of defined disease severity and activity, while in clinical practice, it is known that this often waxes and wanes. The presence of co-morbidity often leads to the exclusion of patients, yet it is known that up to 17% of rheumatoid arthritis patients are depressed. While concomitant therapy is not permitted during randomized clinical trials, it is generally almost always implemented in normal clinical practice. Drug dosage in a clinical trial is not variable, while in practice it is. The greatest difference is found in the measurement of efficacy, where the randomized clinical trial emphasizes the number of tender and swollen joints, acute phase reactants, disease activity indexes, to assess improvement, while for a typical patient, efficacy is measured in terms of non-evolution of radiologic alterations, work capacity and deformity, and/or the need for a joint prosthesis. The objective of the clinical trial is to seek improvement, while a patient with rheumatoid arthritis may consider simply the lack of worsening over a 5-10 year period as a success. Contrary to clinical trials, observational studies function well in this situation. In response to the difficulty that randomized trials have in reflecting the clinical reality of rheumatological outcomes, the solution is to utilize within the trial, the aspects of the disease course considered fundamental by the patient (that is, chronic pain, disability, radiographic alterations), parameters that are generally omitted from trials. A radical alternative, already proposed, is to abandon the randomized clinical trial model completely and adopt open approaches--much less stringent than randomized trials although as stringent as possible outside the framework of the trial model--that are able to reflect the problems of the patient and to respond to them.