[Guidelines for economic evaluation of post-marketing Chinese patent medicine].

With the premise of drug safety and effectiveness, pharmacoeconomic evaluation can provide optimal solutions for diversified decision-making application scenarios from different research perspectives while maximizing the rational utilization of existing healthcare resources. Chinese patent medicine is an essential component of pharmaceutical utilization in China and a significant part of healthcare expenditure in China. However, the economic evaluation of post-marketing Chinese patent medicine is lacking. These evaluations often lack standardization, exhibit varying quality, and are unable to effectively support healthcare decisions, indicating a need for improvement in overall quality. Given this situation, this project has gathered leading experts from China and has strictly adhered to the requirements of the group standards set by the China Association of Traditional Chinese Medicine in developing Guidelines for economic evaluation of post-marketing Chinese patent medicine, aiming to provide methodological guidance for the post-market pharmacoeconomic evaluation of Chinese patent medicine, enhancing the standardization of pharmacoeconomic evaluations of Chinese patent medicine and the scientific validity of research results, and thereby elevating the overall quality of pharmacoeconomic evaluations for post-marketing Chinese patent medicine. The guidelines adhere to the framework provided by relevant laws and regulations in China and technical guidance documents. It is based on guidance from traditional Chinese medicine(TCM) theories, focusing on the unique characteristics of TCM. It covers various aspects of pharmacoeconomic evaluation, including fundamental principles, research topic selection, research question definition, study design type selection, cost identification and measurement, health outcomes, and evaluation methods. The guidelines offer methodological recommendations and decision guidance to address common issues and challenges in the pharmacoeconomic evaluation of post-marketing Chinese patent medicine.

Post-marketing surveillance of zinc acetate dihydrate for hypozincemia in Japan.

Zinc is an essential microelement, and its deficit causes various diseases and symptoms. In adults, especially in elderly individuals, zinc shortage can cause symptoms such as taste disorder, dermatitis, and susceptibility to infection. In children, zinc deficiency can lead to growth retardation. In 2017, the indication for zinc acetate dihydrate (NOBELZIN®) was expanded from Wilson's disease to include hypozincemia, leading to wider use of zinc acetate dihydrate. At five years after this broadening of use, we conducted a post-marketing study (PMS) to investigate the utilization, safety, and effectiveness of zinc acetate dihydrate. Over 52 weeks, the overall incidence of adverse drug reactions (ADRs) was 9.4% (87/928). The most common ADR was copper deficiency (2.4%), followed by nausea (1.4%). Among 928 patients, 19 (2%) developed serious ADRs. Of the patients with copper deficiency, 92% were >65 years of age, and all had comorbidities at baseline. Physicians evaluated the effectiveness of zinc acetate dihydrate using three categories: "effective", "not effective", and "indeterminate". The overall efficacy rate was 83.0%. The average serum zinc levels were elevated from 50-60 µg/dL to >90 µg/dL within 12 weeks, and were maintained up to 52 weeks after administration. Among the symptomatic sub-categories, the efficacy rate was highest in pressure ulcer (96.2%; 25/26), followed by in stomatitis (87.5%; 42/48), and taste disorder (87.4%; 181/207). Among pediatric patients with developmental symptoms, an efficacy rate of 66% was achieved. In conclusion, zinc acetate dihydrate has been safely used, and has produced beneficial effects on various diseases and symptoms.

An 8-Year Prospective, Observational, Multi-centre Post-Marketing Safety Surveillance Study Conducted in South Korea (2014-2022) Following the Introduction of GSK's Inactivated Quadrivalent Seasonal Influenza Vaccine (Fluarix Tetra) for Subjects Aged 6 Months and Older.

INTRODUCTION: Seasonal influenza is associated with substantial public health burden. The objective of this study was to assess the safety of inactivated quadrivalent seasonal influenza vaccine (IIV4, Fluarix Tetra, GSK, Belgium) in subjects aged ≥ 6 months in Korea. METHODS: This prospective, observational, non-comparative, multi-centre post-marketing surveillance study was conducted in Korea in subjects aged ≥ 3 years for 6 years (2014-2020) and extended to subjects aged 6-35 months for 4 years (2018-2022). Subjects received IIV4 in routine clinical practice according to local prescribing information. Adverse events (AEs) were recorded over 21 days post-vaccination. RESULTS: The group aged ≥ 3 years included 701 subjects (mean 31.97 years, range 3-86 years, 46.36% male), and the group aged 6-35 months included 687 subjects (mean 16.31 months, 47.02% male). In the group aged ≥ 3 years, 98 subjects (13.98%) reported 140 AEs, of which 42 events in 34 subjects (4.85%) were adverse reactions to vaccine (ARVs). Most of the ARVs were expected, mainly administration site reactions. There were seven mild unexpected ARVs. In the group aged 6-35 months, 248 AEs were reported in 149/687 subjects (21.69%). ARVs were reported in 25/687 subjects (3.64%, 29 events); one was considered unexpected. There were five serious AEs overall, none of which were considered related. CONCLUSION: No safety concerns were found during this surveillance study of IIV4 in subjects aged ≥ 6 months in Korea. The findings of this study suggest IIV4 is safe and well tolerated for use in all age groups with a vaccine indication.

Seasonal influenza is associated with over 5000 deaths annually in Korea, mainly in older adults. Annual vaccination is the most effective way of preventing seasonal influenza. The influenza virus strains in the vaccine are updated each year as the strains circulating change constantly. Monitoring of any unwanted medical incidents (adverse events) after vaccination is required to help assess vaccine safety. In this study, we monitored adverse events reported within 21 days of administration of Fluarix Tetra seasonal influenza vaccine (IIV4) in participants aged 6 months and older in Korea over a period of 4­6 years. Of the participants aged ≥ 3 years, 98 (14%) reported 140 adverse events, most commonly infections and infestations (most commonly nasopharyngitis such as the common cold), or general disorders and administration site conditions (most commonly pain or swelling at the injection site). In the participants aged 6­35 months, 149 (22%) reported 248 adverse events, also most commonly infections and infestations (such as the common cold) or general disorders and administration site conditions (most commonly fever or swelling at the injection site). There were five serious adverse events in total (adverse events that are life threatening or require hospitalization), but none of them were related to IIV4. In this study, we did not find any safety concerns for IIV4 in participants aged ≥ 6 months in Korea. The findings of this study suggest IIV4 is safe and well tolerated in all age groups with a vaccine indication.

Safety and effectiveness of avelumab in patients with Merkel cell carcinoma in general clinical practice in Japan: Post-marketing surveillance.

Avelumab, a programmed cell death ligand 1 blocking antibody, was approved for its first indication in Japan in September 2017 to treat unresectable Merkel cell carcinoma (MCC). Given that the pivotal JAVELIN Merkel 200 study only included a few Japanese patients, this post-marketing surveillance (PMS) evaluated the safety and effectiveness outcomes of patients with MCC who received avelumab in general clinical practice in Japan. This prospective, non-comparative, multicenter PMS included data from all patients with unresectable MCC who received avelumab between November 22, 2017 (avelumab launch date) and October 31, 2019. The primary objective was to evaluate avelumab safety (i.e., adverse events [AEs], adverse drug reactions [ADRs], and ADRs of safety specifications). The secondary objective was to evaluate avelumab effectiveness (i.e., objective response rate and overall survival [OS] rate). Seventy-five evaluable patients were included, of whom 81.3% experienced AEs of any grade (57.3% experienced AEs of grade ≥ 3; 41.3% experienced AEs of grade 5) and 61.3% experienced ADRs (14.7% experienced ADRs of grade ≥ 3; no grade 5 ADRs were observed). The most common ADRs were pyrexia (18.7%), infusion related reaction (10.7%), and chills (6.7%). The most common ADRs of safety specifications were infusion reactions (any grade: n = 21 [28.0%]; grade 3 or 4: n = 3 [4.0%]), thyroid dysfunction (n = 7 [9.3%]), and hepatic function disorders (n = 4 [5.3%]). The median observation period was 51 weeks. An objective response was achieved by 34/75 patients (45.3%; complete response, 24.0%; partial response, 21.3%) and 6- and 12-month OS rates were 77.7% and 59.6%, respectively. This PMS confirmed the clinical tolerability and effectiveness of avelumab in patients with MCC, with no new safety concerns. The risk-benefit profile of avelumab was comparable with that observed in clinical trials and remains favorable for use in general clinical practice in Japan.

Safety and Effectiveness of a Biosimilar Recombinant Human Growth Hormone in Children Requiring Growth Hormone Treatment: Analysis of Final Data from PATRO Children, an International, Post-Marketing Surveillance Study.

Purpose: Omnitrope® (somatropin) was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Here, we report final data from the PAtients TReated with Omnitrope® (PATRO) Children study, a post-marketing surveillance study designed to monitor the long-term safety and effectiveness of this treatment in pediatric patients. Methods: The study population included all pediatric patients treated with Omnitrope® (biosimilar rhGH), administered via daily injection, in routine clinical practice. The primary objective was to assess long-term safety, with effectiveness assessed as a secondary objective. Results: In total, 7359 patients were enrolled and treated in the PATRO Children study; 86.0% were treatment-naïve at baseline. Growth hormone deficiency was the most frequent indication (57.9%), followed by patients born small for gestational age (SGA; 26.6%). The mean (SD) duration of exposure to biosimilar rhGH was 3.66 years (2.39). A total of 16,628 adverse events (AEs) were reported in 3981 (54.1%) patients, most of which were mild/moderate. AEs suspected to be treatment related occurred in 8.3% of patients, most frequently headache (1.6%), injection-site pain (1.1%), or injection-site hematoma (1.1%). The incidence rate (IR) of type 2 diabetes mellitus was 0.11 per 1000 person-years (PY) across all patients, and 0.13 per 1000 PY in patients born SGA. The IR of newly diagnosed primary malignancies was 0.22 per 1000 PY across all patients. In the 6589 patients included in the effectiveness population, a sustained catch-up growth was observed across all indications. After 5 years of treatment, height SDS increased from baseline by a median (range) of +1.79 (-3.7 to 6.2) in treatment-naïve patients and +0.73 (-1.4 to 3.7) in pretreated patients. Conclusion: This final analysis of the PATRO Children study indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice. These data are consistent with the well-characterized safety profile of rhGH treatment in pediatric patients.

Characteristics of patients with longer treatment period of lenvatinib for unresectable hepatocellular carcinoma: A post-hoc analysis of post-marketing surveillance study in Japan.

Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment.

Post-marketing surveillance of intussusception after Rotarix administration in Afghanistan, 2018-2022.

BACKGROUND: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants. METHODS: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods. RESULTS: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose. CONCLUSION: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants.

Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.

The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.

Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications.

In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's Accelerated Approval Program, we observe a tendency towards fast approval for exploratory studies with non-randomised, uncontrolled designs and surrogate endpoints. This issue raises concerns about the robustness and effectiveness of accepted treatments, leaving patients and health-care professionals in a state of uncertainty. A substantial number of accelerated approvals have recently been withdrawn in the USA, with some still authorised in Europe, emphasising discrepancies in regulatory standards that affect both patients and society as a whole. We highlight examples of drugs, authorised on the basis of surrogate endpoints, that were later withdrawn due to an absence of overall survival benefit. Our findings address the challenges and consequences of accelerated approval pathways in oncology. In conclusion, this Policy Review calls for regulatory bodies to better align their procedures and insist on robust evidence, preferably through unbiased randomised controlled trials. Drug approval processes should prioritise patient benefit, overall survival, and quality of life to minimise risks and uncertainties for patients.

Post-marketing active surveillance of Guillain Barré Syndrome following COVID-19 vaccination in persons aged ≥12 years in Italy: A multi-database self-controlled case series study.

BACKGROUND: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy. METHODS: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods. RESULTS: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28). CONCLUSIONS: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events.

A patient safety knowledge graph supporting vaccine product development.

BACKGROUND: Knowledge graphs are well-suited for modeling complex, unstructured, and multi-source data and facilitating their analysis. During the COVID-19 pandemic, adverse event data were integrated into a knowledge graph to support vaccine safety surveillance and nimbly respond to urgent health authority questions. Here, we provide details of this post-marketing safety system using public data sources. In addition to challenges with varied data representations, adverse event reporting on the COVID-19 vaccines generated an unprecedented volume of data; an order of magnitude larger than adverse events for all previous vaccines. The Patient Safety Knowledge Graph (PSKG) is a robust data store to accommodate the volume of adverse event data and harmonize primary surveillance data sources. METHODS: We designed a semantic model to represent key safety concepts. We built an extract-transform-load (ETL) data pipeline to parse and import primary public data sources; align key elements such as vaccine names; integrated the Medical Dictionary for Regulatory Activities (MedDRA); and applied quality metrics. PSKG is deployed in a Neo4J graph database, and made available via a web interface and Application Programming Interfaces (APIs). RESULTS: We import and align adverse event data and vaccine exposure data from 250 countries on a weekly basis, producing a graph with 4,340,980 nodes and 30,544,475 edges as of July 1, 2022. PSKG is used for ad-hoc analyses and periodic reporting for several widely available COVID-19 vaccines. Analysis code using the knowledge graph is 80% shorter than an equivalent implementation written entirely in Python, and runs over 200 times faster. CONCLUSIONS: Organizing safety data into a concise model of nodes, properties, and edge relationships has greatly simplified analysis code by removing complex parsing and transformation algorithms from individual analyses and instead managing these centrally. The adoption of the knowledge graph transformed how the team answers key scientific and medical questions. Whereas previously an analysis would involve aggregating and transforming primary datasets from scratch to answer a specific question, the team can now iterate easily and respond as quickly as requests evolve (e.g., "Produce vaccine-X safety profile for adverse event-Y by country instead of age-range").

US FDA's Dose Optimization Postmarketing Requirements and Commitments of Oncology Approvals and the Impact on Product Labels from 2010 to 2022: An Emerging Landscape from Traditional to Novel Therapies.

BACKGROUND: Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA's Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs. METHODS: Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010-2015 and 2016-2022) due to differences in available information. RESULTS: From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes. CONCLUSION: Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA's Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting.

Real-world effectiveness and safety of ibrutinib in relapsed/refractory mantle cell lymphoma in Japan: post-marketing surveillance.

Efficacy and safety data for ibrutinib in Japanese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) were limited at the time of its approval in Japan. All-case post-marketing surveillance was conducted in Japanese R/R MCL patients who began ibrutinib treatment between December 2016 and December 2017, and patients were followed until 30 June 2020. In the effectiveness analysis set (n = 202), the overall response rate was 59.9%, 52-week progression-free survival was 47.5%, and overall survival was 69.3%. Safety was assessed in 248 patients (median age 74.0 years). When ibrutinib treatment was started, patients had received a median of three prior lines of therapy. The overall incidence of adverse events (AE) was 74.6%, and AE frequency and severity grade distribution were similar between patients with 1 versus more than 1 prior line of therapy. The most common AE was platelet count decreased (all grades; 10.4%), similarly to previous observations in patients with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma. Five patients (2.0%) developed atrial fibrillation. The effectiveness and safety of ibrutinib were consistent with its known profile at approval in Japan. These results suggest that ibrutinib is effective and safe in Japanese R/R MCL patients in routine clinical practice.

The safety and effectiveness of remdesivir in a postmarketing surveillance study in Japan.

BACKGROUND: To evaluate the occurrence of adverse drug reactions (ADRs) and to assess mortality and health status in participants receiving remdesivir in real-world settings in Japan. METHODS: This postmarketing surveillance study used an all-case surveillance method for enrollment. Participants with SARS-CoV-2 infection administered remdesivir from July 2020 to November 2021 in Japan were eligible for inclusion. The observation period was from remdesivir treatment initiation to 4 weeks after the end of treatment or treatment discontinuation. Clinical status and outcomes were analyzed by Kaplan-Meier plots and compared across subgroups at baseline, Day 14, Day 28, and the final observation point. RESULTS: The analysis included 2128 participants (mean age, 67 years; 71.4 % male; 84.1 % with current comorbidities). ADRs and serious adverse drug reactions (SADRs) were reported among 10.4 % and 1.2 % participants, respectively. Overall, 191/2127 participants died (mortality rate [95 % confidence interval], 11.10 [9.66-12.75] per 100 person-months), 1511/2127 showed clinical improvement (117.8 [112.0-123.9] per 100 person-months), 1392/2127 recovered (103.9 [98.6-110.0] per 100 person-months), and 216/324 were extubated (107.0 [93.6-122.3] per 100 person-months). CONCLUSIONS: The incidence of ADRs and SADRs was low, and no new safety concerns were identified. Observed mortality and clinical improvement results were consistent with prior studies, confirming remdesivir's benefits in real-world settings in Japan.

Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance.

OBJECTIVE: Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. METHODS: To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis. RESULTS: Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1-2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2 cycles, a lower proportion of patients receiving 3-10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. CONCLUSIONS: Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.

A descriptive analysis of postmarketing requirement studies and clinical trials.

PURPOSE: Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA has the authority to require applicants to conduct postmarketing studies or clinical trials. These postmarketing requirements (PMRs) provide additional data on the safety of the drug product. The purpose of the study was to conduct a descriptive analysis of FDAAA PMRs and the resulting regulatory actions. METHODS: This study evaluated FDAAA PMRs established between 2013 and 2019. We used the Medical Dictionary for Regulatory Activities (MedDRA) to map preferred terms (PTs) for serious risks associated with the PMRs. Relevant documents available in the FDA's document archiving, reporting, and regulatory tracking system (DARRTS), including but not limited to internal letters and reviews, documents submitted by applicants, and publicly available data sources were assessed for data collection of study elements. RESULTS: Of the 1079 new FDAAA PMRs established between January 01, 2013, and December 31, 2019, 82% (n = 884) were associated with new drug applications (NDAs) and 18% (n = 195) with biologic license applications (BLAs). Most PMRs were established at the time of drug approval (73%, n = 789) compared to post-approval (27%, n = 290). The majority of PMRs had an open status (59%, n = 639) and 41% (n = 440) were closed. The median time from the PMR establishment date to submission of the results to the FDA was 690 days (interquartile range [IQR]: 748 days) for 167 completed clinical trials and 483 days (IQR: 603 days) for 241 completed studies. Approximately 53% (180/339) of fulfilled FDAAA PMRs resulted in labeling changes. CONCLUSIONS: FDAAA PMRs are useful in informing postmarket safety of drugs. Most FDAAA PMRs were established at the time of drug approval, reflecting safety signals identified during the review of the marketing application, and over half of fulfilled FDAAA PMRs resulted in regulatory action.

Bayesian safety surveillance with adaptive bias correction.

Postmarket safety surveillance is an integral part of mass vaccination programs. Typically relying on sequential analysis of real-world health data as they accrue, safety surveillance is challenged by sequential multiple testing and by biases induced by residual confounding in observational data. The current standard approach based on the maximized sequential probability ratio test (MaxSPRT) fails to satisfactorily address these practical challenges and it remains a rigid framework that requires prespecification of the surveillance schedule. We develop an alternative Bayesian surveillance procedure that addresses both aforementioned challenges using a more flexible framework. To mitigate bias, we jointly analyze a large set of negative control outcomes that are adverse events with no known association with the vaccines in order to inform an empirical bias distribution, which we then incorporate into estimating the effect of vaccine exposure on the adverse event of interest through a Bayesian hierarchical model. To address multiple testing and improve on flexibility, at each analysis timepoint, we update a posterior probability in favor of the alternative hypothesis that vaccination induces higher risks of adverse events, and then use it for sequential detection of safety signals. Through an empirical evaluation using six US observational healthcare databases covering more than 360 million patients, we benchmark the proposed procedure against MaxSPRT on testing errors and estimation accuracy, under two epidemiological designs, the historical comparator and the self-controlled case series. We demonstrate that our procedure substantially reduces Type 1 error rates, maintains high statistical power and fast signal detection, and provides considerably more accurate estimation than MaxSPRT. Given the extensiveness of the empirical study which yields more than 7 million sets of results, we present all results in a public R ShinyApp. As an effort to promote open science, we provide full implementation of our method in the open-source R package EvidenceSynthesis.

Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.

OBJECTIVES: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER: NCT01932372.

Implementing methods in the ELEGANCE registry to increase diversity in clinical research.

OBJECTIVE: Women and underrepresented minorities (URMs) who are at an increased risk of presenting with severe peripheral artery disease (PAD) and have different responses to treatment compared with non-Hispanic White males yet are underrepresented in PAD research. METHODS: ELEGANCE is a global, prospective, multi-center, post-market registry of PAD patients treated with drug-eluting device that aims to enroll at least 40% women and 40% URMs. The study design incorporates strategies to increase enrollment of women and URMs. Inclusion criteria are age ≥18 years and treatment with any commercially available Boston Scientific Corporation drug-eluting device marketed for peripheral vasculature lesions; exclusion criterion is life expectancy <1 year. RESULTS: Of 750 patients currently enrolled (951 lesions) across 39 sites, 324 (43.2%) are female and 350 (47.3%) are URMs (21.6% Black, 11.2% Asian, 8.5% Hispanic/Latino, and 5.3% other). Rutherford classification is distributed differently between sexes (P = .019). Treatment indication differs among race/ethnicity groups (P = .003). Chronic limb-threatening ischemia was higher for Black (38.3%) and Hispanic/Latino (28.1%) patients compared with non-Hispanic White (21.8%) and Asian patients (21.4%). De-novo stenosis was higher in Asian patients (92.3%) compared with Black, non-Hispanic White, and Hispanic/Latino patients (72.2%, 68.7%, and 77.8%, respectively; P < .001). Mean lesion length was longest for Black patients (162.7 mm), then non-Hispanic White (135.2 mm), Asian (134.8 mm), and Hispanic/Latino patients (128.1 mm; P = .008). CONCLUSIONS: Analyses of data from the ELEGANCE registry show that differences exist in baseline disease characteristics by sex and race/ethnicity; these may be the result of other underlying factors, including time to diagnosis, burden of undermanaged comorbidities, and access to care.