Antibiotic clinical trials - The witley park symposium summary

Abstract

Objective. To identify the strengths and weaknesses of antibiotic clinical trials in relation to the diverse users of their results, and to make preliminary proposals for the future. Methods. Experts from clinical microbiology, infectious diseases, pediatrics, medical statistics, mathematical modeling, epidemiology, general practice, general medicine, regulatory agencies, clinical pharmacology, pharmacy, pharmacoeconomics, pharmaceutical medicine and healthcare assessment met in syndicate groups and plenary sessions, and a report was compiled based on their deliberations. Results. Current clinical trial practice is an important part of the expensive and protracted process of development of new antibiotics by the pharmaceutical industry. Users of the results include the pharmaceutical company, registration agencies, politicians (on behalf of the general public), prescribers, and patients. Each has different requirements. Strengths and weaknesses of current trial practice, for all these users, were listed in relation to the concept, design, conduct, interpretation (with special reference to validity) and application of the results. Conclusions. Current comparative, double-blind clinical trials of antibiotics follow well- developed scientific principles which limit the effects of chance and of bias, and are amenable to meta-analysis. However, they seldom demonstrate the superiority of one drug over another (although capable of doing so), they suffer randomization problems (since the pathogen is seldom fully characterized at the beginning of therapy), they produce results for the average patient and thus may lack external validity for the individual patient, and they are susceptible to subtle bias. Because they are based on comparison with drugs that are of historically established efficacy (but sometimes never satisfactorily established, or currently less effective because of acquired antibiotic resistance), they may include patients unlikely to benefit from any antimicrobial chemotherapy. Furthermore, they cannot detect uncommon unwanted events, and they do not often study long-term events of any kind. It was concluded that overall current clinical trials are of most use to the pharmaceutical industry and to registration authorities and of limited use to prescribers and individual patients. It was proposed that the antibiotic clinical trial of the future should include: Phase I. No change. Phase II. Establishment of pharmacokinetic and pharmacodynamic predictors of efficacy in in vitro and animal models, using human volunteer pharmacologic data in order to predict effective dosing regimens. Phase IIIA. Intensive, small-scale open studies by accredited experts, on the microbiology, clinical progress (with validated scoring schemes), safety, laboratory parameters, and pharmacokinetics and pharmacodynamics in selected patients. These patients would be representative of those suffering from a variety of clinical syndromes, each able to show benefit from antibiotic therapy, but infected with organisms that may be sensitive or resistant in vitro. This would result in the study of much smaller but more targeted and clinically relevant applications, but would result in fewer patients being assessed for safety. Provisional registration Phase IIIB. Prospective controlled trials conducted with close liaison between accredited members of the pharmaceutical company developing the drug and the accredited clinical investigator to demonstrate safety, efficacy (including superiority) and full costs of therapy, based on relevant validated outcome measures.