Therapeutic innovation & regulatory science最新文献

The thalidomide tragedy of the 1960s led to restrictions and limitations in the participation of pregnant women in clinical trials. Despite the paucity of information on the safe and effective use of medicines in this population, most pregnant women are prescribed medications. A landscape assessment review of guidelines and legislation governing the use of medicines in pregnancy and during breastfeeding was conducted by the TransCelerate Pharmacovigilance Pregnancy and Breastfeeding Team. Insights from the landscape assessment review were compiled to identify important points to consider concerning the use of medicines in pregnancy throughout a product lifecycle. Four main areas were identified for consideration for use of medicines in pregnancy: (1) Product development considerations: Key points on the disease itself, the medicine characteristics, non-clinical and clinical development. (2) Interventional study considerations: Key aspects in enrollment of pregnant women in clinical trials and the follow-up requirements for such women. (3) Post-marketing considerations: Key elements in spontaneous case reporting of medicines exposure during pregnancy, implementation of appropriate risk management plans for medicines likely to be used in pregnancy. (4) Full lifecycle considerations: Activities required by regulators to ensure safety surveillance and maintenance throughout product lifecycle. There is a need for harmonized guidance on how to study the use of medicine in pregnancy. This paper addresses regulatory considerations, to aid in the planning and execution of research programs focused on developing medicines for use in pregnancy when permissible under established regulatory framework.

India is currently among the top 10 pharmaceutical markets by value and is the third largest by volume in 2024; it manufactures more than 65,000 generic drugs across 60 therapeutic segments. Holding a 20% market share of generics, the industry is a key supplier to Africa and the USA and other markets. Following the Drugs and Cosmetics Act of 1940, for the manufacture of drugs in India, there is always legal supervision on the quality of the products being manufactured in the country. The IP, published every ten years by the IPC, which is an autonomous body of the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, is the official reference for drug standards in India for the purpose of guaranteeing drug quality and effectiveness. The IPC, set up in 1948 under the Ministry of Health and Family Welfare, monitors the publication and changes of the IP in consultation with other agencies. The IPC consists of four major divisions: Governing, Scientific, General, and Executive, which deal with the policy, scientific and academic standards, performance, organizational, and administrative work, respectively. The Indian Pharmacopoeia Laboratory has also proactively adapted or added to its roles in areas of research, writing monographs, and providing the public with drug standards. The monograph development in the IP undergoes an evaluation by the specialist, public comment, and the need to update and align with the current scientific research and internationally recognized guidelines. There are significant changes on average every 4 to 5 years, with supplements and addenda between revisions. This review article focuses on India's position as the world's largest supplier of generic medicines, the mechanisms of drug safety and quality control and the IPC's current and further endeavours to harmonize Indian standards with those of the global world. It also provides information about the position of India in the global market of pharmaceuticals, the large production and export of the Indian generics and vaccines.

Background: The global drug development regulatory community, through the International Council for Harmonisation (ICH) guidelines for the development of pharmaceuticals for human use, has long encouraged the use of quality by design (QBD) principles in clinical trials. Risk-based Quality Management (RBQM) offers an approach to improve clinical research quality and performance by identifying and mitigating risks related to critical safety and efficacy data based on Quality by Design (QbD) principles. Several studies have been published quantifying current levels of RBQM adoption, but a systematic study mapping the stages of adoption maturity has not been conducted. This lens is needed to inform organizations on adoption paths that have been followed and to facilitate more rapid RBQM adoption considering recent regulatory guidance (ICH E6 R3).

Methods: The Tufts Center for the Study of Drug Development conducted a global online survey and collected responses from 119 individual pharmaceutical and biotechnology companies. Responses related to the use of 32 distinct RBQM practices in ongoing clinical trials in late 2022 and early 2023, and were analyzed and used to (1) develop an adoption maturity model, (2) map levels of adoption by company size, and to (3) isolate the characteristics and barriers experienced by five RBQM maturity cohorts: Innovators, Early Adopters, Early Majority, Late Majority, and Resisters.

Results: RBQM components are used primarily by larger companies-those conducting more than 25 clinical trials annually. These companies tend to fall in the Innovators, Early Adopters, and Early Majority RBQM maturity cohorts. These companies have implemented nearly all of 32 RBQM components in at least one trial. The most common areas of reported use are in the documentation and resolution of risk areas. The areas with lowest rates of use are the detection of duplicate patients, statistical data monitoring, reduced/targeted SDR, identification of critical to quality factors, and documentation of updates to definitions.

Introduction: Policy reforms in drug regulation and reimbursement have encouraged drug research and development in China. However, there is a lack of insights on industry trends for dermatology research. We aim to describe trends and features of clinical trials for dermatology drugs in China, understand recent achievements, and forecast development trends.

Methods: Clinical trial records posted on the Registration and Information Disclosure Platform of Center for Drug Evaluation (CDE) were screened. All trials for dermatological drugs, posted on platform between 2016 and 2022 were included.

Results: A total of 1172 trial records were identified, among which studies for skin infection, immune-mediated and inflammatory skin disease (IMIDs) and skin malignancy accounted for 48.9% (n = 573), 42.0% (n = 492) and 9.1% (n = 107), respectively. Most trials focused on generic drugs (n = 728, 62.1%). Multi-regional clinical trials (MRCTs) accounted for less than 6% of all trials. The number of trials on dermatology drugs increased sharply from 2016 to 2018 followed by a decline, which is mainly driven by the drop in bioequivalence evaluation (BE) studies for generic drugs indicated for skin infection. A growing trend in the number of trials for innovative drugs was observed. After removing duplicated drugs based on generic name, a total of 607 tested dermatology drugs were identified among which 51.9% were indicated for IMIDs. The number of innovative drugs exceeded generic drugs from 2020 to 2022. The geographic distribution of lead sites (the site where the principal investigator being employed) was uneven, with most of them located in east China. Of 1,068 trials sponsored by Chinese firms, most were BE (n = 692, 64.8%) and generic drugs (n = 722, 67.6%), while among 104 trials sponsored by multinational corporations (MNC), a majority were phase III (n = 53, 51.0%) trials and focused on innovative drugs (n = 94, 90.4%).

Conclusion: Findings demonstrated positive consequences of reforms in the healthcare industry in China. Nevertheless, long-term policies are expected to enhance the innovative capabilities of Chinese pharmaceutical companies while ensuring accessible and affordable drug supply with generics, encourage early participation in global drug R&D activities to shorten "drug lag", and promote investment in innovative drugs.

The United Kingdom (UK)'s regulatory profile is changing following the UK's exit from the European Union (EU). As a consequence, the Medicines and Healthcare products Regulatory Agency (MHRA) became more independent. Since then, numerous attempts have been made to ease the separation of the UK from the European Union, focusing mainly on Northern Ireland (NI), which is part of the UK but shares a land border with the EU. The Windsor Framework facilitates the relationship between the EU and the UK, including the role of the European Medicines Agency (EMA) and MHRA in NI. The review throws light on the implementation of the Windsor Framework detailing the key aspects, and the pre- and post-implementation changes in Northern Ireland, Great Britain and the Republic of Ireland. The Framework is useful for industries such as pharmaceuticals where regulatory approval and an uninterrupted supply chain are critical. Evaluating the Framework illuminate's areas for improvement, threats, and scope for cooperation between the UK and EU authorities. The review details efficiency, costs, and market accessibility of medicines, to give a better representation of the regulatory position in NI. The study reveals the pros and cons of the Framework, to assist stakeholder evaluation of Marketing Authorisation Holders (MAHs) that have registered both in UK and EU markets.

Background: In Japan, anticancer drugs are often approved based on the objective response rate (ORR) when the conduct of a confirmatory study is difficult or expected to take a considerably long time. However, it remains unclear how frequently post-marketing confirmatory studies are conducted and for which indications they are implemented. We aimed to understand the status of post-marketing confirmatory studies for anticancer drugs approved based on ORR.

Methods: We investigated the status of post-marketing confirmatory studies on anticancer drug indications approved based on ORR in Japan between 2015 and 2022. In addition, we compared the status of post-marketing requirements and subsequent regulatory actions between Japan and the US for the indications commonly approved in both countries.

Results: We found that 60% of the indications did not have planned confirmatory studies, with many receiving orphan drug designations. This observation is consistent with the Japanese regulations that allow the approval of anticancer drugs based on ORR, for which confirmatory studies are difficult to conduct or expected to take a long time. Indications received conditional approval in Japan were fewer compared to those received accelerated approval in the US, and post-marketing confirmatory studies were less frequently requested from the regulatory authority in Japan. Although the results of post-marketing confirmatory studies were often utilized in regulatory actions in Japan (including modifications to approved indications), no indications were found where these results led to withdrawal of approval or additional confirmatory study requirements, and the evaluations of the results were not disclosed when they did not lead to regulatory actions.

Conclusions: To facilitate smoother regulatory actions based on the results of post-marketing confirmatory studies, it would be beneficial to require the submission of the results of post-marketing confirmatory studies if it is feasible following the approval based on ORR.

Objective: Achieving first-cycle approval in Abbreviated New Drug Applications (ANDAs) is a critical goal in the generic drug industry, as it enables faster market entry. This study covers common areas of deficiency within ANDA submissions that often lead to delays and multiple review cycles. This review also delves into FDA initiatives aimed at improving first-cycle approval rates and case study analysis that assess deficiencies impact on approval timelines.

Method: A literature-based analysis was conducted, reviewed industry reports, regulatory guidelines, and published articles available on various databases to identify trends in ANDA deficiencies.

Result: Identifies key areas where applicants frequently fall short, such as incomplete data submissions, inadequate manufacturing, labelling and DMF requirements, and insufficient bioequivalence studies.

Conclusion: Overall, it provides valuable insights and practical guidance for generic drug developers to refine their submissions, aiming for higher first-cycle approval success in alignment with FDA standards.

In the high-stakes world of clinical trials, where a company's multimillion-dollar drug development investment is at risk, the increasing complexity of these trials only compounds the challenges. Therefore, the development of a robust risk mitigation strategy, as a crucial component of comprehensive risk planning, is not just important but essential for effective drug development, particularly in the RBQM (Risk-Based Quality Management) ecosystem and its component-RBM (Risk-Based Monitoring). This emphasis on the urgency and significance of risk mitigation strategy can help the audience understand the gravity of the topic. The paper introduces a novel modeling framework for deriving an efficient risk mitigation strategy at the planning stage of a clinical trial and establishing operational rules (thresholds) under the assumption that contingency resources are limited. The problem is solved in two steps: (1) Deriving a contingency budget and its efficient allocation across risks to be mitigated and (2) Deriving operational rules to be aligned with risk assessment and contingency resources. This approach is based on combining optimization and simulation models. The optimization model aims to derive an efficient contingency budget and allocate limited mitigation resources across mitigated risks. The simulation model aims to efficiently position each risk's QTL/KRI (Quality Tolerance Limits/Key Risk Indicators at a clinical trial level) and Secondary Limit thresholds. A case study illustrates the proposed technique's practical application and effectiveness. This example demonstrates the framework's potential and instills confidence in its successful implementation, reassuring the audience of its practicality and usefulness. The paper is structured as follows. (1) Introduction; (2) Methodology; (3) Models-Risk Optimizer and Risk Simulator; (4) Case study; (5) Discussion and (6) Conclusion.

Introduction: Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act's Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.e., small molecule vs. biologic).

Methods: This cross-sectional study evaluated oncology drugs first approved by the FDA from 2008 to 2018 and later approved for one or more additional indications. Numbers, types, and approval timelines of subsequent indications were recorded at the drug level, with drugs grouped by quartile based on the pacing of post-approval development (i.e., "rapid pace" to "measured pace").

Results: Multi-indication oncology drugs (N = 56/86, 65.1%) had one or more subsequent indication approved in a new: cancer type (60.7%), line of treatment (50.0%), combination (41.1%), mutation (32.1%), or stage (28.6%). The median time between FDA approvals for indications increased from 0.6 years (IQR: 0.48, 0.74) in the "rapid pace" group to 1.6 years (IQR: 1.32, 1.66), 2.4 years (IQR: 2.29, 2.61), and 4.9 years (IQR: 3.43, 6.23) in the "moderate," "measured-moderate," and "measured" pace groups, respectively. Drugs in the "rapid pace" group often received their first subsequent indication approval within 9 months of initial approval (median: 0.7 years; IQR: 0.54, 1.59), whereas the "measured pace" group took a median of 5.7 years (IQR: 3.43, 6.98). Across all multi-indication drugs, the median time to the most recent approval for a subsequent indication was 5.5 years (IQR: 3.18, 7.95). One quarter (25%) of drugs were approved for their most recent subsequent indication after the time at which they would be DPNP-eligible.

Conclusion: Approval histories of new oncology drugs demonstrate the role of post-approval indications in expanding treatment options towards new cancer types, stages, lines, combinations, and mutations. Heterogeneous clinical development pathways provide insights into potential unintended consequences of IRA-related changes surrounding post-approval research and development.

Recent progress in materials chemistry has resulted in the development of several ceramic materials that are now being used in dental implants. The advantages of ceramic materials over conventional metallic materials are that they do not induce allergic reactions in individuals with metal allergies, they do not interfere with magnetic resonance imaging, and they provide improved esthetics. In addition, some ceramic materials are tougher than metallic materials and less brittle. However, despite these advantages, few ceramic dental implant materials are currently approved for use in Japan. In FY2022, the Ministry of Health, Labour and Welfare of Japan commissioned a project called the "Project for the Development of a Guideline for the Evaluation of Ceramic Dental Implants," the goal of which was to consider how best to facilitate swift clinical development and approval of emerging ceramic dental implant materials. At a meeting of experts from professional societies, related industry organizations, and government agencies, the issues related to evaluation of the efficacy and safety of ceramic implant were discussed. Here, we summarize the outcomes of that meeting as a set of principles for the premarketing evaluation of ceramic dental implant materials in Japan.