Conducting randomized controlled trials in clinical settings of a pilot study.

Sir,

This is regarding an article entitled, “Efficacy and safety of methylcobalamin, alpha lipoic acid, and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes-associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study” published in Annals of Indian Academy of Neurology (Ann Indian Acad Neurol 2014; 17:19-24).[1] The authors need to be appreciated for their effort.

The authors state that the study was an open, randomized, and controlled parallel group 12-week pilot study conducted at a single centre in Chennai, Tamil Nadu, India for which a total of 30 patients were screened. The authors further elaborate on the methodology adopted for conducting randomization which is commendable. However, I would like to draw the attention of the authors to following points.

The term controlled (as used by the authors) scientifically is reserved for randomized controlled trials (RCT). When the term controlled is used, we usually mean a study in which groups receiving the experimental treatment are compared with control groups receiving no treatment (a placebo-controlled study). Furthermore, not all randomized clinical trials are randomized controlled trials (and some of them could never be, in cases where controls would be impractical or unethical to institute).

Second, the practical difficulty of conducting randomization on a sample size limits its use in case of a study like the one conducted by the authors. Randomization in its simplest form is like tossing of a coin; therefore, the chance of being equally distributed in two groups in a small sample is rare. Basically, there are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations. This may be a simple random assignment of patients to any of the groups at equal probabilities, may be “restricted,” or may be “adaptive.” A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients is not revealed prior to definitively allocating them to their respective groups. Both of these procedures are effective in generating patient distribution capable of yielding unbiased results. Non-random “systematic” methods of group assignment, such as alternating subjects between one group and the other, can cause “limitless contamination possibilities” and can cause a breach of allocation concealment.

The authors have done a decent enough job in describing in detail the process of randomization, but an average reader would have been benefited if some details on the points as mentioned above was provided.