Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.Copyright © 2023, Matrix Medical Communications. All rights reserved.

Beyond Value Assessment: Payer Perceptions of ICER's Policy Initiatives

Objectives: To assess how the Institute for Clinical and Economic Review (ICER) has evolved its policy scope beyond value assessments in the last 7 years and explore payer perceptions of ICER's new policy initiatives. Method(s): Completed ICER assessments and policy papers published from 2016-2022 were counted to quantify ICER's activities and output. Double-blinded, web-based surveys of US healthcare payers were fielded through Xcenda's research panel, the Managed Care Network, in October 2020 (N=47) and June 2022 (N=51) to explore perceptions of ICER initiatives, including policy papers, Unsupported Price Increase (UPI) reports, and ICER Analytics. Result(s): ICER has published 65 value assessments and 17 policy papers since 2016. ICER's output of policy papers has increased in recent years (mean of 1.3 publications annually, 2016-2018 vs 3.7 annually, 2020-2022), whereas the number of value assessments has remained flat (mean of 9.3 assessments annually, 2016-2018 and 2020-2022). Payers perceive ICER's policy initiatives to be of varying degrees of usefulness. In 2020, the subset of payers reporting familiarity with ICER initiatives found the policy paper on valuing cures to be the most useful initiative (42% reporting extremely or very useful [n=38 reporting familiarity]), followed by the UPI report (40% [n=40]);the policy paper on COVID-19 pricing models was viewed as least useful (22% [n=37]). In 2022, the most useful initiatives among payers reporting familiarity were ICER Analytics (51% [n=49]) and the policy paper on orphan drugs (45% [n=47]);the policy paper on fair access was perceived as least useful (29% [n=44]). Conclusion(s): ICER's output of annual policy papers has increased over time, demonstrating ICER's growing investment in policy initiatives. Payer perceptions of the usefulness of ICER initiatives vary, with ICER Analytics being the most useful in 2022. Additional research is needed to better understand how payers use ICER's policy papers/initiatives to inform decision making.Copyright © 2023

FDA Approvals of Biologics in 2022.

The year 2022 witnessed the control of the COVID-19 pandemic in most countries through social and hygiene measures and also vaccination campaigns. It also saw a decrease in total approvals by the U.S. Food and Drug Administration (FDA). Nevertheless, there was no fall in the Biologics class, which was boosted through the authorization of 15 novel molecules, thus maintaining the figures achieved in previous years. Indeed, the decrease in approvals was only for the category of small molecules. Monoclonal antibodies (mAbs) continued to be the drug class with the most approvals, and cancer remained the most targeted disease, followed by autoimmune conditions, as in previous years. Interestingly, the FDA gave the green light to a remarkable number of bispecific Biologics (four), the highest number in recent years. Indeed, 2022 was another year without the approval of an antimicrobial Biologic, although important advancements were made in targeting new diseases, which are discussed herein. In this work, we only analyze the Biologics authorized in 2022. Furthermore, we also consider the orphan drugs authorized. We not only apply a quantitative analysis to this year's harvest, but also compare the efficacy of the Biologics with those authorized in previous years. On the basis of their chemical structure, the Biologics addressed fall into the following classes: monoclonal antibodies; antibody-drug conjugates; and proteins/enzymes.

Changing Landscape of Orphan Drug Reimbursement - Evidence From EU-4 and England

Objectives: This study compares the rates of positive reimbursement decisions in EU-4 and England for ODs approved by the European Commission (EC) in 2015 and 2020 to determine whether patient access to Orphan Drugs (ODs) is improving. Method(s): ODs approved by the EMA in 2015 and 2020 were identified. Their reimbursement status in EU-4 and England was recorded as of June 2017 and June 2022 respectively. Time to Reimbursement (TTR) was calculated for reimbursed ODs. Result(s): 12 ODs approved by EMA in 2015 and 22 ODs approved in 2020 were analysed. The percentage of positive recommendations (out of those which entered the HTA process) remained the highest in Germany (92%->100%), increased in Italy (50->73%) and England (20%->41%), and decreased in Spain (45%->39%). A decrease was also noted in France (64%->33%), however, thanks to the early access program (ATU), patients could access respectively 81% and 94% of assessed ODs. Germany remained the country with the shortest median TTR (1.1->1.3 months). For the remaining countries, an overall improvement can be seen in median TTR in Italy (13.6->10.1 months) and France (14->11.1 months), while median TTR in Spain (12.6->18 months) and England (8.7->12.2 months) increased. Conclusion(s): Germany continuously provides the most robust patient access to ODs, owing to the strategy of not limiting the access during the price negotiation. Wide access to ODs is maintained in France despite an increased percentage of ODs still in the price negotiation due to the Early Access programme. The largest improvement can be seen in Italy which corresponds to the legislative changes in the pricing negotiation process and their COVID-19 mitigating strategies. In England, the increased percentage of positive recommendations coincides with the increased median TTR, presumably due to the higher number of ODs in the reimbursement process. With issues identified in previous research prevailing, Spain remains the most challenging market. Copyright © 2022

Capture and passive predation in times of COVID-19 pandemic.

In the midst of a health crisis, a drug in development and candidate for COVID-19 contagious disease was granted orphan-drug designation (ODD). This decision by the US Food and Drug Administration was immediately denounced as an abuse of the Orphan Drug Act (ODA). This paper outlines how this decision may be considered as the result of a complex case of capture along the regulatory process. Therefore, a case study of the remdesivir episode is conducted, combining the definition of a framework for the analysis of capture and the identification of stylized facts marking the trajectory of a repositioned drug and candidate for COVID-19. In doing so, arguments are put forward to show to what extent this granting of ODD can be described as the result of a series of captures, a case of weak capture however that calls for an amendment of the ODA to preclude drugs for contagious and communicable epidemic diseases from obtaining orphan status in the first place.

In vitro activity of cysteamine against SARS-CoV-2 variants.

Global COVID-19 pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Continuous emergence of new variants and their rapid spread are jeopardizing vaccine countermeasures to a significant extent. While currently available vaccines are effective at preventing illness associated with SARS-CoV-2 infection, these have been shown to be less effective at preventing breakthrough infection and transmission from a vaccinated individual to others. Here we demonstrate broad antiviral activity of cysteamine HCl in vitro against major emergent infectious variants of SARS-CoV-2 in a highly permissible Vero cell line. Cysteamine HCl inhibited infection of wild type, alpha, beta, gamma, delta, lambda, and omicron variants effectively. Cysteamine is a very well-tolerated US FDA-approved drug used chronically as a topical ophthalmic solution to treat ocular cystinosis in patients who receive it hourly or QID lifelong at concentrations 6 times higher than that required to inhibit SARS CoV-2 in tissue culture. Application of cysteamine as a topical nasal treatment can potentially1) mitigate existing infection 2) prevent infection in exposed individuals, and 3) limit the contagion in vulnerable populations.

Abstracts of the 13th International Society for Priorities in Health Conference

The proceedings contain 114 papers. The topics discussed include: responsibility in a pandemic: should vaccination status be used to distribute scarce medical resources?;a global redistributive auction for vaccine allocation;developing and implementing a framework for priority setting in health and social care in Scotland;gaps in healthcare services leading to high extra-pulmonary tuberculosis un-addressed high economic burden of extra-pulmonary tuberculosis patients;the ideas behind charging for non-attendance in healthcare: an analysis of key policy documents in Denmark and Norway;criteria for priority setting in the COVID-19 pandemic plans: a global comparative analysis;stakeholder involvement in the COVID-19 pandemic response and preparedness plans: a synthesis of findings in 86 countries;global health governance in pandemic preparedness at world health organization. topics and forthcoming debates;and there something special about rare diseases? examining societal preferences for exempting orphan drugs from cost-effectiveness criteria for reimbursement.

CRISPR gene editing: a revolution in progress

CRISPR is a gene editing technique that has revolutionised research and has the potential to transform the treatment of many diseases. This article discusses the principles of the technique, its therapeutic applications and potential safety issues.

Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics.

The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band > 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8-5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients.