Advancing rare disease treatment: EMA's decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation

Abstract

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency's Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

Fig. 1. Types of data submitted (left) versus those accepted (right) to support the MP criterion in OD applications received for genetically engineered ACT (N = 36).

The number of OD applications that included specific types of data and the proportion of these are given in each coloured box. Data derived from clinical studies is marked in blue, data from both clinical- and non-clinical in vivo studies is marked in orange, data based on non-clinical in vivo studies alone is marked in grey, and pure in vitro data is marked in yellow.

Fig. 2. Clinical data used to support an assumption of MP for OD applications.

A Overview of cases where clinical data were submitted and those accepted as evidence to support MP and the studies the data were collected from (N = 36). B Summary of numbers of patients, divided into four main categories, which were evaluated in the clinical data provided in the submissions and those accepted as evidence for efficacy to support MP (n = 32). C Overview of the clinical endpoints accepted to support MP in the submissions excluding those that were not supported by clinical data (n = 29). CRR complete response rate, CUP compassionate use programme, DCR disease-control rate (including ORR and stable disease), EFS event-free survival, IIS Investigator-initiated study, None No clinical data was provided in the submissions, ORR objective/overall response rate, PFS progression-free survival.

Fig. 3. Arguments for SB (left) versus the claims accepted (right) to support the SB criterion in applications received for OD and maintenance of the status for genetically engineered ACT.

The numbers of submissions were grouped in different coloured boxes according to the arguments given by the sponsors for SB and the claims which were accepted for fulfilling the SB criterion A at the initial OD stage (N = 36) and B at time of review of the criteria for maintenance of OD (N = 14). CRA clinically relevant advantage, E efficacy, MCPC major contribution to patient care, No SB criterion was not considered fulfilled, pts patients, S safety.

Fig. 4. Clinical data used to demonstrate SB in applications for maintenance of the OD at time of MA or MA extension (N = 14).

A Overview of numbers of patients and patient populations evaluated in the clinical data derived from the sponsors’ own studies of the new products which were used to justify SB. B The primary- (x-axis) and secondary endpoints (y-axis) of the clinical studies conducted by the sponsors used to support SB. C Numbers of submissions highlighting the type of comparative data presented and those accepted for demonstrating SB. “No” denotes those two cases where SB was not considered fulfilled. ALL acute lymphoblastic leukaemia, CRA clinically relevant advantage, CRR complete response rate, DLBCL diffuse large B-cell lymphoma, EFS event-free survival, FL follicular lymphoma, INV investigator, IRC independent review committee, ITT intent-to-treat (patients enroled), MCL mantle cell lymphoma, mITT modified ITT (patients infused/treated), MM multiple myeloma, ORR objective/overall response rate, OS overall survival, PFS progression-free survival, PMBCL Primary mediastinal large B-cell lymphoma, pts patients, 2 L second-line therapy, 2 L+ second- and later lines of therapy, 3 L+ third- and later lines of therapy, 4 L+ fourth- and later lines of therapy.