Food And Drug Administration Warning Research Articles

2092. Acceptability and Effectiveness of Implementation Strategies on Fluoroquinolone (FQ) Prescribing

BackgroundThe Food and Drug Administration (FDA) has issued multiple FQ safety warnings and recommends prescribing FQ only where alternatives are not available. We sought to assess the effectiveness and acceptability of differing implementation strategies on inpatient FQ prescribing.MethodsAntimicrobial stewardship champions at 15 PBRN sites completed a survey in April 2018 regarding local use and acceptability of differing strategies to improve FQ prescribing. Sites with audit and feedback (PAF) and/or prior approval (PA) were compared with sites without these strategies. Antibiotic days of therapy (DOT) per 1000 days-present (DP) were extracted from the VA Corporate Data Warehouse for 2017–2018. Independent t-tests, contingency tables and simple linear regression were applied.Results60% of sites had PAF or PA implemented for FQ. When compared with sites with no strategies in place (64.2 ± 34.4 DOT/DP), mean FQ prescribing rates were lower for sites that employed PAF/PA (35.5 ± 9.8; P = 0.03) and decreased over the 2-year period (P < 0.001 for trend by month). This decrease occurred without an increase in third/fourth-generation cephalosporins for the PAF/PA group (83.5 ± 18.8; P = 0.1 for trend), but increased for sites with no strategies in place (93.6 ± 55.2; P < 0.01 for trend). However, total antibiotic prescribing rates were not different for sites with PAF/PA (561.7 ± 77.8) or without strategies (644.1 ± 157.7; P = 0.2) and did not change over time (p> 0.2). Sites with PAF/PA that reported FQ implementation strategies were “completely” accepted had lower FQ rates than where it was moderately accepted (34.2 ± 5.7 vs. 48.7 ± 4.5; P < 0.01). The PBRN sites perceived that clinical pathways/local guidelines (93% of 15 sites), PA (93%), and order forms (80%) “would” or “may” be effective in improving FQ use. While most sites (73%) indicated that requiring infectious disease consults “would” or “may” be effective in improving FQ use, 87% perceived implementation to be difficult.ConclusionPAF and PA implementation strategies focused on FQ were associated with lower FQ prescribing rates, but not overall antibiotic use, indicating class substitution. This may indicate increased acceptability of implementation strategies and/or sensitivity to the FDA warnings.Disclosures All authors: No reported disclosures.

1364 Tips & Tricks: Step by Step How to Do Two-Port Contained Power Morcellation in A Specialized Bag

Video Objective To explain and demonstrate: 1. Laparoscopic port placement, 2. Step by step technique for the two-port contained power morcellation in a specialized bag (Morcellation Containment System by Espiner Medical), 3. Tips and tricks on each step of contained morcellation Setting Risks of electromechanical morcellation are spreading undiagnosed cancer, diffuse leiomyomatosis, and visceral injury. Food and Drug Administration (FDA) safety communication discouraged use of power morcellators for leiomyoma extraction after the case of disseminated leiomyosarcoma following a laparoscopic hysterectomy. Since FDA warning, laparoscopic contained (in bag) morcellation became popular. However, it can be challenging. Interventions A 27 years old, G0P0, woman was presented with heavy periods and pelvic pain. Her medical and surgical history was unremarkable. Ultrasound showed and anterior/broad ligament fibroid with size of 7.6 × 5.2 × 5.5 cm. After discussing the treatment option, she was consented and had laparoscopic myomectomy and two-port contained morcellation in a specialized bag. Post-operative care was uneventful. Patient was discharged home same day. Histopathology showed benign fibroid. Conclusion The Morcellation Containment System is a feasible tool to extract a pelvic mass. However, it is important to be aware of its challenges like any other contained morcellation system.

Consumer Perception of Biotin Supplementation.

Biotin is an essential cofactor for metabolic pathways in humans. It is frequently self-prescribed by consumers and often recommended by dermatologists and primary care physicians, despite limited evidence of its effect on skin, hair, and nail disorders. A recent Food and Drug Administration (FDA) warning stated that biotin can interfere with laboratory tests. Our objectives were to determine the perception of biotin by Amazon consumers, including perception of improvement in hair, skin, or nails with biotin supplementation and consumers' awareness of the FDA warning on biotin. The keyword biotin was searched on Amazon.com, and the top 1 percentile of biotin products according to average consumer review were analyzed for dosage, indications, price, quantity, warnings, number, and average score of reviews. From 16 biotin products analyzed, the mean review score was 4.38. The mean percentage of reviews stating that biotin helped hair, nails, and skin was 27.2%, 15.03%, and 2.8%, respectively. No biotin products mentioned the FDA warning, and only 1 reviewer referenced the warning. These findings suggest that biotin supplementation is prevalent and perceived as helpful despite limited evidence of improvement. The majority of biotin users were unaware that biotin interacted with laboratory testing demonstrating the need for biotin manufacturers to include a warning label about the FDA warning and for physicians to warn their patients on the risks and benefits of biotin supplementation.

Laparoscopic Hysterectomy Route, Resource Use, and Outcomes: Change After Power Morcellation Warning.

To examine changes in utilization of different types of laparoscopic hysterectomy, as well as their associated resource use and surgical outcomes, after the U.S. Food and Drug Administration (FDA) safety statement in April 2014 regarding power morcellation. We retrospectively analyzed data from the 2012-2016 American College of Surgeons National Surgical Quality Improvement Program and identified 145,746 women undergoing hysterectomy for benign indications. We measured use of laparoscopic supracervical hysterectomy compared to total laparoscopic hysterectomy (including laparoscopic-assisted vaginal hysterectomy) in these patients, as well as operative time, surgical setting (inpatient vs outpatient), length of stay, and 30-day surgical outcomes (wound complication, medical complication, reoperation, and readmission). We used an interrupted time series analysis to examine the association between FDA warning and changes in utilization and outcomes of laparoscopic hysterectomy. After adjusting for patient characteristics and background trends in practice, use of laparoscopic supracervical hysterectomy was significantly lower in the postwarning than prewarning period (odds ratio [OR]=0.49, 95% CI 0.45-0.53), whereas use of total laparoscopic hysterectomy was not affected (OR 1.01, 95% CI 0.96-1.06). Overall, after an initial reduction, use of laparoscopic hysterectomy (laparoscopic supracervical hysterectomy and total laparoscopic hysterectomy combined) increased over time in the postwarning period (adjusted OR of utilization for each calendar quarter elapsed=1.03, 95% CI 1.02-1.03). After the FDA warning, operative time for laparoscopic supracervical hysterectomy increased by 11.45 minutes (95% CI 6.22-16.69), whereas the decreasing trend in the likelihood of inpatient stay for total laparoscopic hysterectomy was attenuated (OR for each calendar quarter elapsed=0.92 in prewarning period, 95% CI 0.91-0.93; and 0.97 in postwarning period, 95% CI 0.97-0.98). There was no significant change in 30-day surgical outcomes after the FDA warning. Rates of laparoscopic supracervical hysterectomy fell in association with power morcellation safety warnings, whereas rates of other laparoscopic hysterectomies continued to rise. There was no change in patient outcomes among laparoscopic hysterectomies.

Evaluation of FDA Boxed Warning on Prescribing Patterns of Fluoroquinolones for Uncomplicated Urinary Tract Infections.

Background: Little is known regarding the impact of the Food and Drug Administration (FDA) boxed warning on prescribing rates of fluoroquinolone (FQ) antibiotics in the outpatient setting. Objective: The primary objective of this study was to evaluate the 2016 FDA boxed warning update on FQ prescribing rates for uncomplicated urinary tract infection (uUTI). Methods: This was a single-center retrospective cohort study conducted at 6 family medicine practices, including women aged 18 to 65 years with an outpatient visit for uUTI from January 1, 2016, to December 31, 2016. Results: A total of 436 patients met inclusion. FQs were prescribed in 38% of patients before the FDA boxed warning and in 30% of patients after (8% reduction). Non-FQ prescribing had a corresponding 8% increase, comprising 62% of uUTI prescribing before the FDA boxed warning and 70% after (P = 0.08). The likelihood of being prescribed a FQ was not significantly different following release of the FDA boxed warning (adjusted odds ratio = 0.67 [95% CI = 0.41-1.10]). Variables significantly associated with an increase in FQ prescribing based on logistic regression were age ≥58 years and chronic kidney disease. Concordance of antibiotic prescribing with the Infectious Diseases Society of America clinical practice guidelines for uUTI was low, and the incidence of treatment failure was low. Conclusion and Relevance: The 2016 FDA boxed warning was not significantly associated with decreased FQ prescribing for uUTI across a large academic family medicine practice. Methods to improve education and disseminate FDA warnings in practice are needed.

The FDA “Black Box” Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?

The decision made in the year 2004 by the U.S. Food and Drug Administration (FDA) to require a boxed warning on antidepressants regarding the risk of suicidality in young adults still represents a matter of controversy. The FDA warning was grounded on industry-sponsored trials carried one decade ago or earlier. However, within the past decade, an increasing number of reports have questioned the actual validity of the FDA warning, especially considering a decline in the prescription of the antidepressant drugs associated with an increase in the rate of suicidal events among people with severe depression. The present report provides an overview of the FDA black box warning, also documenting two Major Depressive Disorder patients whose refusal to undergo a pharmacological antidepressant treatment possibly led to an increased risk for suicidal behaviors. The concerns raised by the FDA black box warning need to be considered in real-world clinical practice, stating the associated clinical and public health implications.

Hysterectomy Practice Patterns in the Postmorcellation Era.

To characterize long-term national trends in surgical approach for hysterectomy after the U.S. Food and Drug Administration (FDA) warning against power morcellation for laparoscopic specimen removal. This was a descriptive study using data from the American College of Surgeons National Surgical Quality Improvement Program from 2012 to 2016. We identified hysterectomies using Current Procedural Terminology codes. We used an interrupted time-series analysis to evaluate abdominal and supracervical hysterectomy trends surrounding The Wall Street Journal article first reporting morcellation safety concerns and the FDA safety communication. We compared categorical and continuous variables using χ, t, and Wilcoxon rank sum tests. We identified 179,950 hysterectomies; laparoscopy was the most common mode of hysterectomy in every quarter. Before The Wall Street Journal article, there was no significant change in proportion of abdominal hysterectomies (0.3% decrease/quarter, P=.14). After The Wall Street Journal article, use of abdominal hysterectomy increased 1.1% per quarter for two quarters through the FDA warning (P<.001), plateaued for three quarters until March 2015 (P=.65), then decreased by 0.8% per quarter through 2016 (P<.001). Supracervical hysterectomy volume continuously decreased after the FDA warning (1.0% decrease per quarter, P<.001) and after three quarters (0.7% decrease per quarter, P=.01), then plateaued from April 2015 through 2016 (0.05% decrease per quarter, P=.40). Mode of supracervical hysterectomy was unchanged from 2012 to 2013 (P=.43), followed by two quarters of significant increase in proportion of supracervical abdominal hysterectomies (11.7%/quarter, P<.001). This change in mode of supracervical hysterectomy then plateaued through 2016 (P=.06). Despite early studies suggesting that minimally invasive hysterectomy decreased in response to safety concerns regarding power morcellation, we found that this effect reversed 1 year after the FDA safety communication. However, there was a sustained decline in supracervical hysterectomy, and the remaining supracervical hysterectomies were more likely to be performed using laparotomy.

The Effect of Azithromycin on Relapse in Patients with Moderate-Severe Chronic Graft Versus Host Disease (CGVHD)

BACKGROUND A recent U.S. Food and Drug Administration (FDA) safety communication (Aug 2018) warned prescribers of the risk of relapse in patients receiving azithromycin as prophylaxis for bronchiolitis obliterans syndrome (BOS) following hematopoietic cell transplant (HCT). However, the FDA warning was based upon a single multicenter trial, in which patients were randomized to receive azithromycin for 2 years, starting at the time of conditioning. We now examine relapse rates in a cohort of patients treated with azithromycin for management of moderate-severe CGVHD. PATIENT POPULATION A retrospective review of our HCT database (2010-2017) identified 239 patients (median age 55 years, range 4-72) with moderate-severe CGVHD following an allogeneic HCT for a primary hematologic malignancy. NIH consensus criteria (2015) were used for CGVHD grading. Patients were divided into 2 cohorts, a) those receiving an extended course of azithromycin (≥ 14 days) for CGVHD management (cohort 1, n=86) and b) those who did not (cohort 2, n=153). Patients in cohort 2 either did not receive any azithromycin (n=122) or had received an abbreviated ( RESULTS Decreased rates of relapse and improved survival were noted for patients treated with azithromycin for CGVHD. At 2 years, the cumulative incidence of relapse was 2% (95% CI:1-9%) for patients in cohort 1 vs 16% (95% CI: 11-23%) in cohort 2, p=0.001. Overall survival (2-year OS) in cohort 1 was 93% (95%CI: 88-99%) vs 78% (95% CI:72-85%) for cohort 2, p=0.003. Overall, 7 of 86 (8.1%) CGVHD patients treated with an extended course of azithromycin (cohort 1) have relapsed, the median time to relapse 876 days (range 379-1303) post-HCT. In comparison, 28 of 153 (18.3%) in cohort 2 have relapsed, a median 371 days (range 98-1252) post-HCT. CONCLUSION The use of azithromycin for the management of moderate to severe CGVHD was not associated with an increased risk of relapse in patients undergoing HCT for a hematologic malignancy. Azithromycin therapy for patients with CGVHD should not be contra-indicated in this patient population.

1842. Fluoroquinolone Usage Reduction in the Outpatient Setting

BackgroundFluoroquinolones (FQ) are the leading class of antibiotics prescribed during adult ambulatory care visits, resulting in over 20 million outpatient prescriptions annually. Overuse of this class of antibiotics has contributed to increased antibiotic resistance and risk for Clostridioides difficile infection. In 2016, the Food and Drug Administration (FDA) updated the Boxed Warnings advising against FQ use for patients with uncomplicated sinusitis, bronchitis, or cystitis as the risk for potential serious side effects outweighs the benefit.MethodsThe antimicrobial stewardship team at Parkland Health and Hospital System undertook a multi-interventional approach to decrease outpatient FQ usage (Figure 1). First, the FDA warning was added to all oral FQ orders in the electronic medical record and education regarding risk and appropriate use of FQ was given to providers in the primary care clinics and emergency department. Secondly, ciprofloxacin susceptibilities were suppressed by the laboratory when organisms were susceptible to third-generation cephalosporins. To assess the impact of these interventions, FQ utilization was compared across the same time period, each one year apart. Pre-education was assessed from November 2015 to February 2016, post-education from November 2016 to February 2017, and post-education plus susceptibility suppression from November 2017 to February 2018.ResultsComparative utilization data by site was collected (Figure 2) with all sites demonstrating a decrease in FQ utilization and one site showing an 85% decrease. We observed an overall 19% decrease in outpatient FQ prescribing after education alone and 14% decrease after susceptibility suppression plus continuing education. Compared with pre-intervention baseline, there was a total 30% decrease in FQ utilization after both interventions were implemented, corresponding to approximately 150 fewer prescriptions per month (Figure 3). ConclusionEducational efforts alone proved effective in decreasing outpatient FQ usage. Additional improvement was observed when change was implemented at a system level via susceptibility suppression. Further decrease in FQ utilization is expected with ongoing education and additional system changes.Disclosures All authors: No reported disclosures.

Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006\u20132015)

BackgroundThe objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)‘s study results (October 2009) and the US Food and Drug Administration (FDA)’s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia.MethodsA retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used.ResultsBetween 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67–0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03–1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94–1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06–1.23) and 31% (OR = 1.31, 95% CI: 1.22–1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase.ConclusionsAfter the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT’s recommendations for anemia treatment for non- dialysis dependent CKD patients.

Maternal Epidural Steroids to Prevent Neonatal Exposure to Hyperthermia and Inflammation.

Epidural analgesia is associated with a fourfold increased rate of intrapartum fever. The likely pathophysiology is a noninfectious maternal inflammatory activation. Safe interventions to reduce maternal and neonatal exposures to intrapartum fever and inflammation are needed. The purpose of this study was to determine if prophylactic epidural steroids decrease fetal exposure to hyperthermia and inflammatory cytokines following epidural analgesia. This is a randomized, double-blinded, placebo controlled trial. Term nulliparous women requesting epidural analgesia received 80 mg methylprednisolone or preservative-free normal saline via the epidural catheter at placement. The primary outcome was maternal temperature >100.4°F. Secondary outcomes included fetal exposure to inflammation as assessed by cord blood interleukin-6 (IL-6) levels and rates of funisitis. Power analysis estimated a sample size requirement of 276, but new Food and Drug Administration (FDA) recommendations advising a black box warning on epidural steroids resulted in early study termination. A total of 116 subjects were enrolled: 58 treatments and 58 placebos. There was no difference in the rate of maternal intrapartum fever or cord blood IL-6 levels between treatment arms. No complications listed in the FDA warning occurred. Prophylactic epidural methylprednisolone was not effective in reducing intrapartum fever or neonatal inflammation following epidural analgesia. Alternate mechanisms and preventative strategies should be considered.

Unapproved Pharmaceutical Ingredients Included in Dietary Supplements Associated With US Food and Drug Administration Warnings

Over half of adults in the United States report consuming dietary supplements. The US Food and Drug Administration (FDA) has warned of numerous dietary supplements containing undeclared, unapproved pharmaceutical ingredients. These FDA warnings have not been comprehensively analyzed for recent years. To summarize trends across adulterated (containing unapproved ingredients) dietary supplements associated with a warning released by the FDA from 2007 through 2016. In this quality improvement study, data were extracted from the FDA's Center for Drug Evaluation and Research, Tainted Products Marketed as Dietary Supplements_CDER database from 2007 through 2016. Data from each warning were recorded unless multiple warnings were issued for the same product within a 6-month period. Date, product name, company, hidden ingredient(s), product category, source of sample, and warning document type were recorded for each included warning. Data analysis was conducted from February 2017 to June 2017. From 2007 through 2016, 776 adulterated dietary supplements were identified by the FDA and 146 different dietary supplement companies were implicated. Most of these products were marketed for sexual enhancement (353 [45.5%]), weight loss (317 [40.9%]), or muscle building (92 [11.9%]), with 157 adulterated products (20.2%) containing more than 1 unapproved ingredient. The most common adulterants were sildenafil for sexual enhancement supplements (166 of 353 [47.0%]), sibutramine for weight loss supplements (269 of 317 [84.9%]), and synthetic steroids or steroid-like ingredients for muscle building supplements (82 of 92 [89.1%]). There were 28 products named in 2 or 3 warnings more than 6 months apart. Of these products, 19 (67.9%) were reported to contain new unapproved ingredients in the second or third warning, consistent with the assumption that the FDA found the product to be adulterated more than once. In recent years (2014-2016), 117 of 303 adulterated samples (38.6%) were identified through online sampling and 104 of 303 (34.3%) were identified through the examination of international mail shipments. Active pharmaceuticals continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after FDA warnings. The drug ingredients in these dietary supplements have the potential to cause serious adverse health effects owing to accidental misuse, overuse, or interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement.

Trends in prolapse surgery in England.

Women have a lifetime risk of undergoing pelvic organ prolapse (POP) surgery of 11-19%. Traditional native tissue repairs are associated with reoperation rates of approximately 11% after 20years. Surgery with mesh augmentation was introduced to improve anatomic outcomes. However, the use of synthetic meshes in urogynaecological procedures has been scrutinised by the US Food and Drug Administration (FDA) and by the European Commission (SCENIHR). We aimed to review trends in pelvic organ prolapse (POP) surgery in England. Data were collected from the national hospital episode statistics database. Procedure and interventions-4 character tables were used to quantify POP operations. Annual reports from 2005 to 2016 were considered. The total number of POP procedures increased from 2005, reaching a peak in 2014 (N = 29,228). With regard to vaginal prolapse, native tissue repairs represented more than 90% of the procedures, whereas surgical meshes were considered in a few selected cases. The number of sacrospinous ligament fixations (SSLFs) grew more than 3 times over the years, whereas sacrocolpopexy remained stable. To treat vault prolapse, transvaginal surgical meshes have been progressively abandoned. We also noted a steady increase in uterine-sparing, and obliterative procedures. Following FDA and SCENIHR warnings, a positive trend for meshes has only been seen in uterine-sparing surgery. Native tissue repairs constitute the vast majority of POP operations. SSLFs have been increasingly performed to achieve apical support. Urogynaecologists' training should take into account shifts in surgical practice.

Responsiveness of Veterans Affairs Health Care System to Zolpidem Safety Warnings.

Sedative hypnotic medications are routinely prescribed for insomnia treatment, but have been associated with significant risks of morning-after impairment. We evaluated responsiveness in the Veterans Health Administration (VHA) facilities to two drug safety warnings recommending against high-dose zolpidem use-a 2007 Veterans Administration Pharmacy Benefits Management Service warning and a 2013 Food and Drug Administration (FDA) warning. We used interrupted time-series design to assess how the two warnings influenced prescribing within the VHA in outpatients from 2005 to 2014. We assessed two outcomes: monthly outpatient use of (1) higher-than-recommended dose of zolpidem among zolpidem users and (2) any-dose zolpidem among all VHA users. In sensitivity analyses, we compared zolpidem prescribing to prescribing other sleep medications not subject to safety warnings. After the 2007 VHA warning, high-dose zolpidem use decreased significantly among both sexes from approximately 10% to 2%. Following the 2013 FDA warning, high-dose zolpidem use declined again; however, approximately half of women Veterans remained on high doses. Overall zolpidem use nearly quadrupled between the 2007 VHA and 2013 FDA warnings, but the overall use declined after the 2013 FDA warning. Increase in sedating antidepressant use was seen after the FDA warning, suggesting potential substitution. Higher than recommended dose use within the VHA decreased after each zolpidem high dose warning. Although overall use also decreased after the FDA warning, almost 50% of high-dose use among women Veterans is concerning. Different strategies to communicate the warnings should be examined. A commentary on this article appears in this issue on page 1093.

Counter-Point: Staying Honest When Policy Changes Backfire.

Despite the good intentions of the Food and Drug Administration (FDA), many drug warnings are ineffective or have unintended consequences, particularly if the media exaggerates the messages and scares the public. The controversial 2003 to 2004 FDA warnings on youth suicidality associated with antidepressant use are a case in point. In a 10-year interrupted time series (ITS) analysis in 11 health plans, we found that the warnings and hyped media coverage led to substantial reductions in antidepressant use (declines in antidepressant use and overall care corroborated in several studies), and small, visible increases in emergency room and inpatient poisonings with psychotropic drugs. In a gross misunderstanding of the method, Dr Stone calls ITS, "an intuition based upon false analogies, fallacious assumptions and analytical error." We demonstrate visually using published studies that the ITS method is one of the oldest (hundreds of years) and strongest quasi-experimental study designs, and that the alternative data analyses proposed by Dr Stone do not have rates (denominators), nor baselines, so the measures of change are invalid.

Cardiovascular safety signals with dipeptidyl peptidase-4 inhibitors: A disproportionality analysis among high-risk patients.

In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015. We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE. Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05=2782.47) and saxagliptin (EB05=2.40), myocardial infarction with alogliptin (EB05=290.11), and cerebral infarction with sitagliptin (EB05=2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset. Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

PD05-08 SURGICAL MANAGEMENT OF FEMALE STRESS URINARY INCONTINENCE: 22-YEAR POPULATION-LEVEL TRENDS

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Female Incontinence: Therapy I1 Apr 2018PD05-08 SURGICAL MANAGEMENT OF FEMALE STRESS URINARY INCONTINENCE: 22-YEAR POPULATION-LEVEL TRENDS Joseph LaBossiere, Christopher Wallis, Lesley Carr, Refik Saskin, Robert Nam, and Sender Herschorn Joseph LaBossiereJoseph LaBossiere More articles by this author , Christopher WallisChristopher Wallis More articles by this author , Lesley CarrLesley Carr More articles by this author , Refik SaskinRefik Saskin More articles by this author , Robert NamRobert Nam More articles by this author , and Sender HerschornSender Herschorn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.416AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Available in Canada since 1999, transvaginal sling (TVS) procedures are an effective treatment for women with stress urinary incontinence (SUI). Though rare, complications associated with transvaginal mesh led to warnings from the U.S. Food and Drug Administration (FDA) and Health Canada in 2008 and 2010, respectively. We hypothesized that these warnings would significantly decrease the utilization of TVS procedures for SUI. Therefore, we sought to characterise trends in the surgical management of SUI in a single-payer healthcare system in Ontario, Canada over a 22-year period. METHODS We performed an interrupted time-series analysis using segmented regression among women aged 18 years and older undergoing surgical treatment for SUI between January 1, 1994 and December 31, 2016 in Ontario, Canada. The passage of time was considered the primary exposure. The outcome was the annual population-adjusted rates of SUI surgery over time stratified by modality: urethropexy, TVS, abdominal/vaginal sling and transurethral bulking agents. RESULTS We identified 120 999 women who underwent SUI surgery between 1994 and 2016. The total number of SUI procedures did not significantly change between 1994-2000 (mean 95 per 100 000 population, p=0.89). From 2000-2009, the total number of SUI procedures significantly increased (95 to 147 per 100 000 population, p<0.001) driven by a significant increase in TVS procedures (19 to 129 per 100 000 population, p<0.001). During this time period, the number of urethropexy, abdominal/vaginal sling and bulking agent procedures significantly decreased (p<0.001). After 2009, annual rates of any SUI procedure decreased, a trend which continued during the remainder of the study period (147 to 64 per 100 000 population, p<0.001). This trend was associated with a significant decrease in TVS procedures (130 to 60 per 100 000 population, p<0.001) over the same period as well as significant declines in each of the other SUI treatment modalities (p<0.001). CONCLUSIONS In this large, population-based cohort, we identified a significant influence of the FDA and Health Canada warnings on patient and physician behaviour regarding the management of SUI. Prior to 2009, the overall number of SUI surgeries performed was significantly increasing, driven by increasing utilization of TVS procedures. Following the regulatory warnings, the overall rate of SUI procedures significantly declined, comprising both TVS procedures and other operative interventions. These data suggest that the regulatory warnings had a significant effect on how patients and physicians approach surgical management of SUI. Further, it suggests that many women may be living with untreated SUI. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e147-e148 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Joseph LaBossiere More articles by this author Christopher Wallis More articles by this author Lesley Carr More articles by this author Refik Saskin More articles by this author Robert Nam More articles by this author Sender Herschorn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort.

Utilization of general anesthesia in children has important policy, economic, and healthcare delivery implications, yet there is little information regarding the epidemiology of these procedures in the United States. The primary objective of this study was to describe in a geographically defined population the incidence of procedures requiring general anesthesia up to the child's third birthday, and the patient characteristics associated with receiving these procedures. A secondary objective was to determine the proportion of children in the population who meet the risk criteria promulgated by the Food and Drug Administration (FDA). A retrospective cohort of children born from 1994 to 2007 in Olmsted County, MN was established. Birth certificate information and receipt of general anesthesia before age 3 were collected. Proportional hazard regressions were performed to evaluate the association between characteristics of children and incidence of general anesthesia. Among the 20 922 children in the cohort, 3120 (14.9%) underwent at least 1 general anesthesia before age 3. In multivariate regression, factors independently associated with receiving at least 1 procedure included prematurity, male sex, lower birth weight, cesarean delivery, a non-Hispanic mother, and a White mother, controlling for multiple gestation, number of children previously born, age, education, and marital status of the mother. Seven hundred and twenty-three children (3.5%) had at least 1 subsequent procedure. Estimated gestational age <32 weeks and low birth weight were independently associated with receiving repeated anesthesia. Eight hundred and twenty children (3.9%) had a single prolonged exposure above 3 hours, multiple exposures prior to age 3, or both. Approximately 1 in 7 children were exposed to at least 1 episode of general anesthesia before age 3, and approximately 1 in 4 children who received general anesthesia fall within the high-risk category as defined by the recent FDA warning. The apparent disparities in surgical utilization related to race and ethnicity in this study population deserve further exploration.

A Retrospective Analysis of Clinical Research Misconduct Using FDA-Issued Warning Letters and Clinical Investigator Inspection List From 2010 to 2014.

The US Food and Drug Administration (FDA) conducts inspections of clinical investigation sites as a component of clinical trial regulation. The FDA describes the results of these inspections in the Clinical Investigator Inspection List (CLIIL). More serious violations are followed up in FDA warning letters issued to investigators. The primary objective of the current study is to qualitatively and quantitatively describe the CLIIL data and contents of FDA-issued warning letters from 2010 to 2014. We retrospectively analyzed the CLIIL and FDA warning letters. For the CLIIL, we quantified the frequency of each violation among other data points. We compared recent data (2010-2014) to the previous 5 years (2005-2009). To analyze FDA warning letters, we developed a coding system to quantify the frequency of violations found. We analyzed 3637 inspections in the CLIIL database and 60 warning letters. Overall, there was a decrease or no change in all violations in the CLIIL database. The largest violation code reported was "failure to follow investigational plan" in both the 2005-2009 and 2010-2014 timeframes. Coding of FDA warning letters shows that the most common violations reported were failing to maintain accurate case histories (10.82%), enrolling ineligible subjects (8.85%), and failing to perform required tests (8.52%). The overall decrease in violations is encouraging. But, the high proportion of violations related to failure to follow the investigational plan is concerning as the complexity of trials increases. We conclude that more detailed information is necessary to accurately evaluate these violations. The current study provides a model for creating more granular data of violations to better inform clinical investigators and improve clinical trials.

Assessing Responsiveness of Health Systems to Drug Safety Warnings

In 2011-2012 the U.S. Food and Drug Administration (FDA) issued safety announcements cautioning providers against prescribing high doses of citalopram given concerns for QT prolongation. The authors evaluated Veterans Affairs (VA) national trends in citalopram use and dose compared with alternative antidepressants after the FDA warnings. Time series analyses estimated the effect of the FDA warnings on citalopram and other antidepressant across three periods: before the first FDA warning in August 2011, after the 2011 FDA warning until the second warning in March 2012, and after the 2012 FDA warning. In a National VA health system, adult VA outpatients prescribed citalopram or alternative antidepressants from February 2010 to September 2013 were studied. Outpatient use of high-dose citalopram (>40 or >20 mg daily in adults aged > 60 years) including the proportion of patients prescribed citalopram and difference between study periods. Between the first and second FDA warnings, among patients aged 18-60, high-dose citalopram use decreased by 2.0% per month (p < 0.001) and by 1.9% per month (p < 0.001) for older adults. After the second FDA warning in 2012, 30.7% of older patients remained on doses higher than the newly recommended dose of 20 mg. Reductions in overall use of citalopram were accompanied by significant increases in prescriptions of alternative antidepressants, with sertraline most widely prescribed. Although trends in high-dose citalopram use declined after the 2011-2012 FDA warnings, roughly one-third of older adults still remained on higher than recommended doses. Concomitant increases in sertraline and other antidepressant prescriptions suggest potential substitution of these medications for citalopram.