Challenges and opportunities for Real World Evidence in Radiotherapy – A view from the UK::Proceedings of a national workshop

Real-world data (RWD) is defined as information collected about patients as a routine part of treatment. To understand the status of RWD initiatives in oncology in the UK an online survey and in-person workshop were conducted which aimed to characterise current perceptions of RWD, establish where real-world evidence (RWE) could support unmet clinical need and to identify the barriers and solutions to obtaining this evidence.Self-selecting healthcare professionals including oncologists, physicists, radiographers and health data researchers, as well as patient representatives, participated in an anonymous survey (N=55) and/or a 1-day workshop (N=46).The workshop consisted of introductory presentations followed by three 1-hour grouped breakout sessions. An inductive thematic analysis synthesizing the outcomes of the survey and workshop was performed post-hoc. Despite issues of perceived poor data quality and the prevalence of unstructured data, 92% of survey respondents recognised the potential of RWD to provide novel evidence. Suggested applications of RWE were validation of trial results in the general population, continuous evaluation of new technologies, decision making in rare disease groups and resource allocation. Barriers to progression of RWD initiatives identified were data accessibility, data quality and prioritisation. Potential solutions include streamlining information governance processes, training staff in data science skills and demonstrating clinical benefit.The potential of RWD to provide novel evidence is strongly recognised in the UK radiotherapy community. While barriers to progress were identified, none of them are insurmountable. To move forwards, the profile of RWE needs to be elevated to attract higher prioritisation and resourcing

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The ortho-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type-I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para-position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells. [Image: see text