Real-world evidence to support regulatory decision making: New or expanded medical product indications.

There is increasing interest in utilizing real-world data (RWD) to produce real-world evidence (RWE) on the benefits and risks of medical products that could support regulatory approval decisions. The field of pharmacoepidemiology has a long history of focusing on data and evidence that would now be termed "real-world," including evidence from healthcare claims, registries, and electronic health records. However, several emerging trends over the past decade are converging to support the use of these and other RWD sources for approval decisions, and there are several recent examples and ongoing research that demonstrate how RWE may be used to support regulatory approval of new or expanded indications. The goal of this article is to review the current landscape and future directions of the use of RWE in this context. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

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.

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.

Trends in rates of acetaminophen-related adverse events in the United States.

PURPOSE: The goal of this study is to summarize trends in rates of adverse events attributable to acetaminophen use, including hepatotoxicity and mortality. METHODS: A comprehensive analysis of data from three national surveillance systems estimated rates of acetaminophen-related events identified in different settings, including calls to poison centers (2008-2012), emergency department visits (2004-2012), and inpatient hospitalizations (1998-2011). Rates of acetaminophen-related events were calculated per setting, census population, and distributed drug units. RESULTS: Rates of poison center calls with acetaminophen-related exposures decreased from 49.5/1000 calls in 2009 to 43.5/1000 calls in 2012. Rates of emergency department visits for unintentional acetaminophen-related adverse events decreased from 58.0/1000 emergency department visits for adverse drug events in 2009 to 50.2/1000 emergency department visits in 2012. Rates of hospital inpatient discharges with acetaminophen-related poisoning decreased from 119.8/100 000 hospitalizations in 2009 to 108.6/100 000 hospitalizations in 2011. After 2009, population rates of acetaminophen-related events per 1 million census population decreased for poison center calls and hospitalizations, while emergency department visit rates remained stable. However, when accounting for drug sales, the rate of acetaminophen-related events (per 1 million distributed drug units) increased after 2009. Prior to 2009, the rates of acetaminophen-related hospitalizations had been slowly increasing (p-trend = 0.001). CONCLUSIONS: Acetaminophen-related adverse events continue to be a public health burden. Future studies with additional time points are necessary to confirm trends and determine whether recent risk mitigation efforts had a beneficial impact on acetaminophen-related adverse events. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Long-acting beta2-adrenergic agonist in pediatric and adolescent asthma patients, 2003-2011.

OBJECTIVES: To evaluate changes in the dispensing patterns of long-acting beta2-adrenergic agonist (LABA) in pediatric and adolescent asthma patients in relation to multiple Food and Drug Administration (FDA) regulatory activities from 2003 to 2011. METHODS: We estimated LABA dispensing to pediatric asthma patients across three periods: 2003-2004 (after the first labeling change), 2005-2009 (after regulatory activities in 2005 and before 2010 LABA labeling change) and 2010-2011 (after 2010 LABA labeling change), using the IMS Health Plan Claims database. We estimated dispensing patterns over time for single-ingredient (SI) LABA and fixed-dose combination (FDC) of inhaled corticosteroid (ICS) and LABA (FDC-ICS/LABA). We also evaluated prior use of non-LABA asthma-control medication (ACM) before LABA initiation. RESULTS: Of the 147 862 pediatric and adolescent asthma patients who initiated a LABA during the entire study period, the majority (96%) were FDC-ICS/LABA initiators. The proportion of SI-LABA among any LABA initiators was small and declined (9%, 4% and 2%, trend test p < 0.001) for the three periods. Among the patients who initiated, the proportions with prior use of an ACM (1-90 days prior) were 35%, 36% and 39% for the three periods. CONCLUSIONS: The significant decline in the proportion of SI-LABA initiation over these years is consistent with FDA's recommendations. However, the favorable trend cannot be solely attributed to FDA activities as changes to clinical practice guidelines, and media publicity may have played a role. Investigating the reasons for the low ACM use before LABA initiation may inform approaches to further improve appropriate use of LABA in young asthma patients.

Antidepressant medication dispensing among montelukast initiators.

OBJECTIVE: This study investigates the potential association between montelukast use and psychiatric adverse events by monitoring changes in antidepressant medication dispensing rates before and after initiating montelukast. METHODS: The primary study group of montelukast initiators was identified using the Wolters Kluwer's SOURCE Lx® pharmacy claims database (WK). This group included 232,159 patients ≤45 years old who had at least two montelukast prescriptions from 2003 to 2007. Comparison groups comprised of 264,704 fluticasone initiators and 89,635 long-acting ß-agonist corticosteroid (LABA/ICS) initiators were also identified. Antidepressant medication dispensing rates in these three groups were determined using WK, and changes in rates before and after the first asthma controller medication prescription date were evaluated using interrupted time-series analysis (ITS). ITS was performed separately for four age categories, with a focus on youth (12-17 years) and young adult (18-24 years). RESULTS: For patients 18-24 years old, antidepressant medication dispensing rates increased significantly after initiating montelukast [1.93% (1.55-2.32%, p < 0.001)] but also after initiating fluticasone and LABA/ICS [1.72% (1.30-2.15%, p < 0.001) and 2.76% (2.35-3.17%, p < 0.001)]. Similar patterns were observed across the three medication groups for other age categories but these differences were not all significant. CONCLUSIONS: Small increases in antidepressant medication dispensing rates occurred after initiating montelukast. However, similar increases were observed in the fluticasone and LABA/ICS comparison groups. The results of this study cannot support a specific association between initiation of montelukast treatment and an increase in psychiatric adverse effects.

Reporting of meta-analyses of randomized controlled trials with a focus on drug safety: an empirical assessment.

BACKGROUND: Due to the sparse nature of serious drug-related adverse events (AEs), meta-analyses combining data from several randomized controlled trials (RCTs) to evaluate drug safety issues are increasingly being conducted and published, influencing clinical and regulatory decision making. Evaluation of meta-analyses involves the assessment of both the individual constituent trials and the approaches used to combine them. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting framework is designed to enhance the reporting of systematic reviews and meta-analyses. However, PRISMA may not cover all critical elements useful in the evaluation of meta-analyses with a focus on drug safety particularly in the regulatory-public health setting. PURPOSE: This work was conducted to (1) evaluate the adherence of a sample of published drug safety-focused meta-analyses to the PRISMA reporting framework, (2) identify gaps in this framework based on key aspects pertinent to drug safety, and (3) stimulate the development and validation of a more comprehensive reporting tool that incorporates elements unique to drug safety evaluation. METHODS: We selected a sample of meta-analyses of RCTs based on review of abstracts from high-impact journals as well as top medical specialty journals between 2009 and 2011. We developed a preliminary reporting framework based on PRISMA with specific additional reporting elements critical for the evaluation of drug safety meta-analyses of RCTs. The reporting of pertinent elements in each meta-analysis was reviewed independently by two authors; discrepancies in the independent evaluations were resolved through discussions between the two authors. RESULTS: A total of 27 meta-analyses, 12 from highest impact journals, 13 from specialty medical journals, and 2 from Cochrane reviews, were identified and evaluated. The great majority (>85%) of PRISMA elements were addressed in more than half of the meta-analyses reviewed. However, the majority of meta-analyses (>60%) did not address most (>80%) of the additional reporting elements critical for the evaluation of drug safety. Some of these elements were not addressed in any of the reviewed meta-analyses. LIMITATIONS: This review included a sample of meta-analyses, with a focus on drug safety, recently published in high-impact journals; therefore, we may have underestimated the extent of the reporting problem across all meta-analyses of drug safety. Furthermore, temporal trends in reporting could not be evaluated in this review because of the short time interval selected. CONCLUSIONS: While the majority of PRISMA elements were addressed by most studies reviewed, the majority of studies did not address most of the additional safety-related elements. These findings highlight the need for the development and validation of a drug safety reporting framework and the importance of the current initiative by the Council for International Organizations of Medical Sciences (CIOMS) to create a guidance document for drug safety information synthesis/meta-analysis, which may improve reporting, conduct, and evaluation of meta-analyses of drug safety and inform clinical and regulatory decision making.

Characterization of long-acting beta2-adrenergic agonists utilization in asthma patients.

OBJECTIVE: Because of the serious safety risks, Food and Drug Administration (FDA) has recommended that long-acting beta2-adrenergic agonists (LABAs) be reserved for patients whose asthma cannot be adequately managed with asthma control medication. The objective of the study is to assess prescribing patterns for LABAs prior to the FDA's drug safety communication issued on 2 June 2010. METHODS: Data were extracted from IMS Health Plan Claims database for asthma patients who had a new LABA therapy during 2005-2009. The proportion of LABA incident episodes preceded by inhaled corticosteroid (ICS) or leukotriene receptor antagonists (LTRAs) was examined. The medication-concurrent ratio (MCR), defined as the ratio of overlapping therapy days of single-ingredient (SI) LABAs and non-LABA products to the total days of SI LABAs, was calculated. Four criteria were used to estimate poorly controlled asthma prior to LABA initiation. RESULTS: Of the 228 047 asthma patients, fixed-dose combination (FDC) LABAs were used by the majority of patients (96%). Prior use of ICS or LTRAs was observed in 64% and 31% of SI and FDC LABA incident episodes, respectively. The median MCR for SI LABAs was 62%. Approximately half of the patients met at least one criterion for poorly controlled asthma prior to LABA use. CONCLUSIONS: Substantial proportion of patients was prescribed LABAs without prior use of ICS or LTRAs, or other indicators of poor asthma control. These findings suggest that asthma guidelines were not entirely followed in clinical practice during the study period.

The Certainty Framework for Assessing Real-World Data in Studies of Medical Product Safety and Effectiveness.

A fundamental question in using real-world data for clinical and regulatory decision making is: How certain must we be that the algorithm used to capture an exposure, outcome, cohort-defining characteristic, or confounder is what we intend it to be? We provide a practical framework to help researchers and regulators assess and classify the fit-for-purposefulness of real-world data by study variable for a range of data sources. The three levels of certainty (optimal, sufficient, and probable) must be considered in the context of each study variable, the specific question being studied, the study design, and the decision at hand.

The effect of maternal smoking and drinking during pregnancy upon (3)H-nicotine receptor brainstem binding in infants dying of the sudden infant death syndrome: initial observations in a high risk population.

The high rate of the sudden infant death syndrome (SIDS) in American Indians in the Northern Plains (3.5/1000) may reflect the high incidence of cigarette smoking and alcohol consumption during pregnancy. Nicotine, a neurotoxic component of cigarettes, and alcohol adversely affect nicotinic receptor binding and subsequent cholinergic development in animals. We measured (3)H-nicotine receptor binding in 16 brainstem nuclei in American Indian SIDS (n = 27) and controls (n = 6). In five nuclei related to cardiorespiratory control, (3)H-nicotinic binding decreased with increasing number of drinks (P < 0.03). There were no differences in binding in SIDS compared with controls, except upon stratification of prenatal exposures. In three mesopontine nuclei critical for arousal there were reductions (P < 0.04) in binding in controls exposed to cigarette smoke compared with controls without exposure; there was no difference between SIDS cases with or without exposure. This study suggests that maternal smoking and alcohol affects (3)H-nicotinic binding in the infant brainstem irrespective of the cause of death. It also suggests that SIDS cases are unable to respond to maternal smoking with the "normal" reduction seen in controls. Future studies are needed to establish the role of adverse prenatal exposures in altered brainstem neurochemistry in SIDS.

Determining the predictive value of Read/OXMIS codes to identify incident acute myocardial infarction in the General Practice Research Database.

PURPOSE: To determine (1) the positive predictive value (PPV) of multiple Read/OXMIS codes to identify incident acute myocardial infarction (AMI) cases in General Practice Research Database (GPRD); (2) the ability to capture the correct timing of the clinical event. METHODS: A random sample of 238 records (from 155 general practitioner (GP) practices) with AMI codes, between 1 January 1997 and 31 December 2004, was selected from GPRD. Questionnaires were sent to the GPs to verify the diagnosis and timing of code-identified incident AMI events and collect supporting information. We calculated the PPV of the AMI codes as the proportion of code-identified AMIs that the GPs confirmed as AMI cases. Two physicians from Food and Drug administration (FDA), blinded to the GP response, reviewed the supporting hospital records returned by GPs for 98 AMI cases. RESULTS: A total of 217 questionnaires were completed (91% response rate). The PPV of the AMI codes was 93% (201/217). Thirty one (15%) cases had a different event date than the one recorded in the electronic medical records (EMR); 28 (90%) of the dates were within 15 days. One GP indicated that a patient had a previous AMI, 110 days before the codes that captured the AMI diagnosis. A total of 159 (79%) AMI cases were hospitalized; hospital records were provided for 98 patients. Physician review of the hospital records found that 96% of these records had enough information for classification, but not independent diagnosis, of AMI. CONCLUSIONS: Information in GPRD is sufficient to identify incident AMI cases and determine the event date with reasonable accuracy.

The US Food and Drug Administration's drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003-2012.

BACKGROUND: Emerging safety issues associated with long-acting beta2-agonist (LABA) have led to multiple regulatory activities by the US Food and Drug Administration (FDA) since 2003, including Drug Safety Communications (DSCs) in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. METHODS: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1) contraindicated use of single-ingredient (SI)-LABA without an asthma controller medication (ACM); 2) a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs) or ACM; and 3) step-down asthma therapy (e.g., discontinue LABA) when asthma control is achieved. RESULTS: There were 477,922 adults (18-64 years old) dispensed a new LABA during 2003-2012. Among LABA initiators, patients who initiated an SI-LABA and who did "not" have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change) to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model). The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. CONCLUSION: Although the decrease in SI-LABA initiation is consistent with FDA's recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts to move toward the recommended safe practices.

Infant mortality trends and differences between American Indian/Alaska Native infants and white infants in the United States, 1989-1991 and 1998-2000.

OBJECTIVES: To describe changes in infant mortality rates, including birthweight-specific rates and rates by age at death and cause. METHODS: We analyzed US linked birth/infant-death data for 1989-1991 and 1998-2000 for American Indians/Alaska Native (AIAN) and White singleton infants at > or =20 weeks' gestation born to US residents. We calculated birthweight-specific infant mortality rates (deaths in each birthweight category per 1000 live births in that category), and overall and cause-specific infant mortality rates (deaths per 100000 live births) in infancy (0-364 days) and in the neonatal (0-27 days) and postneonatal (28-364 days) periods. RESULTS: Birthweight-specific infant mortality rates declined among AIAN and White infants across all birthweight categories, but AIAN infants generally had higher birthweight-specific infant mortality rates. Infant mortality rates declined for both groups, yet in 1998-2000, AIAN infants were still 1.7 times more likely to die than White infants. Most of the disparity was because of elevated post-neonatal mortality, especially from sudden infant death syndrome, accidents, and pneumonia and influenza. CONCLUSIONS: Although birthweight-specific infant mortality rates and infant mortality rates declined among both AIAN and White infants, disparities in infant mortality persist. Preventable causes of infant mortality identified in this analysis should be targeted to reduce excess deaths among AIAN communities.

Serotonergic brainstem abnormalities in Northern Plains Indians with the sudden infant death syndrome.

The rate of the sudden infant death syndrome (SIDS) among American Indian infants in the Northern Plains is almost 6 times higher than in U.S. white infants. In a study of infant mortality among Northern Plains Indians, we tested the hypothesis that receptor binding abnormalities to the neurotransmitter serotonin (5-HT) in SIDS cases, compared with autopsied controls, occur in regions of the medulla oblongata that contain 5-HT neurons and that are critical for the regulation of cardiorespiration and central chemosensitivity during sleep, i.e. the medullary 5-HT system. Tritiated-lysergic acid diethylamide binding to 5-HT(1A-D) and 5-HT2 receptors was measured in 19 brainstem nuclei in 23 SIDS and 6 control infants using tissue receptor autoradiography. Binding in the arcuate nucleus, a part of the medullary 5-HT system along the ventral surface, in the SIDS infants (mean age-adjusted binding 7.1 +/- 0.8 fmol/mg tissue, n = 23) was significantly lower than in controls (mean age-adjusted binding 13.1 +/- 1.6 fmol/mg tissue, n = 5) (p = 0.003). Binding also demonstrated significant diagnosis x age interactions (p < 0.04) in 4 other nuclei that are components of the 5-HT system. These data suggest that medullary 5-HT dysfunction can lead to sleep-related, sudden death in affected SIDS infants, and confirm the same binding abnormalities reported by us in a larger dataset of non-American Indian SIDS and control infants. This study also links 5-HT abnormalities in the arcuate nucleus with exposure to adverse prenatal exposures, i.e. cigarette smoking (p = 0.011) and alcohol (p = 0.075), during the periconceptional period or throughout pregnancy. Prenatal exposure to cigarette smoke and/or alcohol may contribute to abnormal fetal medullary 5-HT development in SIDS infants.

Contribution of late fetal deaths to US perinatal mortality rates, 1995-1998.

We analyzed US fetal death and linked infant birth-death certificate data for 1995-1998 to evaluate perinatal deaths (late fetal deaths [> or = 28 weeks' gestation] and early neonatal deaths [< or = 7 days of life]) by race, Hispanic ethnicity, state of residence, and selected demographic characteristics. We also compared components of perinatal mortality, late fetal deaths, and early neonatal deaths, by birthweight, gestational age, and selected maternal medical conditions during pregnancy. From 1995 through 1998, there were 221,767 fetal deaths at > or = 20 weeks' gestation and infant deaths at less than 1 year. Of these, 113,421 (51%) were perinatal deaths; late fetal deaths accounted for 47% of perinatal deaths. The total perinatal mortality rate declined 5.3%, from 7.5 to 7.1 per 1,000 live births plus late fetal deaths. Blacks experienced higher perinatal mortality rates than whites (rate ratio = 2.1). Among perinatal deaths > or = 28 weeks' gestation, the ratio of fetal to neonatal deaths was 3.4 among blacks and 2.4 among whites. State-specific rates ranged from 5.2 to 13.1 per 1,000 live births plus late fetal deaths. Although late fetal deaths are not included in routine statistics of pregnancy outcomes, these deaths represent a large proportion of adverse pregnancy outcomes. Surveillance of perinatal mortality provides a more complete picture of the health of women, fetuses, and newborns. Improving the quality of surveillance data regarding fetal deaths is essential for more effective use of these data. This information can be used to prevent excess perinatal deaths and reduce disparities in pregnancy outcomes among high-risk subgroups identified by individual and population characteristics.

Using registries to identify adverse events in rheumatic diseases.

The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring.

Review of quality assessment tools for the evaluation of pharmacoepidemiological safety studies.

OBJECTIVES: Pharmacoepidemiological studies are an important hypothesis-testing tool in the evaluation of postmarketing drug safety. Despite the potential to produce robust value-added data, interpretation of findings can be hindered due to well-recognised methodological limitations of these studies. Therefore, assessment of their quality is essential to evaluating their credibility. The objective of this review was to evaluate the suitability and relevance of available tools for the assessment of pharmacoepidemiological safety studies. DESIGN: We created an a priori assessment framework consisting of reporting elements (REs) and quality assessment attributes (QAAs). A comprehensive literature search identified distinct assessment tools and the prespecified elements and attributes were evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the percentage representation of each domain, RE and QAA for the quality assessment tools. RESULTS: A total of 61 tools were reviewed. Most tools were not designed to evaluate pharmacoepidemiological safety studies. More than 50% of the reviewed tools considered REs under the research aims, analytical approach, outcome definition and ascertainment, study population and exposure definition and ascertainment domains. REs under the discussion and interpretation, results and study team domains were considered in less than 40% of the tools. Except for the data source domain, quality attributes were considered in less than 50% of the tools. CONCLUSIONS: Many tools failed to include critical assessment elements relevant to observational pharmacoepidemiological safety studies and did not distinguish between REs and QAAs. Further, there is a lack of considerations on the relative weights of different domains and elements. The development of a quality assessment tool would facilitate consistent, objective and evidence-based assessments of pharmacoepidemiological safety studies.

Safety monitoring of drugs receiving pediatric marketing exclusivity.

OBJECTIVES: The Food and Drug Administration Modernization Act provided for an additional 6-month period of marketing exclusivity to companies that perform pediatric drug trials in response to a Food and Drug Administration-issued written request. Because many safety concerns cannot be detected until after the introduction of a product to a larger and more diverse market, the Best Pharmaceuticals for Children Act required the Food and Drug Administration to report to the Pediatric Advisory Committee on adverse events occurring during the 1-year period after granting pediatric exclusivity. We sought to describe the Pediatric Advisory Committee's recommendations made in response to safety reviews informed by data from the Food and Drug Administration Adverse Event Reporting System in 67 drugs granted exclusivity. PATIENTS AND METHODS: Pediatric Advisory Committee meetings and data presented by the Food and Drug Administration for all drugs were reviewed from June 2003 through April 2007. We divided the drugs into 2 groups: those that were returned to routine adverse event monitoring and those that had specific Pediatric Advisory Committee recommendations. RESULTS: Forty-four (65.7%) drugs were returned to routine monitoring for adverse events. The Pediatric Advisory Committee, sometimes working with other advisory committees, recommended label changes for 12 (17.9%) drugs, continued monitoring for 10 (14.9%), production of MedGuides for 9 (13.4%), and an update on label changes resulting from discussions with the sponsor for 1 (1.5%) drug. Some drugs had >1 action. Several of the adverse events revealed during this process were rare and life-threatening. CONCLUSIONS: Safety monitoring during the early postmarketing period is crucial to detect rare, serious, or pediatric-specific adverse events. Fortunately, the majority of drugs given exclusivity had no adverse events of a frequency or severity that prevented a return to routine adverse event monitoring.