Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

Estimating Baseline Incidence of Conditions Potentially Associated with Vaccine Adverse Events: a Call for Surveillance System Using the Korean National Health Insurance Claims Data.

BACKGROUND: Vaccines against coronavirus disease 2019 (COVID-19) are raising concerns about vaccine safety, particularly in the context of large-scale immunization. To address public concerns, we measured the baseline incidence rates of major conditions potentially related to vaccine-related adverse events (VAEs). We aimed to provide a basis for evaluating VAEs and verifying causality. METHODS: Conditions of interest were selected from the US Vaccine Adverse Event Reporting System Table of Reportable Events and a recent report from a European consortium on vaccine surveillance. We used the National Health Insurance Service database in Korea to identify the monthly numbers of cases with these conditions. Data from January 2006 to June 2020 were included. Prediction models were constructed from the observed incidences using an autoregressive integrated moving average. We predicted the incidences of the conditions and their respective 95% confidence intervals (CIs) for January through December 2021. In addition, subgroup analysis for the expected vaccination population was conducted. RESULTS: Mean values (95% CIs) of the predicted monthly incidence of vasovagal syncope, anaphylaxis, brachial neuritis, acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, encephalopathy, optic neuritis, transverse myelitis, immune thrombocytopenic purpura, and systemic lupus erythematosus in 2021 were 23.89 (19.81-27.98), 4.72 (3.83-5.61), 57.62 (51.37-63.88), 0.03 (0.01-0.04), 8.58 (7.90-9.26), 0.26 (0.18-0.34), 2.13 (1.42-2.83), 1.65 (1.17-2.13), 0.19 (0.14-0.25), 0.75 (0.61-0.90), and 3.40 (2.79-4.01) cases per 100,000 respectively. The majority of the conditions showed an increasing trend with seasonal variations in their incidences. CONCLUSION: We measured the incidence of a total of 11 conditions that could potentially be associated with VAEs to predict the monthly incidence in 2021. In Korea, conditions that could potentially be related to VAEs occur on a regular basis, and an increasing trend is observed with seasonality.

QT Prolongation Risk Assessment in Oncology: Lessons Learned From Small-Molecule New Drug Applications Approved During 2011-2019.

The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question-and-answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small-molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT-related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration-QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT-related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit-to-risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.

A Broad Safety Assessment of the 9-Valent Human Papillomavirus Vaccine.

Parents indicate that safety is their top concern about human papillomavirus (HPV) vaccination. A data-mining method not requiring prespecification of health outcome(s) or postexposure period(s) of potentially increased risk can be used to identify possible associations between an exposure and any of thousands of medically attended health outcomes; this method was applied to data on the 9-valent HPV vaccine (HPV9) to detect potential safety problems. Data on 9- to 26-year-olds who had received HPV9 vaccine between November 4, 2016, and August 5, 2018, inclusive, were extracted from the MarketScan database and analyzed for statistically significant clustering of incident diagnoses within the hierarchy of diagnoses coded using the International Classification of Diseases and temporally within the 1 year after vaccination, using the self-controlled tree-temporal scan statistic and TreeScan software. Only 56 days of postvaccination enrollment was required; subsequent follow-up was censored at disenrollment. Multiple testing was adjusted for. The analysis included 493,089 doses of HPV9. Almost all signals resulted from temporal confounding, not unexpected with a 1-year follow-up period. The only plausible signals were for nonspecific adverse events (e.g., injection-site reactions, headache) on days 1-2 after vaccination, with attributable risks as low as 1 per 100,000 vaccinees. Considering the broad scope of the evaluation and the high statistical power, the findings of no specific serious adverse events should provide reassurance about this vaccine's safety.

Pharmacodynamic analysis of hypertension caused by lenvatinib using real-world postmarketing surveillance data.

Lenvatinib is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor used against nonoperative thyroid cancer; however, hypertension is a major dose-limiting side effect. In this study, hypertension caused by lenvatinib was described through a novel population pharmacodynamic model using postmarketing surveillance data obtained in Japan. The model consists of two maximum effect model components based on the (1) concentration of lenvatinib in plasma and (2) cumulative area under the curve of lenvatinib. In addition, antihypertensive drug of either an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or calcium channel blocker accounted for by lowering effect on diastolic blood pressure. Based on virtual simulations, the combination of antihypertensive drug and dose adjustment of lenvatinib showed a reduction in the probability of grade greater than or equal to 3 hypertension. The present model provides useful guidance in managing hypertension during treatment with lenvatinib in the real-world setting.

Project Orbis: Global Collaborative Review Program.

In 2019, the FDA Oncology Center of Excellence launched Project Orbis, a global collaborative review program to facilitate faster patient access to innovative cancer therapies across multiple countries. Project Orbis aims for concurrent submission, review, and regulatory action for high-impact clinically significant marketing applications among the participating partner countries. Current Project Orbis partners (POP) include the regulatory health authorities (RHA) of Australia, Brazil, Canada, Singapore, and Switzerland. Project Orbis leverages the existing scientific and regulatory partnerships between the various RHA under mutual confidentiality agreements. While FDA serves as the primary coordinator for application selection and review, each country remains fully independent on their final regulatory decision. In the first year of Project Orbis (June 2019 to June 2020), a total of 60 oncology marketing applications were received, representing 16 unique projects, and resulting in 38 approvals. New molecular entities, also known as new active substances, comprised 28% of the received marketing applications. The median time gap between FDA and Orbis submission dates was 0.6 months with a range of -0.8 to 9.0 months. Across the program, the median time-to-approval was similar between FDA (4.2 months, range 0.9-6.9, N = 18) and the POP (4.4 months, range 1.7-6.8, N = 20). Participating countries have signified a strong commitment for continuation and growth of the program. Project Orbis expansion considerations include the addition of more countries and management of more complex applications.

Association Between Topical Calcineurin Inhibitor Use and Keratinocyte Carcinoma Risk Among Adults With Atopic Dermatitis.

Importance: Topical calcineurin inhibitors (TCIs), primarily used to treat atopic dermatitis (AD), carry a black box label warning users about the potential for increased skin cancer risk. The risk associated with keratinocyte carcinoma (KC), the most common cancer, defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remains poorly defined because findings from large-scale postmarketing surveillance studies have not been reported. Objectives: To examine KC risk overall and by subtype (BCC and SCC) among adults with AD exposed to TCIs compared with those exposed to topical corticosteroids (primary comparator group) and those unexposed to TCIs or topical corticosteroids (alternative comparator group) as well as alterations in risk with TCI dose, frequency, and duration of exposure. Design, Setting, and Participants: A retrospective cohort study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system, of adults 40 years or older (n = 93 746) with a physician-rendered diagnosis of AD or dermatitis. Patients who were diagnosed from January 1, 2002, to December 31, 2013, were included, with follow-up through December 31, 2017. Data analysis was conducted from June 1, 2016, to October 1, 2018. Exposures: Time-varying pharmacy-dispensed TCI exposure (n = 7033) over the study period was compared with topical corticosteroids (n = 73 674) and no TCI or topical corticosteroid exposure (n = 46 141). Main Outcomes and Measures: Electronic pathologic testing-validated incident KCs (n = 7744). Results: Among a cohort of 93 746 members, the mean (SD) age was 58.5 (12.7) years, and 55 023 patients (58.7%) were women. Multivariable Cox proportional hazards regression revealed no association between TCI exposure and KC risk (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.93-1.13) compared with topical corticosteroid exposure. Similarly, there were no significant differences in BCC risk (aHR, 1.01; 95% CI, 0.90-1.14, TCI vs topical corticosteroids) or SCC risk (aHR, 0.94; 95% CI, 0.82-1.08, TCI vs topical corticosteroids). Changing the comparator group to unexposed individuals yielded similar findings (aHR, 1.04; 95% CI, 0.91-1.19, TCI vs unexposed for basal cell carcinoma). There were no associations between TCI dose, frequency, and duration of use and BCC, SCC, or overall KC risk. Conclusions and Relevance: The results of this postmarketing surveillance study of adult health plan members with AD revealed no apparent association between TCI exposure and overall KC, BCC, or SCC risk. Secondary analyses examining dose, frequency, and duration of TCI exposure revealed no associations. These findings suggest that use of TCIs may be safe with respect to KC risk among adults with AD.

Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Safety and Effectiveness of Anti-Tumor Necrosis Factor-Alpha Biosimilar Agents in the Treatment of Psoriasis.

Biologic drugs have revolutionized the treatment of psoriasis and other chronic inflammatory diseases. In recent years, many tumor necrosis factor-alpha 'biosimilar' agents have been developed. These biosimilars are similar in structure and function to their originator molecules, although they are not identical. Given that the safety and efficacy of the original biologic have already been proven, biosimilars are only required to show bioequivalence, or non-inferiority, to the reference biologic to be approved. Based on extrapolation of these non-inferiority data, biosimilars may be subsequently approved for all indications of the originator biologic, even without being directly studied in these various conditions. These biosimilar agents have been purported as a method to reduce the costs of biologic therapies, thereby increasing the accessibility of these medications and subsequently improving the treatment of psoriasis worldwide. The US Food and Drug Administration and/or the European Medicines Agency have approved biosimilars of adalimumab (Amjevita/Amgevita/Solymbic, Cyltezo, Imraldi/Hadlima, Hyrimoz/Hefiya/Halimatoz, Idacio, Hulio, Abrilada), etanercept (Erelzi, Benepali/Eticovo), and infliximab (Inflectra/Remsima, Renflexis/Flixabi, Ixifi/Zessly) for the treatment of psoriasis, and others are under review. There are many phase III data supporting the bioequivalence of these anti-tumor necrosis factor-alpha biosimilar agents in treating psoriasis and rheumatologic disease, which are discussed here. In general, these biosimilar agents have been shown to have equivalent efficacy, tolerability, and immunogenicity profiles compared to their originators in patients with rheumatologic disease, although studies in patients with psoriasis are fairly limited. Additional switching studies and post-marketing safety analyses are needed to assess the interchangeability of biosimilar agents with their reference products.

Postmarket Experience of Polymethylmethacrylate-Collagen Gel Dermal Filler.

BACKGROUND: This report synthesizes 12 years of postmarket surveillance data (PMSD) for polymethylmethacrylate (PMMA)-collagen gel dermal filler. OBJECTIVE: To present PMMA-collagen gel PMSD findings on real-world safety. METHODS: Postmarket surveillance data were collected from January 2007 to December 2018 and evaluated to determine the overall adverse event (AE) complaint rate, the nature of reported AEs, and whether the complaint included on-label, off-label, both, or unknown areas. RESULTS: In the 12 years examined, 754,229 PMMA-collagen gel syringes were distributed worldwide, and 839 product-related complaints (including those classified as unknown) resulted in an overall complaint rate of 0.11%. The 3 most frequent primary complaints in AE reports were lump/bump (309/839, 37%), nodule (152/839, 18%), and swelling (138/839, 16%). Histologically confirmed granuloma accounted for 17/839 complaints (2.0%; overall complaint rate of 0.002%), and histologically unconfirmed granuloma accounted for 66/839 complaints (8%; overall rate of 0.009%). There were 666 complaints representing AEs related to off-label injection in which the periocular area was most frequently represented. CONCLUSION: Although a limiting factor across all PMSD is voluntary reporting and resultant underrepresentation of AEs, the PMSD reported here are consistent with safety findings from US clinical studies in more than 1,500 patients with up to 5 years of follow-up.

The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor.

CONTEXT: The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. OBJECTIVE: To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. DESIGN: Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. RESULTS: Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. CONCLUSIONS: These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.

Use of real-world registry data: a hernia mesh example.

PURPOSE: Clinical performance of hernia mesh devices is poorly understood due to a lack of relevant clinical trial and real-world data (RWD). Registries offer a means to capture longitudinal data in real-world practice. This report highlights the need for data quality, completeness, and appropriate analysis methodology for more accurate and informed interpretation of RWE of medical devices. METHODS: Hernia mesh registry data were used to cross-tabulate the 30-day infection rate of patients who received one of four mesh types. RESULTS: Initial data review suggested lower infection rate for permanent mesh versus absorbable mesh. Additional registry RWD were factored into the analysis, providing more context in the interpretation of the results. CONCLUSIONS: High-quality registries can be used to generate real-world evidence (RWE) to support surveillance and other regulatory decisions.

Innovative Thinking on Endpoint Selection in Clinical Trials.

In clinical trials, selection of appropriate study endpoints is critical for an accurate and reliable evaluation of safety and effectiveness of a test treatment under investigation. In practice, however, there are usually multiple endpoints available for measurement of disease status and/or therapeutic effect of the test treatment under study. For example, in cancer clinical trials, overall survival, response rate, and/or time to disease progression are usually considered as primary clinical endpoints for evaluation of safety and effectiveness of the test treatment under investigation. Once the study endpoints have been selected, sample size required for achieving a desired power is then determined. It, however, should be noted that different study endpoints may result in different sample sizes. In practice, it is usually not clear which study endpoint can best inform the disease status and measure the treatment effect. Moreover, different study endpoints may not translate one another although they may be highly correlated one another. In this article, we intend to develop an innovative endpoint namely therapeutic index based on a utility function to combine and utilize information collected from all study endpoints. Statistical properties and performances of the proposed therapeutic index are evaluated theoretically. A numerical example concerning a cancer clinical trial is given to illustrate the use of the proposed therapeutic index.

Development of an algorithm to detect methotrexate wrong frequency error using computerized health care data.

PURPOSE: We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. METHODS: We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. RESULTS: The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). CONCLUSION: Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.

Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration's Adverse Event Reporting System, 2010-2017.

Importance: Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. Objective: To describe the postmarketing safety experience for sipuleucel-T. Design, Setting, and Participants: In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. Main Outcomes and Measures: Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T-event pairs. Selected adverse events and death reports were individually reviewed. Results: In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). Conclusions and Relevance: Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.

Comparison of post-marketing surveillance approaches regarding infections related to tumor necrosis factor inhibitors (TNFi's) used in treatment of autoimmune diseases.

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi's). Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using EvidexTM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss's kappa and Cohen's kappa (κ) were calculated to determine agreement across all three sources and between each two sources. Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss' kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM. Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.

The Dutch Breast Implant Registry: Registration of Breast Implant-Associated Anaplastic Large Cell Lymphoma-A Proof of Concept.

BACKGROUND: The Dutch Breast Implant Registry (DBIR) was established in April of 2015 and currently contains information on 38,000 implants in 18,000 women. As a clinical registry, it evaluates the quality of breast implant surgery, including adverse events such as breast implant-associated (BIA) anaplastic large cell lymphoma (ALCL). To examine the efficacy of the DBIR, the capture rate of BIA-ALCL was compared to the registration of BIA-ALCL in the Dutch Nationwide Network and Registry of Histo- and Cytopathology (PALGA) as a gold standard, in combination with matching these databases to obtain complementary information. METHODS: All BIA-ALCL patients diagnosed and registered in The Netherlands in 2016 and 2017 were identified separately in the PALGA and DBIR databases. In addition, both databases were matched using indirect key identifiers. Pathologic information from the PALGA and clinical and device characteristics from the DBIR were obtained for all patients. RESULTS: Matching of both databases gave a capture rate of BIA-ALCL in the DBIR of 100 percent (n = 6) in 2016 and 70 percent (n = 7) in 2017. In total, 17 patients were identified in the PALGA, of which 14 patients were also identified in the DBIR; three patients were not registered; and 10 patients were registered false-positive. Of all confirmed patients, symptoms, staging results, treatment, and implant information were registered. CONCLUSIONS: Currently, the DBIR contains 2 full registration years and captures most of the BIA-ALCL patients despite overestimation. Therefore, pathology confirmation remains essential. By matching these databases, complementary clinical and implant information could be retrieved, establishing the DBIR as an essential postmarketing surveillance system for health risk assessments.

Identifying Data Elements to Measure Frailty in a Dutch Nationwide Electronic Medical Record Database for Use in Postmarketing Safety Evaluation: An Exploratory Study.

INTRODUCTION: The role of frailty in postmarketing drug safety is increasingly acknowledged. Few European electronic medical records (EMRs) have been used to explore frailty in observational drug safety research. OBJECTIVE: The aim of this study was to identify data elements, beyond multimorbidity and polypharmacy, that could potentially contribute to measuring frailty among older adults in the Dutch nationwide Integrated Primary Care Information (IPCI) database. METHODS: Persons aged between 65 and 90 years in the IPCI database were identified from 2008 to 2013. Clinical non-disease, non-drug measurements that could potentially contribute to measuring frailty were identified and selected if they were recorded in > 0.005% of patients and could be included in at least one of three definitions of frailty: the frailty phenotype model, the cumulative deficit model, and direct evaluations of frailty through standardized frailty scores. The frequency of these measures was calculated. RESULTS: Overall, 314,191 (17% of the source population) elderly persons were identified. Of these, 7948 (2.53%) had one or more of 12 clinical measurements identified that could potentially contribute to measuring frailty, such as clinical evaluations of cognition, mobility, and cachexia, as well as direct measures of frailty, such as the Groningen Frailty Index. Three of five measurements required for the frailty phenotype were identified in < 0.5% of the population: cachexia, reduced walking speed, and reduced physical activity; weakness and fatigue were not identified. The measurements outlined above may be appropriate for the cumulative deficit definition of frailty, provided that at least 30 deficits, including comorbidities and drug utilization, are evaluated in total. The most commonly recorded item identified that could potentially be used in a cumulative frailty model was the Mini-Mental State Examination score (N= 2850; 0.91%); the only recorded direct measurement of frailty was the Groningen Frailty Index (N = 2382; 0.76%). CONCLUSION: Non-disease, non-drug clinical data that could potentially contribute to a frailty model was not commonly recorded in the IPCI; less than 3% of a cohort of elderly persons had these data recorded, suggesting that the use of these data in postmarketing drug safety evaluation may be limited.