268 Chapter 11 Focus on research priorities: precision medicine considerations in future clinical trials The promise of precision medicine in advancing the care of sepsis patients is fast approaching and highly anticipated to be a breakthrough in the development of new sepsis therapeutics [59]. Failure to account for the intrinsic heterogeneity of septic patients when constructing prospective clinical trials has been a longstanding issue. We all acknowledge that a wide array of disparate subpopulations of patients exist when we randomly assign them into one of two groups, treatment with investigational medicinal product (IMP) versus placebo and standard care. Variations in the treatment effect size for the same experimental agent could reasonably be expected due to variations across pathogens, site of infection, pre-existing co-morbidities and predisposing factors, duration of sepsis, patient age and gender, and the state of immune function at the time of randomization [59, 60]. A myriad of other unmeasured patient and pathogen factors likely play a significant role in determining patient outcome. With the increasing availability of rapid nucleic acid sequencing, along with epigenomic, metabolomic and proteomic-based tools to interrogate the molecular basis of host variability, the molecular substrates that govern individual host responses are now coming into focus [43]. This emerging field of genomic medicine has already revolutionized the care of patients with malignancies, where genomic signatures in cancer cells have proven to be more reliable as prognostic indicators than traditional histopathologic findings or standard clinical staging criteria [61-65]. Bioinformatics and big data analyses to identify potential (rare) genotypes and associations are expected to play a significant role in the future of sepsis management. Challenges are to establish a proper infrastructure to make optimal use of both clinical and “omics” big data. Data should not only be shared within health institutions, but we must strive towards a system where worldwide sharing of big data reaps benefits through collaboration [66, 67]. In many respects, personalized medicine has come at a critical juncture in caring for septic patients as the spectre of extreme, MDR pathogens is fast approaching, which demands a more precise and individualized approach to the recognition and treatment of life-threatening systemic infections [68-71]. While there is general consensus that molecular diagnostics will have a major impact on clinical trial design in sepsis in the future, challenges in study design, ethics and implementation remain before personalized medicine becomes the norm in patients presenting with sepsis [72]. A major unmet medical need in sepsis research and clinical trial design is the ability to determine the functional immune status of each patient with sepsis entering into a clinical trial. It is now possible to categorise patients at the transcriptional level [43, 44]. These critically important immune distinguishing events were not detectable at the bed side using standard clinical, laboratory, or hemodynamic measures. Such information will be essential before safely choosing who should be given an experimental immune inhibitory agent versus an immune adjuvant therapy. Other innovative technologies such as rapid HLA haplotype measures [73], T cell receptor diversity assays [74] or other rapid assays need to become available to fully realize the promise of personalized medicine in the ICU. Such companion assays that can predict benefit or avoid toxicity will need to be co-developed, standardized and validated by regulatory agencies and researchers [74].
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