Trend changes of national zolpidem users and exposure cases after FDA drug safety communications.

PURPOSE: To evaluate the impact of FDA's 2013 zolpidem Drug Safety Communications (DSCs), which recommended lowering the initial dose to mitigate drowsiness, on national estimates of zolpidem users and zolpidem exposure cases. METHODS: We analyzed trend changes of national zolpidem users from the IQVIA Total Patient Tracker (TPT) and zolpidem exposure cases reported to the National Poison Data System (NPDS), 2009-2018. To control for time varying confounding, the adjusted trends were analyzed using simple and controlled interrupted time series (ITS). We also adjusted for seasonal changes. Three sedating antidepressants were used together as a control. RESULTS: The national estimates of high-dose zolpidem users in TPT decreased significantly in the month immediately post-DSC; the absolute level decrease was -12.51 (95% CI: -14.12, -10.89) per 10 000 U.S. population relative to sedating antidepressants. The trend continuously decreased post-DSC, resulting in a 59% overall decrease by the end of the study period. There was a larger decrease in high-dose zolpidem use in females than in males. There was a level decrease of zolpidem exposure cases in the NPDS immediately post-DSC, -0.37 absolute decline (95% CI, -0.53, -0.20) per 10 000 national zolpidem users; or -1.33 absolute decline (95% CI, -1.54, -1.13) per 1000 total NPDS exposure cases relative to sedating antidepressants. Similar patterns were observed for cases reporting drowsiness. The results from the single ITS and controlled ITS were similar. CONCLUSIONS: Zolpidem users and exposure cases decreased significantly post-DSC, suggesting practitioners and patients became aware of and responded to the zolpidem DSCs.

A COVID-19-ready public health surveillance system: The Food and Drug Administration's Sentinel System.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment.

Leveraging the Capabilities of the FDA's Sentinel System To Improve Kidney Care.

The Sentinel System is a national electronic postmarketing resource established by the US Food and Drug Administration to support assessment of the safety and effectiveness of marketed medical products. It has built a large, multi-institutional, distributed data network that contains comprehensive electronic health data, covering about 700 million person-years of longitudinal observation time nationwide. With its sophisticated infrastructure and a large selection of flexible analytic tools, the Sentinel System permits rapid and secure analyses, while preserving patient privacy and health-system autonomy. The Sentinel System also offers enhanced capabilities, including accessing full-text medical records, supporting randomized clinical trials embedded in healthcare delivery systems, and facilitating effective collection of patient-reported data using mobile devices, among many other research programs. The nephrology research community can use the infrastructure, tools, and data that this national resource offers for evidence generation. This review summarizes the Sentinel System and its ability to rapidly generate high-quality, real-world evidence; discusses the program's experience in, and potential for, addressing gaps in kidney care; and outlines avenues for conducting research, leveraging this national resource in collaboration with Sentinel investigators.

Changes in emergency department visits for zolpidem-attributed adverse drug reactions after FDA Drug Safety Communications.

Purpose: To identify possible changes in U.S. emergency department (ED) visits from zolpidem-attributed adverse drug reactions (ADRs) after 2013 Food and Drug Administration (FDA) Drug Safety Communications (DSCs), which notified the public about FDA's new dosing recommendations for zolpidem. Methods: We estimated the occurrence of ED visits from zolpidem-attributed ADRs using nationally representative, public health surveillance of medication harms (National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, 2010-2017). We estimated the number of zolpidem prescriptions using IQVIA National Prescription Audit, 2010-2017. We calculated rates of ED visits for zolpidem-attributed ADRs per 10 000 dispensed zolpidem prescriptions and identified time trends and potential inflection points using joinpoint regression. For comparison, we repeated these analyses for sedating antidepressants commonly used to treat disordered sleep (trazodone, doxepin, and mirtazapine). Results: The best-fit regression model for rates of ED visits for zolpidem-attributed ADRs by 6-month intervals identified a single inflection point in the second half of 2014 (P = .024) with a 6.7% biannual decrease from 2010 to 2014 ([-13.1%, 0.3%], P = .059) and a 13.9% biannual increase from the second half of 2014 through 2017 ([-1.1%, 31.3%], P = .068). No change or inflection points were identified for rates of ED visits for sedating antidepressant-attributed ADRs. Conclusions: While there was a nominal decline in the rate of ED visits for ADRs in the time period before and for 18 months after FDA's 2013 zolpidem DSCs, the decrease was not sustained, and thus questions remain concerning the long-term impact of the zolpidem DSCs on ADRs.

Changes in prescribing and healthcare resource utilization after FDA Drug Safety Communications involving zolpidem-containing medications.

PURPOSE: Products containing the sedative/hypnotic zolpidem were subject to Drug Safety Communications (DSCs) in January and May 2013 describing the risk of next-morning impairment and recommending lower starting doses particularly for women. This study aimed to assess whether zolpidem DSCs were associated with prescribing-pattern changes between January 2011 and December 2013. METHODS: We assessed overall dispensings of zolpidem-containing products between January 2011 and December 2013 by conducting a time-series analysis. Analyses were stratified by gender because the DSC contained gender-specific information. Participants were patients drawn from the Optum Clinformatics data source of commercially insured people in the USA. We evaluated changes in mean prescribed dose of the two drugs and health care utilization metrics. RESULTS: Each month of the study, more than 80 000 patients received a zolpidem-containing product and approximately one-tenth as many received eszopiclone. The two DSCs did not affect the downward trajectory of new zolpidem prescriptions. However, there was an increase in use of lower-dose forms of zolpidem (30% increase, p < 0.001), coupled with a reduction in higher-dose forms (13% decrease, p = 0.03), so that the average dose decreased after the DSCs (from 9.7 mg to 9.4 mg, p < 0.001), a change that was not seen with eszopiclone (from 2.74 mg to 2.74 mg, p = 0.45). CONCLUSION: The DSCs related to zolpidem-containing products shifted prescribing toward the lower-dose formulations, consistent with the recommendations in the DSCs. Copyright © 2017 John Wiley & Sons, Ltd.

Media Coverage of FDA Drug Safety Communications about Zolpidem: A Quantitative and Qualitative Analysis.

FDA issues Drug Safety Communications (DSCs) to alert health care professionals and the public about emerging safety information affecting prescription and over-the-counter drugs. News media may amplify DSCs, but it is unclear how DSC messaging is transmitted through the media. We conducted a content analysis of the lay media coverage reaching the broadest audience to characterize the amount and content of media coverage of two zolpidem DSCs from 2013. After the first DSC, zolpidem news stories increased from 19 stories/week in the preceding 3 months to 153 following its release. Most (81%) appeared in the lay media, and 64% focused on the DSC content. After the second DSC, news stories increased from 24 stories/week in the preceding 3 months to 39 following. Among the 100 unique lay media news stories, at least half correctly reported three key DSC messages: next-day impairment and drowsiness as common safety hazards, lower doses for some but not all zolpidem products, and women's higher risk for impairment. Other DSC messages were reported in fewer than one-third of stories, such as the warning that impairment can happen even when people feel fully awake. The first-but not the second-zolpidem DSC generated high-profile news coverage. The finding that some messages were widely reported but others were not emphasizes the importance of ensuring translation of key DSC content.

Orphan therapies: making best use of postmarket data.

BACKGROUND: Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. METHODS: We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. KEY RESULTS: Sequential analyses detect effect sizes earlier or at the same time as non-sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90% for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/100 person-years. CONCLUSIONS: We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance.

Minimizing signal detection time in postmarket sequential analysis: balancing positive predictive value and sensitivity.

PURPOSE: Outcome misclassification in retrospective epidemiologic analyses has been well-studied, but little is known about such misclassification with respect to sequential statistical analysis during surveillance of medical product-associated risks, a planned capability of the US Food and Drug Administration's Sentinel System. METHODS: Using a vaccine example, we model and simulate sequential database surveillance in an observational data network using a variety of outcome detection algorithms. We consider how these algorithms, as characterized by sensitivity and positive predictive value, impact the length of surveillance and timeliness of safety signal detection. We show investigators/users of these networks how they can perform preparatory study design calculations that consider outcome misclassification in sequential database surveillance. RESULTS: Non-differential outcome misclassification generates longer surveillance times and less timely safety signal detection as compared with the case of no misclassification. Inclusive algorithms characterized by high sensitivity but low positive predictive value outperform more narrow algorithms when detecting rare outcomes. This decision calculus may change considerably if medical chart validation procedures were required. CONCLUSIONS: These findings raise important questions regarding the design of observational data networks used for pharmacovigilance. Specifically, there are tradeoffs involved when choosing to populate such networks with component databases that are large as compared with smaller integrated delivery system databases that can more easily access laboratory or clinical data and perform medical chart validation.

Measures to quantify the abuse of prescription opioids: a review of data sources and metrics.

PURPOSE: The abuse and nonmedical use of prescription opioids and its subsequent consequences are an important public health concern. This phenomenon has paralleled the increase in the therapeutic use of opioids for pain management. There is thus a need to measure prescription opioid abuse to understand trends over time and to compare abuse of one product to another. The purpose of this review is to provide an overview of the strengths and weaknesses of frequently used numerators and denominators in "abuse ratios" (ARs). METHODS: For this review, we critically evaluated the various measures to quantify drug availability and the available data sources to measure prescription opioid abuse. RESULTS: There are currently no commonly adopted metrics for measuring either the prevalence of opioid abuse, or abuse relative to drug availability. Because the settings, manifestations, and severity of abuse can vary from one person to the next, no one measure of abuse, abuse-related outcome, or drug exposure is ideal. Each measure of abuse captures a specific facet of abuse, but not the whole spectrum. Reliable estimation of population-adjusted or utilization-adjusted rates of abuse can be accomplished with a prescription opioid AR. This metric estimates the prevalence of abuse in a given population or abuse relative to how much drug is available, and, in certain cases, can be used to compare abuse among various opioid drugs. AR measurements in the literature vary in the inclusion of specific measures of abuse and availability, and there is little consensus in the field regarding which measures allow for the most appropriate approximation of the extent of abuse, and for comparisons among opioids. Crude numbers of outcomes related to abuse (e.g., emergency department visits, treatment admissions, and overdoses) cannot be properly understood without context as these may overestimate or underestimate the true scope and severity of prescription opioid abuse. They can, however, serve as numerators in properly constructed ARs. The denominator of the AR provides the necessary context by accounting for populations at risk or drug availability (e.g., prescriptions or tablets dispensed, unique recipients of dispensed drug, total patient days of therapy, or kilograms sold), and each comes with its own set of assumptions to consider. CONCLUSIONS: Moving forward, it is important that there be a common understanding in the scientific community regarding how to select appropriate measures to serve as numerators and denominators in AR calculations, and how to interpret the resultant findings. There is no single best measure of abuse for use as a numerator in an AR, and each must be chosen and interpreted in the context of what it measures. For public health considerations, one must always look at both absolute numbers and adjusted numbers. When conducting multiple analyses using different measures of exposure as denominators, differences in ARs are not unexpected, but one should explore why there are differences and assess the appropriateness of each of the denominators.

Sociodemographic Characteristics of Adverse Event Reporting in the USA: An Ecologic Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a vital source of new drug safety information, but whether adverse event (AE) information collected from these systems adequately captures experiences of the overall United States (US) population is unknown. OBJECTIVE: To examine determinants of consumer AE reporting in the USA. METHODS: Five-year AE reporting rate per 100,000 residents per US county were calculated, mapped, and quartiled for AE reports received directly from consumers between 2011 and 2015. Associations between county-level sociodemographic factors obtained from County Health Rankings and AE reporting rates were evaluated using negative binomial regression. RESULTS: Reporting rates were variable across US counties with > 17.6 reports versus ≤ 5.5 reports/100,000 residents in the highest and lowest reporting quartile, respectively. Controlling for drug utilization, counties with higher reporting rates had higher proportions of individuals age ≥ 65 years (e.g., 2.4% reporting increase per 1% increase in individuals age > 65, incidence rate ratio (IRR): 1.024, 95% confidence interval (CI): 1.017-1.030), higher proportions of females (IRR: 1.027, 95% CI 1.012-1.043), uninsured (IRR: 1.009, 95% CI 1.005-1.013), higher median log household incomes (IRR: 1.897, 95% CI 1.644-2.189) and more mental health providers per 100,000 residents (IRR: 1.003, 95% CI 1.001-1.004). Lower reporting was observed in counties with higher proportions of individuals age ≤ 18 years (IRR: 0.966, 95% CI 0.959-0.974), American Indian or Alaska Native individuals (IRR: 0.991, 95% CI 0.986-0.996), individuals not proficient in English (IRR: 0.978, 95% CI 0.965-0.991), and individuals residing in rural areas within a county (IRR: 0.998, 95% CI 0.997-0.998). CONCLUSIONS: Observed variations in consumer AE reporting may be related to sociodemographic factors and healthcare access. Because these factors may also correspond to AE susceptibility, voluntary AE reporting systems may be suboptimal for capturing emerging drug safety concerns among more vulnerable populations.

How Do Risk Evaluation and Mitigation Strategies Impact Clinical Practice? A National Survey of Physicians.

The US Food and Drug Administration can require risk evaluation and mitigation strategy (REMS) programs for prescription drugs to ensure the benefits of use outweigh the risks. We conducted a national survey of physicians' experiences prescribing eight REMS-covered drugs: (1) ambrisentan; (2) bosentan; (3) clozapine; (4) isotretinoin; (5-7) the multiple myeloma (MM) drugs lenalidomide, pomalidomide, thalidomide; and (8) sodium oxybate. Between May 2022 and January 2023, we surveyed 5,331 physician prescribers of these drugs, and 1,295 (24%) returned surveys (range: 149 for bosentan to 226 for MM drugs). Although 765 (68%) respondents thought the certification process provided useful drug information, 757 (67%) wanted materials to include benefit data and 944 (84%) non-REMS-related risk data. A majority (704, 63%) thought the safe use requirements facilitated discussion with patients, but a similar number (637, 57%) attributed delayed medication access to these requirements. In multivariable modeling, MM drug and isotretinoin respondents were less likely than sodium oxybate respondents to agree that the certification process provided useful drug information (MM drug: odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.25-0.55; isotretinoin: OR = 0.39, 95% CI = 0.25-0.61), and isotretinoin, clozapine, and bosetan respondents were more likely than sodium oxybate respondents to agree that the safe use requirements often delayed medication access (isotretinoin: OR = 5.83, 95% CI = 3.70-9.19; clozapine: OR = 1.65, 95% CI = 1.08-2.54; bosentan: OR = 1.78, 95% CI = 1.12-2.85). Most physicians believe REMS programs convey useful drug safety information and facilitate discussion with patients but also seek information on benefits and non-REMS-related risks and better integration of REMS processes into clinical workflows.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

INTRODUCTION: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. OBJECTIVE: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. METHODS: Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. RESULTS: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. CONCLUSION: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

Removing the FDA's Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan.

Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.

Role of postmarketing surveillance in contemporary medicine.

Contemporary medicine is a large and complex system involving many participants, all of whom play a critical role in managing the risks intrinsic to medical product use. Despite the robust premarket review and approval process of the U.S. Food and Drug Administration (FDA), new information will inevitably be learned in the postmarketing period about the safety of medicines and how they are and should be used. For much of this information, FDA relies on public reports about possible adverse events. In turn, the public depends on FDA to communicate the most up-to-date safety information on medical products to better inform treatment decisions. Expanding the scope and strengthening the capabilities of the drug safety surveillance system are among key FDA projects designed to reduce avoidable injury and death from medication use. Although improving drug safety is our goal and obligation to the public, FDA cannot protect the public adequately without the active involvement of all participants in healthcare.

Six Years of the US Food and Drug Administration's Postmarket Active Risk Identification and Analysis System in the Sentinel Initiative: Implications for Real World Evidence Generation.

Congress mandated the creation of a postmarket Active Risk Identification and Analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first 6 years of ARIA utilization in the Sentinel System (2016-2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations, whereas the rest remain in progress. If the ARIA system and the FDA's Adverse Event Reporting System are deemed insufficient to address a safety concern, then the FDA may issue a postmarket requirement to a product's manufacturer. One hundred ninety-seven ARIA insufficiency determinations have been made. The most common situation for which ARIA was found to be insufficient is the evaluation of adverse pregnancy and fetal outcomes following in utero drug exposure, followed by neoplasms and death. ARIA was most likely to be sufficient for thromboembolic events, which have high positive predictive value in claims data alone and do not require supplemental clinical data. The lessons learned from this experience illustrate the continued challenges using administrative claims data, especially to define novel clinical outcomes. This analysis can help to identify where more granular clinical data are needed to fill gaps to improve the use of real-world data for drug safety analyses and provide insights into what is needed to efficiently generate high-quality real-world evidence for efficacy.

The Use of Real-World Data to Assess the Impact of Safety-Related Regulatory Interventions.

The regulation of medicines seeks to ensure the efficacy, safety, and quality of prescription and non-prescription medicines. Given that the conditions under which a medicine's benefits outweigh its risks are complex, it is essential that communications about the safe and effective use of medicines be clear and actionable. Assessing the impact of interventions to improve the safe and effective use of medicines is a developing area, and one in which real-world data are playing an increasingly important role. Although real-world data are commonly used to assess the impact of regulatory interventions, there are several areas where their use could be improved. Specific areas for improvement include assessing regulatory interventions across a wider range of medicines, rather than concentrating on a relatively few therapeutic areas; assessing more clinically relevant outcomes rather than relying on measures such as changes in the number of prescriptions, which may not always correlate with the desired impact; assessing the potential unintended or negative consequences of regulatory interventions; applying methods to address potential confounders; assessing long-term, rather than just short-term, impacts of an intervention; increasing the use of comparator groups, when feasible; and evaluating the impact of regulatory interventions from multiple dimensions, rather than from a single dimension. Expanded use of real-world data could inform some of these efforts, although data sources beyond administrative claims data will likely be necessary to achieve all these goals.

The US Food and Drug Administration Sentinel System: a national resource for a learning health system.

The US Food and Drug Administration (FDA) created the Sentinel System in response to a requirement in the FDA Amendments Act of 2007 that the agency establish a system for monitoring risks associated with drug and biologic products using data from disparate sources. The Sentinel System has completed hundreds of analyses, including many that have directly informed regulatory decisions. The Sentinel System also was designed to support a national infrastructure for a learning health system. Sentinel governance and guiding principles were designed to facilitate Sentinel's role as a national resource. The Sentinel System infrastructure now supports multiple non-FDA projects for stakeholders ranging from regulated industry to other federal agencies, international regulators, and academics. The Sentinel System is a working example of a learning health system that is expanding with the potential to create a global learning health system that can support medical product safety assessments and other research.