Therapeutic innovation & regulatory science最新文献

The JPMA conducted a survey among its member companies regarding the use of Established Conditions (ECs) under ICH Q12. ECs can be set by companies that develop new drugs using the Quality by Design (QbD) approach defined in ICH Q8 and have an effective Pharmaceutical Quality System (PQS) as per ICH Q10. The survey revealed that while the use of QbD has increased, surpassing 70% in Japan since 2021, the adoption of ECs in New Drug Application (NDA) submissions remains low due to a lack of legal framework and internal understanding. More companies were using ECs in post-approval changes (PACs) compared to NDA submissions. The survey also found that companies prefer the existing systems in each region when determining the change category during change initiation. While Europe and the US believe that risk assessment of changes and ECs are consistent with an effective PQS, Japan perceives a mismatch between change assessment and predetermined change categories at the time of approval. This results in Japan willing to have an option applying the risk assessment at change control to reporting category evaluation. Considering these circumstances, it is anticipated that the use of ECs will gradually expand, primarily in PACs. The discrepancies in change procedures among countries may hinder a stable supply, so Japan should consider introducing change guidelines similar to those in Europe and the US to facilitate a hybrid approach to approvals that can accommodate the expanded use of ECs.

Introduction: During the COVID-19 pandemic, regulatory and market access actions were taken to expedite the market entry of COVID-19 medicines. This study aims to (i) capture multi-stakeholder views on these actions, and (ii) provide recommendations for future-proofing routine and health-emergency frameworks.

Methods: Semi-structured interviews were conducted with policy makers/advisors (i.e. regulators, HTA assessors, and payers), and pharmaceutical industry representatives across Europe to elicit their perspectives on marketing authorisation and market access practices during the COVID-19 pandemic. Interviews were transcribed ad verbatim and transcripts analysed via the thematic framework method.

Results: The interviews (n = 16) resulted in an overview of stakeholder-perceived benefits and limitations for four key regulatory advice or authorisation procedures (i.e. emergency task force, rapid scientific advice, rolling review, conditional marketing authorisation) and one market access procedure (i.e. joint procurement) applied during the COVID-19 pandemic. Highlighted benefits of the procedures relate to a reduction in timelines, enhanced collaboration and alignment, procedural flexibilities, and often a combination of these. Challenges are linked to inefficient allocation of time and resources for both industry representatives and policymakers/advisors and decreased transparency in certain procedures. In addition, several recommendations for the optimisation of both the routine and health-emergency healthcare framework were proposed. Emphasis is placed on the need for enhanced interaction and alignment between industry representatives and policymakers/advisors but also within stakeholder groups, development of more pragmatic and flexible procedures, and application of clear and transparent eligibility criteria for facilitating actions.

Conclusion: This study provides an overview of the perceptions from regulatory, and market access practices during COVID-19, highlighting how these experiences can inform regulatory and market access practices both in routine times and during health emergencies. Taking stock of stakeholder reflections and lessons learned are valuable for improving preparedness and responsiveness in future health crises.

This paper proposes a next-generation regulatory framework for opioid analgesics that integrates real-world data, adaptive licensing and labelling, and community-driven surveillance to overcome the shortcomings of traditional, static regulatory approaches. The framework is built on four pillars: first, an AI-augmented surveillance system that combines clinical data with social determinants of health to dynamically identify high-risk areas; second, adaptive licensing with evolving labels that use continuous real-world data submissions to update risk-benefit profiles in near-real time; third, pharmacist-led surveillance networks employing secure, automated reporting systems to enhance early detection of misuse; and fourth, the incorporation of harm reduction metrics through partnerships with community organizations and non-traditional data sources. This dynamic, process-oriented approach enables timely regulatory adjustments, ensures better alignment with FDA's REMS and post-marketing requirements (PMRs), and addresses ethical concerns related to AI bias and patient privacy. By proposing a framework under the FDA's Opioid Data Initiative, this paper aims to provide actionable recommendations for policymakers and stakeholders to mitigate opioid misuse and improve public health outcomes.

Aims: The study aimed to assess whether pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, increases the risk of venous thromboembolism (VTE) in real-world clinical practice in Japan.

Methods: In this retrospective cohort study, we utilized a claims database with data from December 2017 to July 2023. The exposed group consisted of patients with dyslipidemia using pemafibrate, while the control group included patients not using fibrate drugs. Each exposed patient was randomly matched with five control patients at a 1:5 ratio using time-matching. The primary endpoint was the number of days until the first occurrence of VTE, which was defined using ICD-10 codes and anticoagulant prescription records. We used a Cox proportional hazards model with standardized mortality ratio weight (SMRW) to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI) for the exposed group relative to the control group.

Results: The study included 23,195 patients in the exposed group and 115,975 in the control group. In the full analysis population, 46.6% of patients were women, with a median age of 70.0 years and a median BMI of 23.6. VTE occurred in 1.2% (286/23,195) of the exposed group and 2.0% (2297/115,975) of the control group, with an incidence rate of 0.95 and 1.33 per 100 person-years, respectively. There was no significant increase in the risk of VTE in the exposed group (HR, 0.925; 95%CI, 0.809-1.058).

Conclusions: We found no increase in VTE risk associated with pemafibrate in clinical practice in Japan.

Although past research has quantified the proportion and types of procedures that support clinical trial endpoints, little is known about the volume and nature of data collected by these procedures and their impact on participant and site burden. In response, Tufts CSDD and 15 TransCelerate Biopharma sponsor companies convened to update benchmarks and gather new insights into opportunities to optimize clinical trial data collection. In all, 105 multi-therapeutic protocols with a primary completion date after 2018 were analyzed. Data volume by study and by participant were analyzed and procedures were categorized into core, standard and non-core based on the endpoints they supported. Study results show that total data volume continues to grow with 5.9 million datapoints now collected on average per phase III protocol, up 11% annually since 2020. Non-core procedures comprise 17.8% of total phase II and 16.2% of total phase III procedures per protocol, a downward trend from the proportion of non-core procedures observed in 2020. Nearly half (46%) of phase II and 35% of phase III non-core procedures gather data for exploratory and future use purposes. On average, 6.6% and 12.6% of procedures supporting core and standard endpoints from phase II and phase III protocols are deemed non-essential (i.e., procedures determined by the clinical team or protocol authors as being performed in excess of the number of times required to demonstrate a clinical outcome), and their associated data represents 8.2% to 17.1% of the total datapoints collected. Combined, nearly one-third of all procedures and datapoints collected per protocol is classified as non-core or are non-essential procedures supporting core standard/required endpoints with more than half of this data associated with clinical and patient-reported questionnaires. As much as 30% of participant and site burden is associated with non-core procedures or are non-essential procedures supporting core, standard/required endpoints. The implications of these results and potential strategies to simplify protocol designs and lower site and participant burden, including reduction in the volume of data collected by non-core and non-essential procedures, are discussed.

To verify safety profiles of generic statins in a real-world setting, the risk of liver dysfunction as a common adverse event was compared between generic and brand drugs. A new user cohort design was employed in which patients prescribed one of six statins (atorvastatin, simvastatin, pitavastatin, pravastatin, fluvastatin, or rosuvastatin) in Japan between January 1, 2014 and March 31, 2022 were identified in the MID-NET^® database. Adjusted hazard ratios (aHRs) for generic drugs compared with their corresponding brand drug for the occurrence of first liver dysfunction were estimated using high-dimensional propensity score-weighted Cox models. Among the six statins, no increased trends in aHRs were observed in the primary analysis, except for atorvastatin. The primary analysis showed an aHR of 2.08 (95% confidence interval [CI]: 1.20-3.63) for atorvastatin. In an additional analysis with shorter follow-up periods, aHRs for atorvastatin gradually approached 1.00 (1.74 [95% CI: 0.94-3.22] within 360 days, 1.65 [95% CI: 0.84-3.25] within 180 days, 1.49 [95% CI: 0.73-3.01] within 90 days, and 1.33 [95% CI: 0.60-2.96] within 30 days). Results suggest that risks of liver dysfunction by generic statins are similar to those for brand drugs, facilitating our understanding about the safety of generic drugs. The aHR for atorvastatin was inconsistent between the primary and additional analyses, which suggests that the observed increased risk of generic atorvastatin may be affected by other factors and does not necessarily indicate a different safety profile between generic and brand drugs.

Background: Post-marketing risk minimization measures for medicines, e.g. package leaflets and patient cards, aim to ensure that patients and health care professionals receive timely and relevant medicines safety information. The use of digital technologies for risk minimization is emerging but still limited, despite being central in patients' and healthcare professionals' information access. There is currently limited high-level, strategic discussion about the digitalization of additional risk minimization measures.

Objective: To elicit key expert stakeholders' future visions of digital risk minimization measures in the European Union and to explore possible policy and healthcare implications of future digital risk minimization technologies.

Methods: Co-design workshops were conducted in three EU member states with clinicians, industry representatives, regulators, health information technology developers, and legal experts. Workshop transcripts and visual products were analyzed thematically in two coding cycles.

Results: Digitalizing risk minimization measures will transform roles, responsibilities, and collaborations, as stakeholders revise their remits with digital strategies and forge new collaborations to ensure the effectiveness and sustainability of new digital solutions. Success depends on revised implementation pathways that reflect patients' and healthcare professionals' digital access to medicines information and the diverse information ecosystems across the EU. Patients may gain new roles as active data subjects through remote monitoring, raising new ethical and legal considerations.

Conclusion: Digital risk minimization in the EU offers opportunities for timely, personalized interventions but presents challenges in implementation complexity, healthcare professionals' workload, and patient ethics, warranting more focused policy deliberation and research on digital health.

Background: Options for patients to receive unauthorised medicines through compassionate use (CU) in Europe vary greatly. There are two CU pathways: cohort programmes, regulated uniformly by the Regulation across EU member states, and individual patient requests (IPRs) governed by the Directive. The latter allows member states to determine their own laws, resulting in heterogeneous regulatory requirements and challenges in operationalization. Consequently, patients may experience delays in accessing CU medicines depending on their country of residence. To compare CU availability across European countries and formulate recommendations for improvement, we analyzed 8,934 patient requests from 30 European countries.

Methods: An exploratory post-hoc analysis was conducted using pooled collaborative data from 8,934 patient requests provided by Merck KGaA, Novartis, Roche, and Sanofi, tracked from January 1, 2020 to April 30, 2023 across 30 countries. All requests with complete dates for submission, company approval, relevant Ethics Committees or Health Authorities, and shipment dates were included.

Results: While internal company CU approval steps were found to be similar with a median approval time of 5 days (median interquartile range (IQR) of 1 (0-6) for cohorts; median IQR 4 (1-8) for IPRs), the time from company approval until shipment varied between cohort requests (median IQR 5 (1-16) days) and IPRs (median IQR 8 (1-22) days). Challenges experienced included differences in the use of CU terminologies, scope, settings, regulatory, and operational requirements.

Conclusion: Our findings indicate that differing national requirements across Europe lead to operational challenges and inter-country variability in CU implementation posing operational challenges for stakeholders, highlighting the need for improved harmonization.

Background: In January 2024, China officially implemented the patent term extension (PTE) system, that is, began to implement PTE for innovative drugs approved after June 1, 2021. This study analyzed the PTE system's outcomes in China and its potential impact on drug accessibility.

Methods: We conducted a simulation analysis of the PTE duration and effective patent life after listing (EPLL) of innovative drugs approved by Chinese regulatory authorities from June 2021 to December 2024, using data collected from public databases such as China's marketed drug patent registration platform.

Results: A total of 148 innovative drugs were included in the study. Among them, 61% were able to obtain PTE, with a median PTE duration of 5 years (IQR: 2.3-5). The median EPLL before adding PTE was 9 years (IQR: 6.1-11.7), and the median EPLL after adding PTE was 14 years (IQR: 11.1-14), an increase of 55.6%. Furthermore, the study reveals variations across drug types and therapeutic areas.

Conclusions: Compared to findings from prior studies on the U.S. and the European Union, the median PTE duration for innovative drugs in China is longer, while the median EPLL is only marginally extended. Both Chinese domestic stakeholders and foreign enterprises should evaluate the potential impact by considering both the incremental PTE periods and the overall EPLL levels.