OBJECTIVES: While the trend for pairing development of Companion Diagnostics (CDx) with drugs at an earlier stage of development is growing, a number of clinical and health economics hurdles are rising, due to the lack of a consistent HTA assessment framework, driven by uncertainties on how to achieve the necessary robust clinical outcomes for populating cost-effectiveness models. The objective of this analysis is to understand the different reimbursement pathways for CDx in the EU-4, identifying key challenges, opportunities and stakeholder evidence requirements, value drivers and decision criteria. METHODS: The latest CDx HTA submissions between 2010 and 2016 were examined in GER (15), UK (18), ITA (9), FRA (11) and key appraisal mechanisms were analysed to identify final outcomes, the level of consistency in decision-making criteria and differences in weighting of clinical and health economics factors. RESULTS: In Germany, reimbursement of CDx is mandatory if testing is required according to the EMA label, but legislation around coverage at sickness fund level is lacking. In UK, NICE has been assessing CDx together with the respective drug, but the appropriateness of the ICER methodology assessing CDx value can be challenged. In France, a dedicated committee- CNEDIMTS, evaluates CDx separately from the respective Rx, and final reimbursement is mainly driven by added clinical benefit for the targeted sub-populations. In Italy, separate assessment and different levels of decision-making were found to lead to budget-impact considerations. CONCLUSIONS: CDx appraisal processes that leverage outcomes research are facing challenges in calculating with certainty the clinical and economic benefit for patient segments, especially on long-term time horizons. These are key factors found to be leading to unsynchronised and inconsistent HTA assessments, delays and access inequalities. Prospectively defined biomarkers can more readily lead to “payer tailored” trial designs which can generate the necessary robust evidence to achieve positive HTA outcomes.