Cladribine Tablets treatment in multiple sclerosis: systematic review and meta-analysis of the real-world experience

The term Real World Evidence (RWE) refers to information obtained from the analysis of patient data (RWD, Real World Data) generated during everyday clinical practice, i.e. outside of traditional randomized controlled trials (RCTs). RWE become relevant to overcome a specific limitation of clinical trials, namely the inability to generalize the produced information to the population that actually receive (or will receive) the treatment, be it a drug, a medical device, or another type of product. After authority approval, in fact, it is vital to monitor the efficacy and safety of the treatment on a larger and more heterogeneous population than that of clinical trials. In this sense, RWE provides valuable information that can reveal rare side effects, identify subgroups of patients who respond better to treatment, or discover new therapeutic indications. These data help to optimize the use of drugs, improve treatment strategies, and strengthen the trust of patients and healthcare professionals. Medicine, as is known, is moving towards an increasingly personalized approach: RWE becomes, in this sense, a pillar to ensure that the benefits of a newly approved drug are translated into tangible therapeutic successes for all patients. RWE studies are based on data from observational studies, administrative databases, population or disease registers, insurance registers, electronic medical records, population health surveys and, more recently, social media and data from mobile devices and apps. RWE studies allow to evaluate the safety of a treatment in a longer period than that of the RCTs, verify its quality and cost effectiveness, allow us to trace the natural history of a disease conditioned or not by a treatment, give us relevant information on compliance and on adherence to treatments and allow us to identify service models and patient preferences. Considering that both clinical and observational studies conducted on a specific topic are generally more than one, with a different number and with results that are not always convergent, it is very often necessary to resort to the meta-analysis method. Meta-analysis is a statistical technique that aims to analyze multiple studies conducted on the same topic in order to obtain a synthesis of the results, quantify the combined 4 effect (typical effect) of a treatment by aggregating the results of multiple studies relating to the same drug and identifying on the basis of predefined inclusion criteria. Furthermore, by aggregating multiple studies, the estimate of the effect of a certain treatment obtained with the meta-analysis has a greater precision (i.e. a narrower confidence interval) than that of the individual studies. The basis of meta-analysis is the assumption that the differences observed between individual studies do not reflect a real diversity but are the expression of random oscillations (random variation). This PhD project is based on cladribine tablets, an oral treatment for patients with Multiple Sclerosis (MS) approved in 2017 by European Medicines Agency (EMA) and reimbursed in Italy in 2019 by Italian Medicines Agency. The aim of the project was to characterize in the real world setting the risk/benefit ratio of cladribine tablets in patients with MS (pwMS) through two different meta-analyses carried out respectively to estimate the incidence and severity of Covid-19 events recorded with the treatment and the overall efficacy through the evaluation of the main clinical and radiological outcomes in the published RW cohorts. In addition, an observational study on cladribine tablets was also designed and carried out to investigate the therapeutic choices and clinical disease activity of patients who completed the two-year courses with this drug.