Therapeutic innovation & regulatory science最新文献

Background: The Malaysian National Pharmaceutical Regulatory Agency (NPRA) has partnered with the Centre for Innovation in Regulatory Science (CIRS) since 2018 to analyze the approval processes for new active substances (NASs) and biosimilars. Findings from the study on approvals in the year 2017 led to the introduction of several improvement strategies. This study provides an overview of the current review process, including registration pathways, and compares approval times for NASs approved in 2019 vs 2017 to evaluate the impact of the improvement strategies.

Methods: NPRA representatives completed the Country Report using CIRS' Optimizing Efficiencies in Regulatory Agencies (OpERA) questionnaire, identifying key milestones, target timelines, good review and quality decision-making practices, and provided metrics on 24 NASs approved in 2019.

Results: Most indicators for good review practices were implemented by NPRA, with guidelines, standard operating procedures, review templates, and several identifiable quality decision-making practices being in place. NPRA has also introduced several registration pathways with the aim of accelerating approval timelines. Median total approval time decreased from 515 calendar days in 2017 to 399 calendar days in 2019. Reductions were also noted in the median time between dossier receipt and initiation of NPRA scientific assessment.

Conclusions: The study indicates that improvement strategies implemented in 2018 favorably reduced approval times, based on a comparison of products approved in the year 2017 and 2019. Ongoing evaluation of regulatory processes and performance is crucial to identify areas for improvement, eliminating unnecessary steps, and enabling a streamlined and efficient approach.

Implementation of decentralized approaches can improve access to clinical trials. The Australian government has focused on a teletrial model, which resources and upskills health care organisations to enable collaboration in trials to extend to rural and remote areas. This commentary describes the Australian teletrial model, its context within the established DCT model, its value, and likely challenges moving forward.

Purpose: Chimeric Antigen Receptor (CAR)-T cell therapies have emerged as potential therapy for hematological malignancies, however, their safety profiles should be monitored after approval. Therefore, we aimed in this study to explore and analyze individual case safety report (ICSRs) associated with CAR-T cell therapies and reported to the World Health Organization (WHO) global database (VigiBase).

Methods: A retrospective pharmacovigilance study was conducted to describe and characterize Adverse drug reactions (ADRs) reported to Vigibase from inception to March 31st, 2024 and associated with use of the following CAR-T cell therapies: Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel, Lisocabtagene maraleucel, Idecabtagene vicleucel, and Ciltacabtagene autoleucel.

Results: A total of 11,693 ICSRs were identified with the use of CAR-T cell therapies in VigiBase (Axicabtagene ciloleucel (N = 5668, 48.5%), Tisagenlecleucel (N = 3364, 28.8%), Brexucabtagene autoleucal (N = 1027, 8.8%), Lisocabtagene maraleucel (N = 304, 2.6%), Idecabtagene vicleucel (N = 579, 4.9%), and Ciltacabtagene autoleucel (N = 751, 6.4%)). ICSRs completeness score was averaged between 0.2 and 0.57 among all included products and the majority of reported ADRs were serious (67-91%). Among serious ADRs, death was reported with an average percentage of (8.8-21.5%). The majority of ADR reports with fatal outcome occurred in accordance with their approved indications. About 18% of fatal events reported with Tisagenlecleucel as the suspected drug were in the pediatric population.

Conclusion: Our study provides an overall exploration of the post-marketing safety profiles of currently approved CAR-T cell therapies. The significant proportion of fatalities occurred in accordance with approved indications, emphasizes the need for ongoing investigation into ADRs with fatal outcomes, particularly in the pediatric population.

Nirogacestat is the first drug specifically approved for desmoid tumours (DTs), rare, locally invasive tumours originating from connective tissue. This study aimed to explore potential safety concerns associated with nirogacestat, thereby providing references and research directions for subsequent clinical studies. We extracted data on nirogacestat from the FDA Adverse Event Reporting System (FAERS) database between Q4 2023 and Q4 2024 and mined adverse events (AEs) using the reporting odds ratio (ROR). For a separate retrospective analysis, we searched articles from PubMed, Cochrane, and EMBASE from the establishment of the databases until January 25, 2025.The study included 588 patients who were administered nirogacestat. Among all AEs, 89.78% were classified as non-serious. The most frequently reported preferred terms included diarrhoea [ROR (95% CI): 10.58 (9.22-12.13)], nausea [ROR (95% CI): 6.00 (5.06-7.12)], fatigue [ROR (95% CI): 3.77 (3.11-4.58)]. Disproportionality analysis revealed high signal strength for ovarian dysfunction [ROR (95% CI): 963.62 (306.61-3028.55)], ovarian failure [ROR (95% CI): 254.92 (101.73-638.79)], decreased blood phosphorus [ROR (95% CI): 107.66 (64.14-180.70)] and photopsia [ROR (95% CI): 91.19 (54.41-152.83)]. Notably, the risk ratios for alopecia, dermatitis acneiform, and ovarian toxicity were significantly higher in the nirogacestat group than in the placebo group. Despite the wide use of nirogacestat, most common AEs are not serious. Nevertheless, healthcare workers should proactively monitor patients for indicators of ovarian toxicity and hepatotoxicity. Additionally, photopsia and haematuria may be newly identified AEs. Further studies are required to validate our findings and explain the causal relationship between nirogacestat and AEs.

This study systematically evaluated the impact of China's drug review system reform on pediatric drug approval efficiency using 310 pediatric drug registration records (2015-2024) from the CDE of China's NMPA supplemented with the YaoZhi Database, with comparative analysis of adult drug review patterns. Post-2019 amendments to the DAL significantly reduced pediatric review timelines from a median of 450 days (2015-2019) to 377 days (2020-2024; P < 0.0001), representing a 16.4% reduction versus adult drugs (451 days). The standard review pathway showed even greater pediatric acceleration (385 days vs. adult 497.5 days; 22.6% reduction, P < 0.0001), demonstrating targeted regulatory resource allocation. While biologics exhibited significant review advantages (342 days vs. chemical drugs' 403 days; P = 0.0085), structural imbalances persisted: high import dependency (73.9% imported vs. 26.1% domestic), inadequate child-appropriate formulations (< 10%), and critical therapeutic gaps (traditional Chinese medicines: 1.3%; rare disease drugs: < 5%). Efficiency gains were linked to expanded priority review adoption and optimized technical standards, yet unresolved deficits necessitate: establishing a dedicated pediatric review database with unified standards and conditional access; optimizing resource allocation for clinically urgent drugs; enhancing rare disease incentives; and accelerating age-appropriate formulation innovation-collectively enhancing regulatory science to address pediatric clinical needs.

Introduction: Early health technology assessment (HTA) advice provides value to pharmaceutical companies during drug development by identifying potential data gaps, refining study designs, and improving understanding of HTA agencies' evidentiary requirements. This study evaluated the landscape, benefits, and challenges of early HTA advice, with a focus on European agencies and global practices amid the transition to the EU HTA Regulation.

Methods: A perception survey involving 12 pharmaceutical companies explored engagement with HTA agencies, challenges, and strategic priorities. Additionally, a forum was conducted with 22 company representatives, discussing internal and external best practices. Key topics included the evolving role of Joint Scientific Consultations (JSCs), integration of real-world evidence (RWE), and incorporation of patient-reported outcomes (PROs) into advice processes.

Results: The findings highlighted active engagement with national agencies such as NICE and G-BA and European initiatives like EUnetHTA Joint Actions. NICE advice was valued for cost-effectiveness insights, but its post-Brexit absence reduced collaboration at the European level. JSCs under the EU HTA Regulation were seen as critical, but resource constraints and limited availability posed challenges. Companies prioritized topics such as comparator choices, outcome measures, and RWE but faced internal barriers like resource allocation and unclear decision criteria. Outside Europe, uptake of advice services, such as those from CDA-AMC, remained limited but underscored the potential of lifecycle approaches for iterative learning.

Conclusions: Early HTA advice is essential in pharmaceutical development. Enhancing JSC capacity, stakeholder engagement, and feedback mechanisms will strengthen alignment between companies and HTA agencies, fostering evidence-based decision-making and improved health outcomes.

Introduction: A Japanese risk management plan (RMP) is a proactive planning tool for managing safety concerns (important identified risk [IIR], important potential risk [IPR], and important missing information [IMI]) for each drug and is continuously updated. However, no studies have examined the dynamic changes of safety concerns in RMPs throughout the drug lifecycle.

Methods: We conducted a longitudinal descriptive analysis of safety concerns in RMPs of drugs approved for new active ingredients in 2014 in Japan. We compared safety concerns in RMPs between the first version at approval and the latest version 8 years after the approval date using the Sankey diagram. We also investigated the evidence for RMP changes.

Results: This analysis included 38 drugs, whose first version RMPs included 155 IIRs, 119 IPRs, and 59 IMIs. Among them, all IIRs and 88% of the IPRs and the IMIs remained in the latest version of the RMPs 8 years after the approval date. During follow-up, 29 IIRs, 20 IPRs, and 3 IMIs were newly added, 14 IPRs were upgraded to IIRs, and 7 IMIs were deleted; thus, the final numbers of IIRs, IPRs, IMIs were 198, 125, and 55, respectively. Evidence for RMP changes was more often obtained from pharmacovigilance activities than from clinical/non-clinical studies conducted for additional approvals.

Conclusions: Most of the safety concerns identified at the first approval remained over 8 years, and the number of IIRs and IPRs tended to increase after approval. Most of the RMP changes were based on pharmacovigilance activities.

Objectives: To identify and describe patient experience data (PED)-related guidance issued by regulatory and health technology assessment (HTA) agencies in North America, Europe, and Asia Pacific.

Methods: National agency websites were manually searched (October 2021, updated October-December 2023) to identify standalone PED guidance, and general submission/clinical trial or disease-specific guidance in four therapy areas, including PED-related recommendations. Identified documents were reviewed for requirements/expectations on types of PED; concepts of interest and instruments/tools; validation, analysis, and interpretation; study design, and endpoint definitions.

Results: A total of 34 regulatory and 21 HTA documents were reviewed across 7 and 11 agencies, respectively. Most regulatory agencies expected data collected via clinical outcome assessments; concepts of interest were similar; specific tools were not usually recommended, although the use of validated instruments was expected; and meaningful within-patient change was generally considered key to interpretation. HTA guidance on PED varied primarily based on country requirement for utility estimates to inform economic evaluation (little/no guidance beyond the concept of interest) versus interest in PED on signs, symptoms, or disease impact on functioning (generally more comprehensive details on PED expectations).

Conclusion: Through PED, patient voice is an increasingly important factor in regulatory, access, and reimbursement decision-making. Regulatory and HTA agencies in North America, Europe, and Asia Pacific have varying expectations regarding PED. This misalignment can necessitate the collection of multiple types of PED to meet all requirements (resulting in complex clinical trial protocols and significant patient burden), and lead to differences in data interpretation or gaps in the expected data. Therefore, PED measurement standards should be harmonized globally, and the collection of required PED should be ensured early during drug development to ensure decisions can be made based on valid and reliable data.