Clinical trials are used to test the effectiveness and safety of new treatments. In recent years they have become more and more expensive and have high rates of failure. New technology means that a large amount of biological information (summarised by measurements called biomarkers) can be measured. Often this information is likely to tell us how much a patient will benefit from being given a treatment. To make best use of this information, new approaches to clinical trials are needed. A new type of clinical trial design allows testing of the effectiveness of several new treatments simultaneously while considering that the effect may depend on biomarker measurements. A number of real trials are using this approach. Some of these trials will allow new treatments to be included as they become available. This has some benefits and makes the cost of developing and testing treatments lower. However the effect of doing this on important characteristics of the trial, such as the chance of incorrectly recommending a poor treatment for use in practice, is not well understood. We will work on ways of doing these trials in the most appropriate way. This will include getting a good understanding of how the trials work. It will also involve developing the best approaches to when new treatments should be added and when treatments in the trial should be recognised as being effective. Our team includes a wide range of expertise that will mean we can develop suitable methods and support their use in real trials. The developed methods will help patients on trials have a better chance of getting the most suitable new treatment. It will also mean better quality information comes from the trial and that future patients will be treated more effectively.

Clinical trials are research studies involving patients or healthy volunteers which aim to test whether a new treatment is safe and 'better' than current treatment. Clinical trials are grouped into stages (or phases) and researchers aim to answer different questions at each of the phases. The earliest of these, Phase I, aims to test whether a treatment is safe, to investigate side effects and to and to recommend a dose of the treatment for further testing. Phase I trials involve small numbers of participants who may be healthy volunteers or patients. The first group of participants in a phase I trial are given a low dose of treatment and if shown to be safe and without many side effects, the next group of participants are given a higher dose. Further groups of participants are enrolled; with the dose, being raised for each successive group until a dose is reached that has too many negative side effects. The decision whether to give patients the same, a higher, or lower dose of treatment is carefully made before the treatment is given. These trials are called "dose-escalation" or "dose-finding" trials. Once a clinical trial is complete, the results are reported to the clinical research community and to the public. To make sure that these reports are reliable and helpful for further research, a set of guidelines of the important items to be reported, Consolidated Standards of Reporting Trials (or CONSORT for short) have been published. It sets out a standard way for authors to report how the trial is designed, analysed and interpreted and has been instrumental in promoting transparent reporting. The original CONSORT guidelines were developed for specific types of trials and their design features often differ from dose-finding trials. This is important as currently trial reports of Phase I trials often miss out important information about how they were designed and conducted, which can make it difficult for the reader to interpret and gauge the validity of the trials. This wastes time and resources, but more importantly, may unethically expose participants to ineffective or even harmful interventions. Making the best decisions in a Phase I trial, on whether to give a patient the same dose, or a higher or lower dose, is key to the success of the trial. The statistical methods used to guide these decisions have advanced significantly over the past 25 years, so that safer trials with more reliable results can be conducted. But these methods are often complex, and have additional transparency and reporting demands. To address these problems, we will develop an 'extension' to the CONSORT guidelines, which is relevant to all early phase dose-finding designs in different diseases. The main CONSORT Statement has now been extended in 7 other design areas, primarily in later phase trials (www.consort-statement.org/extensions). A CONSORT extension for dose-finding trials is long overdue. To develop an internationally agreed way to report such trials, we have brought together a multi-disciplinary, international team of experts in the design, running and reporting of early phase trials who work in academic institutions or pharmaceutical industry, and those with expertise in developing reporting guidelines of trials. Finally, to ensure that the developed CONSORT extension will be widely adopted, we will involve key groups throughout this research: the trial community, journal editors (who publish articles on dose-finding trials), peer reviewers (who assess research papers), regulators, patients and the public. We will publicise our outputs at relevant meetings and to local/national Patient and Pubic Involvement (PPI) groups, and will use social media to raise awareness. We will conduct practical workshops, highlighting common reporting flaws and how to use the new guideline. We will co-produce two lay papers with our PPI representative to effectively involve, engage and inform patients and the public about the importance of this work.

Rare diseases like the autoimmune disease giant cell arteritis (GCA) are at risk of not getting the attention they deserve in research funding. In GCA, blood vessels become inflamed and blocked. Without treatment, this can lead to blindness, strokes and tearing or bursting of major blood vessels, such as the aorta. However, this does not affect all patients and this disease shows great variation in severity between different individuals. Prompt treatment is critical in order to prevent permanent tissue damage and loss of vision but, because the disease is rare, the symptoms can be unfamiliar to busy family doctors and early warnings of this diagnosis can be missed for some weeks or months. Currently all patients are treated with steroids at high doses, but this is a non-specific treatment that causes dangerous side effects in a very large proportion of patients (86%). These include high blood pressure, diabetes, mental-health problems, muscle weakness and fragile skin and bones, leading to breaks. This is particularly serious because GCA affects older people (>50 years) who often have other medical conditions. There is virtually no clinical trial evidence to guide doctors as to how quickly they should be reducing the steroid dose, how long treatment should be continued and the benefits of using other immune-suppressing drugs to minimise steroid requirements. Treatment trials traditionally lump all GCA patients together and have so far failed to convincingly demonstate improved outcomes when these alternative treatments have been added to steroids. We propose that by accurately classifying patients in terms of their pattern of disease, dominant immune pathway and risk for developing steroid side effects, will allow us to identify subgroups of patients who will respond better than others to newer therapies. We will also use outcome measure assessment to identify good prognosis, non-relapsing groups who may require lower steroid doses for shorter durations; allowing us to minimize therapy and reduce toxicity in those patients whose disease is under better control. GCA is sufficiently rare that no single centre can access sufficient numbers of patients to perform the analyses required at the necessary scale. There is therefore a compelling need for a national partnership approach, capitalising on key UK strengths and building on recent experience of succesful delivery of large, collaborative studies in other rare diseases that have already delivered new treatments for use in the NHS. Our proposed partnership will bring together specialist GCA clinicians and researchers from across the UK so that they can work together to tackle the causes, diagnosis and treatment of GCA. We already have the consent and active engagement of many patients with GCA and the partnership will expand this to create a comprehensive patient network across the UK. The funding will provide state-of-the-art infrastructure, including equipment and staff to manage the clinical data collected, x-rays and scans, along with data collected from blood and tissue biopsies; irrespective of whether the tests were performed within the NHS or for research. The Partnership will make use of a substantial MRC investment in computing power and bioinformatics at the University of Leeds and Leeds Teaching Hospitals NHS Trust to safely store and manage these data. The proposed research activity will make a world-leading contribution to the discovery of better diagnostic tests for use in the NHS. It will also attract investment and research to the UK from the pharmaceutical industry who will work closely with the partnership to develop new treatment strategies for GCA. The approach developed by the partnership will provide an exemplar to inform future consolidation of rare disease research around state-of-the-art bioinformatics infrastructure.

Despite dramatic advances in x-ray crystallography and electron microscopy, we do not have a way to visualise functional proteins in motion. This fellowship will lead the required breakthroughs and develop the first optical instrument to visualise proteins in real-time and at the level of single molecules. We propose to develop an instrument to probe single proteins in a specific and sensitive manner, while disturbing them as little as possible. The vision is to create a 'molecular scanner' that can characterise an arbitrary protein and its dynamics, a technology that is beyond the current state-of-the-art. Realising this sensor will lead to a new fundamental understanding of how the machinery of life functions. The micro-optical sensor will allow us to analyse proteins in entirely new ways. We will be able to detect proteins specifically, from optically-induced vibrational motions, on portable coin-sized laboratories. The advances I envisage will result in a completely new approach for the analysis and diagnosis of protein-misfolding diseases (proteinopathies) such as prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, and a wide range of other disorders. Our sensor platform will be able to contribute to the development of artificial molecular machinery by providing laboratory test beds that observe the motions of nano-machines in real time. We will realise this instrument with optoplasmonic sensors. Optoplasmonic sensors enhance detection signals by reflection-driven circulation of the light. They concentrate the light at the nanoscale where they probe single proteins. We aim to scan the nanoscale light field across a single protein to provide information on the protein structure and its dynamics, resolving protein motions and vibrations at a temporal scale of nanoseconds and at a spatial scale of single bonds and atoms. The optical technique developed in this fellowship will instigate entirely new domains in protein analysis. It will measure and visualise protein structure and its dynamics in-situ, in solution and at surfaces. It will accomplish one of the "holy-grails" of proteomics. Also, this technique can be integrated on a chip, allowing the identification of misfolded proteins from a trace amount of sample, with minimal sample preparation. Thereby it will create new analysis methods, biomarkers and standards for the pharmaceutical and chemical analysis industries. A multitude of industries will be benefitted by the advances of this fellowship, including analytical sensing instrumentation, a $48.4 billion international market. The medical community desperately needs this analysis tool to rapidly detect and characterise intrinsically disordered proteins which cause the debilitating proteinopathies such as Parkinson's and Alzheimer's disease affecting more than 47 million worldwide, at an annual healthcare cost of ~$604 billion (WHO 2017).

Clinical pharmacologists are physicians and scientists whose focus is developing and understanding existing and new drug therapies; they work in a variety of settings in academia, the NHS, industry and government. In the clinical setting, they work directly with patients, participate in trials, and investigate how patients respond to drugs, including why certain patients develop side effects to drugs. The total number of academic clinical pharmacologists trained in the UK is small, and there is an imperative to continue to train more clinical pharmacologists and other specialists with expertise in clinical pharmacology who can work between academia, healthcare and industry. In 2010, the Government recognised that the provision of high quality-care and better interaction with Industry requires clinicians to be familiar with the relevant practices in clinical pharmacology. The universities of Liverpool and Manchester, in collaboration with industry partners, were awarded funding from the MRC to address this unmet need in clinical pharmacology: The North West England MRC Clinical Research Training Fellowship Programme in Clinical Pharmacology and Therapeutics. This programme has allowed 13 clinical fellows (high flying trainee doctors), rigorously selected from across all medical specialties e.g. dermatology, rheumatology, paediatrics etc., to study for PhDs on a variety of clinical pharmacology related research topics such as drug safety and stratified medicine - matching the right drug to the right patient. In addition to their research work the fellows received without walls training with industry and modular training in key aspects of clinical pharmacology. The programme has been a tremendous success with 56 scientific journal publications, 21 conference presentations, 13 prizes and interactions with 61 NHS Trusts. All fellows will also get a PhD. We now wish to renew the scheme with the MRC and with 4 industry partners - Lilly, Novartis, Roche and UCB Pharma, to appoint 13 more fellows. The previous successful format and structure will be retained as will joint leadership from the two universities. Refinements to the programme include: increasing the number of industry partners thereby allowing us to cover more therapeutic areas including cancer; lengthening of the recruitment process to give potential fellows, their supervisors and industry representatives more time to develop research projects with strong alignment; identification of a lead industry partner for each fellow from the beginning of the programme to develop a partnership from the outset; ensuring, where possible, that fellows can spend up to one year with the industry partner at their site(s) performing different aspects of their project. These changes will enhance fellows' training with industry, and also increase the input provided by industry in individual projects. There will be very strong patient and public engagement (as in the current scheme) with involvement of patients in the planning of research proposals, a number of public lectures and involvement of fellows at events such as the Manchester Science Spectacular. The Fellowship Programme will go some way to producing academics with expertise in clinical pharmacology and helping to optimise the safe, targeted prescribing of existing drugs and the development of new therapies for human disease.