Results of health technology assessments of orphan drugs in Germany-lack of added benefit, evidence gaps, and persisting unmet medical needs.

Background: The number of orphan drug (OD) approvals has increased sharply in Europe. In Germany, all ODs are initially subject to a limited assessment after market access. Their added benefit over the standard of care is accepted as established upon EU approval; a regular health technology assessment (HTA) is performed only in certain cases.

Objective: We assessed whether the increase in OD approvals has led to improvements in patient-relevant outcomes as supported by the evidence submitted by market authorization holders (MAHs) for HTA in Germany. We also examined the extent to which these ODs address unmet medical needs.

Methods: The results of limited assessments and regular HTAs of ODs in Germany (January 2011-September 2021, plus January-December 2023) were analyzed to determine their added benefit based on MAH-submitted dossiers. Added benefit was reported separately for each research question generated from the EU-approved therapeutic indications and any sub-indications (e.g., different subpopulations or control interventions) specified for HTA in Germany.

Results: Eighty-nine ODs (limited assessments: sixty-nine; regular HTAs: twenty) were evaluated in 175 research questions (limited assessments: ninety-seven; regular HTAs: seventy-eight). The added benefit granted in limited assessments was non-quantifiable in nearly eighty percent of the ninety-seven questions. In regular HTAs, no proof of added benefit was shown in fifty-four percent of the seventy-eight questions, mainly due to insufficient comparative data with the standard of care. Established treatments were available for fifty-eight percent of the seventy-eight questions; more than half of which addressed oncology indications (although these account for only eight percent of rare diseases).

Conclusions: Due to evidence gaps in post-approval HTA, many ODs approved in the EU lack proof of added benefit in terms of improving patient-relevant outcomes. Moreover, most approved ODs are indicated for diseases with established treatments and oncology indications, while many unmet medical needs remain. Incentives are required to encourage research in areas of unmet medical need and to generate comparative data with the standard of care.