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young men. Women are not usually candidates for phase I studies because the chemicals may exert unknown and harmful effects on their ova. In addition, the cyclical changes in female hormones can add further complexity. However, some studies will recruit women provided they are using contraceptives, have produced a negative pregnancy test or are postmenopausal. Men produce sperm daily, so there is less potential for complete destruction or alteration of the sperm. Single doses of the drug under test are given to the volunteers. Investigators obtain data on how the drug is absorbed, distributed, metabolized and excreted; the biological effects of the drug; adverse effects and toxicity and also the appropriate dosage for subsequent studies. At the end of phase I studies, many drugs are dropped from the process because they may cause unacceptable adverse effects, for example. If phase I studies are successful, then investigations move on to phase II studies. Phase II Studies Phase II studies are the fi rst opportunity for clinical investigators to try the drug on patients who have the disease that the drug is designed to treat. Patients are told about the possible benefi ts of the drug and are invited to participate in the study. Those patients who consent to participate are fully informed about possible risks and are monitored very closely to evaluate the drug’s effects. Usually, phase II studies are performed at various sites across the country – in hospitals, clinics and GPs’ surgeries – and are monitored by representatives of the pharmaceutical company studying the drug. These studies provide information on the optimal dose and also the therapeutic potential of the drug. The therapeutic potential is often determined in comparison with a placebo , a substance or treatment the patient believes will have a therapeutic effect; or to the existing standard treatment. At the end of phase II studies, a drug may be removed from further investigation for the following reasons: • It is less effective than anticipated. • It is too toxic when used with patients. • It produces unacceptable adverse effects. • It has a low benefi t-to-risk ratio, meaning that the therapeutic benefi t it provides does not outweigh the risk of potential adverse effects that it causes. • It is no more effective than other drugs already on the market, making the cost of continued research and production less attractive to the drug company. A drug that continues to show promise as a therapeutic agent receives additional scrutiny in phase III studies. Phase III Studies Phase III studies involve use of the drug in a larger patient group (250 to >1000 subjects) for a period of 2 to 5 years. As in phase II studies, the drug under test will be compared with either a placebo or an existing treatment. The larger group size enables evaluation of the effi cacy of the drug in patients from different groups, for example age, ethnicity, and others. Patients are observed very closely and monitored for any adverse effects. It is possible that more adverse effects are recorded from a wider sample of the patient population and following long-term drug administration. Prescribers sometimes ask patients to keep journals and record any symptoms they experience. Prescribers then evaluate the reported effects to determine whether they are caused by the disease or by the drug. This information is collected by the drug company that is developing the drug and is shared with the MHRA. A drug that produces unacceptable adverse effects or unforeseen reactions is usually removed from further study by the drug company. In some cases, the MHRA may have to request that a drug be withdrawn from the market. Final Drug Approval Drugs that successfully complete phase III studies are evaluated by regulatory authorities in the country where approval is sought. These authorities rely on committees of experts familiar with the specialty area in which the drugs will be used. Only those drugs that receive approval and are granted a product licence may be marketed. These preclinical tests and clinical trials may take up to 12 years to complete, resulting in a so-called drug lag. However, public safety is paramount in drug approval, so the process remains strict. In certain instances involving the treatment of deadly diseases,
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