The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005-2011.

OBJECTIVE: Evidence of safety issues associated with long-acting beta2-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. METHODS: A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single-ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. RESULTS: LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. CONCLUSION: The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities.

Evaluation of the US Food and Drug Administration sentinel analysis tools in confirming previously observed drug-outcome associations: The case of clindamycin and Clostridium difficile infection.

PURPOSE: The Food and Drug Administration's Sentinel System developed parameterized, reusable analytic programs for evaluation of medical product safety. Research on outpatient antibiotic exposures, and Clostridium difficile infection (CDI) with non-user reference groups led us to expect a higher rate of CDI among outpatient clindamycin users vs penicillin users. We evaluated the ability of the Cohort Identification and Descriptive Analysis and Propensity Score Matching tools to identify a higher rate of CDI among clindamycin users. METHODS: We matched new users of outpatient dispensings of oral clindamycin or penicillin from 13 Data Partners 1:1 on propensity score and followed them for up to 60 days for development of CDI. We used Cox proportional hazards regression stratified by Data Partner and matched pair to compare CDI incidence. RESULTS: Propensity score models at 3 Data Partners had convergence warnings and a limited range of predicted values. We excluded these Data Partners despite adequate covariate balance after matching. From the 10 Data Partners where these models converged without warnings, we identified 807 919 new clindamycin users and 8 815 441 new penicillin users eligible for the analysis. The stratified analysis of 807 769 matched pairs included 840 events among clindamycin users and 290 among penicillin users (hazard ratio 2.90, 95% confidence interval 2.53, 3.31). CONCLUSIONS: This evaluation produced an expected result and identified several potential enhancements to the Propensity Score Matching tool. This study has important limitations. CDI risk may have been related to factors other than the inherent properties of the drugs, such as duration of use or subsequent exposures.

Sentinel Modular Program for Propensity Score-Matched Cohort Analyses: Application to Glyburide, Glipizide, and Serious Hypoglycemia.

Sentinel is a program sponsored by the US Food and Drug Administration to monitor the safety of medical products. We conducted a cohort assessment to evaluate the ability of the Sentinel Propensity Score Matching Tool to reproduce in an expedited fashion the known association between glyburide (vs. glipizide) and serious hypoglycemia. Thirteen data partners who contribute to the Sentinel Distributed Database participated in this analysis. A pretested and customizable analytic program was run at each individual site. De-identified summary results from each data partner were returned and aggregated at the Sentinel Operations Center. We identified a total of 198,550 and 379,507 new users of glyburide and glipizide, respectively. The incidence of emergency department visits and hospital admissions for serious hypoglycemia was 19 per 1000 person-years (95% confidence interval = 17.9, 19.7) for glyburide users and 22 (21.6, 22.7) for glipizide users. In cohorts matched by propensity score based on predefined variables, the hazard ratio (HR) for glyburide was 1.36 (1.24, 1.49) versus glipizide. In cohorts matched on a high-dimensional propensity score based on empirically selected variables, for which the program ran to completion in five data partners, the HR was 1.49 (1.31, 1.70). In cohorts matched on propensity scores based on both predefined and empirically selected variables via the high-dimensional propensity score algorithm (the same five data partners), the HR was 1.51 (1.32, 1.71). These findings are consistent with the literature, and demonstrate the ability of the Sentinel Propensity Score Matching Tool to reproduce this known association in an expedited fashion.See video abstract at, http://links.lww.com/EDE/B275.

Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort Study.

BACKGROUND: Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents. OBJECTIVE: To examine the associations of hHF with saxagliptin and sitagliptin. DESIGN: Population-based, retrospective, new-user cohort study. SETTING: 18 health insurance and health system data partners in the U.S. Food and Drug Administration's Mini-Sentinel program. PATIENTS: Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013. MEASUREMENTS: Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.x1, 404.x1, 404.x3, and 428.xx recorded as the principal discharge diagnosis. RESULTS: 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)-stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score-matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles. LIMITATION: Residual confounding and short follow-up. CONCLUSION: In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration.

Changing patterns of asthma medication use related to US Food and Drug Administration long-acting ß2-agonist regulation from 2005-2011.

BACKGROUND: Safety concerns associated with long-acting ß2-agonists (LABAs) have led to many US Food and Drug Administration (FDA) regulatory activities for this class of drugs. Little is known about the effect of these regulatory activities on use of LABA-containing agents or other asthma medications. METHODS: We created rolling cohorts of pediatric and adult asthmatic patients in the Mini-Sentinel Distributed Database between January 2005 and June 2011. The proportions of asthmatic patients using LABA-containing products, inhaled corticosteroids (ICSs), leukotriene modifiers, short-acting ß2-agonists, oral corticosteroids, other bronchodilators, and no medications were measured on a monthly basis, and the changes were evaluated by using interrupted time series with segmented regression analysis. RESULTS: When the 2005 regulatory activity was announced, there were statistically significant decreases in the use of fixed-dose ICS-LABA agents in children (-0.98 percentage points) and adults (-1.24 percentage points). Increased use of ICSs and leukotriene modifiers was observed just after the regulatory activities were announced in both children and adults. Although of smaller magnitude, continued favorable changes in the use of LABA agents were observed after the 2010 FDA regulatory activity. CONCLUSION: The 2005 and 2010 FDA regulatory activities might have contributed to reduced use of LABA agents, as intended; however, their effect, independent of other factors, cannot be determined. Use of other classes of asthma medications was similarly affected.

Validation of acute myocardial infarction in the Food and Drug Administration's Mini-Sentinel program.

PURPOSE: To validate an algorithm based upon International Classification of Diseases, 9(th) revision, Clinical Modification (ICD-9-CM) codes for acute myocardial infarction (AMI) documented within the Mini-Sentinel Distributed Database (MSDD). METHODS: Using an ICD-9-CM-based algorithm (hospitalized patients with 410.x0 or 410.x1 in primary position), we identified a random sample of potential cases of AMI in 2009 from four Data Partners participating in the Mini-Sentinel Program. Cardiologist reviewers used information abstracted from hospital records to assess the likelihood of an AMI diagnosis based on criteria from the Joint European Society of Cardiology and American College of Cardiology Global Task Force. Positive predictive values (PPVs) of the ICD-9-based algorithm were calculated. RESULTS: Of the 153 potential cases of AMI identified, hospital records for 143 (93%) were retrieved and abstracted. Overall, the PPV was 86.0% (95% confidence interval; 79.2%, 91.2%). PPVs ranged from 76.3% to 94.3% across the four Data Partners. CONCLUSIONS: The overall PPV of potential AMI cases, as identified using an ICD-9-CM-based algorithm, may be acceptable for safety surveillance; however, PPVs do vary across Data Partners. This validation effort provides a contemporary estimate of the reliability of this algorithm for use in future surveillance efforts conducted using the Food and Drug Administration's MSDD.

Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration's Mini-Sentinel Distributed Database.

PURPOSE: The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD-9-CM diagnoses in identifying SALI among health plan members in the Mini-Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD). METHODS: We selected random samples of members (149 without liver/biliary disease; 75 with CLD) with a principal hospital diagnosis suggestive of SALI (ICD-9-CM 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) in the MSDD (2009-2010). Medical records were reviewed by hepatologists to confirm SALI events. PPVs of codes and code combinations for confirmed SALI were determined by CLD status. RESULTS: Among 105 members with available records and no liver/biliary disease, SALI was confirmed in 26 (PPV, 24.7%; 95%CI, 16.9-34.1%). Combined hospital diagnoses of acute hepatic necrosis (570) and liver disease sequelae (572.8) had high PPV (100%; 95%CI, 59.0-100%) and identified 7/26 (26.9%) events. Among 46 CLD members with available records, SALI was confirmed in 19 (PPV, 41.3%; 95%CI, 27.0-56.8%). Acute hepatic necrosis (570) or hepatorenal syndrome (572.4) plus any other SALI code had a PPV of 83.3% (95%CI, 51.6-97.9%) and identified 10/19 (52.6%) events. CONCLUSIONS: Most individual hospital ICD-9-CM diagnoses had low PPV for confirmed SALI events. Select code combinations had high PPV but did not capture all events.

Design for validation of acute myocardial infarction cases in Mini-Sentinel.

PURPOSE: To describe the acute myocardial infarction (AMI) validation project, a test case for health outcome validation within the US Food and Drug Administration-funded Mini-Sentinel pilot program. METHODS: The project consisted of four parts: (i) case identification-developing an algorithm based on the International Classification of Diseases, Ninth Revision, to identify hospitalized AMI patients within the Mini-Sentinel Distributed Database; (ii) chart retrieval-establishing procedures that ensured patient privacy (collection and transfer of minimum necessary amount of information, and redaction of direct identifiers to validate potential cases of AMI); (iii) abstraction and adjudication-trained nurse abstractors gathered key data using a standardized form with cardiologist adjudication; and (iv) calculation of the positive predictive value of the constructed algorithm. RESULTS: Key decision points included (i) breadth of the AMI algorithm, (ii) centralized versus distributed abstraction, and (iii) approaches to maintaining patient privacy and to obtaining charts for public health purposes. We used an algorithm limited to International Classification of Diseases, Ninth Revision, codes 410.x0-410.x1. Centralized data abstraction was performed because of the modest number of charts requested (<155). The project's public health status accelerated chart retrieval in most instances. CONCLUSIONS: We have established a process to validate AMI within Mini-Sentinel, which may be used for other health outcomes. Challenges include the following: (i) ensuring that only minimum necessary data are transmitted by Data Partners for centralized chart review, (ii) establishing procedures to maintain data privacy while still allowing for timely access to medical charts, and (iii) securing access to charts for public health uses that do not require approval from an institutional review board while maintaining patient privacy.

Association of area sociodemographic characteristics and capacity for treatment with disparities in colorectal cancer care and mortality.

BACKGROUND: Disparities in treatment and mortality for colorectal cancer (CRC) may reflect differences in access to specialized care or other characteristics of the area where an individual lives. METHODS: Surveillance, Epidemiology and End Results Program-Medicare data for seniors diagnosed with CRC were linked to area measures of the sociodemographic characteristics and the capacity of surgeons, medical oncologists, and radiation oncologists. Outcomes included receipt of stage-appropriate CRC care and mortality. RESULTS: After adjustment, blacks and Hispanics were less likely than whites to undergo surgery (odds ratio [OR] 0.57, 95% confidence interval (CI) 0.52-0.63 and OR 0.82, 95% CI 0.70-0.95, respectively). Individuals who lived in areas with the highest tertile of surgeon capacity were more likely to undergo resection than those in the lowest, and use of surgery declined as the percentage of blacks in the area increased. Adjustment for the area measures resulted in a modest decline in disparities in care relative to whites (5.3% for black). Blacks also experienced greater all-cause and cancer-specific mortality than whites. Further adjustment for area sociodemographics and surgeon capacity reduced the disparity in mortality between blacks and whites. Although there was a similar black/white disparity in the use of adjuvant chemotherapy, the disparity remained after adjustment for area characteristics, although use of chemotherapy was greater in areas with the greatest capacity of medical oncologists. CONCLUSIONS: Sociodemographic characteristics and measures of the availability of specialized cancer providers in the area in which an individual resides modestly mediated disparities in the receipt of CRC care and mortality, suggesting that other factors may also be important.

Participation in an ambulatory e-pharmacovigilance system.

PURPOSE: There is growing concern about whether passive surveillance can detect adverse drug events (ADEs). Our objective was to demonstrate the reach of an interactive voice response system (IVRS) to systematically monitor symptoms experienced by ambulatory patients prescribed one of 31 medications, and to document whether there were differences in our ability to contact certain populations. METHODS: Patients receiving a prescription for a target medication at one of 11 clinics were eligible for a cross-sectional IVRS survey, "e-pharmacovigilance," with a follow-up survey done 3 months later if the target medication was still listed on the patient's active medication list. RESULTS: 902 patients participated, representing 43.3% of contacted and 25.7% of potentially eligible patients with a working phone. After adjustment for demographics and drug class, patients >66 years were more likely to participate than those 56-65 years (odds ratio 1.47; 95% confidence interval 1.19-1.81). Hispanics were less likely than whites (0.56; 0.42-0.76), and those in low-income communities less likely to participate than those in high-income communities (0.69; 0.58-0.82). Patients prescribed asthma, or seizure medications were more likely to participate than those prescribed medications for insomnia. Of patients reached by the system, those prescribed medications were erectile dysfunction and smoking cessation were less likely, and those prescribed seizure medication were more likely to participate. CONCLUSIONS: IVRS technology can be used to perform ambulatory e-pharmacovigilance for a broad spectrum of patients, particularly older individuals who may at particular risk for ADEs.

Secondary use of electronic health record data: spontaneous triggered adverse drug event reporting.

PURPOSE: Physicians in the United States report fewer than 1% of adverse drug events (ADEs) to the Food and Drug Administration (FDA), but frequently document ADEs within electronic health records (EHRs). We developed and implemented a generalizable, scalable EHR-based system to automatically send electronic ADE reports to the FDA in real-time. METHODS: Proof-of-concept study involving 26 clinicians given access to EHR-based ADE reporting functionality from December 2008 to May 2009. MEASUREMENTS: Number and content of ADE reports; severity of adverse reactions (clinician and computer algorithm defined); clinician survey. RESULTS: During the study period, 26 clinicians submitted 217 reports to the FDA. The clinicians defined 23% of the ADEs as serious and a computer algorithm defined 4% of the ADEs as serious. The most common drug classes were cardiovascular drugs (40%), central nervous system drugs (19%), analgesics (13%), and endocrine drugs (7%). The reports contained information, pre-filled from the EHR, about comorbid conditions (207 reports [95%] listed 1899 comorbid conditions), concurrent medications (193 reports [89%] listed 1687 concurrent medications), weight (209 reports [96%]), and laboratory data (215 reports [99%]). It took clinicians a mean of 53 seconds to complete and send the form. In the clinician survey, 21 of 23 respondents (91%) said they had submitted zero ADE reports to the FDA in the prior 12 months. CONCLUSIONS: EHR-based, triggered ADE reporting is efficient and acceptable to clinicians, provides detailed clinical information, and has the potential to greatly increase the number and quality of spontaneous reports submitted to the FDA.

Trigeminal Neuralgia Secondary to Vertebrobasilar Dolichoectasia Treated with Cyberknife Stereotactic Radiosurgery.

Trigeminal neuralgia caused by vertebrobasilar dolichoectasia is a rare condition. It is characterized by paroxysmal hemifacial pain which is lancinating in type mostly refractory to medical management. This is a report of trigeminal neuralgia secondary to vertebral dolicholectasia refractory to medical management treated with cyber knife stereotactic radiosurgery to the dose of 66 Gy in single fraction to the proximal nerve root. Pain relief was achieved immediately after the treatment and with a follow up period of 2 years, patient is pain free. Cyberknife assisted radiosurgery is relatively safe in delivering high ablative doses with precise conformality to small target regions like proximal nerve root entry of trigeminal nerve with no major toxicities and achieving early pain relief. It is an outpatient and non-invasive procedure. It can be used as a definite treatment modality for trigeminal neuralgia induced by vertebrobasilar dolichoectasia.

Evaluation of the US Food and Drug Administration Sentinel Analysis Tools Using a Comparator with a Different Indication: Comparing the Rates of Gastrointestinal Bleeding in Warfarin and Statin Users.

BACKGROUND: The US Food and Drug Administration's Sentinel System was established to monitor safety of regulated medical products. Sentinel investigators identified known associations between drugs and adverse events to test reusable analytic tools developed for Sentinel. This test case used a comparator with a different indication. OBJECTIVE: We tested the ability of Sentinel's reusable analytic tools to identify the known association between warfarin and gastrointestinal bleeding (GIB). Statins, expected to have no effect on GIB, were the comparator. We further explored the impact of analytic features, including matching ratio and stratifying Cox regression analyses, on matched pairs. METHODS: This evaluation included data from 14 Sentinel Data Partners. New users of warfarin and statins, aged 18 years and older, who had not received other anticoagulants or had recent GIB were matched on propensity score using 1:1 and 1:n variable ratio matching, matching statin users with warfarin users to estimate the average treatment effect in warfarin-treated patients. We compared the risk of GIB using Cox proportional hazards regression, following patients for the duration of their observed continuous treatment or until a GIB. For the 1:1 matched cohort, we conducted analyses with and without stratification on matched pair. The variable ratio matched cohort analysis was stratified on the matched set. RESULTS: We identified 141,398 new users of warfarin and 2,275,694 new users of statins. In analyses stratified on matched pair/set, the hazard ratios (HR) for GIB in warfarin users compared with statin users were 2.78 (95% confidence interval [CI] 2.36-3.28) in the 1:1 matched cohort and 3.10 (95% CI 2.76-3.49) in the variable ratio matched cohort. The HR was lower in the analysis of the 1:1 matched cohort not stratified by matched pair (2.22, 95% CI 1.97-2.49), and highest early in treatment. Follow-up for warfarin users tended to be shorter than for statin users. CONCLUSIONS: This study identified the expected GIB risk with warfarin compared with statins using an analytic tool developed for Sentinel. Our findings suggest that comparators with different indications may be useful in surveillance in select circumstances. Finally, in the presence of differential censoring, stratification by matched pair may reduce the potential for bias in Cox regression analyses.

Prospective Postmarketing Surveillance of Acute Myocardial Infarction in New Users of Saxagliptin: A Population-Based Study.

OBJECTIVE: The cardiovascular safety of saxagliptin, a dipeptidyl-peptidase 4 inhibitor, compared with other antihyperglycemic treatments is not well understood. We prospectively examined the association between saxagliptin use and acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: We identified patients aged ≥18 years, starting from the approval date of saxagliptin in 2009 and continuing through August 2014, using data from 18 Mini-Sentinel data partners. We conducted seven sequential assessments comparing saxagliptin separately with sitagliptin, pioglitazone, second-generation sulfonylureas, and long-acting insulin, using disease risk score (DRS) stratification and propensity score (PS) matching to adjust for potential confounders. Sequential testing kept the overall chance of a false-positive signal below 0.05 (one-sided) for each pairwise comparison. RESULTS: We identified 82,264 saxagliptin users and more than 1.5 times as many users of each comparator. At the end of surveillance, the DRS-stratified hazard ratios (HRs) (95% CI) were 1.08 (0.90-1.28) in the comparison with sitagliptin, 1.11 (0.87-1.42) with pioglitazone, 0.79 (0.64-0.98) with sulfonylureas, and 0.57 (0.46-0.70) with long-acting insulin. The corresponding PS-matched HRs were similar. Only one interim analysis of 168 analyses met criteria for a safety signal: the PS-matched saxagliptin-pioglitazone comparison from the fifth sequential analysis, which yielded an HR of 1.63 (1.12-2.37). This association diminished in subsequent analyses. CONCLUSIONS: We did not find a higher AMI risk in saxagliptin users compared with users of other selected antihyperglycemic agents during the first 5 years after U.S. Food and Drug Administration approval of the drug.

Association of local capacity for endoscopy with individual use of colorectal cancer screening and stage at diagnosis.

BACKGROUND: Limited capacity for endoscopy in areas in which African Americans and Hispanics live may be a reason for persistent disparities in colorectal cancer (CRC) screening and stage at diagnosis. METHODS: The authors linked data from the National Health Interview Survey on the use of CRC screening and data from Surveillance, Epidemiology, and End Results-Medicare on CRC stage with measures of county capacity for colonoscopy and sigmoidoscopy (endoscopy) derived from Medicare claims. RESULTS: Hispanics lived in counties with less capacity for endoscopy than African Americans or whites (for National Health Interview Survey, an average of 1224, 1569, and 1628 procedures per 100,000 individuals aged > or = 50 years, respectively). Individual use of CRC screening increased modestly as county capacity increased. For example, as the number of endoscopies per 100,000 residents increased by 750, the odds of being screened increased by 4%. Disparities in screening were mitigated or diminished by adjustment for area endoscopy capacity, racial/ethnic composition, and socioeconomic status. Similarly, among individuals with CRC, those who lived in counties with less endoscopy capacity were marginally less likely to be diagnosed at an early stage. Adjustment for area characteristics diminished disparities in stage for Hispanics compared with whites but not African Americans. CONCLUSIONS: Increasing the use of CRC screening may require interventions to improve capacity for endoscopy in some areas. The characteristics of the area where an individual resides may in part mediate disparities in CRC screening use for both African Americans and Hispanics, and disparities in cancer stage for Hispanics.