Patient- and area-level predictors of prostate cancer among South Carolina veterans: a spatial analysis.

BACKGROUND: Racial and socio-economic status (SES) disparities exist in prostate cancer (PrCA) incidence and mortality. Less is known regarding how geographical factors, including neighborhood social vulnerability and distance traveled to receive care, affect PrCA risk. The purpose of this research was to use the Veterans Administration Medical System, which provides a unique means for studying PrCA epidemiology among diverse individuals with ostensibly equal access to healthcare, to determine whether area-level characteristics influence PrCA incidence while accounting for individual-level risk factors. METHODS: From the US Veteran's Health Administration (VHA) electronic medical records (EMR) database from January 1999 to December 2015, we identified 3,736 PrCA patients and 104,017 cancer-free controls from South Carolina (SC). The VHA EMRs were linked to the US census which provided area-level factors. US census data were used to construct the Social Vulnerability Index which is a continuous composite measure of area-level vulnerability and was divided into tertiles for modeling purposes. Data were analyzed using a Bayesian multivariate conditional autoregressive model (CAR) which accounted for individual-level factors, area-level factors, spatial random effects, and autocorrelation, which were used to identify areas of higher- or lower-than-expected PrCA incidence after controlling for risk factors. RESULTS: As expected, after accounting for age (sixfold and 13-fold increases in men 40-50 years and > 50 years, respectively), race was an important risk factor, with threefold higher odds among Blacks in the fully adjusted model [ORadj 2.98 (2.77, 3.20)]. After accounting for all other factors, residing in a ZIP code tabulated areas (ZCTA) with the greatest level social vulnerability versus the lowest, least vulnerable ZCTA's, increased PrCA risk by 39% [ORadj 1.39 (1.11, 1.75)]. CONCLUSIONS: While accounting for known risk factors for PrCA, including age, race, and marital status, we found geographic areas in SC characterized by higher than average social vulnerability with higher rates of incident PrCA among veterans. Outreach for screening, education, and care coordination may be needed for veterans in these areas.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Regulatory and clinical considerations for biosimilar oncology drugs.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Hospitalizations Among Veterans Treated for Metastatic Prostate Cancer With Abiraterone or Enzalutamide.

BACKGROUND: Abiraterone and enzalutamide are second generation androgen receptor pathway inhibitors (ARPIs) used to treat advanced or metastatic prostate cancer. Without head-to-head comparative studies identifying 1 agent as preferred initial therapy, physician preferences guide initial ARPI choice. This study compares hospitalizations among patients treated initially with abiraterone versus enzalutamide. PATIENTS AND METHODS: United States veterans treated with abiraterone or enzalutamide between May 13, 2011 and December 31, 2019; then compared hospitalization rate during first treatment with ARPI in the Veterans Healthcare Administration. Baseline incidence rate of hospitalization was determined from data 1 year prior to ARPI. Incidence Rate Difference (IRD) was calculated using χ2 test and difference in IRD using Poisson Regression. RESULTS: 19,775 veterans were identified; 13,527 (68.4%) were initially treated with abiraterone and 6248 (31.6%) initially with enzalutamide. The enzalutamide cohort was older (75.8 vs. 74.5 years, P < .001) and had higher baseline comorbidities at ARPI initiation (4.4 vs. 4.0, P < .001). Patients were treated with enzalutamide longer than abiraterone (median 9.0 vs. 8.0 months, P < .001). Total hospitalizations increased from 465 per 1000 person-years in the year prior to treatment with abiraterone to 567 during treatment. Total hospitalizations increased from 417 per 1000 person-years in the year prior to treatment with enzalutamide to 430 during treatment. Total rate of hospitalization increased 22% for abiraterone compared to a 3% increase for enzalutamide in the 12 months after ARPI initiation (P < .0001). Abiraterone was associated with greater increase in rates of acute heart failure, atrial fibrillation, acute kidney injury, urinary tract infections, sepsis, and pneumonia. CONCLUSION: By comparing the rate of hospitalization before vs. during treatment, real world analyses identified a 22% versus 3% increase in hospitalizations with abiraterone compared to enzalutamide respectively, despite being used in a younger population with less comorbid disease. Abiraterone was also associated with higher risk of infections, a novel finding.

United States' regulatory approved pharmacotherapies for nuclear reactor explosions and anthrax-associated bioterrorism.

INTRODUCTION: Nuclear reactor incidents and bioterrorism outbreaks are concerning public health disasters. Little is known about US Food and Drug Administration (FDA)-approved agents that can mitigate consequences of these events. We review FDA data supporting regulatory approvals of these agents. AREAS COVERED: We reviewed pharmaceutical products approved to treat Hematopoietic Acute Radiation Syndrome (H-ARS) and to treat or prevent pulmonary infections following Bacillus anthracis (anthrax) exposure. Four drugs were approved for H-ARS: granulocyte-colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor, pegylated G-CSF, and romiplostim. For bioterrorism-associated anthrax, the FDA approved five antibiotics (doxycycline, penicillin-G, levofloxacin, moxifloxacin, and ciprofloxacin), two monoclonal antibodies (obiltoxaximab and raxibacumab), one polyclonal antitoxin (Anthrax Immune Globulin Intravenous) and two vaccines (Anthrax Vaccine Adsorbed and Anthrax Vaccine Adsorbed with an adjuvant). A national stockpile system ensures that communities have ready access to these agents. Our literature search was based on data included in drugs@FDA (2001-2023). EXPERT OPINION: Two potential mass public health disasters are aerosolized anthrax dissemination and radiological incidents. Five agents authorized for anthrax emergencies only have FDA approval for this indication, five antibiotics have FDA approvals as antibiotics for common infections and for bacillus anthrax, and four agents have regulatory approvals for supportive care for cancer and for radiological incidents.

A spatial assessment of prostate cancer mortality-to-incidence ratios among South Carolina veterans: 1999-2015.

PURPOSE: To assess veteran-specific prostate cancer (PrCA) mortality-to-incidence ratios (MIR) in South Carolina's (SC) veteran population. METHODS: U.S. Veterans Health Administration electronic medical records from January 1999 to December 2015 identified 3,073 PrCA patients residing in 345 ZIP code tabulation areas (ZCTA) within SC. MIRs were calculated for all SC ZCTAs and by key patient- and neighborhood-level risk factors for PrCA. Comparisons between ZCTAs identified as part of a spatial cluster were compared with non-significant ZCTAs using t tests. RESULTS: The MIR was 0.17 overall, ranging from a low of 0.15 among Black men to 0.20 among White men. Among metropolitan ZCTAs, the MIR was 0.18 compared to 0.16 in non-metropolitan ZCTAs. Two clusters of higher-than-expected MIRs were found in the Upstate region. CONCLUSIONS: Identification of spatial clusters of higher- or lower-than-expected MIRs allows for further testing of possible explanatory factors, and the capacity to target resources and policies according to greatest need.

Community collaboration in a community H1N1 vaccination program.

This community's utilization of their Medical Reserve Corps (MRC) unit proved to be a valuable resource in their vaccination clinics as part of their response to the novel influenza A (H1N1) virus. Early planning, mock vaccination drills, and use of a strategic analysis process aided in the formulation and development of an efficient vaccination campaign.

Importance of routine public health influenza surveillance: detection of an unusual W-shaped influenza morbidity curve.

Seasonal influenza causes excess morbidity and mortality at the extremes of age: It disproportionately affects the very young and the very old, typically resulting in "U"-shaped age-distributed curves. By means of a well-established public health department surveillance system using positive influenza tests submitted from sentinel sites, the authors generated annual influenza-specific morbidity curves over a 10-year period (1998-2008) for St. Louis County, Missouri. The authors detected an unusually high incidence of cases of medically attended test-positive influenza, particularly in young adults, during the 2007-2008 season, resulting in an unexpected "W"-shaped age-distributed morbidity curve that was distinctly unique in comparison with the prior 9 influenza seasons. Public health influenza surveillance programs are useful tools for detecting emerging epidemiologic trends that may have clinical importance.

Major hemorrhage in chronic lymphocytic leukemia patients in the US Veterans Health Administration system in the pre-ibrutinib era: Incidence and risk factors.

Chronic lymphocytic leukemia (CLL) patients are at increased risk for major hemorrhage (MH). We examined incidence of and risk factors for MH in CLL patients before introduction of newer CLL therapies such as ibrutinib, which includes bleeding risk. This study included 24 198 CLL patients treated in the VA system before FDA approval of ibrutinib as CLL therapy. Data came from VA databases from 1999 to 2013. MH incidence was 1.9/100 person-years (95% CI: 1.8-1.9), with cumulative incidences of 2.3%, 5.2%, and 7.3% by year 1, 3, and 5, respectively. Median time from CLL diagnosis to MH was 2.8 years (range: 0-15.7 years). In multivariate analyses, concurrent anticoagulant and antiplatelet use (HR: 4.2; 95% CI: 3.2-5.6), anticoagulant use only (HR: 2.6; 95% CI: 2.3-3.1), and antiplatelet use only (HR: 1.5; 95% CI: 1.3-1.7) increased MH risk vs not receiving those medications; being nonwhite, male, having MH history, renal impairment, anemia, thrombocytopenia, and alcohol abuse were associated with increased MH risk. These pre-ibrutinib data are important for providing context for interpreting MH risk in ibrutinib-treated patients. As ibrutinib clinical use is increasing, updated analyses of MH risk among ibrutinib-treated VA patients with CLL may provide additional useful insight.

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR).

A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab-associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004-2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8-possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab-treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network.

BACKGROUND: The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. OBJECTIVE: To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. METHODS: 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. RESULTS: Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). LIMITATIONS: Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. CONCLUSION: Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

Hospital-associated Clostridium difficile infection: is it necessary to track community-onset disease?

OBJECTIVES: To compare Clostridium difficile infection (CDI) rates determined with use of a traditional definition (ie, with healthcare-onset CDI defined as diagnosis of CDI more than 48 hours after hospital admission) with rates determined with use of expanded definitions, including both healthcare-onset CDI and community-onset CDI, diagnosed within 48 hours after hospital admission in patients who were hospitalized in the previous 30 or 60 days, and to determine whether differences exist between patients with CDI onset in the community and those with CDI onset in a healthcare setting. DESIGN: Prospective cohort. SETTING: Tertiary acute care facility. PATIENTS: General medicine patients who received a diagnosis of CDI during the period January 1, 2004, through December 31, 2005. METHODS: CDI was classified as healthcare-onset CDI, healthcare facility-associated CDI after hospitalization within the previous 30 days, and/or healthcare facility-associated CDI after hospitalization within the previous 60 days. Patient demographic characteristics and medication exposures were obtained. The CDI incidence with use of each definition, CDI rate variability, patient demographic characteristics, and medication exposures were compared. RESULTS: The healthcare-onset CDI rate (1.6 cases per 1,000 patient-days) was significantly lower than the 30-day healthcare facility-associated CDI rate (2.4 cases per 1,000 patient-days; P< .01) and the 60-day healthcare facility-associated CDI rate (2.6 cases per 1,000 patient-days; P< .01). There was good correlation between the healthcare-onset CDI rate and both the 30-day (correlation, 0.69; P< .01) and 60-day (correlation, 0.70; P< .01) healthcare facility-associated CDI rates. There were no months in which the CDI rate was more than 3 standard deviations from the mean. Compared with patients with healthcare-onset CDI, patients with community-onset CDI were less likely to have received a fourth-generation cephalosporin (P= .02) or intravenous vancomycin (P+ .01) during hospitalization. CONCLUSIONS: Compared with the traditional definition, expanded definitions identify more patients with CDI. There is good correlation between traditional and expanded CDI definitions; therefore, it is unclear whether expanded surveillance is necessary to identify an abnormal change in CDI rates. Cases that met the expanded definitions were less likely to have occurred in patients with fourth-generation cephalosporin and vancomycin exposure.

Identification of a pseudo-outbreak of Clostridium difficile infection (CDI) and the effect of repeated testing, sensitivity, and specificity on perceived prevalence of CDI.

OBJECTIVE: To describe a pseudo-outbreak of Clostridium difficile infection (CDI) caused by a faulty toxin assay lot and to determine the effect of sensitivity, specificity, and repeated testing for C. difficile on perceived CDI burden, positive predictive value, and false-positive results. DESIGN: Outbreak investigation and criterion standard. PATIENTS: Patients hospitalized at a tertiary care hospital who had at least 1 toxin assay for detection of C. difficile performed during the period from July 1, 2004, through June 30, 2006. METHODS: The run control chart method and the chi(2) test were used to compare CDI rates and the proportion of positive test results before, during, and after the pseudo-outbreak. The effect of repeated testing was evaluated by using 3 hypothetical models with a sample of 10,000 patients and various assay sensitivity and specificity estimates. RESULTS: In November of 2005, the CDI rate at the hospital increased from 1.5 to 2.6 cases per 1,000 patient-days (P < .01), and the proportion of positive test results increased from 13.6% to 22.1% (P < .01). An investigation revealed a pseudo-outbreak caused by a faulty toxin assay lot. A decrease of only 1.2% in the specificity of the toxin assay would result in a 32% increase in perceived incidence of CDI at this institution. When calculated by use of the manufacturer's stated specificity and sensitivity and this institution's testing practices, the positive predictive value of the test decreased from 80.6% to 4.1% for patients who received 3 tests. CONCLUSION: Specificity is as important as sensitivity when testing for CDI. False-positive CDI cases can drain hospital resources and adversely affect patients. Repeated testing for C. difficile should be performed with caution.