Aarthi Iyer

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

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).

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

To validate an algorithm based upon International Classification of Diseases, 9th revision, Clinical Modification (ICD‐9‐CM) codes for acute myocardial infarction (AMI) documented within the Mini‐Sentinel Distributed Database (MSDD).

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

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.

Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug‐Adverse Event Association

The US Food and Drug Administrations Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol‐driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81–3.27) comparing angioedema in patients initiating angiotensin‐converting enzyme (ACE) inhibitors vs. beta‐blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta‐blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86–3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol‐driven assessment.

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.

Changing patterns of asthma medication use related to US Food and Drug Administration long-acting β2-agonist regulation from 2005-2011

BACKGROUND Safety concerns associated with long-acting β2-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 β2-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.

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.

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

The Food and Drug Administrations 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.

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

ABSTRACT 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.

C-A4-05: Design for Identification, Retrieval and Adjudication of Acute Myocardial Infarction Cases in the Mini-Sentinel Distributed Database

Background/Aims The goal of the FDA’s Mini-Sentinel pilot is to inform development of an active safety surveillance system, the Sentinel System, for monitoring medical product safety. Mini-Sentinel is a collaborative endeavor by Data and Academic Partners including the HMORN and Kaiser, designed to evaluate barriers to the creation of this surveillance system. Orchestrated via the Mini-Sentinel Coordinating Center (MSCC), the Acute Myocardial Infarction (AMI) Validation project is a test case for medical outcome validation within a distributed system designed for medical product safety surveillance. Methods A 3-component process for validation of medical outcomes was used : Case definition and identification: Development of a clinical definition of AMI, an algorithm for identifying likely AMI from Mini-Sentinel Distributed Databases (ICD-9 code-based) and a sampling strategy to select approximately 100 likely AMI cases for chart retrieval; Chart retrieval: Agreement between the MSCC and Data Partners regarding: amount of de-identified medical information to be extracted ; mode of data transfer to the MSCC; and approach to maintaining the privacy and security of protected health information; Abstraction and Adjudication: creation of abstraction forms for use by trained nurse abstractors; and an adjudication process for cardiologist reviewers. Results Challenges encountered to date include: the number of participating Mini-Sentinel Data Partners; decision-making surrounding centralized vs. decentralized abstraction; and concerns over privacy of transmitted health information and medical record de-identification for centralized review. Ultimately, concern over quality and variability of abstraction at the Data Partners’ sites, together with small numbers of charts requested from each Data Partner, led to selection of a centralized abstraction process. Procedures needed to be established for this novel activity that addressed how to proceed with this project as a public health activity exempt from IRB review. Conclusions The Sentinel System can yield timely data for active surveillance of medical product safety, and may be useful for other purposes, including research and quality improvement. Ongoing challenges include ensuring the minimum necessary amount of data is transmitted from Data Partners for centralized chart review and adhering to established procedures to maintain data security.