Therapeutic innovation & regulatory science最新文献

Purpose: The orphan legislation came into force in the European Union (EU) in 2000, providing incentives for the development of orphan medicines. To be eligible for incentives, the applicant needs to apply for an orphan designation (OD). However, at any time, the marketing authorisation holder (MAH) can request the removal of the OD. The possible motives underpinning premature removal of OD have been the subject of speculation. Our aim is to study every early OD removal for the orphan medicinal products (OMPs) approved in the EU between 2000 and 2024 and determine the main reasons behind this phenomenon.

Methods: We identified all the orphan medicines approved between 2000 and 2024. We considered approval date by the European Commission (EC), orphan designation (OD) status, company name, active substance name, trade name, ATC code and Therapeutic Area, and the date of the removal of the OD. Information on the OD withdrawal was cross-checked with the documents on the EMA website, and the legal status of the patent and supplementary protection certificates (SPC) was checked at the European Patent Register.

Results: During the period 2000-2024, 285 OMPs were approved by the EC. Overall, 41 (11.8%) orphan designations were prematurely removed, corresponding to 23 different OMPs.

Conclusions: Three main motives for the early removal of the OD were identified: lack of clinical evidence supporting the significant benefit for the new indication proposed, the companies' preference towards SPC extensions for the paediatric indication (instead of the two additional years of marketing exclusivity), or the new therapeutic indication added is not rare. There is no evidence of commercial "pay to enter" agreements between pharmaceutical companies.

Background: Data integrity (DI) has become a cornerstone of regulatory oversight in pharmaceutical manufacturing. The COVID-19 pandemic coincided with increased digitalization and wider use of remote inspection approaches, drawing renewed attention to data governance. In response, global regulatory agencies emphasized structured DI compliance through harmonized guidelines. However, empirical studies quantifying longitudinal enforcement patterns remain limited.

Methods: This study conducted a full-enumeration analysis of 1766 FDA Warning Letters issued between 2016 and 2023. DI-related violations were reclassified into nine categories based on the ALCOA and ALCOA + frameworks using a predefined rubric derived from EMA, PIC/S, and WHO guidance. Violations were segmented into pre-pandemic (2016-2019) and post-pandemic (2020-2023) periods. Descriptive statistics and exploratory t-tests and chi-square analyses were used to identify directional trends.

Results: Although statistical tests did not yield significant differences between the two periods, violations related to "Endurance," "Availability," and "completeness" showed year-over-year increases after 2020. The average number of DI violations per company increased in 2023. Because fewer firms were cited that year, this pattern may reflect more targeted inspections or an atypical case mix. However, causality cannot be inferred.

Conclusion: The observed patterns are consistent with a regulatory emphasis on risk-based DI oversight, particularly under remote or hybrid inspection models. For manufacturers-especially in PIC/S member countries where hybrid documentation persists-these findings underscore the practical importance of strengthening electronic quality systems. By offering a standardized ALCOA/ALCOA + -based rubric aligned with international guidance, this study provides a replicable framework for future DI inspection analysis and policy discussion.

Background: The Biomarker Qualification Program (BQP), formally established in 2016 under the 21st Century Cures Act, is a key pathway for developing novel biomarkers for regulatory use. We evaluated eight years of BQP experience to assess whether it has facilitated the qualification of novel biomarkers.

Methods: We collected characteristics and submission dates for accepted biomarker qualification projects from the FDA's Drug Development Tool Qualification Project Search database.

Results: As of July 1, 2025, 61 projects were accepted into the BQP. Safety (30%), Diagnostic (21%), and PD Response (20%) biomarkers were the most common. Projects primarily used molecular (46%) and radiologic/imaging (39%) methods and were split between measures of a disease/condition or drug response/effect of exposure. Few projects included surrogate endpoint biomarkers (n = 5). Half of the accepted projects remained at the initial Letter of Intent (LOI) stage, and only eight biomarkers were qualified through the program. LOI and Qualification Plan (QP) reviews frequently exceeded FDA targets by three months and seven months, respectively. For projects reaching the QP stage, QP development took a median of 32 months, with surrogate endpoints taking 47 months.

Conclusion: The BQP supports the development of certain biomarkers but has seen limited use for biomarkers intended as surrogate endpoints. Coupled with longer timelines for their QP development, these trends demonstrate the program may not be well-suited for advancing novel response biomarkers. Given significant stakeholder interest in novel surrogate measures, a dedicated program may better support novel response biomarker development, particularly for biomarkers with applicability across multiple drug development programs.

Introduction: Generic drug entry into the pharmaceutical market typically leads to a substantial decline in originator sales. Understanding the extent and trajectory of this erosion is essential for effective lifecycle management and strategic planning. This study quantified sales erosion after generic entry for originator drugs approved in the United States between 2010 and 2019 and developed a model to predict year-specific sales retention based on key product- and market-level characteristics.

Methods: A total of 140 originator drugs were analyzed using FDA approval records and sales data from Evaluate Pharma. Five-year retention patterns were modeled using a three-parameter exponential decay function. Subgroup analyses were conducted by year of generic entry, therapeutic class, and product-specific features. A polynomial regression model using 700 product-year observations incorporated three binary market indicators and linear and quadratic time terms.

Results: Sales retention declined from 73.1% in the first year after generic entry to 31.7% by year five. The exponential decay model demonstrated a strong goodness-of-fit (root mean squared error [RMSE] = 0.006), capturing the initial steep decline and subsequent stabilization. Subgroup analyses showed faster erosion for blockbuster drugs and in markets with multiple first-generation generics. The regression model explained 96.4% of annual variation in retention (RMSE = 0.033), accounting for product and market heterogeneity.

Conclusion: Sales decline after generic entry follows a predictable yet heterogeneous trajectory shaped by product and market factors. Exponential decay and polynomial regression models together offer a robust framework for forecasting sales retention and guiding strategic decisions in the pharmaceutical industry.

Background: The method of collecting electronic patient-reported outcome (ePRO) data using the bring your own device (BYOD) approach has become very common recently, especially in clinical trials. We conducted a preliminary study to evaluate the processes before introducing ePRO using BYOD in regulatory-required observational post-marketing surveillance (PMS) in Japan.

Methods: We conducted a multicenter observational study using a two-period, two-sequence, cross-over design. Participants were allocated to Group 1 (starting with ePRO) or Group 2 (starting with paper PRO). The observation period was 14 days in total: seven days each for ePRO and paper PRO. We assessed the usability, implementation process, support system, and materials for ePRO through questionnaires.

Results: All participants in Group 1 (n = 78) and Group 2 (n = 73) were included in the analysis set. The collection of information with ePRO was comparable to that with paper PRO. We found no remarkable difference in data entry status between ePRO and paper PRO based on sex and no trend toward a higher proportion of missing data in ePRO with age. More than half of the participants responded favorably to most of the questionnaire items about ePRO. Although the investigators considered the materials for the ePRO system useful, there is still room for improvement.

Conclusion: Our two-week pilot indicates that ePRO can achieve data completeness comparable to paper in motivated clinics. The points to consider when using ePRO in actual PMS were confirmed. Further assessment in actual studies conducted in compliance with local regulations is needed.

Background: Legislative initiatives have spurred an increase in pediatric drug development programs. However, some drug products studied in the pediatric population have not received an approved pediatric indication, and efforts have been made to improve the outcomes of a greater percentage of pediatric trials.

Objective: This analysis evaluated the rate of failure and the factors associated with those unsuccessful outcomes of recent pediatric drug development programs in comparison to earlier pediatric drug development programs.

Methods: Publicly available information for non-oncology pediatric drug development programs submitted to the FDA between 2015 and 2022 were reviewed.

Results: FDA reviews and drug product labeling for 211 drug products were examined. Of these, 32 (32/211, 15%) drug products for which pediatric trials were conducted did not receive an approved pediatric indication. The reasons for these unsuccessful outcomes were failure to demonstrate effectiveness only (18/32, 56%), failure to demonstrate safety only (7/32, 22%), or failure to demonstrate both effectiveness and safety (7/32, 22%). The psychiatry (8/32, 25%) and pain (5/32, 17%) therapeutic areas had the highest number of drug products that did not receive a pediatric indication.

Conclusion: The findings from this review suggest that, although this represents an improvement from pre-2012 pediatric drug development programs, that basic problems are still encountered in pediatric trial designs and dose selection. The 15% failure rate may represent close to a best-case scenario for pediatric drug development presently, but an increased use of pediatric extrapolation could change that.

Background: In Japan, prescription drug labeling has transitioned to a new structured format aimed at improving clarity and consistency, with full implementation in March 2024. Abnormal kidney function, a critical determinant of drug safety, necessitates clear and consistent contraindication labeling. However, current labeling practices have not been comprehensively evaluated.

Objective: To systematically assess how kidney-related contraindications are described in Japanese package inserts under the new labeling format.

Methods: We reviewed all electronically available prescription drug package inserts as of October 1, 2024. Using 20 kidney-related keywords, we extracted and analyzed statements in Sect. 2 ("Contraindications"), categorizing them into four domains: type of impairment, severity, disease progression, and quantitative criteria. Additionally, a network diagram of co-occurring terms was developed to illustrate the consistency and diversity of terminology.

Results: A total of 233 kidney-related contraindication statements were identified across 182 pharmaceutical ingredients. Type of impairment was mentioned in 81.5%, severity in 54.9%, and quantitative criteria in 38.2%. However, the terminology and threshold values used were inconsistent. Terms such as "severe abnormal kidney function" were used without standardized definitions, and quantitative parameters (e.g., creatinine clearance, estimated glomerular filtration rate) varied across products.

Conclusion: Despite regulatory efforts to enhance labeling structure, kidney-related contraindication descriptions in Japan remain variable and lack standardization. These inconsistencies may hinder safe prescribing practices and the integration of labeling into clinical decision support systems. Adoption of internationally harmonized terminology, such as KDIGO staging, and clearer regulatory guidance may improve the clinical utility of drug labeling.

Background: The World Health Organization (WHO) developed the WHO Global Benchmarking Tool (GBT) to assess and benchmark the drug regulatory systems and practices in national medicines regulatory authorities (NMRAs). The objective of the study was to identify strengths and opportunities for improvement by comparing the regulatory performance of the NMRAs in Egypt, Ghana, Nigeria, South Africa, Tanzania and Zimbabwe, all which have attained maturity level 3 status for medicines and /or vaccines, in order to enhance regulatory review processes and patients' access to medicines and/or vaccines.

Methods: The NMRAs selected for the study completed a questionnaire that collected data and metrics that facilitated comparative studies among the NMRAs.

Results: The comparative study showed that similarities among these authorities also translated into their strengths. The study revealed that the human resource capacity in African NMRAs is inadequate to fully execute regulatory mandates. Review process map comparison revealed the important observation that these NMRAs conducted labelling review early in the review process rather than in the latter stages of the process.

Conclusion: The study has identified the regulatory best practices that led to the NMRAs achieving WHO GBT maturity level 3. The African Medicines Agency should engage these maturity level-3 NMRAs to explore ways of benefiting from their experience and resources. It is hoped that through such engagement, the NMRAs will be encouraged to further develop their capacity to help the AMA to achieve its mandate. Additionally, by addressing the identified gaps and recommendations in the study these NMRAs can achieve WHO GBT maturity level 4 whilst NMRAs who have not yet reached GBT maturity level 3 can also benefit from this study in order to reach higher maturity levels.

Background: Patients often have suboptimal understanding of informed consent in clinical trials, impeding their ability to make informed decisions about participation. Additionally, translating complex informed consent information from English into other languages can introduce new areas of misunderstanding for patients. This qualitative study examined how English- and Spanish-speakers understood and perceived a complex clinical informed consent form.

Methods: We tested an informed consent form for a clinical trial on a gynecological medication with women who represented the study population. We conducted 18 semi-structured interviews with English- (n = 9) and Spanish-speaking (n = 9) participants to explore areas of misunderstanding, concerns, and preferences. With Spanish-speakers, we tested two professionally translated versions of the informed consent form-one generated by general translators and the second by translators with medical and scientific expertise. We used thematic analysis to explore patterns in the data.

Results: Five themes were common across both English- and Spanish-speakers: difficulty with medical jargon; unfamiliarity with the drug development and testing process; desire for understandable numeric information; aversion to uncertain or conflicting evidence; and affective reactions to information. Spanish-speakers generally preferred language from the medical translation over the general version, though this preference was not consistent.

Conclusions: Findings underscore the importance of pretesting informed consent materials to ensure that they are understandable, avoid difficult language, and do not evoke negative emotions or reactions, particularly when communicating about risk and uncertainty. Findings also suggest using a combination of translation approaches, when resources allow, and reinforce the value of using plain language familiar to audiences.