Introduction The rise in healthcare expenditure and advancement in innovative therapies increased attention on value-based assessment approaches to guide decision-making. Additionally, the global direction toward the use of health technology assessment (HTA) has led to a growing emphasis on country-specific guidelines for economic evaluation. This thesis was undertaken at a time when HTA was announced in the Kingdom of Saudi Arabia (KSA) following the country's Vision 2030 initiatives. The research question is how to assess the value for money of new health interventions relevant to the KSA healthcare system for reimbursement decisions. The primary aim of the thesis was to develop and pilot a customised approach for economic evaluation, as a specific component of HTA, to determine the value for money of a new health technology relevant to the KSA. This proposed approach was formulated to establish a guideline for conducting economic evaluations within the Saudi healthcare system. Methods The value assessment approach in this thesis began with two reviews focusing on economic evaluations. The first review provided an overview of HTA and the health economic analytical methodologies. The second was a systematic review evaluating the technical approaches used in published economic evaluations for Saudi Arabia. This systematic review assessed the limitations reported by the respected authors, which impacted the ability to conduct economic evaluations effectively. These limitations were classified into four key domains: the definition of perspective, identification of the comparator, estimation of costs and resources, and finally the use of incremental cost-effectiveness ratios (ICERs). The next stage involved developing a customized, country-specific guideline for conducting economic evaluation in Saudi Arabia. Guideline's statements were adapted from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS II) statement, focusing only on methodological items related to "conducting" economic evaluation. A real-time Delphi study was conducted to achieve consensus on the guideline's relevance to the Saudi healthcare system. Quantitative analysis was performed for the consensus, and qualitative analysis of experts' comments, included sentiment and content analyses. The consensus criteria were determined a priori, with an agreement threshold of 80% and an interquartile range less than 3, on a 9-point Likert scale. Natural language processing (NLP) was employed to explore the relationship between experts' comments and the consensus decision. The final stage involved applying the developed guideline to assess a new health technology. A cost-effectiveness analysis (CEA) was conducted to compare trastuzumab deruxtecan (T-DXd) to the physician's choice of chemotherapy (PCC) for patients with HER2-low metastatic breast cancer (MBC) from the Saudi healthcare payers' perspective. A three-state semi-Markov cohort model was developed with a one-month cycle length and a 10-year time horizon. Transition probabilities were derived from the Destiny Breast-04 registration trial. Costs and benefits were discounted at 3%. The analysis outcomes included life years (LYs), quality-adjusted life-years (QALYs), and ICERs. Sensitivity analyses were conducted to assess the impact of key parameters on base-case results. The feasibility of the developed guideline was evaluated based on the author's perspective using a four-point scale, with additional comments provided to address challenges and suggest solutions. Results The HTA review highlighted the expansion of the analytical methodologies for economic evaluation. The systematic review revealed a scarcity of CEA studies in Saudi Arabia, with only 12 evaluations identified within 10 years (2010 to 2020). Furthermore, analysis of the four key domains indicated either missing, unclear, or incomplete data within the published CEAs. The guideline concluded with a consensus on 76% of the recommendations, while four remained undetermined, including discount rate, use of similar discount rates for both health benefits and costs, outcome selection, and adoption of gross costing. These remaining items were listed as general statements in the developed guideline. The overall analysis for the expert's comments revealed a statistically significant association between the consensus decisions and the NLP results. The application of the guideline was feasible; however, challenges were encountered in identifying relevant comparators, estimating resources and costs, addressing modelling complexities, assessing equity impacts, and engaging patients and other stakeholders. These difficulties were primarily due to limited national data and technical expertise. The CEA demonstrated 0.48 QALYs and 0.69 LYs, with an ICER of SAR 448,868 per QALY, exceeding Saudi Arabia's willingness-to-pay (WTP) threshold of SAR 120,000 per QALY gain. One-way sensitivity analysis identified the cost of T-DXd as the most influential factor on the ICER. Probabilistic sensitivity analysis showed that achieving a 50% probability of cost-effectiveness for T-DXd would require a substantial price reduction of 80%. Conclusion This research represents the first guideline on economic evaluation for Saudi Arabia. The consensus achieved by national experts enhances its credibility, while its application demonstrates feasibility for national HTA use. The findings of this thesis emphasise the importance of localised data and the integration of economic evaluation into the healthcare decision-making process to ensure evidence-based resource allocation.