Current trends in Higher Education Pedagogies include an ongoing discussion about active learning strategies. Technology-based interventions such as personal response systems (PRS) have gained momentum, especially since the advent of cloud-/web-based solutions. One model that supports the transition from traditional lecturing towards active learning by maintaining a balance between instruction and self-learning is the 'Sandwich Model'. In the present study, we investigated the impact of the Sandwich Model combined with PRS in student learning, engagement and satisfaction by a randomised trial in a large undergraduate biomedical/medical sciences class. A teaching session on epigenetics was delivered either as a traditional lecture (C-group) or as a PRS-including Sandwich-based session (S-group). The major finding of our experiment was the significantly enhanced performance of the S-group over the control, suggesting that the Sandwich Model improves learning gain. We also provide strong evidence that the Sandwich Model enhances student engagement and satisfaction. However, the effect of the Sandwich Model in learning gain and student attitudes was not dependent on PRS incorporation per se and students seemed to favour non-PRS activities over PRS, as evidenced by their feedback. Although further experimental research is needed in order to conclusively compare and contrast PRS and non-PRS activities regarding learning gain, we propose the usage of the Sandwich Model with a variety of in-class learning activities, both PRS and non-PRS-based. Altogether, our work shows that the Sandwich Model is a powerful pedagogical approach that exerts a positive impact on student perceptions for learning and satisfaction and that can support the teaching of challenging biomedical concepts, such as epigenetics.