Presentation (CTI)

OBJECTIVES: Drugs for orphan diseases have historically faced regulatory and HTA challenges due to small patient populations, limited natural-history data, reliance on single-arm trials, and high acquisition costs. Thus, it is harder to demonstrate substantial evidence of effectiveness, ultimately delaying patient access where there is an unmet need. Regulatory authorities are reassessing how therapies for rare diseases should be evaluated; the FDA has proposed a plausible mechanism pathway that would permit approval of certain treatments based on limited clinical evidence, coupled with post-approval evidence generation. The purpose of this analysis is to explore key drivers of FDA decision making.
METHODS: FDA website and grey literature were searched to identify orphan drug NDAs which resulted in Complete Response Letters (CRL) in 2025. Outcomes included drivers of the decision and what recommendations were made by the FDA. Positive decisions and considerations for HTA will also be explored in the full analysis.
RESULTS: Thirteen orphan medicines were identified which received a CRL from the FDA in 2025. Manufacturing issues and evidence issues were the key reason in seven and six cases, respectively. Of these six, substantial evidence of efficacy was not demonstrated in two cases, the benefit-risk profile was considered not to be favorable in one case, and trials were considered inadequate in three cases; one of these was due to inherent issues with externally controlled/RWE studies.
CONCLUSIONS: Recent FDA decisions highlight the extent to which flexibility in the evidence package for orphan diseases is required. Where significant changes to the clinical evidence are needed, sponsors and patient groups raise concerns that a generation of patients may go without access to a potentially life-saving therapy; the proposed plausible mechanism pathway could be an important step in bridging this gap, although this will lead to implications for HTAs and how they review each new technology and determine value.