About the Project
In making treatment decisions clinicians must take into account evidence from relevant randomised controlled trials (RCTs). There is concern that external validity of RCT results are often poor, with results lacking generalisability to patient populations outside of an RCT setting, a perception that has led to underuse of treatments that are effective.(1) Unfortunately the results of RCTs will never be relevant to all patients and all settings, and hence the effectiveness of clinical interventions using real world evidence is becoming increasingly important for informing clinical practice.(2) For this proposal we plan to evaluate the effectiveness of SGLT-2 and GLP-1RAs for type 2 diabetes, comparing results from RCTs with real world evidence from the Clinical Practice Research Datalink (CPRD).(3) We will do this by fulfilling the following objectives:
• Use population matching techniques to extract patient data from the Clinical Practice Research datalink (CPRD), to assess if RCT results from the major cardiovascular outcome trials (CANVAS, EMPA-REG and DECLARE) are replicated in a real world UK population.
• Assess effectiveness of SGLT-2 inhibitors and GLP-1RAs in the clinical population who receive the treatment in the UK (which will be more diverse than the RCT populations) and assess the impact of patient characteristics such as age, ethnicity, gender and co-morbidities on clinical effectiveness.
CPRD is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of approximately 11.3 million patients. To assess if key RCT results from recent trials (CANVAS, EMPA-REG and DECLARE) are replicated in a the real world setting, population matching techniques will be used.(4) This will enable adjusted treatment effect estimates from CPRD to be produced, from the available individual patient level data. The estimates will be adjusted to be comparable to the RCT studies, where only aggregate data will be available, using regression modelling techniques. The data in the CPRD will be reweighted so that the mean baseline characteristics match with the mean characteristics in the RCTs.(5) Utilising CPRD in this way would enable us to assess if the results of the three main trials to date, are repeated outside of a controlled RCT environment.
A further analysis will be carried out on all patients within CPRD who have been prescribed SGLT-2 inhibitors and GLP-1RA agonists. This will allow current use and potential real world impact to be assessed, as has been done comprehensively in other real world evidence datasets outside of the UK.(6) Clinical effectiveness of the medication will be assessed in terms of absolute efficacy and risk of adverse events. The association of treatment effectiveness with patient characteristics such as age, gender, ethnicity and other co-morbidities will be evaluated to better understand variation in clinical effectiveness. Differences will be reported in terms of relative and absolute effects, the latter being relevant given the dissimilar baseline risk of outcomes in RCTs vs “real-world” patients with diabetes.
Eligibility criteria
Residence requirements for MRC studentships:
• British nationals who have lived in the UK all their lives are eligible.
• Also eligible are non-British nationals who have settled status (i.e. no restrictions on how long they can stay in the UK) AND have been resident in the UK for 3 years immediately prior to the date of the start of the course.
• EU nationals, EEA and Swiss nationals (EEA migrant workers) should refer to the full RCUK guidelines to check eligibility (you may be eligible for a fees only award).
Academic requirements
• It is expected that applicants will hold (or have completed by the start date) a Masters degree in statistics, medical statistics, health technology assessment or health economics.
• First class or upper second class undergraduate degree or an equivalent overseas qualification with a high statistical content
• Standard English language entry requirements for the University of Leicester: https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs
Applications
For this PhD you need to submit your application in two places:
Apply for funding at
https://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/apply.aspx
Apply for Health Sciences PhD at
https://www2.le.ac.uk/research-degrees/phd/applyphd
References
1. Rothwell, P.M. External validity of randomised controlled trials: “To whom do the results of this trial apply?”, The Lancet (2005) Volume 365, Issue 9453, pp 82-93
2. C. Saunders, C. D. Byrne, B. Guthrie, R. S. Lindsay, J. A. McKnight, S. Philip, N. Sattar, J. J. Walker, S. H. Wild. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet. Med. 30, 300–308 (2013)
3. McGovern, A., Feher, M., Munro, N. et al. Diabetes Ther (2017) 8: 365. https://doi.org/10.1007/s13300-017-0254-7
4. Hartman E, Grieve R, Ramsahai R, Sekhon JS. From sample average treatment effect to population average treatment effect on the treated: combining experimental with observational studies to estimate population treatment effects. J. R. Statist. Soc. A (2015) 178, Part 3, pp. 757–778
5. Phillippo, D.M., Ades, A.E., Dias, S., Palmer, S., Abrams, K.R., Welton, N.J. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submission to NICE.
6. Suzanne V Arnold, Silvio E Inzucchi, Fengming Tang, Darren K McGuire, Sanjeev N Mehta, Thomas M Maddox, Abhinav Goyal, Laurence S Sperling, Daniel Einhorn, Nathan D Wong, Kamlesh Khunti, Carolyn SP Lam, and Mikhail Kosiborod Real-world use and modeled impact of glucose-lowering therapies evaluated in recent cardiovascular outcomes trials: An NCDR® Research to Practice project European Journal of Preventive Cardiology Vol 24, Issue 15, pp. 1637 - 1645
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