Assessing the Efficacy and Safety of Psychotropic Drugs (Clinical Trials and their Importance)

Assessing the Efficacy and Safety of Psychotropic Drugs (Clinical Trials and their Importance) Prior to 1962, trials of new medications were largely based on a series of uncontrolled testimonials by clinicians associated with the studies. The change in the conduct of clinical trials arose largely in response to the public concern, and that of the medical profession, expressed as a result of the thalidomide disaster in which thousands of women in Europe produced offspring with serious limb deformations which occurred after taking the drug for the treatment of morning sickness during the first trimester of pregnancy. This tragedy resulted in the establishment of regulatory authorities in most European countries who established legal guidelines, mainly based on those of the Food and Drug Administration in the USA, which ensured that all new drugs would be subjected to adequate preclinical and clinical assessment before they could be marketed. This is not the place to describe in detail the pre-clinical and clinical studies which are now required by the Medicine Boards which were established by the European Commission to ensure that optimal standards are reached before any drug is made available for clinical use. However, the following summary will hopefully serve to illustrate the procedures involved in ensuring the efficacy and safety of drugs. Pre-clinical testing Drug discovery, almost without exception, is dependent on the pharmaceutical industry. This is understandable due to the enormous costs involved. Although there have been major developments in drug design (particularly with the application of combinatorial chemistry which enables the random synthesis of low molecular weight compounds by automated technology) that have helped to rationalize the methods used to identify novel compounds, the discovery of genuinely original drugs is still largely dependent on serendipity. Nowhere is this more apparent than in the area of psychopharmacology where, with few exceptions, the application of structure–activity relationships for the synthesis of new drugs has been disappointing. Thus it is still necessary for a lead compound to undergo extensive in vitro and in vivo testing to determine whether it will justify clinical development. Once it has been established that the compound is pharmacologically active at doses that do not cause major adverse side effects in rodents, and that it may offer benefits over the drugs that are already available, the compound is then submitted to extensive toxicological testing. This requires an assessment of the dose-related toxicity in at least two different species of mammal so that a risk–benefit assessment may be made regarding its suitability for further clinical development. In addition, information is obtained regarding the pharmacokinetic characteristics of the compound with regard to its bioavailability, metabolism, excretion and the occurrence of potentially toxic metabolites. Details of the manufacturing processes involved, together with details of the final dosage form which will be used in the initial clinical studies, must also be provided by the pharmaceutical company to the Medicines Board before the compound can undergo further testing. The processes involved in preclinical testing can take at least 5–7 years to complete in the case of a novel chemical entity but the period can be shorter if the compound is structurally related to a drug which is already in therapeutic use. One of the major problems facing the researcher who is attempting to discover novel drugs to treat psychiatric disorders lies in the difficulty of obtaining relevant animal models of the human disorder. It is self-evident that only man appears to suffer from any of the major psychiatric disorders, which therefore restricts the researcher to studying changes in behavioural parameters that show some similarity to those observed in the model following drug treatment (accurately predict its activity in the patient?), face validity (are the behavioural or physiological changes observed in the model similar to those seen in the patient?) and construct validity (are the causes of the changes observed in the model similar to those causing the disorder in man?). As the biological basis of all major psychiatric disorders, and most neurological disorders, is far from certain and the behavioural repertoire of most animals is quite different from that of humans, it is understandable why no animal model meets the optimum criterion. Despite these limitations it is still possible to obtain information by studying the effects of novel compounds on animals (usually rodents) that offer some predictive validity. The introduction of ‘‘knock-out’’ mice, or mice in which specific receptors, neurotransmitters or toxic proteins (such as the human beta-amyloid protein) are over-expressed (see p. 128), has helped in understanding the relationship between the changes in central neurotransmitter function and abnormalities in behaviour whichare amenable to drug treatment.