Randomised controlled trials usually assess efficacy, i.e. the effects of a treatment when used under controlled conditions (e.g. in a precisely defined population of patients who are closely monitored). Therefore, care is needed in extrapolating research results to countries where cultures, races, etc. may differ. It is crucial to consider the value of the new drug in terms of the population and health system of your own country. For example, the effectiveness of a specific intervention may vary, depending on factors such as age, comorbidities, pregnancy, culture, race, and also on economic and other factors (e.g. facilities for diagnosis, storage etc.).
The following are factors to consider:
• The width of the safety margin (i.e. the difference between toxic range and therapeutic range) of the drug. For example, the safety margins of digoxin and theophylline are both narrow, and the toxic effects are sometimes serious and can result in death. Use of these drugs (e.g. aminophylline for severe asthma) requires close monitoring, including perhaps measurement of the serum concentration of the drug. But if therapeutic drug monitoring cannot be easily done in your country because of the costs or lack of resources, these drugs cannot be safely used, especially in infants aged less than one year, even in status asthmaticus.
• Inter-racial variation in the activity of metabolizing enzymes. The isoenzyme cytochrome P450 (CYP) 2D6 is involved in the metabolism of several important groups of drugs, including antiarrhythmics, antidepressants and neuroleptics. Some people have CYP 2D6 isoenzymes with decreased or absent activity and so have reduced capacity to metabolise drugs that are substrates for this enzyme, leading to their accumulation during therapy and an increased risk of unwanted effects. For example, around 7% of Caucasians, but only 1% of Asians are poor metabolisers of the antihypertensive drug debrisoquine.18
• Inter-racial variation in the spectrum of susceptibility to diseases and responsiveness to treatment. Between 20-25% of Caucasian people die from ischaemic heart disease (IHD), compared with only 7% of Japanese people. Consequently, even if the efficacy of some statins were proven in Caucasian people, the evidence may not be relevant to Japanese people and this may be the same for people living in developing countries.
• Inter-individual variation in response to the drug. The activities of the cytochrome P450 enzymes can also differ between individuals: e.g. the activity of isoenzyme CYP3A4 can vary up to 40-fold between individuals. As many drugs are metabolised mainly by this enzyme, the enzyme’s activity can affect an individual’s response to a drug.
• Whether the development of serious adverse reactions can be predicted, prevented or detected. The optimal dose of a drug which is eliminated entirely through the kidneys can be calculated according to the patient’s renal function and monitored by therapeutic drug monitoring if possible and if necessary. However, poor metabolisers of major cytochrome P450 enzyme subtypes, who are therefore at risk of high plasma concentrations of the drugs, cannot be identified before the drug is started.
• Whether developed serious adverse reactions should be controlled or treated. Many adverse reactions are difficult to control once they occur, e.g. torsade de pointes, cerebral or intra-meningeal haemorrhage, stroke, pulmonary embolism, neuropathy and/or nerve injuries. These adverse reactions must be considered serious even though they are relatively uncommon. In this context, if a drug induces some mild adverse reactions preceding these serious and irreversible reactions, such a drug should be preferred. Although extrapyramidal symptoms such as dystonia, akathisia and parkinsonism are not trivial effects, they are less serious and easier to control than torsade de pointes. Sedation is an inconvenient adverse effect accompanying the treatment of urticaria or allergic rhinitis. But contrast this with the use of high doses of the non-sedating antihistamine terfenadine to avoid sleepiness which incurs a risk of hazardous cardiac arrhythmias.