Therapeutic innovation & regulatory science最新文献

The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I-IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments-77%-were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.

In this note, we express our viewpoint regarding power considerations, via simulation studies, in clinical study design using hierarchical composite endpoint and Finkelstein-Schoenfeld test.

The past years have sharpened the industry's understanding of a Quality by Design (QbD) approach toward clinical trials. Using QbD encourages designing quality into a trial during the planning phase. The identification of Critical to Quality (CtQs) factors and specifically Critical Data and Processes (CD&Ps) is key to such a risk-based monitoring approach. A variable that allows monitoring the evolution of risk regarding the CD&Ps is called a Quality Tolerance Limit (QTL) parameter. These parameters are linked to the scientific question(s) of a trial and may identify the issues that can jeopardize the integrity of trial endpoints. This paper focuses on defining what QTL parameters are and providing general guidance on setting thresholds for these parameters allowing for the derivation of an acceptable range of the risk.

Background: Risk-based monitoring (RBM) and risk-based quality management (RBQM) offer a compelling approach to increase efficiency, speed and quality in clinical trials by prioritizing and mitigating risks related to essential safety and efficacy data. Since 2013, the FDA and EMA have encouraged the use of RBM/RBQM, however adoption has been slow with limited understanding of the barriers to adoption.

Methods: The Tufts Center for the Study of Drug Development conducted an online survey among pharmaceutical, biotechnology, and contract research organizations and gathered 206 responses on 32 distinct RBQM practices.

Results: On average, companies implemented RBQM in 57% of their clinical trials. Lower levels of adoption were observed among companies conducting fewer than 25 trials annually (48%) compared to those conducting more than 100 trials annually (63%). Primary barriers to adoption include lack of organizational knowledge and awareness, mixed perceptions of the value proposition of RBQM, and poor change management planning and execution. Insights into improving the level of adoption are discussed.

Conducting clinical trials (CTs) has become increasingly costly and complex in terms of designing and operationalizing. These challenges exist in running CTs on novel therapies, particularly in oncology and rare diseases, where CTs increasingly target narrower patient groups. In this study, we describe external control arms (ECA) and other relevant tools, such as virtualization and decentralized clinical trials (DCTs), and the ability to follow the clinical trial subjects in the real world using tokenization. ECAs are typically constructed by identifying appropriate external sources of data, then by cleaning and standardizing it to create an analysis-ready data file, and finally, by matching subjects in the external data with the subjects in the CT of interest. In addition, ECA tools also include subject-level meta-analysis and simulated subjects' data for analyses. By implementing the recent advances in digital health technologies and devices, virtualization, and DCTs, realigning of CTs from site-centric designs to virtual, decentralized, and patient-centric designs can be done, which reduces the patient burden to participate in the CTs and encourages diversity. Tokenization technology allows linking the CT data with real-world data (RWD), creating more comprehensive and longitudinal outcome measures. These tools provide robust ways to enrich the CT data for informed decision-making, reduce the burden on subjects and costs of trial operations, and augment the insights gained for the CT data.

The International Council on Harmonisation E8 Guidance Revision 1 (ICH E8(R1)) calls for creating a Culture of Quality that "values and rewards critical thinking and open, proactive dialogue about what is critical to quality." Across the biopharma landscape, clinical sites, sponsors, and service providers are working to translate this far-reaching guideline into working practices. This manuscript deconstructs key elements that comprise the critical thinking and open, proactive Culture of Quality "enablers." In addition, maturity models are provided so readers can visualize what a Culture of Quality looks like in their clinical research organization. These provide examples of high performing cultures of quality and useful tools for teams or organizations to measure and evolve their respective quality cultures.

Background: Central monitoring aims at improving the quality of clinical research by pro-actively identifying risks and remediating emerging issues in the conduct of a clinical trial that may have an adverse impact on patient safety and/or the reliability of trial results. This paper, focusing on statistical data monitoring (SDM), is the second of a series that attempts to quantify the impact of central monitoring in clinical trials.

Material and methods: Quality improvement was assessed in studies using SDM from a single large central monitoring platform. The analysis focused on a total of 1111 sites that were identified as at-risk by the SDM tests and for which the study teams conducted a follow-up investigation. These sites were taken from 159 studies conducted by 23 different clinical development organizations (including both sponsor companies and contract research organizations). Two quality improvement metrics were assessed for each selected site, one based on a site data inconsistency score (DIS, overall -log₁₀ P-value of the site compared with all other sites) and the other based on the observed metric value associated with each risk signal.

Results: The SDM quality metrics showed improvement in 83% (95% CI, 80-85%) of the sites across therapeutic areas and study phases (primarily phases 2 and 3). In contrast, only 56% (95% CI, 41-70%) of sites showed improvement in 2 historical studies that did not use SDM during study conduct.

Conclusion: The results of this analysis provide clear quantitative evidence supporting the hypothesis that the use of SDM in central monitoring is leading to improved quality in clinical trial conduct and associated data across participating sites.

The Access Consortium New Active Substance Work-Sharing Initiative, or "Access" for simplicity, allows regulatory authorities (RAs) of the Access Consortium countries to jointly review applications for the registration of new active substances or for new indications. Using a survey developed by the pharmaceutical industry trade associations of the five Access Consortium countries-Australia, Canada, Singapore, Switzerland, and the United Kingdom (UK)-this study gathered insights into the perceptions and experiences of the Access pathway held by affiliates of pharmaceutical companies. Understanding industry perceptions of Access is important for the success of the initiative, as participation is voluntary. Findings indicate that affiliates who participated in Access had mostly positive experiences with this pathway; most affiliates were satisfied with their interactions with the Access RAs and appeared willing to continue to participate in the initiative. Affiliates' reasons for not having yet participated in Access included a lack of opportunity to do so and perceived barriers, such as the Access pathway being too complicated to manage. Recommendations to improve Access cover six key areas: ensure predictability, increase guidance and transparency, streamline processes, maintain flexibility, increase harmonization, and advance RA-industry cooperation. This study should facilitate informed discussions among relevant stakeholders on how to improve Access to maximize efficiencies, accelerate approvals, and improve patient access to innovative medicines.

Background: Biosimilar medicines are defined as biological products highly similar to an already licensed biological product (RP). The market entry of biosimilars is expected to reduce the costs of biological treatments.

Objective: This study aims to evaluate the range of differences between the prices of biosimilars and the corresponding RP for biologicals approved in four countries.

Method: This is a cross-national comparison of pricing of biosimilars in Argentina, Australia, Brazil, and Italy. The study examined online price databases provided by the national authorities of the investigated countries. Biosimilar price difference was calculated by subtracting the unit price of the biosimilar by the unit price of the RP, and then dividing it by the unit price of the RP. The results were presented as percentage.

Results: Brazil had the highest median price reduction (- 36.3%) in biosimilars price, followed by Italy (- 20.0%) and Argentina (- 18.6%). All the biosimilars in Italy were priced below the RP presenting a minimum reduction of 6.3%, while in Australia, most of the prices of biosimilars were equal to the RP. In Argentina, one infliximab-biosimilar displayed price above the RP (40.7%) while the lower priced brand had a reduction of 14.4%. Brazil had four biosimilars with prices above the respective RP, including isophane insulin (1), insulin glargine (1) and somatropin (2).

Conclusion: The study revealed a marked dispersion in the price's differences between biosimilars and RP across the studied countries. Governments should evaluate whether their policies have been successful in improving affordability of biological therapies.