Therapeutic innovation & regulatory science最新文献

Internationally, medical regulators are seeking to make better use of real-world data (RWD) to support their decision making. While the UK National Health Service collects population-wide cradle-to-grave data, challenges remain around siloing, interoperability and access to data across different care settings. In 2023, a `Study-A-Thon' was held to explore how mobilisation of a UK distributed data network might be used to generate real-world evidence (RWE) for regulatory purposes by increasing availability of RWD in a timely manner. Two research questions focusing on high-priority data gaps (medical devices and secondary care prescribing) were selected as case studies to support this work. This paper summarises details of the Study-A-Thon and discusses key learnings for the UK's Medicines and Healthcare products Regulatory Agency (MHRA), UK stakeholders and international partners to reflect on when developing and implementing RWD strategies. Shortcomings of the data are discussed, such as a lack of follow-up for patients across care settings and the need to develop common data models to capture relevant information on medical product utilisation. The importance of local data and clinical expertise for success is highlighted, from encouraging better data collection at point of care through to appropriate interpretation of results. Successful delivery of results for both studies supports the view that, with further development, a UK federated data model could enhance national regulatory decision-making across the product lifecycle.

Background: Personalized cancer treatment using combination therapies offers substantial therapeutic benefits over single-agent treatments in most cancers. However, unmet clinical needs and increasing market competition pressure drug developers to quickly optimize combination doses and clearly demonstrate the contribution of each component when developing and evaluating new combination treatments.

Methods: We propose a Bayesian optimal phase II drug-combination (BOP2-Comb) design that optimizes the combination dose and evaluates the proof-of-concept as well as the contribution of each component in two seamless stages. Our optimal calibration scheme minimizes the total trial sample size while controlling incorrect decision rates at nominal levels. This calibration procedure is Monte Carlo simulation-free and provides a theoretical guarantee of false-positive control.

Results: We demonstrate the superior finite-sample operating characteristics of the proposed design through extensive simulations, achieving reduced sample sizes and improved control of both correct and incorrect decision rates compared to existing approaches. To illustrate its utility, we apply the BOP2-Comb design to redesign a real phase II trial evaluating the combination therapy of bevacizumab and lomustine.

Conclusions: The BOP2-Comb design provides a valuable framework for designing future randomized phase II trials of combination therapies, particularly when both dose optimization and assessment of component contributions are required.

The Mixed Model for Repeated Measures (MMRM) is widely used in clinical trials, however, its reliance on the Missing at Random (MAR) assumption and the exclusion of subjects lacking post-baseline data have been points of scrutiny, particularly due to misalignment with the Intent-to-Treat (ITT) principle. This paper presents an application of Multiple Imputation (MI) to address missing data in a hypertension clinical trial and discusses the subsequent interactions with regulatory authorities requesting additional analyses predominantly based on a Missing not at Random (MNAR) assumption. While MNAR-based approaches have been traditionally used for sensitivity analyses, we present an example demonstrating that regulatory agencies are increasingly expecting their integration into primary analyses.

Background: Clinical trial participation is critical for ensuring new medical treatments are safe and effective for all populations. Native Hawaiian (NH), Pacific Islander (PI), and Filipino individuals experience a disproportionate burden of type 2 diabetes yet remain underrepresented in clinical trials. The primary objective was to generate insights into the motivations, barriers, and communication preferences around clinical trial participation among hospitalized patients from diverse racial/ethnic backgrounds, particularly groups that have been historically underrepresented in research.

Methods: We conducted in-person, semi-structured interviews with 56 hospitalized patients at a medical center in Hawai'i. Participants ranked reasons for joining or not joining a clinical trial and responded to open-ended questions. Quantitative data were summarized descriptively. Qualitative responses were analyzed using Rapid Qualitative Analysis and organized by race/ethnicity.

Results: While 84% expressed willingness to join a trial, most had never been asked. NH participants prioritized helping their community and accessing new treatments. PI participants emphasized helping their doctor and advancing science. Filipino participants valued new treatments and contributing to science. White participants ranked financial incentives and community benefit. Major barriers included concerns about unknown medication risks, lack of understanding, and mistrust-particularly among PI and Filipino participants. Many NH and PI participants noted that helping family members was a key motivator. Across all groups, preferred communication strategies included physician referrals, text messaging, and physical mail.

Conclusion: Tailored recruitment strategies emphasizing family and community benefits, involvement of trusted local providers, and culturally relevant communication may enhance clinical trial participation among underrepresented populations with type 2 diabetes.

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.