Risk-benefit ratios, clinical trials

The pharmacoeconomics of the anxiety disorders has received litde attention. In the past drug costs were largely incurred by use of benzodiazepines, most of which are available in generic forms and are cheap. They are effective and acceptable in the short term. Long-term use is associated with the risk of physical dependence, with an adverse risk—benefit ratio and high cost terms to facilitate withdrawal. There is now a trend towards the use of antidepressants in the anxiety disorders. Clinical experience has been followed by formal trial evaluation. 

Clinical trials are effective tools primarily designed for assessing efficacy and risk-benefit ratio, but in most cases they are neither large enough nor long enough to provide all information on a drug s safety. 

The risk-benefit ratio should be analyzed and, wherever possible, clinical trial subjects should be subjected to minimal risk and maximal benefit. The risk-benefit ratio should be based on proven scientific data gathered at the pre-clinical stage. A clinical trial should not be conducted if there is a doubt about the risk-benefit ratio. 

If the drug proves safe and effective, phase III trials are initiated. (In the context of clinical trials, safe and effective are rarely used in the absolute sense. Safe generally refers to a favourable risk beneht ratio, i.e. the benefits should outweigh any associated risk. A drug is rarely 100 per cent effective in all patients. Thus, an acceptable level of efficacy must be defined, ideally prior to trial commencement. Depending upon the trial context, efficacy could be defined as prevention of death/prolonging of life by a specific time-frame. It could also be defined as alleviation of disease symptoms or enhancement of the quality of life of sufferers (often difficult parameters to measure objectively). An acceptable incidence of efficacy should also be defined (particularly for phase II and III trials), e.g. the drug should be efficacious in, say, 25 per cent of all patients. If the observed incidence is below the minimal acceptable level, then clinical trials are normally terminated. 

Recent publications on major clinical trials whose implications will involve a recommendation to change clinical practice have included summary statistics that quantify the risk of benefit or harm that may occur if the results of a given trial are strictly applied to an individual patient or to a representative cohort. Four simple calculations will enable the non-statistician to answer the simple question How much better would my chances be (in terms of a particular outcome) if I took this new medicine, than if I did not take it . These calculations are the relative risk reduction, the absolute risk reduction, the number needed to treat, and the odds ratio (see Box 6.3). 

Human studies are designed to determine Does the drug work To provide an answer, pharmaceutical companies, through a series of controlled clinical trials, must, according to the FDA, collect and submit substantial evidence of effectiveness, as well as confirmation of relative safety in terms of the risk-to-benefit ratio for the disease that is to be treated. It is critical from the outset to design clinical studies that pose the right question and provide an answer to the question in the intended patient population. 

In an effort to improve the benefit-to-risk ratio of PTH in the context of the uncertain relevance of the findings in rodents, it was strongly recommended that participation in clinical studies be limited to adults with severe osteoporosis who have completed bone maturation. It was further advised that any case of osteosarcoma (or other bone tumor) be immediately reported and long-term follow-up be conducted for patients treated with PTH. Importantly, subjects in clinical trials of PTH and PTH analogues should be informed about the occurrence of osteosarcomas in rodents. 

Objective 4 is to confirm drug effectiveness in large-scale clinical trials. The results of these trials are summarized in the Integrated Summary of Efficacy (ISE) portion of the NDA/BLA submission and play an important role in determining appropriate therapeutic indications, dose regimens, and benefit/risk ratios for various patient populations. 

Some diseases are so rare that the prospects of conducting a clinical trial are remote. It is unlikely that enough patients could ever be collected at any reasonably small number of study sites for any useful randomization. These diseases may be found in the literature as case reports. In these cases, probably the best that can be accomplished is to collect and retrospectively analyze as many such cases as possible. If the drug of interest has been used in a sufficient number of patients, then retrospective risk ratios for benefit and harm can be calculated. This may be the strongest evidence that can ever be collected about a particular drug under these rare conditions, albeit never as strong as a controlled clinical trial. One example is the effectiveness of dantrolene in malignant hyperthermia (Strazis and Fox, 1993). 

For the application for a marketing authorisation clinical trials have to be performed. An official European body, the European Medicines Agency (EMA), assesses the therapeutic benefit risk ratio. 

First, the applicant must offer evidence through one or more clinical trials of the efficacy of the drug. That is, there must be clear and cogent evidence that the drug does what it claims to do. In addition, it must be shown to have the same effect as the current standard treatment of the condition being studied. Second, side effects (e.g., adverse reactions) of the drug must be carefully studied and reported. The criterion for approval of the applicant product is then based upon an assessment of the benefit risk ratio. 

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