Clinical trials are considered as the most valid assessment of an intervention and tobacco cessation randomized clinical trials (RCTs) seem to be the most valuable of tobacco control activities. To effectively design RCTs that mitigate tobacco-related harms in LMICs, further understanding of RCTs in this environment is key to success. Greater understanding around tobacco cessation RCTs may also help to enhance tobacco cessation awareness, policy and implementation globally, perhaps mitigating the tobacco epidemic. The rising prevalence of smoking in LMICs and the unique challenges of implementing smoking cessation in these regions mandate a specific focus on the efficacy of clinical trials for smoking cessation in LMICs in order to guide smoking cessation treatment efforts in these regions. Therefore, the goal of this work is to conduct a systematic review of the already conducted clinical trials evaluating efficacy of THR products in smoking cessation interventions. On the basis of this literature review, protocols for a randomized, double-blind, two-arm parallel, clinical trial have been developed to compare effectiveness of different THR products in general adult population residing in LMIC. The suggested clinical trial might be conducted in any LMIC to generate evidence based data befitting into the local context for provision of accurate information on efficacy of THR products to the healthcare professionals, researchers, and influential leaders to help smokers as well as non-smokers to make healthier choices.