Therapeutic innovation & regulatory science最新文献

Purpose: TransCelerate BioPharma surveyed its member biopharmaceutical companies to understand current practices and identify opportunities to complement safety signal assessment with rapid real-world data (RWD) analysis.

Methods: A voluntary 30-question questionnaire regarding the use of RWD in safety signal assessment was disseminated to subject matter experts at all TransCelerate member companies in July 2022. Responses were blinded, aggregated, summarized, and presented.

Results: Eighteen of 20 member companies provided responses to the questionnaire. Sixteen (89%) companies reported actively leveraging RWD in their signal assessment processes. Of 18 respondent companies, 8 (44%) routinely use rapid approaches to RWD analysis, 7 (39%) utilize rapid RWD analysis non-routinely or in a pilot setting, 2 (11%) are considering using rapid RWD analysis, and 1 (6%) has no plans to use rapid RWD analysis for their signal assessment. Most companies reported that RWD adds context to and improves quality of signal assessments. To conduct RWD analysis for signal assessment, 16 of 17 (94%) respondent companies utilize or plan to utilize internally available data, 8 (47%) utilize both internal and external data, and 3 (18%) utilize data networks. Respondents identified key challenges to rapidly performing RWD analyses, including data access/availability, time for analysis execution, and uncertainties regarding acceptance of minimal or non-protocolized approaches by health authorities.

Conclusion: Biopharmaceutical companies reported that they see value in the use of rapid RWD analyses for complementing signal assessments. Future work is recommended to offer a framework and process for use of rapid use of RWD analyses in signal assessment.

The results of observational studies using real-world data, known as real-world evidence, have gradually started to be used in drug development and decision-making by policymakers. A good quality management system-a comprehensive system of process, data, and documentation to ensure quality-is important in obtaining real-world evidence. A risk-based approach is a common quality management system used in interventional studies. We used a quality management system and risk-based approach in an observational study on a designated intractable disease. Our multidisciplinary team assessed the risks of the real-world data study comprehensively and systematically. When using real-world data and evidence to support regulatory decisions, both the quality of the database and the validity of the outcome are important. We followed the seven steps of the risk-based approach for both database selection and research planning. We scored the risk of two candidate databases and chose the Japanese National Database of designated intractable diseases for this study. We also conducted a quantitative assessment of risks associated with research planning. After prioritizing the risks, we revised the research plan and outcomes to reflect the risk-based approach. We concluded that implementing a risk-based approach is feasible for an observational study using real-world data. Evaluating both database selection and research planning is important. A risk-based approach can be essential to obtain robust real-world evidence.

Background: The importance of pharmacovigilance (PV) in ensuring drug safety, especially in the detection and prevention of adverse drug reactions (ADRs) is critical. However, PV activities in Nigeria still face many challenges, such as very low spontaneous reporting rates, and inadequate training and funding. This study assessed the state of pharmacovigilance in the federal capital territory of Nigeria (FCT), using WHO pharmacovigilance indicators.

Methods: A cross-sectional questionnaire-based survey was carried out among secondary healthcare facilities in the FCT. The WHO Pharmacovigilance Indicators Questionnaire, which consists of the structural, process and outcome measures, was used to collect data from the focal person for pharmacovigilance at all the consenting facilities. Descriptive statistics were used to summarize all variables. Ethical approval was obtained from the Ethics Review Committee of the FCT development authority.

Results: Of the 14 secondary healthcare facilities in the FCT, 11 agreed to the study (response rate = 84.6%). Among the respondents, 4 (36.4%) were females, and 2 (18.2%) had 9 years of experience in pharmacovigilance. For the core structural indicators, 7 (63.6%) of the facilities had a pharmacovigilance center while only 4 (36.4%) had a copy of the Nigerian pharmacovigilance policy. Regarding financial provisions, 10 (90.9%) hospitals reported that there was no regular financial provision for the center while 10 (90.9%) centers had a standard adverse drug reaction reporting form. For the core process indicators, the mean ± SD of the nine core process indicators ranged from 0.9 ± 3.0 to 75.6 ± 38.6 and the total number of reports in the local database, therapeutic ineffectiveness, and medication error were limited.

Conclusion: The assessment of pharmacovigilance activities in the Federal Capital Territory of Nigeria revealed significant gaps in infrastructure, financial support, and process implementation. Despite the presence of pharmacovigilance centers in the majority of facilities, the lack of consistent financial support and limited adherence to core process indicators highlight the need for enhanced training, resources, and policy enforcement to improve ADR reporting and overall drug safety monitoring. Strengthening these areas is crucial for advancing pharmacovigilance practices and ensuring patient safety in Nigeria.

During discussions at the Data Science Roundtable meeting in Japan, there were instances where the adoption of the BOIN design was declined, attributed to the extension of study duration and increased sample size in comparison to the 3 + 3 design. We introduce an accelerated BOIN design aimed at completing a clinical phase I trial at a pace comparable to the 3 + 3 design. Additionally, we introduce how we could have applied the BOIN design within our company, which predominantly utilized the 3 + 3 design for most of its clinical oncology dose escalation trials. The accelerated BOIN design is adaptable by using efficiently designated stopping criterion for the existing BOIN framework. Our approach is to terminate the dose escalation study if the number of evaluable patients treated at the current dose reaches 6 and the decision is to stay at the current dose for the next cohort of patients. In addition, for lower dosage levels, considering a cohort size smaller than 3 may be feasible when there are no safety concerns from non-clinical studies. We demonstrate the accelerated BOIN design using a case study and subsequently evaluate the performance of our proposed design through a simulation study. In the simulation study, the average difference in the percentage of correct MTD selection between the accelerated BOIN design and the standard BOIN design was - 2.43%, the average study duration and the average sample size of the accelerated BOIN design was reduced by 14.8 months and 9.22, respectively, compared with the standard BOIN design.

Whereas AI/ML methods were considered experimental tools in clinical development for some time, nowadays they are widely available. However, stakeholders in the health care industry still need to answer the question which role these methods can realistically play and what standards should be adhered to. Clinical research in late-stage clinical development has particular requirements in terms of robustness, transparency and traceability. These standards should also be adhered to when applying AI/ML methods. Currently there is some formal regulatory guidance available, but this is more directed at settings where a device or medical software is investigated. Here we focus on the application of AI/ML methods in late-stage clinical drug development, i.e. in a setting where currently less guidance is available. This is done via first summarizing available regulatory guidance and work done by regulatory statisticians followed by the presentation of an industry application where the influence of extensive sets of baseline characteristics on the treatment effect can be investigated by applying ML-methods in a standardized manner with intuitive graphical displays leveraging explainable AI methods. The paper aims at stimulating discussions on the role such analyses can play in general rather than advocating for a particular AI/ML-method or indication where such methods could be meaningful.

The globalization and rapid advancements in medical technologies necessitate the harmonization of international regulatory frameworks to ensure the efficient and timely clinical application of medical products, including pharmaceuticals and medical devices. Regulatory reliance, a critical component of this harmonization process, is a powerful tool that provides efficient access for economic entities and regulatory authorities, promoting predictable decision-making and accelerating approvals. The Medical Device Single Audit Program (MDSAP) serves as a regulatory reliance framework for medical device inspections. Implemented by countries including Japan, the United States, Canada, Australia, and Brazil, MDSAP allows third-party certification bodies, recognized by these regulatory authorities, to conduct audits on medical device manufacturers. The outcomes of these audits are shared with the regulatory authorities, who use them for regulatory assessments and decision-making. Since transitioning to its implementation phase in 2017, MDSAP has been widely utilized in various countries. This review provides an overview of the adoption and utilization of MDSAP in major countries, exploring the program's impact on regulatory processes and its potential as a method of regulatory reliance to facilitate timely access to effective and safe medical devices.

The increasing global drug shortage poses a substantial challenge to national healthcare systems and affects access to essential therapies. In Japan, this problem is exacerbated by a large-scale government campaign to switch from brand-name products to generic drugs and manufacturing/marketing authorization holders with poor development and manufacturing controls. Regulatory bodies, such as the U.S. Food and Drug Administration and the European Medicines Agency have developed guidelines aimed at ensuring continuous drug supply and mitigating manufacturing risks. However, Japan's efforts have primarily relied on voluntary industry guidelines, lacking the robust regulatory frameworks of other developed nations. Therefore, this study proposes a draft guideline for Japan's pharmaceutical industry to manage drug shortages effectively. The Japanese government needs to establish a framework system that will enable pharmaceutical companies to effectively maintain a stable supply based on the proposals developed in this study.

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs). While some promising developments have been made with the use of reliance pathways for initial marketing authorizations, reliance is still not widely used for PACs. With the support of the European Medicines Agency (EMA) and WHO, Roche launched a reliance pilot based on EMA approval to file a supply critical variation for a monoclonal antibody. The variation constitutes major changes to the approved manufacturing process. Sameness of the product is ensured by submitting to all participants the same variation package as in the EU. The objectives of the pilot are to ensure continuous supply of this critical medicine by targeting global approval in 6.5 months, to promote regulatory convergence by waiving country specific requirements, and enhance greater transparency by sharing EMA Committee for Medicinal Products for Human Use (CHMP) final assessment report and Q&As to participating NRAs. Globally 48 NRAs have agreed to join the pilot. This article outlines the process of establishing the pilot project, including a planning phase and an engagement phase with the EMA, WHO and the participating NRAs.