ATMPs in Germany - Orphan Drug Reassessment

👉 For ATMPs being orphan drugs keep in mind the risk of reassessment – challenges and learnings from the orphan drug reassessment of Yescarta.

In German HTA, orphan drugs are privileged: they don’t need to prove the additional benefit vs. an appropriate comparator. 🏷 In fact, the orphan drug status itself proves the additional benefit. The minimum additional benefit for orphan drugs is “non-quantifiable”, no matter what evidence was submitted for HTA. Quantification would be possible, if an RCT shows significant advantages of the orphan drug in patient-relevant endpoints – regardless of the comparator used in the trial.  

📈 If the sales of an orphan drug, e.g. Yescarta, through the statutory health insurance exceed € 30 million in the last twelve months, the orphan drug has to undergo reassessment and has to prove the additional benefit vs. the appropriate comparator.

Yescarta was launched in Germany in November 2018, in December 2022 Yescarta exceeded the € 30 million, this led to reassessment in July 2023. ➡️ Of note, the German HTA body exclusively defined the other CAR-T cell therapies Kymriah and Breyanzi as the appropriate comparator for the new HTA of Yescarta.

By this definition, the German HTA body gave credit to the relevance of CAR-T cell therapies in the German health care context and to recommendations of the German S3-guideline on DLBCL from October 2022. In this version, the S3-guideline recommends CAR-T cell therapies for patients in the indication of Yescarta for the first time.

⁉ Even though, the definition of the appropriate comparator reflects the current standard of care, by time of trial conduction for Yescarta (before 2018) a correct implementation of the (current) appropriate comparator was just impossible. Consequently, the resolution on German HTA from December 2023 resulted in no additional benefit for Yescarta.

Many times, orphan drugs fail in reassessment because direct comparative data vs. the appropriate comparator does not exist. In case of Yescarta, generating such evidence was additionally challenging because the appropriate comparators are CAR-T cell therapies only. It is currently unclear how CAR-T cell therapies can be implemented as comparators in clinical trials.

💡Generating direct comparative evidence for orphan drugs vs. the appropriate comparator can be challenging or even impossible. In addition, ATMPs are becoming more frequently standard of care in Germany in orphan indications and thus possible appropriate comparators in reassessment. Nonetheless, an upside of this trend is the opportunity to reference treatment costs of ATMPs, e.g. CAR-T cell therapies, in reimbursement price negations.

Therefore, early anticipation of the future appropriate comparator, potential trial designs and the possibility of exceeding annual sales of € 30 million is highly advisable for German HTA strategy planning.