Drug Development

Early Phase II (often called Phase IIa) studies are conducted in the target patient population. Selection of the study population is important; for example, the tolerability of a new drug for Alzheimer's disease in healthy volunteers aged 20 may be very different from that encountered in those aged 60-70. Patients in these trials have little opportunity to derive therapeutic benefit as result of participation; it is important that this is made entirely clear when obtaining consent, especially in vulnerable groups (e.g. those with cancer). The main points of interest in these studies are safety and tolerability but obtaining evidence of a pharmacodynamic effect and its relationship to dose is also an important objective.

In the traditional model of drug development, Phase IIb studies represent the 'learning' phase used to define the dose or dose range to be used in 'confirmatory' phase III studies. This model works well for a drug such as a histamine H2 receptor antagonist for peptic ulcer. The Phase IIb study could evaluate ulcer healing by endoscopy after 6 weeks using a range of doses. The optimal dose could then be taken forward into similar large scale Phase III studies (probably with an extension to examine durability of effect). However, the desired therapeutic outcomes of many new drugs only become evident after several years of treatment (e.g. fracture rate for osteoporosis, attenuation of deterioration in multiple sclerosis, prevention of myocardial infarction). In these cases, Phase II studies commonly use a surrogate marker of effect (e.g. bone mineral density, MRI scans) (Table 2). Whereas surrogate endpoints limit the required size and duration of Phase II studies, they carry forward much greater uncertainty about the magnitude of the efficacy associated with the drug into Phase III. There is also a risk that the changes in biomarkers and surrogate endpoints fail to translate into clinical benefit.