The clinical trials are used to determine whether a drug is safe and effective in the target population with the overall aim of improving patient care. The process is split into four phases.
Phase I is where the drug is first introduced into humans to determine whether the drug is safe and to establish a tolerable dose. The pharmacokinetics (how the drug is absorbed, transported, distributed and excreted by the body) and phamacodynamics (how the drug affects the body) are studied in small numbers of healthy volunteers (when ethical). The dose of drug is increased in successive cohorts until the appropriate dose can be established. Data to be analysed could include the comparison between test and control groups, comparison between test groups, temporal factors during dosing and any adverse events recorded.
Phase II studies test the activity of the drug against the disease in larger cohort of patients to observe one or several endpoints. Any drug effects are considered in light of existing therapies or the control arm and observed toxicities. Studies can be single arm with a comparator of a prior clinical trial or clinical experience or, randomised to compare against a control (placebo or standard therapy) or another experimental arm (different doses). One method which increases the likelihood of observing a difference begins with all subjects receive the experimental arm then are randomised between continuing in the experimental arm or being assigned to the control arm.
Phase III involves large randomised studies to demonstrate the efficacy of the drug in the disease setting. Study design needs to take into account the existing therapies used in the target population and how representative would the selected participants be to the target population. Primary and secondary endpoints are assessed.
An example of a phase III study is that of Bapineuzumab (Johnson & Johnson and Pfizer), a monoclonal antibody against beta-amyloid and was tested for efficacy in Alzheimer’s Disease (clinical trials details (2012): http://clinicaltrials.gov/ct2/show/NCT00574132)
General Results: had some biological effect, reducing tau in CSF (Blennow et al., 2012) and accumulation of Ab in the brain (results of the above trial presented at the 16th EFNS Congress, Stockholm, Sweden 2012). First of four Phase III trials, Bapineuzumab failed to meet co-primary endpoints (Alzheimer’s Disease Assessment Scale (ADAS-cog) and; Disability Assessment Scale for Dementia (DAD)) and Pfizer halted development.
Phase IV studies are conducted after the drug has been approved for marketing. If requested for regulatory reasons, studies are continued to collect data on toxicity in much larger populations.