UNCOUPLING THE TOXICOLOGICAL MORASS IN THE DEVELOPMENT OF NEW ANTIRHEUMATIC DRUGS—IS THERE ANY HOPE?

Abstract

ALL classes of anti-arthriti c drugs are very toxic. The high incidence of severe adverse reactions among these drugs is well known, and the mortality and morbidity therefrom is among the highest of all drugs reported to national drug regulatory authorities [1—4]. This is related, partly, to their widespread use, untoward reactions from combinations with other drugs (e.g. antihypertensives, antidiuretic agents), and patterns of use [1-5]. It is also possible that there is a lack of respect on the part of the medical community resulting from the apparently innocuous appearance of the various pills and capsules readily prescribed at the stroke of the pen; the influence of sales techniques and the demands from patients for a quick cure all.giving the ingredients to this lack of respect for the drugs being nothing more than poisons. Aside from these aspects, there is no doubt we have reached the stage where something has to be done about preventing the occurrence of toxic reactions to anti-arthriti c drugs, especially the newer range of agents in development which are perched on the horizon to join the large and, to many, an everbewildering therapeutic armamentarium. Thus, some major re-thinking is required in the ways in which preclinical and early-stage clinical toxicology is undertaken in drug development; the evaluating criteria employed by drug-regulatory authorities (DRAs); and the political and legal criteria set by government agencies which form the inevitable umbrella under which DRAs, industry, and the medical and scientific professions are forced to act. On the latter aspect, it must be said that the politicolegal criteria are too often enforced from without the medicoscientific community and that it is high time that more appropriate sound scientific criteria be established, the more realistically and critically to set the basis upon which the toxicology and overall therapeutic evaluation of drugs is performed by DRAs. Admittedly, some efforts have been made in the past few years to inject more science into the decision-making progress, but the progress is slow and inflexible. Some 3-4 years ago at a symposium on rheumatoid arthritis in London I espoused some of these ideas, and one of my close colleagues who is a senior vice-president of a research division of a large US company quickly pointed out to me afterwards that if I thought there was any prospect of changing the way of thinking of the US Food and Drug Administration (FDA) then I had no hope. The same comments could be addressed,