Committee For Orphan Medicinal Products Research Articles

Inherited retinal dystrophies and orphan designations in the European Union.

Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.

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.

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.” In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them.

Current state of developing advanced therapies for rare diseases in the European Union

ABSTRACT Objective Advanced Therapy Medicinal Products (ATMPs) present significant therapeutic advantages for inherited rare diseases. However, the development of orphan ATMPs is challenging due to their complexity and unpredictable biological activity. This study aims to comprehensively describe the current state of orphan ATMPs in Europe. Methods Orphan drugs (ODs) granted by European Commission until March 2020 were investigated. The characteristic of diseases and ATMPs were extracted from the public summary reports of ODs from Committee for Orphan Medicinal Products. The methodology for the pivotal studies of ATMPs was extracted. Results A total of 274 ATMPs were identified, covering 116 rare diseases, with metabolic, optical, and oncologic diseases being the most targeted. A total of 158 ATMPs were indicated for life-threatening diseases, 129 ATMPs targeted diseases currently lacking authorized or satisfactory treatment available. Twenty-eight ATMPs are being investigated in the phase II/IIII or phase III studies. The median patient size of pivotal studies was 127, 15 were open-label studies, 8 were single-arm trials, and 14 reported surrogate outcomes. Conclusion There are rapid growths in developing ATMPs for life-threatening diseases with high unmet clinical needs. Optimizing the study methodology and exploring innovative design to facilitate the market access is paramount.

Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations

To maintain orphan drug status at the time of market authorization, orphan medicinal products (OMPs) need to be assessed for all criteria, including significant benefit, by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). Subsequently, health technology assessment (HTA) organizations evaluate the same OMPs in their relative effectiveness assessments (REAs). This review investigates the similarities and differences between the two frameworks for six HTA organizations, including the European Network for HTA. We discuss differences between both assessment frameworks within five domains (clinical evidence used, patient population, intervention, comparators, and outcome measures) for all drugs. Five illustrative cases studies were selected for a qualitative review.

Orphan drug designation in Europe: A booster for the research and development of drugs in rare diseases

The research and drug development process in rare diseases is challenging in addition to those for common diseases. To stimulate its development, the orphan drug designation (ODD) was introduced in in European Union in 2000. In the present paper, we describe the main characteristics of ODD in European Union in particular the requested criteria for ODD, the overview of the general procedure and the main incentives for Sponsors and finally the predicted factors related to successful development and marketing approval of orphan drugs after designation. In accordance with regulation, an application for ODD must be submitted to European Agency including a scientific part based on relevant scientific literature related to the condition and results on experimental studies with the specific product (and clinical studies if available). Three following criteria are a central position in this application: medical plausibility, rarity and medical significant benefit. The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Even if pre-submission meetings are not mandatory, EMA strongly encourages sponsors to request a pre-submission meeting with the Agency prior to filing an application. Experience has shown that they have a positive impact on the success rate of the applications. The full application should be submitted in English via secure online portal. ODD makes the sponsor eligible for a number of orphan incentives including the 10-year market exclusivity and the protocol assistance by COMP. Based on literature and on the experience accumulated by our team ORPHANDEV F-CRIN-labelled platform the successful translation of rare disease research into orphan drug discovery is dependent of a clearly justified medical significant benefit, the disease class, its prevalence and the disease-specific scientific output, previous experience of the sponsor with a previous successful orphan drug to the market increased.

Blinatumomab for Acute Lymphoblastic Leukemia: The First Bispecific T-Cell Engager Antibody to Be Approved by the EMA for Minimal Residual Disease.

On November 15, 2018, the Committee for Medicinal Products for Human Use (CHMP) recommended the extension of indication for blinatumomab to include the treatment of adults with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab was authorized to treat relapsed or refractory B-precursor ALL, and the change concerned an extension of use. On March 29, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to blinatumomab to treat both adults and children with B-cell precursor ALL who are in remission but still have MRD. On July 26, 2018, the CHMP had originally adopted a negative opinion on the extension. The reason for the initial refusal was that although blinatumomab helped to reduce the amount of residual cancer cells in many patients, there was no strong evidence that it led to improved survival. During the re-examination, the CHMP consulted the scientific advisory group. The CHMP agreed with the expert group's conclusion that, although there was no strong evidence of patients living longer, the available data from the main study (MT103-203) indicated a good durable response to blinatumomab, with an overall complete response rate for the primary endpoint full analysis set (defined as all subjects with an Ig or T-cell receptor polymerase chain reaction MRD assay with the minimum required sensitivity of 1 × 10-4 at central lab established at baseline [n = 113]) as 79.6% (90/113; 95% confidence interval, 71.0-86.6), with a median time to complete MRD response of 29.0 days (range, 5-71). Therefore, the CHMP concluded that the benefits of blinatumomab outweigh its risks and recommended granting the change to the marketing authorization. The Committee for Orphan Medicinal Products, following reassessment, considered that significant benefit continued to be met and recommended maintaining the orphan designation and thus 10 years market exclusivity (the Orphan Designation is a legal procedure that allows for the designation of a medicinal substance with therapeutic potential for a rare disease, before its first administration in humans or during its clinical development). The marketing authorization holder for this medicinal product is Amgen Europe B.V. IMPLICATIONS FOR PRACTICE: Immunotherapy with blinatumomab has excellent and sustainable results, offering new hope for patients with minimal residual disease-positive acute lymphoblastic leukemia, a disease with poor prognosis. New recommendations and change of practice for treatment of this patient group are detailed.

The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

Defining orphan conditions in the context of the European orphan regulation: challenges and evolution.

The definition and acceptability of an orphan condition is pivotal for the assessment of European orphan medicinal product designation applications, and consequently the eligibility for incentives. Here, based on the experiences of the Committee for Orphan Medicinal Products, we discuss how to define orphan conditions in the context of the European regulatory framework.

2.4 - Regulation Of Orphan Medicinal Products In Europe: History Trends And Challenges

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 1000 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 100 orphan drugs have received marketing authorization in Europe. The COMP has dealt with innovation in several forms including cutting-edge therapies and for many years acted as the “gate-opener” at the EMA for innovative and medically plausible research. Although the market exclusivity granted for an orphan product lasts for 10 years (with a 2 years extension for paediatric development), the knowledge gained during the development process is eternal. To face the growing challenges resulting from the advancements in science, strengthened interactions between all stakeholders were necessary, providing more innovative approaches to the development of orphan medicines, thereby bringing science into regulation and regulation into science. The result of this scientific role of EMA in the field of orphan medicines can be translated into a shift of the products under assessment by the Committee of Human Medicinal Products, so that a significant number of orphan medicines are requesting marketing authorization. This undeniably represents the commitment of all stakeholders to providing further scientific innovation and more treatment options for patients affected by rare diseases. In order to translate more research into treatment, a structured responsive capacity to the continuous evolution occurring in the interface of science and regulation is expected aligned with the aim of having more, better, efficacious, and safer orphan medicines in the years to come.

Negotiating prices of drugs for rare diseases.

Rare diseases are often serious, chronic and life-threatening. The European Union (EU) definition of a rare disease is one that affects fewer than 5 in 10 000 people. (1) At present, more than 6000 rare diseases are known; around 80% of them are genetic disorders and half of them occur during childhood. Grouped together, rare diseases affect 6-8% (or about 30 million people) out of the 508 million population of EU countries. (2) This roughly equals the estimated prevalence of diabetes in the World Health Organization European Region, which in 2013 was 6.8% of 658.7 million adults in the 20-79 year age group. (3) This illustrates the paradox of rarity: each disease is rare but collectively, rare diseases affect many people. (4) In 2009, responding to increasing concerns about the issue, the European Council published a recommendation (2009/C 151/02) on action in the field of rare diseases, recommending Member States to adopt and establish national plans for rare diseases by the end of 2013. (2) Rare diseases are associated with a high psychological burden for the patient but they can also have a major impact on a patient's family. (5) In addition to the health burden on patients, few of these diseases have an effective drug treatment available. This is because the drugs to treat rare diseases (called orphan drugs) are not commercially viable for pharmaceutical companies, due to the small number of patients per disease. To encourage pharmaceutical companies to develop and market orphan drugs, the European Parliament and the European Council published the regulation (EC) No 141/2000 on orphan medicinal products in 1999. (1) Orphan designation for a medicine is granted at the European level by the European Medicines Agency (EMA). Three criteria must be met, as stated in the regulation: (i) the medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating; (ii) the prevalence of the condition in the European Union must be no more than 5 in 10 000 or it must be unlikely that the marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and (iii) no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition. (1) The application for orphan designation, which can be submitted by the sponsor of the medicinal product at any stage of drug development, is then examined within 90 days by the Committee for Orphan Medicinal Products of the EMA. When a medicine is granted orphan designation, several incentives are provided to the sponsor of a clinical trial, as stated in regulation (EC) No 141/2000. (1) These incentives include protocol assistance, scientific advice from EMA before the submission for marketing authorization and market exclusivity of 10 years once the medicine is marketed. This period of market exclusivity can be extended by two years for medicines that comply with an agreed investigation plan for medicines for paediatric care. Finally, depending on the status of the sponsor and the type of service required, reductions in fees to be paid for regulatory activities related to the evaluation of orphan medicinal products by EMA (e.g. protocol assistance, application for marketing authorization) can also be available for the sponsor. By the end of 2015, 89 different orphan medicinal products had received authorization to enter the market from the EMA's Committee for Medicinal Products for Human Use, and 123 other medicinal products intended for rare diseases but without the orphan designation in Europe also received the European marketing authorization. (6) In addition, an increasing number of applications for orphan designation are submitted to EMA each year (Fig. 1). (7) As a consequence, an increasing number of applications for a marketing authorization of an orphan medicinal product is observed each year. …

A Collaborative Approach to encourage research and promote new treatments for orphan diseases

The last two decades has seen a significant increase in the development of medicinal products to treat rare “orphan” diseases, largely due to the EU Orphan Medicinal Product Regulation (2000), but also because of the consistent advocacy by patient groups prior to this regulation. These groups from across Europe joined forces under the umbrella of EURORDIS, to secure the implementation of the regulation and ensure that there was patient representation on the committee at EMA (the European Medicines Agency) which would be responsible for assessing and giving opinions on applications, namely COMP (The Committee for Orphan Medicinal Products). As its Vice-Chair I have the privilege to ensure the patient perspective is always considered during these assessments. I will discuss how COMP works as part of the EMA Human Medicines Research and Development Support Division to promote the development of research into medicinal products for the treatment of rare diseases and how this is also encouraged by EU funding through Horizon 2020. Since rare diseases are a global issue, I describe how the EU is also collaborating with IRDiRC (the International Rare Disease Research Consortium) to provide the critical mass in terms of patient population and skills needed to meet the urgent need for new therapies as quickly as possible.

From Lipoproteins to Chondrocytes: A Brief Summary of the European Medicines Agency's Regulatory Guidelines for Advanced Therapy Medicinal Products

From Lipoproteins to Chondrocytes: A Brief Summary of the European Medicines Agency's Regulatory Guidelines for Advanced Therapy Medicinal Products

Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells

The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor drug, involves the rapid and specific activation of sphingomyelin synthase (SMS), leading to a 4-fold increase in SM mass in tumor cells. In the present study, we investigated the source of the ceramides required to sustain this dramatic increase in SM. Through radioactive and fluorescent labeling, we demonstrated that sphingolipid metabolism was altered by a 24 h exposure to 2OHOA, and we observed a consistent increase in the number of lysosomes and the presence of unidentified storage materials in treated cells. Mass spectroscopy revealed that different sphingolipid classes accumulated in human glioma U118 cells after exposure to 2OHOA, demonstrating a specific effect on C16-, C20-, and C22-containing sphingolipids. Based on these findings, we propose that the demand for ceramides required to sustain the SMS activation (ca. 200-fold higher than the basal level) profoundly modifies both sphingolipid and phospholipid metabolism. As the treatment is prolonged, tumor cells fail to adequately metabolize sphingolipids, leading to a situation resembling sphingolipidosis, whereby cell viability is compromised.

Animal models for metabolic, neuromuscular and ophthalmological rare diseases

Animal models are important tools in the discovery and development of treatments for rare diseases, particularly given the small populations of patients in which to evaluate therapeutic candidates. Here, we provide a compilation of mammalian animal models for metabolic, neuromuscular and ophthalmological orphan-designated conditions based on information gathered by the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) since its establishment in 2000, as well as from a review of the literature. We discuss the predictive value of the models and their advantages and limitations with the aim of highlighting those that are appropriate for the preclinical evaluation of novel therapies, thereby facilitating further drug development for rare diseases.

Orphan Dugs in EU / Lieky na zriedkavé choroby v EÚ

Medical and scientific knowledge about rare diseases is minimal or lacking, thus making research difficulties for pharmaceutical industry. Orphan drugs in EU are under supervision of European Commission, European medical agency (EMA) and Committee for orphan medicinal products (COMP). The presentation provides a brief review of all supportive incentives in the field of orphan medicinal products as: the European orphan medicinal product (OMP) regulation, Guideline on Clinical Trials in Small Populations and Commission Regulation (EC) No 2049/2005 / support of small and medium enterprises (SMEs). It also introduces the concept of Clinical added value of orphan medicinal products, as one of the key instruments to increase the availability of orphan medicinal products in the member states. Separately it stresses the necessity of Health technology assessment implementation in whole process of orphan medicinal product development as well as the implementation of the Europlan indicators into the Slovak National plan

The political empowerment of rare disease patient advocates both at EU and national level

Thirty years ago, the patients were left with many uncertainties, no networks and no access. The rarity of the disease made it difficult to identify specialists, little information could be found. Most of the patients were engaged in a longstanding process of obtaining the right diagnosis and treatments when these were available. Significant inequality was the only standard amongst European countries. In this context, the patients, their parents and relatives have formed clusters, reached out to other families and established patient organisations for their own diseases. The scarcity and scattered expertise on rare diseases have led patient organisations in Europe, since the early 1980s to become the link between patients and experts so to support the emergence of specific medical communities, to raise awareness and advocate for patients’ needs. Gradually, National Alliances of Rare Diseases were created to promote their rights at the national level. In March 1997, the European Organisation for Rare Diseases (EURORDIS) was established to build a strong pan-European community and critical mass to voice patients’ common needs and expectations, the European level being the most relevant to develop meaningful solutions. People Living with Rare Diseases have shaped the concept of rare diseases as a public health policy issue: very heterogeneous diseases linked together around the specificity of rarity. Commonalities are: low prevalence, chronic, severe and often life threatening disease, limited scientific and medical knowledge base, lack of investments, winding road to diagnosis and treatment, social exclusion. Rare disease patients’ organisations are advocating across all rare diseases and all European countries. In the 1990s, new catalysing factors included scientific breakthroughs such as the mapping of the human genome and biotech therapies, and the emergence of internet as a powerful tool for information sharing. The Committee for Orphan Medicinal Products constitutes a corner stone in developing treatments for rare diseases as much as to prompt patients’ participation in the decision making processes. Driven by a common agenda, rare disease patients promote innovative approaches to design research and healthcare policies, from medical intervention to quality of life, adapted to small populations. Today, Rare Diseases are high on the European political agenda. European Member States are in the process of adopting national plans for rare diseases integrated within a coherent European policy framework. The active role of patients' representatives is now recognised as a major contribution to innovation and as catalyzing cooperation and sustainable development.

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.

The Digest/The Wire

The Digest/The Wire

Scientific advice for orphan drugs: Critical points and perspectives

The orphan designation procedure relates to medicinal products for human use aimed at the treatment, prevention or diagnosis of diseases. It is a free of charge procedure and can be requested at any stage of the development by a sponsor who can be either a company or an individual, as long as is established in EU, Iceland, Liechtenstein, and Norway. Once the Committee for Orphan Medicinal Products (COMP) adopts opinion on designation, the European Commission grants a decision that gives access to the incentives.