Navigating the orphan medicinal product designation: Evidence requirements for gene therapies in Europe.

To provide insight into regulatory decision-making at the time of granting initial orphan designation by the Committee for Orphan Medicinal Products, we have conducted a retrospective analysis for viral vector-mediated gene therapies in rare non-oncological conditions with respect to the data provided to support the criteria to be met in successful applications. We found that a high proportion of non-clinical in vivo data was used for gene therapies, indicating earlier submissions of products that are at the stage of preclinical research and not in clinical development. Clinical data were submitted in only 13% of the applications, containing preliminary results derived from early-stage clinical trials in few patients.

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.

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.

Orphan Medicinal Products for the Treatment of Pancreatic Cancer: Lessons Learned From Two Decades of Orphan Designation.

Pancreatic cancer has a dismal prognosis and only a few treatment options are available. In the European Union, pancreatic cancer classifies as a rare disease, allowing drug developers to apply for orphan medicinal product (OMP) designation. The aim of this study was to provide more detail on OMPs for pancreatic cancer.

Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit-The EU Regulator's Perspective.

Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the "significant benefit.

Regulatory Standards in Orphan Medicinal Product Designation in the EU.

Twenty years of orphan regulation in Europe have now elapsed, with almost 2,400 orphan designated medicinal products and more than 190 orphan products authorised in the EU. Alongside the evolution in understanding of rare diseases, considerable regulatory knowledge has also been accumulated regarding the level of evidence that would support inclusion of products into the framework. This article reviews publications and regulatory documents pertaining to orphan medicinal product designation in the EU and discusses the general expectations in submitted applications as reflected in the current regulatory practise.

Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries.

Nonclinical data supporting orphan medicinal product designations in the area of rare infectious diseases.

This review provides an overview of nonclinical in vivo models that can be used to support orphan designation in selected rare infectious diseases in Europe, with the aim to inform and stimulate the planning of nonclinical development in this area of often neglected diseases.

Comparative analysis of the scope of European Union paediatric investigation plans with corresponding orphan designations.

Background: Market forces may not be sufficient to stimulate research and development of medicines for small patient populations, such as children and patients with rare diseases. Both the European Union Orphan and Paediatric Regulations were introduced to address the unmet public health needs of these smaller patient populations through the use of incentives, rewards and obligations. Developers for new medicines for rare diseases must agree a paediatric investigation plan (PIP) or waiver with the European Medicines Agency's (EMA) Paediatric Committee (PDCO), and can also apply for an orphan designation (OD) from the EMA's Committee of Orphan Medicinal Products (COMP).

Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions.

Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs.

Establishing rarity in the context of orphan medicinal product designation in the European Union.

In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10,000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation.

Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe.

In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs). We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation.

Evolving prevalence of haematological malignancies in orphan designation procedures in the European Union.

The Committee for Orphan Medicinal Products (COMP) evaluates prevalence of rare conditions as one of the criteria for granting an orphan designation with a prevalence threshold of 5 in 10.000. At the time of Marketing Authorisation (MA) these criteria are reassessed to ensure they are still met.

Establishing medical plausibility in the context of orphan medicines designation in the European Union.

In the European Union, sponsors have the responsibility to demonstrate the "intention to diagnose, prevent or treat" a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as "medical plausibility" and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor.

Use of biomarkers in the context of orphan medicines designation in the European Union.

The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition.

The development and registration of topical pharmaceuticals.

From our own experience we have seen that over the past 60 years topical delivery of drugs with its advantages and disadvantages has become much more widely understood and much more is now known about the disposition of drugs in the skin. Today, pharmaceutical scientists produce dermatological vehicles which are tailored to patients' needs and better appreciate how the formulation may affect rates of drug delivery, and ultimately, efficacy and safety. The guidelines for developing a New Chemical Entity (NCE) to be administered by the topical route are rather straightforward.

European regulation on orphan medicinal products: 10 years of experience and future perspectives.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

Long-term effects of pioglitazone versus gliclazide on hepatic and humoral coagulation factors in patients with type 2 diabetes.

This study compared the long-term effects of pioglitazone and gliclazide on the production of coagulation factors in patients with type 2 diabetes. Patients (n=283) with glycosylated haemoglobin > 7.5% were randomised to receive either pioglitazone (30-45 mg/day) or gliclazide (80-320 mg/day) for one year.

A lifetime modelled economic evaluation comparing pioglitazone and rosiglitazone for the treatment of type 2 diabetes mellitus in the UK.

Introduction: Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin.

Methods: A decision-analytic model employing a first order Monte Carlo simulation of a Markov process was constructed.