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Abstract: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: In the United States (US) and in Europe, cystic fibrosis (CF) qualifies as a rare disease, thus positioning the field to benefit from regulatory incentives provided by orphan drug designation (ODD) to boost pharmaceutical research and development. In this study, we analyzed the pool of products for the treatment of CF that received such incentives from the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) over the past two decades. We describe the characteristics and trends in ODDs over time and explore factors that might be determinants of successful drug development., Methods: We collected the products that received the ODD from the registries of the FDA and the EMA from 2000 to 2021, characterizing their nature, development stage, and type of sponsor. We categorized the study drugs according to the therapeutic target addressed and described trends of drug development over the study period. A logistic regression analysis was done to assess how ODD characteristics were associated with the approval for market authorization., Results: From 2000-2021, 107 ODDs were collectively granted by the FDA and the EMA for products developed for the treatment of CF. Although the trends of the number of ODDs granted remained stable over time, those targeting the CF basic protein defect increased from 6 out of 54 (11.1%) in the first half of the study period up to 20 out of 54 (37.7%) in the second half, while those treating symptoms decreased from 48/54 (88.9%) to 33/53 (62.3%). Overall, 10 products obtained marketing approval: 7 in both the US and Europe, 3 only in Europe. All the approved ODDs were chemical products for chronic use. No statistically significant difference was found across the examinated variables, but we observed possible drivers of successful drug development for ODDs targeting CFTR, as well as for those with active substances previously marketed, and for those developed by large companies and companies with experience in developing orphan drugs. By contrast, our findings suggest that financial issues most hamper the development of ODDs sponsored by small-medium enterprises., Conclusions: Although ODDs for treating infection and other CF sequelae accounted for the majority, we observed a shift of ODDs toward mechanism-based products over the study period. In line with other rare diseases, we found that approximately 1/10 ODDs for CF reached the status of marketing approval. Advances in disease genetics paved the way for a shift in CF drug development; however, we described how the convergence of pharmaceutical technology, the financial environment, and the regulatory ecosystem played a crucial role in successful marketing authorization in CF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In many countries, β-thalassemia (β-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for β-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of β-THAL; at the same time, and even though only one-fifth of β-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for β-THAL., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the development process for new drugs, dose-finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose-finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose-finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose-finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose-related major objections were raised for 9 orphan drugs. Postmarketing dose-finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose-finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose-finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose-finding studies both pre- and postmarketing., (© 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)