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Title: Cost-effectiveness modelling for benefit-risk assessment
Author: Catt, Heather Jane
ISNI:       0000 0004 7964 1424
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Introduction and aims: Benefit-risk assessment is important for summarising the effectiveness and safety profile of an intervention. Current methods for benefit-risk assessment are based upon flawed clinical trial data. For biosimilars, regulatory approval is given on the basis of extrapolated evidence assessed in qualitative benefit-risk frameworks, leading to uncertainties. This thesis aimed to investigate methods for assessing the benefit-risk balance of therapies, including identifying harms data and developing a quantitative framework for assessing whether the cost savings of biosimilars justify the increased uncertainties regarding efficacy and safety. Methods: This thesis reports a novel systematic review of the efficacy and harm outcomes reported in Crohn's disease (CD) randomised clinical trials (RCTs) to 2015. Extracted outcomes and adverse events data were categorised and the results benchmarked against a core outcome set (COS) for inflammatory bowel disease and the commonly used outcome measurement tools in CD RCTs. Summaries of Product Characteristics (SPCs) were investigated as a source of harms data with the use of standardised MedDRA (Medical Dictionary for Regulatory Activities) queries (SMQs). Finally, this thesis presents a one-year decision analytic model of biosimilar versus originator infliximab (IFX) to test the limits of biosimilarity and the value-based price needed to compensate for increasing risks. Results: The systematic review yielded 181 studies, 96.1% of which reported primary or secondary endpoints (median five per trial). The reporting of clinical and objective markers of inflammation, patient reported outcomes and safety outcomes as primary and secondary endpoints all increased over time, but with a lack of standardised definitions. Within the outcome hierarchy, the efficacy outcomes matched to 35 domains, split equally into physical manifestations and the impacts of the health condition. Adverse events matched to a greater number of domains (46), but most were physiological manifestations with few reported life impact adverse events. Key literature for IFX identified five uncertain categories of harms, which matched to six SMQs. Each SMQ included adverse events reported in the SPC but not reported in clinical trials, 28 of which allowed an estimate of risk. Immunogenicity is a key concern for the IFX biosimilar, and was an important variable in the decision analytic model. The base-case analysis predicted annual QALYs of 0.803 for each biologic, and costs of £18,087 and £19,176 for biosimilar and originator, respectively. The incremental net health benefit of 0.04 (95% Central Range 0.00-0.09) favoured the biosimilar. Two-way sensitivity analyses suggested that even at high immunogenicity, the value-based price would exceed the current market price. Conclusions: The results of the systematic review provide a comprehensive inventory of benefit and harm outcomes reported in the literature and could form the basis of a COS development process. Use of additional SPC harms data requires a strong theoretical approach to reduce the 'noise' in the data. Categorising outcomes is useful in lieu of the development and widespread use of a COS and the results presented here should support the development of much needed new outcome measurement tools for Crohn's disease. The study presents a novel framework for the quantitative benefit-risk assessment of biosimilars, which could be used at the point of health technology assessment to trade off the price paid for a biosimilar against the uncertainty in effect and risk of the therapy.
Supervisor: Kirkham, Jamie ; Bodger, Keith ; Hughes, Dyfrig Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral