Читать книгу Clinical Pharmacology and Therapeutics - Группа авторов - Страница 130

The main objective of a Phase III trial is to establish the effect of a new drug while controlling for bias and confounding. This is achieved by randomly allocating trial participants to treatment groups, ensuring blinding is performed where possible, having a representative control group and analysing results on an intention to treat basis. Stratified randomisation is a technique that can be used to balance groups with respect to confounding variables such as age, although it is important to avoid over‐stratification as the trial must include an adequate number of patients for each arm and stratum. Blinding study participants, investigators and/or assessors to allocated drugs helps to reduce bias, although this must be balanced with practicality and cost. For example, in a trial of thrombolytic therapy for acute ischaemic stroke, the drug alteplase is being compared with another drug tenecteplase. Alteplase is administered as an intravenous bolus followed by a 1 hour infusion, whereas tenecteplase is administered only as a bolus, which makes blinding of investigators and participants challenging. The options in this setting are to accept the limitation of only blinding final assessors of the trial data or employing a ‘double‐dummy’ approach that utilises a placebo for each intervention, although the latter approach is often less practical and more expensive.

It is important to carefully select the study population and endpoints to ensure that the population is representative of the target patient group who may benefit from the drug and that the endpoints are of sufficient clinical relevance to justify drug licencing if proven to be effective. The primary endpoint should therefore be clinically relevant, measurable and potentially sensitive to the effects of the new drug. The trial should aim to have a high proportion of subjects with complete data and the results should generally be interpreted on the basis of intention‐to‐treat (all patients who entered the study) rather than per‐protocol (only the patients who completed the protocol). A large dropout rate may indicate a drug that is unlikely to be commercially successful. Additionally, it is also important to ensure that the sample size is large enough for the trial to be sufficiently powered to detect a meaningful difference between the drugs if one exists and avoid a type II error where an effective drug is incorrectly rejected due to the trial being underpowered.