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This thesis explores the challenges of assessing the relative effectiveness of new health technologies earlier in their clinical development and the potential implications on health technology assessment (HTA), including health policy decision-making on the basis of economic decision models. Public appeal for rapid access to new medicines has increased pressures on regulators and payers to approve and market products often before appropriate measures of effectiveness are available. First, this thesis identifies the key evidential and methodological issues posed by early or accelerated regulatory approval, as well as any parallels found in the literature for conditional reimbursement and coverage with evidence. A review of international HTA and pharmacoeconomic methods guidelines is performed to draw on cross-country experience in dealing with evidentiary issues in evidence synthesis and cost-effectiveness (Chapter 2). A summary of methods used in HTA relevant to this thesis is provided in Chapter 3. Using three examples from different therapeutic areas, I explore the impact on HTA outcomes of i) subgroup and comparator selection (Chapter 4), ii) specific search strategies to identify indirect evidence for network meta-analysis (Chapter 5), and iii) bias adjustment techniques to include observational data in evidence synthesis (Chapter 6). Each chapter evaluates how the uncertainty in relative clinical estimates influences cost-effectiveness results. Using a simulation approach, Chapter 7 extends the example in Chapter 4—ticagrelor for acute coronary syndromes—to model evolving evidence within the context of HTA. The pivotal trial data is replicated and truncated at different time points, both in terms of follow-up and calendar time, to assess relative treatment effects and costs under different scenarios of ‘early’ HTA. This thesis illustrates how on-going regulatory changes impact clinical evidence considerations in HTA and how existing HTA methods can be adapted to allow for earlier product assessments and ensure timely access to new health technologies.