Methodological Challenges in Dutch HTA of Non-Oncological Orphan Drugs: A Retrospective Analysis and Price Comparison Using different Pricing Models

Background Cost-effectiveness analyses can have limited informative value for pricing and reimbursement decisions for orphan drugs. In cases where cost-effectiveness cannot be reliably assessed or achieved, value-based pricing principles may not be applicable. As a result, alternative pricing models have been proposed. It remains unclear how these alternative approaches compare to one another and to traditional value-based pricing. This study aims to explore and compare these pricing models in the context of orphan drugs. Methods All cost-effectiveness assessments of non-oncological orphan drugs published by the Dutch National Health Care Institute between 2015 and 2024 were analyzed to identify methodological challenges and recommended value-based price estimates. For each treatment, prices were also estimated using a cost-plus pricing model and a discounted cash-flow model. These estimates were then compared to value-based prices and public list prices. Results Cost-effectiveness assessments of 12 different therapies were found, 11 of which provide information for determining a value-based price. All assessment reports cited major uncertainties or unresolved issues in one or more of the following areas: (1) lack of a suitable comparator, (2) sub-optimal disease understanding, (3) limited evidence to inform models, (4) effect uncertainty and (5) flawed QoL measurement. Only one single treatment was found to be cost-effective at the appropriate threshold. Recommended value-based prices were found to fall below (1 therapy), within (6 therapies) or above (4 therapies) the price ranges of the two alternative models. Conclusion Challenges cited in literature are present in Dutch assessments of the cost-effectiveness of orphan drugs. Although these issues cause considerable uncertainty, they do not negate CEA’s current ability to inform decision-making. Still, orphan drugs tend to be far from cost-effective, providing a challenge for patient access that is both timely and financially feasible. Alternative models like cost-plus pricing and discounted cash-flow tend to generate even lower price estimates and rely on considerable assumptions, making them unlikely to offer a viable solution in their current state.