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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.)

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sini M. Eskola conducts a part-time professional PhD at Utrecht Centre for Pharmaceutical Policy and Regulation. In her daily work, she holds a position as Director Regulatory Strategy and Team Leader at European Federation of Pharmaceutical Industries and Associations (EFPIA). This research is independent and not funded by EFPIA. Andrew Bate is a full-time employee and stock and options holder in GlaxoSmithKline. The views expressed in this article represent the author’s own thoughts and are independent of their employers. This research is independent and not funded by GSK. Hubertus G.M Leufkens, Marie L. De Bruin, and Helga Gardarsdottir are employed by Utrecht University conducting research under the umbrella of the Centre for Pharmaceutical Policy and Regulation. This centre receives no direct funding or donations from private parties, including those in the pharmaceutical industry. Research funding from public–private partnerships (e.g., IMI, The Escher Project (http://escher.lygature.org/), is accepted under the condition that no company-specific product or company-related study is conducted). The centre has received unrestricted research funding from public sources, for example, the World Health Organization (WHO), Netherlands Organization for Health Research and Development (ZonMW), the Dutch National Health Care Institute (ZIN), EC Horizon 2020, the Dutch Medicines Evaluation Board (MEB), and the Dutch Ministry of Health., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

There is a growing trend for pharmaceutical companies to seek scientific advice on drug development from a Health Technology Assessment (HTA) perspective, to improve the efficiency of their studies, enable better trial design, and support the goals of positive HTA recommendation for reimbursement. This study uses information collected directly from companies on individual products to assess their strategies and practices for seeking HTA-related scientific advice in terms of which stakeholders to engage and for what purpose, when to seek scientific advice, and whether to implement that advice within global clinical development., 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 © 2021 Elsevier Ltd. All rights reserved.)

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making., (Copyright © 2018 Elsevier Ltd. All rights reserved.)