Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

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.

[Evidence-based health care with pharmaceuticals for rare diseases: the role of digitalisation]. / Evidenzbasierte Arzneimittelversorgung bei Seltenen Erkrankungen: die Rolle der Digitalisierung.

Knowledge generation in the field of drug development for people with rare diseases (RDs) faces particular difficulties. This paper will show what improvements are expected from increasing digitalisation from the perspective of three healthcare institutions: the Federal Institute for Drugs and Medical Devices, the Institute for Quality and Efficiency in Health Care and the Federal Joint Committee.First, the potential of digitalisation to increase the efficiency of clinical development and regulatory decision-making through earlier collaboration of all stakeholders is proposed. Subsequently, it is argued that digitalisation should be used to reduce barriers to the implementation of care-associated randomised controlled trials, including those based on registries. High-quality registry studies should not only be started after approval but during the approval process, so that the evidence necessary for therapy decisions is available promptly after approval. Finally, it is stated that improving the evidence base through qualitative improvement of the data sources and their linkages directly benefits patients. Usable evidence that can be generated over a longer period of time - also beyond approval - and contribute to decisions within healthcare system ensures effective drug provision.The institutions agree that high-quality indication registries should be developed as product-independent, standing infrastructures so that high-quality data can be accessed early in the development of medicines for RD.

Licensing of Orphan Medicinal Products-Use of Real-World Data and Other External Data on Efficacy Aspects in Marketing Authorization Applications Concluded at the European Medicines Agency Between 2019 and 2021.

Background: Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions. Methods: Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019-2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of "significant benefit" for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review. Results: While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting. Conclusion: Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.

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.

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.

Demonstrating significant benefit of orphan medicines: analysis of 15 years of experience in Europe.

In the European Union demonstration of 'significant benefit' is mandatory if satisfactory methods exist for a disease targeted by a new orphan medicinal product. Significant benefit is required at the time of orphan designation, when it can be supported by preclinical studies, and at the time of marketing authorization, when clinical data are needed. For the first time, our work has identified, defined and organized the scientific grounds on which significant benefit is granted in the European Union, based on a review of the orphan medicinal products authorized in the years 2000-2015, and on the working experience of the Committee of Orphan Medicinal Products. The resulting conceptual framework is a tool for medicine developers to reflect on potential areas of advantage of their candidate products, and for a broad range of stakeholders to stimulate the discussion on the added value of orphan medicines across the whole development lifecycle.

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). The scope of both the OD and the PIP (or waiver) is defined by the agreed condition. OBJECTIVES: The aim of this study was to analyse the approach of PDCO and COMP in defining the appropriate condition for a PIP or OD, respectively, in order to investigate potential challenges in the paediatric development of orphan medicines which have to meet the requirements of both legislations. METHODS: A comparative analysis of PIP conditions and OD conditions was performed for medicines that have been reviewed by both Committees. RESULTS: We found that in the substantial majority of cases there is no divergence between the conclusions of COMP and PDCO with regard to the condition for which a medicine is to be developed. CONCLUSION: These findings demonstrate that a collaborative approach allows both Regulations to work synergistically to foster pharmaceutical development for rare diseases in childhood.

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. These concerns are discussed in detail based on recent examples of applications, which are reflected in published European Medicines Agency (EMA) documents.

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. The COMP has noted discordance between the prevalence of certain haematological malignancies at the time of Orphan Designation and at the time of Marketing Authorisation. Consequently, we conducted a retrospective assessment of Chronic Lymphocytic Lymphoma and Multiple Myeloma/Plasma cell Myeloma as well as several other haematological rare aetiologies frequently subject of orphan designation. These were: Diffuse large B-Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Cutaneous T-Cell Lymphoma (CTCL), Mantle Cell Lymphoma (MCL) and Chronic Myeloid Leukaemia (CML). The review used submissions as well as recent publications and results from external and EMA databases. As a first step in the analysis, an increase over time in the number of people affected was evident for four conditions in the COMP designation documents, whereas for DLBCL, FL, CTCL and MCL there had been no significant change, since the introduction of the Regulation in 2000. Specifically, the prevalence estimates increased from 1.2 to 3.6 per 10,000 for multiple myeloma, from 0.4 to 1.7 in acute lymphoblastic leukaemia, and from 2.7 to 4.85 for chronic lymphocytic leukaemia/small lymphocytic leukaemia and 1 to 2 in 10,000 for chronic myeloid leukaemia. The reasons for the changes in the prevalence of these four haematological conditions over the last 15 years were not assessed but recent publications have alluded to better outcomes due to new treatments being made available. In addition, many orphan diseases have a median age of onset over 60 years so that also the aging of the population may be a relevant contributing factor.

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. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated 'Guideline on the format and context of the applications for designation' and the guidance document 'Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation' available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application.

Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective.

Over the last decades, billions have been spent and huge efforts have been taken in basic and clinical cancer research [CA Cancer J Clin63:11-30]. About a decade ago, the arms race between drugs and cancer cells reached a new level by introduction of tyrosine kinase inhibitors (TKI) into pharmacological anti-cancer therapy. According to their molecular mechanism of action, TKI in contrast to so-called "classic" or "conventional" cytostatics belong to the group of targeted cancer medicines, characterized by accurately fitting with biological structures (i.e. active centers of kinases). Numerous (partly orphan) indications are covered by this new class of substances. Approximately ten years after the first substances of this class of medicines were authorized, patent protection will end within the next years. The following article covers clinical meaning and regulatory status of anti-cancer TKI and gives an outlook to what is expected from the introduction of generic anti-cancer TKI.

First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies.

BACKGROUND: Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide. OBJECTIVES: The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality. SEARCH METHODS: We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries. SELECTION CRITERIA: One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included. DATA COLLECTION AND ANALYSIS: We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias. MAIN RESULTS: Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality. AUTHORS' CONCLUSIONS: We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).