Therapeutic innovation & regulatory science最新文献

Introduction: Hereditary hemochromatosis (HH) is a metabolic disorder characterized by excessive iron absorption, leading to damage of the liver, heart, and pancreas. The patient experience of living with HH has not been extensively described. We therefore aimed to understand the experiences of patients living with HH, including those who are intolerant to currently recommended treatment.

Methods: We consulted eight patients living with HH from North America, Europe, and Oceania, exploring their diagnostic journey and their lives and care management experiences. We also qualitatively assessed patient levels of satisfaction with their current treatment, evaluated their attitudes and views toward clinical research on HH, and identified potential drivers and barriers to clinical trial participation. A thematic approach was used to analyze the data.

Results: Patients were mostly of Northern or Western European ancestry (n = 7) and currently receiving phlebotomy (n = 6). Two patients were receiving iron chelation therapy. Patients ranged in age from their 20s to 70s. The median time since diagnosis was 2 (range 0‒33) years; 2 patients were diagnosed within the past year. Patients expressed varying levels of satisfaction with their treatment, based on experience of side effects (i.e., fainting, extreme fatigue), the emotional toll, needle phobia, treatment logistics, and time burden. Feelings of altruism, connections with the HH community, and the potential for new treatment options were among the motivators to join a clinical trial, while side effects were viewed as the primary barrier.

Conclusion: This research provides insights into the patient experience that can inform treatment management and clinical trial design.

Introduction: The amendments to the International Council for Harmonization (ICH) Good Clinical Practice (GCP) E8 guidelines were introduced to enhance clinical trial quality, patient safety, and efficiency through a more patient-centric, risk-based approach. This study investigates the impact of various study risk factors such as protocol amendments, informed consent changes, protocol complexity, and social determinants of health (SDOH) on protocol deviations and patient retention in clinical trials involving combination products.

Methods: A retrospective analysis of 14 clinical trials with 202 enrolled subjects was conducted. Key risk indicators (KRIs) such as protocol amendments, amendments triggering informed consent changes, study staff experience, and clinical trial phase were evaluated for their association with protocol deviations. The analysis also explored the influence of social factors, including age, gender, race, insurance type, and travel distance on protocol adherence.

Results: Study revealed that longer study participation was associated with an increased number of protocol deviations (p = 0.0003), while no significant associations were found between protocol deviations and demographic factors (p = 0.4039 for gender; p = 0.40650 for age), insurance type (p = 0.0640), or complexity scores (p = 0.7798). The findings highlight the importance of effective informed consent processes, study staff training, and risk management strategies to minimize protocol deviations and enhance data integrity in clinical trials.

Conclusion: while larger numbers of participant were associated with more deviations, site preparedness and patient compliance can mitigate these risks, underscoring the need for robust quality management systems in clinical trials.

Background: Cardiovascular and oncology trials increasingly require large sample sizes and long follow-up periods. Several approaches have been developed to optimize sample size including sample size re-estimation based on the promising zone approach. With time-to-event endpoints, methods traditionally used to test for treatment effects are based on proportional hazards assumptions, which may not always hold. We propose an adaptive design wherein using interim data, Bayesian computation of Predictive Power (PP) guides the increase in sample size and/or the minimum follow-up duration.

Methods: PROTECT IV is designed to evaluate mechanical circulatory support device vs. standard of care during high-risk percutaneous coronary intervention with the initial enrolment of 1252 patients and initial minimum follow-up of 12 months. The primary endpoint is the composite rate of all-cause death, stroke, durable left ventricular assist device implant or heart transplant, myocardial infarction or hospitalization for cardiovascular causes. The study will employ an adaptive increase in sample size and/or minimum follow-up at the Interim analysis. The adaptations utilize simulations to choose a new sample size up to 2500 and new minimal follow-up time up to 36 months that provides PP of at least 90%.

Results: Via extensive simulations, we have examined the utility of the proposed design for situations like delayed treatment effect, early benefit only and in general crossing of survival curves. Separate Piece-wise Constant Hazard Models with non-influential (weakly-informative) Gamma-priors are fitted to the interim data for the two treatment arms, free from the proportional hazards assumptions, thus yielding more robust interim decision making. The Bayesian modeling facilitates sampling of future observations from the posterior predictive distributions with the predictive probability of trial success is computed via Monte-Carlo simulations. Simulation results show that the fitting Bayesian Piecewise Exponential models to the interim data along with the use of the posterior predictive distributions lead to more "specific" adaptation rules compared to the frequentist Conditional Power while the overall operating characteristics, type-I error and power, are similar.

Conclusion: For clinical trials with time-to-event endpoints and where crossing of survival curves might be anticipated at the planning stage, flexible modeling along with wholesome use of patient-level data such as the calculation of predictive power as proposed here, may be more robust and efficient in making interim decisions such as sample size increase than the traditional use of the conditional power based on summary statistics and proportional hazards assumption.

Purpose: This article aims to explore the implications of Paragraph IV certification on generic drug market entry while innovators' patents are still active. It also examines the challenges posed by patent settlements, the BLOCKING Act, and the FDA's decision-making process regarding generic applications. The objective is to shed light on the complexities of pharmaceutical market dynamics, regulatory practices, and the balance between innovation and accessibility.

Methods: The study involves a detailed analysis of the USFDA's recently published Para IV certification list and application statuses from 2020 to 2024. It reviews litigation trends among top generic manufacturers and scrutinizes the impact of patent disputes on market entry. The study also evaluates the potential effects of the BLOCKING Act on the 180-day exclusivity period and generic drug market dynamics.

Results: The analysis reveals that nearly half of the ANDA applications submitted through Paragraph IV certification are deemed 'Eligible,' with significant portions either deferred or extinguished. A peak in eligible ANDA submissions was observed in 2023. Litigation trends show active patent challenges by leading generic companies like Teva, Apotex, and Actavis. The study highlights the FDA's role in facilitating first ANDA approvals, emphasizing the importance of providing safe and effective generic alternatives.

Conclusion: The study concludes that while the FDA supports generic companies in their application processes, patent litigation remains a significant hurdle, delaying the availability of cost-effective generic drugs. The BLOCKING Act, if enacted, is likely to disrupt the 180-day exclusivity incentive, reducing the predictability and value of generic drug market entry.

The use of composite endpoint is a common strategy often employed to enhance statistical power and address the low incidence of individual outcomes, particularly in cardiovascular and kidney outcome studies. By merging multiple clinically relevant events into a single variable, these endpoints negate the need for multiple testing adjustments and augment the event rate, thus enabling studies of reasonable size and duration. However, as underscored by the FDA's guidance, a thorough evaluation of each component's impact is equally important to ensure the clinical relevance of these endpoints. This article delves into controversies surrounding the interpretation of hazard ratios derived from analyzing the composite endpoint and its individual components, exemplified by an observation from the CLEAR outcome trials. It highlights a paradoxical scenario where the combined treatment effect for the composite endpoint appeared less favorable than when assessing individual components separately. Moreover, we did a re-evaluation of the suitability of using Cox proportional hazards model in this context through theoretical investigation and simulation studies.

Background: Less participation by Japan in multi-regional clinical trials (MRCTs) is one of concerns that leads to drug loss in Japan, but the characteristics of Japan's participation in MRCTs have not been well studied.

Purpose: This study investigated Japan's situation in global drug development by characterizing its participation in MRCTs compared with East and South-East Asian countries/regions, with a focus on MRCTs sponsored by small-medium companies to discuss necessary measures in further promoting drug development in Japan.

Methods: Data from MRCTs conducted in East and South-East Asia during the period from January 1, 2013 to December 31, 2022 were analyzed.

Results: Japan's participation in MRCTs conducted in Asia (East Asia and South-East Asia) was limited. In particular, Japan participated in only 15-16% of MRCTs sponsored by Small/Medium-pharma (mainly US-based companies), with even less participation in Early Phase MRCTs. Japan's participation in MRCTs was markedly lower than other Asian countries/regions such as Singapore, South Korea, and Taiwan, although it was relatively higher in MRCTs that targeted neoplasms compared with other diseases.

Conclusion: Results of this study raise significant concern about future potential drug loss in Japan. It is urgent to increase the participation of Japan in MRCTs in order to continuously provide new globally developed drugs to patients in Japan. For that purpose, an integrated approach that includes continuous improvement in pharmaceutical regulations and the clinical trial environment, as well as market attractiveness, will be necessary in parallel with strengthening of collaborations between Japan and other Asian countries/regions.

The rapid advancement of cell and gene therapies (CGT) in the past ten years has inspired biopharmaceutical companies, biotechnologies, and nonprofits to tackle diseases that have traditionally been challenging to treat. Rare diseases, where roughly 80% have a genetic basis, have enjoyed this scrutiny, but the complexity of CGT trial design and implementation have proven challenging. This manuscript offers general guidance for CGT clinical development, current regulatory requirements and guidelines governed by FDA and EMA, considerations around preclinical development, safety monitoring and the need for long-term monitoring and follow up.

The ICH E9 (R1) Addendum provides a framework to define an estimand and perform sensitivity analysis. The clinical endpoint (i.e., variable, response, outcome) is one of the important estimand attributes. In our opinion, the selection of the endpoint in Alzheimer's disease requires more exploration beyond what is used currently. The change in a cognitive and functional assessment scale from baseline to a specific time point of interest is often used as a primary or key secondary endpoint in clinical trials. However, such a change from baseline to the time point of interest may not reflect the benefit of the treatment over the course of treatment duration and may be difficult to intuitively understand by patients and clinicians. For two patients with the same change from baseline, the patient with rapid disease progression in the beginning is considered to have overall worse quality of life compared to the other patient with slow disease progression in the beginning but rapid progression toward the end. We explore time-averaged measurement (TAM) as a new endpoint and propose using the relative change to quantify the treatment difference. Estimands under the ICH E9 (R1) Addendum were considered by using various strategies in handling intercurrent events and used corresponding methods for handling missing data. We illustrate the use of TAM and compare the results with other commonly used estimand endpoints (the change from baseline, the relative disease progression model, and the slope of disease progression) for different estimands and imputation methods from retrospective analyses of a historical study.

Purpose: Regulation (EU) 2017/745, the European Medical Device Regulation (MDR), raises clinical evidence requirements but lacks clarity on what constitutes "sufficient clinical evidence" for medium-risk, Class IIb non-implantable CE-marked devices. This research investigates whether a clinical evaluation of a newly developed Class IIb device can be conducted without a clinical investigation and explores the role of data from the same generic device group in clinical evaluations.

Methods: Expert interviews with notified body reviewers and a survey were conducted to assess the regulatory landscape and the appropriateness of non-clinical data.

Results: Findings reveal inconsistencies in the interpretation of MDR among notified bodies. While some reviewers accepted clinical evaluations based on non-clinical data, others required clinical or equivalent device data. The exclusion of data from the same generic device group under MDR complicates compliance and may impose unnecessary burdens on manufacturers, particularly for standard-of-care devices with well-documented safety profiles. Survey results indicate discrepancies in the role of non-clinical data, with notified bodies favouring standard-based bench testing while manufacturers and consultants advocate for advanced testing methodologies, such as in silico models. The study also highlights differing perspectives on the role of post-market clinical follow-up (PMCF) in clinical evaluations.

Conclusions: This research underscores the need for standardized guidance on clinical data requirements and the role of non-clinical evidence. Addressing these gaps is essential to balance patient safety with innovation and streamline the regulatory pathway for medium-risk medical devices, ensuring a more predictable and efficient approval process in the EU.