General Principles of Randomized Clinical Trials

The controlled clinical trial is a prospective study that compares the effect of an intervention, which could be a diagnostic procedure, a therapy, or a treatment strategy, with a control. The control can be a placebo or an accepted current standard of care. It may include 2 or more intervention groups in which the treatment allocation is randomly assigned, preferably with maximum masking (blinding) for both the study subject and the treating physician. The intervention(s) may be preventive or therapeutic.

As with all clinical research, randomized clinical trials require multiple experts from different fields such as statisticians, clinical trialists, and clinicians to work together to design the best possible trial to address the research question. This research question must be timely and have sufficient equipoise that researchers are willing to accept randomization for their patients they enroll in the clinical trial. The investigator is comfortable that his or her patient may receive any of the randomized arms because there is no clear evidence for either benefit or harm. The issue of timeliness is the feasibility of studying the proposed therapy because it has not yet been widely adopted by clinicians as the standard of care.

There are a number of phases to the randomized clinical trial. Phase 1 is conducted for safety and may not be randomly assigned. It can be an escalation of drug dose to obtain the best possible dose for treatment or the maximum tolerated dose. Phase 2 studies will randomize subjects to evaluate for possible biological activity of the treatment to determine the feasibility of conducting a Phase 3 trial. The emphasis of this report is focused on the Phase 3 trials, which are designed to evaluate the effectiveness and the associated adverse effects of the new intervention. The issues to be considered include the selection of the study population (along with the sample size calculation), the allocation of the therapeutic agent or treatment strategies, the maintenance and assessment of compliance, and the outcome variables. The elimination of bias in these steps is important. The aim of this report is to emphasize the factors that are essential to a successful clinical trial design.

Selection of the Study Population

When a trial is designed, the target population often consists of the people with the highest risk of developing the disease (for prevention) or the highest risk of progressing to a more severe stage of the disease (for a therapeutic study). At the conclusion of a randomized clinical trial, the investigators would like to make recommendations to the general population in whom the results of the study may be applicable. This is considered the generalizability of the study results. The study population of a clinical trial is clearly defined to help focus the research question and to analyze valid conclusions to such a design. In all cases, it may not include every possible scenario in the general population, thus limiting the generalizability of the recommendations for the treatment or intervention.

The study population is chosen with a careful list of predetermined inclusion and exclusion criteria to maximize the number of outcome measurements to be potentially evaluated and to standardize the screening and enrollment procedures. The feasibility of recruitment in the study population must also be considered. For example, studying a prevention therapy for age-related macular degeneration (AMD) in a population under the age of 50 may not be feasible because the development of vision-threatening AMD usually occurs in the sixth decade and later. The cost of recruiting tens of thousands of such subjects and the duration of the study would be prohibitively expensive and daunting.

Selection of the Study Population

When a trial is designed, the target population often consists of the people with the highest risk of developing the disease (for prevention) or the highest risk of progressing to a more severe stage of the disease (for a therapeutic study). At the conclusion of a randomized clinical trial, the investigators would like to make recommendations to the general population in whom the results of the study may be applicable. This is considered the generalizability of the study results. The study population of a clinical trial is clearly defined to help focus the research question and to analyze valid conclusions to such a design. In all cases, it may not include every possible scenario in the general population, thus limiting the generalizability of the recommendations for the treatment or intervention.

The study population is chosen with a careful list of predetermined inclusion and exclusion criteria to maximize the number of outcome measurements to be potentially evaluated and to standardize the screening and enrollment procedures. The feasibility of recruitment in the study population must also be considered. For example, studying a prevention therapy for age-related macular degeneration (AMD) in a population under the age of 50 may not be feasible because the development of vision-threatening AMD usually occurs in the sixth decade and later. The cost of recruiting tens of thousands of such subjects and the duration of the study would be prohibitively expensive and daunting.

The Importance of Randomization and Masking

Random allocation and masking of the treatment is truly the cornerstone of controlled clinical trials. When the participants are randomized, the baseline characteristics of a sufficient sample size tend to be more balanced, in both the known and unknown factors. Any observed differences between the treated and untreated groups are less likely to be attributable to chance but more likely to be attributed to the therapy. The act of randomization helps to reduce treater-selection bias and allows for statistical analyses. If there is heterogeneity in patient responses attributable to patient differences, one can consider stratifying the factors of interest. For example, in the Age-Related Eye Disease Study (AREDS), zinc was known to have little effect on cataract progression. Only those participants who had either early AMD or advanced AMD in 1 eye were stratified to be randomized to zinc and the antioxidant vitamins or placebo in a factorial design, while the participants with no AMD were stratified to be randomly assigned only to antioxidant vitamins or placebo. Problems with randomization can lead to serious difficulties in interpretation of clinical trials data. For example, if randomization is conducted by having envelopes containing the random assignment at each clinical site, the envelope may be opened erroneously prior to the actual enrollment and randomization of the participant. This may result in selection bias of patients because the investigators could attempt to match the treatment assignment to patients they consider to be more suitable for the different treatment arms. This can be eliminated with centralized allocation of the treatment assignment. The generation of random numbers and the randomization scheme, and the use of “block randomization” (ensuring that there are equal numbers of the different treatment arms within a block of a certain number, unknown to the investigators), will help to ensure good randomization practice. Statistical input is crucial in designing the randomization aspect of any clinical trial.

Masking (blinding) is another essential aspect of a clinical trial. Ideally, participants, investigators, and the clinical trial personnel who conduct procedures for patient selection as well as the outcome measurements should be masked. This helps to eliminate the potential sources of bias in participant compliance, loss to follow-up, and investigator evaluation, improving the reliability of the results. It may not be logistically feasible to mask all the individuals involved in the studies. For example, in a study of intravitreal injections for a retinovascular disease wherein subjects are randomly assigned to an actual intravitreal injection vs a sham injection, while the patient may be masked the treating physician may not be masked. However, if the procedure is an invasive therapy such as a vitrectomy or another invasive surgical procedure, the study design is unlikely to include a sham procedure. The unmasking of the patient or the physician may have less consequence on the results if the outcome measurement is obtained by certified personnel who have no knowledge of the randomization and are able to obtain the outcome measurement objectively. An example would be the measurement of the retinal thickness on the optical coherence tomography (OCT) or progression of a disease state with color photographs, which cannot be changed subjectively by the patient.

Studies must have concurrent enrollment of the different treatment groups, including the group assigned to placebo (controls) or those in the standard-of-care group. Using historical controls would indeed invalidate the enormous benefits to a study from the process of randomization. Selection bias of participants will enter into such a situation and the historical controls may be a very different population than the one that was treated. Only with concurrent treatment groups can the comparison be valid.