Therapeutic innovation & regulatory science最新文献

Background: Ensuring regulatory-compliant manufacturing capability is an essential challenge for new treatment modalities, but its internalisation is not easy for pharmaceutical companies, especially start-ups. This study examines the functions and requirements of contracted development and manufacturing organisations (CDMOs) using the development process of antibody medicines as a case study.

Methods: Utilizing PubMed, Cortellis and Patent Integration databases, this study delves into publication and contractual trends in monoclonal antibody drugs (mAbs) development, alongside an analysis of patent filings by CDMOs, offering a comprehensive overview of the evolving landscape in mAbs innovation.

Results: In the early stages of mAbs development, dedicated bio firms (DBFs) led R&D with superior drug discovery technology but lacked manufacturing capability, which was complemented by CDMOs. This collaboration was an opportunity for CDMOs to expand their capabilities beyond manufacturing technology into antibody drug candidate discovery and structural optimisation technology. From mid-development onwards, it established a technology platform based on these capabilities and developed and established partnerships with existing pharmaceutical companies, including mega pharma.

Conclusions: The impact of institutions and regulations on the innovation process was assessed during this development process. These findings are expected to provide valuable insights into the innovation system for new modalities.

Background and objective: Denosumab is widely used for osteoporosis and cancer treatment. However, hypocalcemia induced by denosumab is a frequent adverse event. The objective of this study is to comprehensively investigate the safety signals and the occurrence of hypocalcemia in real-world patient cases reported through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

Methods: Reports from January 1, 2017 to December 31, 2021 were extracted from the FAERS. Only cases of hypocalcemia suspected to denosumab were eligible in pharmacovigilance study. Denosumab-related hypocalcemia safety signal were identified to characterize their clinical features. A safety signal for hypocalcemia was evaluated using reporting odds ratios (ROR).

Results: Among the 102,413 cases related to denosumab, 1042 cases were reported with denosumab-related hypocalcemia. The affected patients were mainly elderly (median age 70 years) and male (n = 568, 63.5%). In available data, the median onset time of 23 (range 0-1601) days. Most patients required drug interruption (n = 226, 72.9%) and can achieve a recovered-resolved state (n = 318, 62.1%). For the whole database, denosumab exhibited a safety signal for hypocalcemia (ROR = 14.09, 95% Cl 13.18, 15.06). In the sensitivity analyses, denosumab also showed a safety signal for hypocalcemia in cancer (ROR = 21.28, 95% Cl 18.79, 24.11) and osteoporosis (ROR = 9.29, 95% Cl 6.80, 12.59). Compared with bisphosphonates, denosumab still has safety signal for hypocalcemia (ROR = 1.88, 95% Cl 1.67, 2.11).

Conclusions: This pharmacovigilance database analysis indicates a high safety signal for hypocalcemia associated with denosumab, particularly in cancer patients.

Background: The lack of label information for the pediatric population has been a global issue, leading to the introduction of several countermeasures by major health authorities. Despite various efforts by Japanese health authorities, some drugs are approved only for adults in Japan, while the United States (US) label includes information on pediatric usage for the same drugs. This suggests a potential for pediatric-specific drug loss in Japan, where overall drug loss has recently become a major concern.

Methods: In this study, we compared the pediatric usage status between Japan and the US, focusing on the indications approved in both countries.

Results: Of the 404 indications, 70 (17.3%) and 102 (25.2%) included pediatric usage in Japan and the US, respectively. The proportion of indications, including pediatric usage, was significantly higher in the US than in Japan (χ² test, p < 0.001). Multivariate analysis of indications for pediatric usage in the US demonstrated that simultaneous development with adults (odds ratio (OR), 24.9; 95% confidence interval (CI), 6.79-91.1) and Japan-first development (OR, 31.5; 95% CI, 2.59-384) were significantly affecting the inclusion of pediatric usage in Japan.

Conclusions: Our results suggest that there was pediatric-specific drug loss in Japan compared to that in the US. The multivariate analysis demonstrated that US-first development and non-simultaneous development had a negative impact on the inclusion of pediatric usage in Japan; however, pediatric assessment request was not a significant factor. Further frameworks to promote pediatric drug development should be introduced in Japan to address pediatric-specific drug loss issues.

Post-marketing surveillance refers to the process of monitoring the safety of drugs once they reach the market, after the successful completion of clinical trials. In this work, we investigate a computational approach using data mining tools to detect safety signals from post-market safety databases, or in other words, to identify adverse events (AEs) with disproportionately high reporting rates compared to other AEs, associated with a particular drug or a drug class. Essentially, we view this as a problem of cluster analysis-based anomaly detection on post-market safety data, where the goal is to 'unsupervisedly' detect the anomalous or the signal AEs. Our findings demonstrate the potential of using a clustering ensemble method to detect drug safety signals. It employs multiple clustering or anomaly detection algorithms, followed by a performance comparison of the candidate algorithms based on a collection of appropriate measures of goodness of clustering results. The method is general enough to include any number of clustering or anomaly detection algorithms and goodness measures, and performs better than any of the candidate algorithms in identifying the signal AEs. Extensive simulation studies illustrate that the ensemble method detects the AE signals from synthetic post-market safety datasets pretty accurately across the different scenarios explored. Based on the cases reported to the FDA Adverse Event Reporting System (FAERS) between 2013 and 2022, we further demonstrate that the ensemble method successfully identifies and confirms most of the adverse events that are known to occur most frequently in reaction to antiepileptic drugs and $\beta$ -lactam antibiotics.

This commentary addresses the recent U.S. Food & Drug Administration (FDA) proposed rule to expand access to nonprescription drugs through additional conditions of nonprescription use (ACNU). It surveys the various pathways to market for pharmaceutical products, noting the distinct requirements for over-the-counter (OTC) products differentiating them from prescription products. It subsequently reviews the ACNU proposed rule, weighing its potential benefits against possible limitations. With a view towards the future, the ACNU proposed rule is acknowledged as part of a longstanding tradition to expand drug channels in a risk-stratified fashion with increasing clinical oversight to address in tandem increasing consumer risks. Finally, the proposed rule also serves as a potential prelude for a future behind the counter drug pathway.

Bayesian borrowing analyses have an important role in the design and analysis of pediatric trials. This paper describes use of a prespecified Pharmacometrics Enhanced Bayesian Borrowing (PEBB) analysis that was conducted to overcome an expectation for reduced statistical power in the pediatric DINAMO trial due to a greater than expected variability in the primary endpoint. The DINAMO trial assessed the efficacy and safety of an empagliflozin dosing regimen versus placebo and linagliptin versus placebo on glycemic control (change in HbA1c over 26 weeks) in young people with type 2 diabetes (T2D). Previously fitted pharmacokinetic and exposure-response models for empagliflozin and linagliptin based on available historical data in adult and pediatric patients with T2D were used to simulate participant data and derive the informative component of a Bayesian robust mixture prior distribution. External experts and representatives from the U.S. Food and Drug Administration provided recommendations to determine the effective sample size of the prior and the weight of the informative prior component. Separate exposure response-based Bayesian borrowing analyses for empagliflozin and linagliptin showed posterior mean and 95% credible intervals that were consistent with the trial results. Sensitivity analyses with a full range of alternative weights were also performed. The use of PEBB in this analysis combined advantages of mechanistic modeling of pharmacometric differences between adults and young people with T2D, with advantages of partial extrapolation through Bayesian dynamic borrowing. Our findings suggest that the described PEBB approach is a promising option to optimize the power for future pediatric trials.

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.

Background: The meaning and characteristics embedded in proprietary drug names have the potential to affect name recall, perceptions of drug benefits and risks, and attitudes toward a drug. In this study, we examined: (1) whether names that reference the drug's medical indication affect consumers' and primary care physicians' (PCPs') perceptions of the drug and (2) whether names that overstate the drug's efficacy affect consumers' and PCPs' perceptions of the drug.

Methods: We conducted an online experiment with 455 PCPs and 450 consumers to test the effects of fictitious proprietary prescription drug names. Participants were randomized to view one neutral drug name, one name that overstated the drug's efficacy, and five names that referenced the drug's medical indication.

Results: Names that referenced the drug's medical indication and names that overstated the drug's benefit both influenced perceptions of efficacy and risk compared to neutral names. For several outcomes, names evoking medical indications had similar effects to those designed to overstate the drug's efficacy. The patterns of effects were similar for PCPs and consumers.

Conclusion: Findings suggest drug names alone can be sufficient to produce attitudes and risk and benefit perceptions about drugs, even in the absence of any information beyond the drug's medical indication.

Introduction: Until around 2000, the number of medicinal products labelled for paediatric use was limited worldwide. Regulatory measures to promote paediatric drug development in the US and Europe and the establishment of an international guideline (ICH-E11) have led to an increase in the number of paediatric labels. In Japan, efforts have been made to promote the development of paediatric drugs. This study was aimed to examine whether these supportive efforts are successful in Japan.

Methods: This study examined the number of new drugs approved for paediatric indications in Japan from 2006 to 2023, as well as the clinical data package, that is, characteristics of the approved paediatric drugs and paediatric clinical trials, and the percentage of extrapolation of adult data, in the most recent 9-year period.

Results: The number of paediatric drug approvals showed an increasing trend between 2006 and 2023 with some fluctuations. The proportion of drugs indicated for paediatric patients to the total number of approved drugs was about 30% until 2022, but increased to 48% in 2023. During the period from 2015 to 2023, simultaneous development in adults and children accounted for 59% (159/269) of paediatric development, but the complete extrapolation of adult data to paediatric populations has not been widely utilized (11.2%, 30/269).

Conclusions: The number of paediatric drug approvals has shown an upward trend, suggesting that measures to promote the development of paediatric drugs may have been exerting a favourable effect in Japan. However, there is still a limited number of drugs that have additional indications for paediatric use. Appropriate development strategies, such as the extrapolation of adult data to paediatric populations, should be considered if scientifically justified.