Specific Recommendations for the Evaluation of Orphan Drugs in Spain: The EvalRare project

Introduction and Objective: Rare diseases (RDs) are low-prevalence conditions that significantly impact patients’ lives, often requiring orphan drugs (ODs) for treatment. This study aims to establish a national framework for assessing the quality of clinical evidence for ODs in Spain, to better manage associated uncertainties and support informed decision-making by stakeholders. Materials and Methods: A qualitative study using focus group methodology was carried out. A review was conducted to identify evaluation criteria from Therapeutic Positioning Reports (TPRs) by the Spanish Agency for Medicines and Health Products (AEMPS) and the GENESIS group of the Spanish Society of Hospital Pharmacy (SEFH). A multidisciplinary focus group of experts from national, regional, and hospital levels discussed and refined these criteria, proposing new variables and reaching consensus on final recommendations. Results: Key evaluation criteria were identified, including study design, comparison type, primary clinical endpoints, study population, and study duration. Recommendations were categorized by acceptability, addressing the specific challenges in OD development. While randomized clinical trials remain the gold standard, alternative designs, such as uncontrolled non-randomized cohort studies, may be acceptable under certain conditions, particularly when there is a significant unmet medical need and no alternative therapies. Both clinical endpoints and validated quality of life metrics are crucial in assessing ODs. Smaller sample sizes and shorter study durations may be acceptable if justified by the disease’s characteristics and the clinical relevance of the outcomes. Conclusion: The proposed framework offers a tailored guide for evaluating the clinical evidence of ODs, providing recommendations that may enhance decision-making by stakeholders for determining patient access to OD treatments. Key words: orphan drugs, evaluation, research methodology, health decision-making, recommendations, rare diseases.