Clinical Trials

❘❙❚■ Chapter 2 | Uncontrolled TrialsIntroductionClinical trials form the basis for evidence-based medicine. The primary aim ofmost clinical trials is to provide an unbiased evaluation of the merits of using oneor more treatment options for a given disease or condition of interest. Ideally,clinical trials should be performed in a way that isolates the effect of treatment onthe study outcome and provides results that are free from study bias. A commonapproach by which to achieve this aim is through randomization, whereby patientsare assigned to a treatment group by random selection. When performedappropriately using a sufficiently large sample size of patients, random treatmentallocation ensures that many of the potential forms of bias are balanced out evenlybetween treated and untreated groups. For example, unknown factors that lead tofavoring one treatment over the other for selected patients at baseline can beprevented through a randomized study design [1]. However, it is not alwayspossible or necessary to have a randomized approach since the objective of thetrial may not be to evaluate the treatment effect against a control. In suchsituations we undertake uncontrolled trials.Uncontrolled clinical trials are a subset of a class of studies referred to asnonrandomized trials, since a comparison group is not utilized. Hence, uncontrolledtrials attempt to evaluate the effect of a treatment in a group of patients who areall offered the same investigational treatment.Rationale for performing an uncontrolled trialWhether a control group is needed in a clinical trial ultimately depends on thegoals of the investigator. There are two settings where uncontrolled trials can beparticularly advantageous. These are when the goal of the study is to:• determine the pharmacokinetic properties of a novel drug (eg, througha Phase I or Phase II clinical trial)• generate new hypotheses for further research (eg, through a case studyor case series study)Phase I trialsIn the early stages of clinical research, a control group might not be desirablesince the pharmacokinetic and safety profiles of a novel drug have not beenestablished. After gathering sufficient data from initial preclinical studies throughin vitro studies or through animal models, an investigator might wish to proceedto the first stage (or ‘phase’) of clinical investigations. This is known as a Phase Iclinical trial.16