Therapeutic innovation & regulatory science最新文献

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.

In multi-regional clinical trials, planning the sample size for participating regions is essential for the evaluation of the treatment effect consistency across regions. Based on the MRCT design and sample size allocation to regions, consistency probability is usually used to predict the consistent trend between regions and the overall population, while preserving a certain proportion of the overall treatment effect. Specific enrollment characteristics in a region of interest should also be considered during the time of the sample size planning. To facilitate efficient and harmonized regional sample size planning, we have developed RegionSizeR, a comprehensive and user-friendly interactive web-based R shiny application that can be obtained from https://github.com/rsr-ss/RegionSizeR . This simulation-based app can serve as an initial point for discussions on sample size allocation plans, following preservation of treatment effect method in ICH E17. The app accommodates various types of endpoints and designs, including continuous, binary, and time-to-event endpoints, for superiority, non-inferiority, and MCP-Mod designs. To ensure the validity of this app, independent testing is conducted allowing a discrepancy of no more than 1% across all results considering various scenarios.

The FDA published a final rule for Medical Devices; Laboratory Developed Tests in the Federal Register on May 6, 2024, which aims to ensure the safety and effectiveness of laboratory developed tests (LDTs) by amending current regulations. The rule also includes a policy to phase out the FDA's general enforcement discretion approach for LDTs, aligning them with other In Vitro Diagnostic Devices. Notably, direct-to-consumer (DTC) testing is exempt from this policy shift, as the FDA believes this category of tests has already met applicable requirements. This rule was first proposed in the Federal Register on October 3, 2023. The publication of this proposed rule sparked a considerable volume of public reactions during the comment period of the rule-making process, comprising general sentiment, key concerns, and suggestions. This commentary analyzes these concerns, particularly focusing on DTC tests, and offers recommendations, including reassessing the FDA's enforcement discretion for hybrid DTC tests, advocating for clear guidance on clinical oversight, and prioritizing a risk-based enforcement approach. Additionally, enhancing public education about the risks of DTC testing is crucial for safeguarding public health.

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.

Background: Clinical trials have become larger and more complex. Thus, eSource should be used to enhance efficiency. This study aimed to evaluate the impact of the multisite implementation of eSource direct data capture (DDC), which we define as eCRFs for direct data entry in this study, on efficiency by analyzing data from a single investigator-initiated clinical trial in oncology.

Methods: Operational data associated with the targeted study conducted in Japan was used to analyze time from data occurrence to data entry and data finalization, and number of visits to the site and time spent at the site by clinical research associates (CRAs). Additionally, simulations were performed on the change in hours at the clinical sites during the implementation of eSource DDC.

Results: No difference in time from data occurrence to data entry was observed between the DDC and the transcribed data fields. However, the DDC fields could be finalized 4 days earlier than the non-DDC fields. Additionally, although no difference was observed in the number of visits for source data verification (SDV) by CRAs, a comparison among sites that introduced eSource DDC and those that did not showed that the time spent at the site for SDV was reduced. Furthermore, the simulation results indicated that even a small amount of data to be collected or a small percentage of DDC-capable items may lead to greater efficiency when the number of subjects per site is significant.

Conclusions: The implementation of eSource DDC may enhance efficiency depending on the study framework and type and number of items to be collected.

Background: Access to medical products of the required efficacy, quality and safety is essential for everyone's health and wellbeing. To achieve this milestone, every country needs a robust and strong performing National Regulatory Authority (NRA) that is independent and outcome oriented. With the help of the World Health Organization (WHO), the global benchmarking tool is the gold standard used to assess the regulatory capacity of NRAs.

Objectives: This study assessed the capacity of the National Medicines Regulatory Authority in Sierra Leone to perform its regulatory functions.

Methods: This descriptive cross-sectional study used both qualitative and quantitative approaches. A self-administered questionnaire was used for the quantitative approach, and the qualitative aspect consisted of a desk review looking at key regulatory documents such as laws, regulations, policies, guidelines, standard operating procedures and reports. The data collection tool used was the WHO global benchmarking tool (GBT) for "Evaluation of National Regulatory System of Medical Product Version VI.

Results: The majority of the participants had a postgraduate degree (60%), and 72% had over 10 years of experience working at the NRA. Out of 251 sub-indicators assessed, 85 (34%) sub-indicators were fully implemented. Of the eight (8) functions assessed, sub-indicators related to clinical trial oversight and vigilance were the most implemented, with 67% and 62%, respectively. Of the 9 indicators assessed, 79% of the sub-indicators that are related to quality and risk management were implemented. The results of this study showed that PBSL operates at maturity level 1. The absence of laws and regulations that give PBSL the mandate to perform its regulatory functions was a major challenge even though other indicators were met. The study reported other challenges toward effective functioning, including but not limited to a lack of sufficient staff, weak enforcement of the sale of medicines and a poorly equipped quality control laboratory.

Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) and other factors including document preparation and response timelines, can lead to long delays in approval (of up to 3-5 years) increasing the risk of disruption and shortages.We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval.With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally.In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group.Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply.