Trends from two decades of orphan designations in paediatric rare neuromuscular diseases.

Rare diseases are characterized by substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Since the inception of EU orphan regulation in 2000 the European Medicines Agency Committee for Orphan Medicinal Products has received several applications for paediatric rare neuromuscular diseases (PERAN) however treatment options remain limited. Here we discuss the results form an observational, retrospective, cross-sectional study to characterize the currently authorised orphan medicinal products (OMP) and orphan designations (OD) given to products for PERAN in the last two decades. In the EU about half of PERAN diseases have at least one active OD approved since 2000, and about half of these are for Duchenne muscular dystrophy (DMD). The large majority of PERAN diseases do not have an authorised medicine with only 6 OMP currently authorised for Spinal muscular atrophy (3); DMD (1) and Myasthenia gravis (2). One in five products have inactive or discontinued regulatory development but clinical trials are ongoing for the vast majority of PERAN diseases, and more than half are in the final stage of clinical research with significantly more products with medical plausibility based in clinical data reaching advanced stages in clinical development.

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

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.

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products.

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

The translational value of animal models in orphan medicines designations for rare paediatric neurological diseases.

Rare diseases are characterized by a substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Appropriate animal models, based on the knowledge of the molecular pathology of the human disease, are a significant element to support the medical plausibility of an orphan designation during the development of orphan medicines for rare neurological diseases. This observational, retrospective study aims to investigate the clinical or nonclinical nature of data submitted to support medical plausibility of orphan designations in the EU (2001-2019), for a group of rare and paediatric neurological diseases. From our sample of 30 diseases, 70% are rare with paediatric onset and 37% have approved orphan designations. The use of nonclinical data was significantly higher than clinical data (65% vs. 35%, p = 0.013) to support medical plausibility. Examples of diseases, with orphan designations based only in nonclinical data, are also discussed: Aicardi-Goutières syndrome and Centronuclear myopathy animal disease models, potentially used to support medical plausibility of medicines. Nonclinical appropriate models, assessing disease relevant endpoints, may contribute to increase the translational value of animal models, in paediatric and rare neurological area, to accelerate research and the effective development of treatment options.

Use of juvenile animal studies to support oncology medicine development in children.

Childhood cancer has remained a challenge because of long-term effects in children. The need to extend access of children into new cancer therapies requires early prediction of specific safety aspects and juvenile animal studies (JAS) are being conducted to screen for age-related toxicities and differences occurring during postnatal development. This paper investigates oncology approved medicines in the EU (1995-2014) and PIP (Paediatric Investigation Plans - 2007-2014), regarding the usefulness of JAS in their non-clinical development by evaluating information on the medicines labelling. The retrospective review from medicines and PIPs revealed a steady use of JAS to better characterize safety: Approximately 1 in 3 oncology medicine or PIP has conducted JAS. For 6 of the cancer medicines with JAS the toxicity profile in adult and juvenile animals showed some differences in study findings. The discussion of these cases is illustrative of the potential significance that JAS have provided in oncology medicines.

Juvenile animal studies in the development of pediatric medicines: experience from European medicines and pediatric investigation plans.

INTRODUCTION: The need for early consideration of pediatric investigation plans (PIP) to support an indication in pediatric population has led to an increased focus on the relevance of nonclinical studies in juvenile animals (JAS). The usefulness of JAS is not yet established and a criterion for request is still a learning process. OBJECTIVE: This article compares data from JAS in all medicines approved by European centralized procedure before Pediatric Regulation (1995-2005) and data from JAS in the nonclinical information on all approved PIP (2007-2009). RESULTS: Of the 226 substances licensed by centralized procedure in 10 years, 31.9% were considered for children and 31 JAS were described in 9.7%. Since 2007, of the 205 PIP decisions, 50 PIP (24.3%) have 87 JAS planned or requested. The mean number of JAS in each medicine or PIP, increased from 1.4 to 1.7 between the two periods and the juvenile rat remained as the prevalent species. CONCLUSIONS: Results demonstrate that JAS planned/performed in EU environment has significantly increased.