Initiation and Persistence of Antipsychotic Medications at Hospital Discharge Among Community-Dwelling Veterans With Dementia.

OBJECTIVES: Adults with dementia are frequently prescribed antipsychotic medications despite concerns that risks outweigh benefits. Understanding conditions where antipsychotics are initially prescribed, such as hospitalization, may offer insights into reducing inappropriate use. DESIGN, SETTING, PARTICIPANTS: Retrospective cohort study of community-dwelling veterans with dementia aged ≥68 with VA hospitalizations in 2014, using Veterans Health Administration (VA) and Medicare data. MEASUREMENTS: The primary outcome was new outpatient antipsychotic prescription at hospital discharge. We used generalized estimating equations to study associations between antipsychotic initiation and patient, hospitalization, and facility characteristics. Among veterans with antipsychotic initiation, we used a cumulative incidence function to evaluate discontinuation in the year following hospitalization, accounting for competing risks. RESULTS: 4,719 community-dwelling veterans with dementia had VA hospitalizations in 2014; 264 (5.6%) filled new antipsychotic prescriptions at discharge. Antipsychotic initiation was associated with discharge unit (surgical vs medical, OR 0.41, 95% CI 0.19-0.87; psychiatric vs medical, OR 6.58, 95% CI 4.48-9.67), length of stay (OR 1.03/day, 95% CI 1.02-1.05), and delirium diagnosis (OR 2.61, 95% CI 1.78-3.83), but not demographic or facility characteristics. Among veterans with antipsychotic initiation, the 1-year cumulative incidence of discontinuation was 18.2% (n = 47); 15.9% (n = 42) of those who were alive and not censored remained on antipsychotics at 1 year. CONCLUSIONS: Antipsychotic initiation at hospital discharge was uncommon among community-dwelling veterans with dementia; however, once initiated, antipsychotic persistence at 1 year was common among those who remained community-dwelling. Hospitalization is a contributor to potentially-inappropriate medications in the community, suggesting an opportunity for medication review after hospitalization.

The prognostic value of metabolic dysfunction-associated steatotic liver disease in acute myocardial infarction: A propensity score-matched analysis.

AIM: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined. METHODS: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan-Meier curve was constructed for long-term all-cause mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality. RESULTS: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow-up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all-cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long-term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long-term all-cause mortality (hazard ratio 1.330, 95% confidence interval 1.106-1.598, p = .002). CONCLUSION: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long-term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI.

One-year outcomes of patients with ST-segment elevation myocardial infarction during the COVID-19 pandemic.

The pandemic has led to adverse short-term outcomes for patients with ST-segment elevation myocardial infarction (STEMI). It is unknown if this translates to poorer long-term outcomes. In Singapore, the escalation of the outbreak response on February 7, 2020 demanded adaptation of STEMI care to stringent infection control measures. A total of 321 patients presenting with STEMI and undergoing primary percutaneous coronary intervention at a tertiary hospital were enrolled and followed up over 1-year. They were allocated into three groups based on admission date-(1) Before outbreak response (BOR): December 1, 2019-February 6, 2020, (2) During outbreak response (DOR): February 7-March 31, 2020, and (3) control group: November 1-December 31, 2018. The incidence of cardiac-related mortality, cardiac-related readmissions, and recurrent coronary events were examined. Although in-hospital outcomes were worse in BOR and DOR groups compared to the control group, there were no differences in the 1-year cardiac-related mortality (BOR 8.7%, DOR 7.1%, control 4.8%, p = 0.563), cardiac-related readmissions (BOR 15.1%, DOR 11.6%, control 12.0%, p = 0.693), and recurrent coronary events (BOR 3.2%, DOR 1.8%, control 1.2%, p = 0.596). There were higher rates of additional PCI during the index admission in DOR, compared to BOR and control groups (p = 0.027). While patients admitted for STEMI during the pandemic may have poorer in-hospital outcomes, their long-term outcomes remain comparable to the pre-pandemic era.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. METHODS: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. RESULTS: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. CONCLUSIONS: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

Association Between Food and Drug Administration Advisory Committee Recommendations and Agency Actions, 2008-2015.

Policy Points Food and Drug Administration (FDA) advisory committee recommendations and the agency's final actions exhibit high rates of agreement, with cases of disagreement tending to reflect the proposed action type and degree of advisory committee consensus. In the case of disagreements, the FDA tended to be less likely than its advisory committees to approve new products, approve new supplemental indications, or enact new safety changes. These findings raise important issues regarding the factors that differentially shape decision making by advisory committees and the FDA as an agency, including institutional or reputational concerns. CONTEXT: The Food and Drug Administration (FDA) convenes advisory committees to provide external scientific counsel on potential agency actions and to inform regulatory decision making. The degree to which advisory committees and their respective agency divisions disagree on recommendations has not been well characterized across product and action types. METHODS: We examined public documents from FDA advisory committee meetings and medical product databases for all FDA advisory committee meetings from 2008 through 2015. We classified the 376 voting meetings in that period by medical product, regulatory, and advisory committee meeting characteristics. We used multivariable logistic regression to determine the associations between these characteristics and discordance between the advisory committee's recommendations and the FDA's final actions. FINDINGS: Twenty-two percent of the FDA's final actions were discordant with the advisory committee's recommendations. Of these, 75% resulted in the FDA making more restrictive decisions after favorable committee recommendations, and 25% resulted in the agency making less restrictive decisions after unfavorable committee recommendations. Discordance was associated with lower degrees of advisory committee consensus and was more likely for agency actions focused on medical product safety than for novel approvals or supplemental indications. Statements by public speakers, advisory committee conflicts of interest, and media coverage were not associated with discordance between the committee and the agency. CONCLUSIONS: The FDA disagrees with the recommendation of its advisory committees a minority of the time, and in these cases it tends to be less likely to approve new products or supplemental indications and take safety actions. Deviations from recommendations thus offer an opportunity to understand the factors influencing decisions made by both the agency and its expert advisory groups.

Comparison of Industry Payments to Physicians and Advanced Practice Clinicians.

This study uses Open Payments data to characterize and compare payments to physicians and advanced practice clinicians.

Factors influencing central nervous system medication deprescribing and behavior change in hospitalized older adults.

BACKGROUND: Central nervous system (CNS) medications are linked to higher morbidity and mortality in older adults. Hospitalization allows for deprescribing opportunities. This qualitative study investigates clinician and patient perspectives on CNS medication deprescribing during hospitalization using a behavioral change framework, aiming to inform interventions and identify recommendations to enhance hospital deprescribing processes. METHODS: This qualitative study focused on hospitalists, primary care providers, pharmacists, and patients aged ≥60 years hospitalized on a general medicine service and prescribed ≥1 CNS medications. Using semi-structured interviews and focus groups, we aimed to evaluate patient medication knowledge, prior deprescribing experiences, and decision-making preferences, as well as provider processes and tools for medication evaluation and deprescribing. Rapid qualitative analysis applying the Capability, Opportunity, Motivation, and Behavior (COM-B) framework revealed themes influencing deprescribing behavior in patients and providers. RESULTS: A total of 52 participants (20 patients and 32 providers) identified facilitators and barriers across deprescribing steps and generated recommended strategies to address them. Clinicians and patients highlighted the opportunity for CNS medication deprescribing during hospitalizations, facilitated by multidisciplinary teams enhancing clinicians' capability to make medication changes. Both groups also stressed the importance of intensive patient engagement, education, and monitoring during hospitalizations, acknowledging challenges in timing and extent of deprescribing, with some patients preferring decisions deferred to outpatient clinicians. Hospitalist and pharmacist recommendations centered on early pharmacist involvement for medication reconciliation, expanding pharmacy consultation and clinician education on deprescribing, whereas patients recommended enhancing shared decision-making through patient education on medication adverse effects, tapering plans, and alternatives. Hospitalists and PCPs also emphasized standardized discharge instructions and transitional care calls to improve medication review and feedback during care transitions. CONCLUSIONS: Clinicians and patients highlighted the potential advantages of hospital interventions for CNS medication deprescribing, emphasizing the necessity of addressing communication, education, and coordination challenges between inpatient and outpatient settings.

Sodium-Glucose Cotransporter-2 Inhibitors After Acute Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cardiovascular disease is on the rise globally, with ischemic heart disease being the leading cause of mortality and morbidity. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiovascular outcomes in patients with heart failure, evidence is limited in guiding initiation in post-acute myocardial infarction (post-AMI) patients. Hence, this study aimed to appraise the current literature on the effect of SGLT2i on the clinical outcomes of post-AMI patients. METHODS: A comprehensive search of PubMed, EMBASE, SCOPUS, and ClinicalTrials.gov was conducted up to 1 May 2024. Only randomized controlled trials studying the use of SGLT2i in post-AMI patients were included. We included adult patients aged 18 years old and older diagnosed with AMI and initiated on SGLT2i in the acute post-AMI setting. SGLT2i studies solely in heart failure settings were excluded. RESULTS: Eight clinical trials were included in the systematic review, comprising 11,436 patients. Compared with placebo, SGLT2i initiation in post-AMI patients significantly reduced total number of heart failure hospitalizations (risk ratio [RR] 0.74, 95% confidence interval [CI] 0.62-0.90) and was associated with a lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) level (- 26.67 pg/ml, 95% CI - 41.74 to - 11.59). There was no difference in all-cause mortality (RR 1.02, 95% CI 0.81-1.28), cardiovascular mortality (RR 1.03, 95% CI 0.83-1.28), change in left ventricular ejection fraction, and glycated hemoglobin (HbA1c), as compared with placebo. CONCLUSION: SGLT2i use in patients with AMI was associated with a reduction in heart failure hospitalizations and a decrease in NT-proBNP. There were no significant differences in mortality outcomes. REGISTRATION: PROSPERO identifier number CRD42024540843.

Clinical trial data sharing: a cross-sectional study of outcomes associated with two U.S. National Institutes of Health models.

The impact and effectiveness of clinical trial data sharing initiatives may differ depending on the data sharing model used. We characterized outcomes associated with models previously used by the U.S. National Institutes of Health (NIH): National Heart, Lung, and Blood Institute's (NHLBI) centralized model and National Cancer Institute's (NCI) decentralized model. We identified trials completed in 2010-2013 that met NIH data sharing criteria and matched studies based on cost and/or size, determining whether trial data were shared, and for those that were, the frequency of secondary internal publications (authored by at least one author from the original research team) and shared data publications (authored by a team external to the original research team). We matched 77 NHLBI-funded trials to 77 NCI-funded trials; among these, 20 NHLBI-sponsored trials (26%) and 4 NCI-sponsored trials (5%) shared data (OR 6.4, 95% CI: 2.1, 19.8). From the 4 NCI-sponsored trials sharing data, we identified 65 secondary internal and 2 shared data publications. From the 20 NHLBI-sponsored trials sharing data, we identified 188 secondary internal and 53 shared data publications. The NHLBI's centralized data sharing model was associated with more trials sharing data and more shared data publications when compared with the NCI's decentralized model.

Consistency between trials presented at conferences, their subsequent publications and press releases.

OBJECTIVE: This study examined the extent to which trials presented at major international medical conferences in 2016 consistently reported their study design, end points and results across conference abstracts, published article abstracts and press releases. DESIGN: Cross-sectional analysis of clinical trials presented at 12 major medical conferences in the USA in 2016. Conferences were identified from a list of the largest clinical research meetings aggregated by the Healthcare Convention and Exhibitors Association and were included if their abstracts were publicly available. From these conferences, all late-breaker clinical trials were included, as well as a random selection of all other clinical trials, such that the total sample included up to 25 trial abstracts per conference. MAIN OUTCOME MEASURES: First, it was determined if trials were registered and reported results in an International Committee of Medical Journal Editors-approved clinical trial registry. Second, it was determined if trial results were published in a peer-reviewed journal. Finally, information on trial media coverage and press releases was collected using LexisNexis. For all published trials, the consistency of reporting of the following characteristics was examined, through comparison of the trials' conference and publication abstracts: primary efficacy endpoint definition, safety endpoint identification, sample size, follow-up period, primary end point effect size and characterisation of trial results. For all published abstracts with press releases, the characterisation of trial results across conference abstracts, press releases and publications was compared. Authors determined consistency of reporting when identical information was presented across abstracts and press releases. Primary analyses were descriptive; secondary analyses included χ2 tests and multiple logistic regression. RESULTS: Among 240 clinical trials presented at 12 major medical conferences, 208 (86.7%) were registered, 95 (39.6%) reported summary results in a registry and 177 (73.8%) were published; 82 (34.2%) were covered by the media and 68 (28.3%) had press releases. Among the 177 published trials, 171 (96.6%) reported the definition of primary efficacy endpoints consistently across conference and publication abstracts, whereas 96/128 (75.0%) consistently identified safety endpoints. There were 107/172 (62.2%) trials with consistent sample sizes across conference and publication abstracts, 101/137 (73.7%) that reported their follow-up periods consistently, 92/175 (52.6%) that described their effect sizes consistently and 157/175 (89.7%) that characterised their results consistently. Among the trials that were published and had press releases, 32/32 (100%) characterised their results consistently across conference abstracts, press releases and publication abstracts. No trial characteristics were associated with reporting primary efficacy end points consistently. CONCLUSIONS: For clinical trials presented at major medical conferences, primary efficacy endpoint definitions were consistently reported and results were consistently characterised across conference abstracts, registry entries and publication abstracts; consistency rates were lower for sample sizes, follow-up periods, and effect size estimates. REGISTRATION: This study was registered at the Open Science Framework (https://doi.org/10.17605/OSF.IO/VGXZY).

Long-Term Prognosis of Patients With Coexisting Obesity and Malnutrition After Acute Myocardial Infarction: A Cohort Study.

BACKGROUND: The double burden of malnutrition, described as the coexistence of malnutrition and obesity, is a growing global health issue. This study examines the combined effects of obesity and malnutrition on patients with acute myocardial infarction (AMI). METHODS: Patients presenting with AMI to a percutaneous coronary intervention-capable hospital in Singapore between January 2014 and March 2021 were retrospectively studied. Patients were stratified into the following: (1) nourished nonobese, (2) malnourished nonobese, (3) nourished obese, and (4) malnourished obese. Obesity and malnutrition were defined according to the World Health Organization definition (body mass index ≥27.5 kg/m2) and Controlling Nutritional Status score, respectively. The primary outcome was all-cause mortality. The association between combined obesity and nutritional status with mortality was examined using Cox regression, adjusted for age, sex, AMI type, previous AMI, ejection fraction, and chronic kidney disease. Kaplan-Meier curves for all-cause mortality were constructed. RESULTS: The study included 1829 AMI patients, of which 75.7% were male and mean age was 66 years. Over 75% of patients were malnourished. Majority were malnourished nonobese (57.7%), followed by malnourished obese (18.8%), nourished nonobese (16.9%), and nourished obese (6.6%). Malnourished nonobese had highest all-cause mortality (38.6%), followed by the malnourished obese (35.8%), nourished nonobese (21.4%), and nourished obese (9.9%, P<0.001). Kaplan-Meier curves demonstrated least favorable survival in malnourished nonobese group, followed by malnourished obese, nourished nonobese, and nourished obese. With nourished nonobese group as the reference, malnourished nonobese had higher all-cause mortality (hazard ratio, 1.46 [95% CI, 1.10-1.96], P=0.010), but only a nonsignificant increase in mortality was observed in the malnourished obese (hazard ratio, 1.31 [95% CI, 0.94-1.83], P=0.112). CONCLUSIONS: Among AMI patients, malnutrition is prevalent even in the obese. Compared to nourished patients, malnourished AMI patients have a more unfavorable prognosis especially in those with severe malnutrition regardless of obesity status, but long-term survival is the most favorable among nourished obese patients.

Prognostically Distinct Phenotypes of Metabolic Health Beyond Obesity in Aortic Stenosis.

Although current evidence is in favor of metabolic health and nonobesity in the reduction of incident cardiovascular disease, little is known regarding the prognosis across the metabolic phenotypes once cardiovascular disease occurs. This study examined the prognosis of patients with significant aortic stenosis (AS) on the basis of the presence of metabolic health and obesity. This a retrospective cohort study on consecutive patients who presented with moderate-to-severe AS to a tertiary hospital between 2010 and 2015. Patients were allocated into 4 groups on the basis of obesity and metabolic health: metabolically healthy obese (MHO), metabolically healthy nonobese (MHNO), metabolically unhealthy obese (MUO), and metabolically unhealthy nonobese (MUNO). Metabolic health was defined in accordance to the Adult Treatment Panel III criteria. The primary outcome was all-cause mortality. Cox regression examined independent associations between mortality and metabolic phenotypes, adjusting for aortic valve area, ejection fraction, age, gender, chronic kidney disease, and aortic valve replacement as a time-dependent covariate. Of 727 patients, the majority (51.6%) were MUNO, followed by MUO (32.7%), MHNO (11.4%), and MHO (4.3%). MHNO had the highest mortality (43.0%), followed by the MUNO (37.5%), MUO (30.0%), and MHO (6.9%) groups (p = 0.001). Compared with MHNO, MHO (hazard ratio 0.159, 95% confidence interval 0.038 to 0.668, p = 0.012) and MUO (hazard ratio 0.614, 95% confidence interval 0.403 to 0.937, p = 0.024) were independently associated with lower all-cause mortality rates after adjusting for confounders. In patients who are obese, metabolic health had favorable survival compared with metabolically unhealthy (p = 0.015), but this protective impact of metabolic health was not observed in patients with overweight or normal weight. Obesity had favorable survival compared with overweight and normal weight in both patients who are metabolically healthy (p = 0.002) and unhealthy (p = 0.007). In conclusion, patients who are MHO with AS have the most favorable prognosis, whereas the seemingly healthy MHNO group had the worst survival. There should be a paradigm shift toward prioritizing metabolic health rather than weight reduction in patients with significant AS.

Long-term Prognosis in Patients With Concomitant Acute Coronary Syndrome and Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) and acute coronary syndrome (ACS) share similar cardiovascular risk factors. The incidence of concomitant AS and ACS is increasing with aging population, yet studies investigating the prognosis of these patients remain scarce. METHODS: This retrospective single-centre cohort study examined consecutive patients who presented with ACS and AS from January 1, 2011, to March 31, 2021. The cohort was divided into mild, moderate, and severe AS based on the index echocardiogram. The primary outcome was all-cause mortality. RESULTS: Of 563 patients, 264 (46.9%) had mild, 193 (34.3%) moderate, and 106 (18.8%) severe AS. The mean follow-up duration was 2.5 years. All-cause mortality was higher among patients with moderate and severe AS compared with mild AS within 30 days (17.0% vs 13.0% vs 6.4%, respectively; P = 0.005) and in the long term (49.7% vs 51.4% vs 35.6%; P = 0.002). Concomitant moderate (hazard ratio [HR] 1.453, 95% confidence interval [CI] 1.020-2.068; P = 0.038) or severe AS (HR 1.873, 95% CI 1.176-2.982; P = 0.008) was an independent predictor of all-cause mortality. Kaplan-Meier curves demonstrated higher mortality in patients with moderate and severe AS compared with mild AS (P < 0.001). Similar survival trends were observed regardless of ACS type and in those with preserved left ventricular ejection fraction. Patients with reduced left ventricular ejection fraction had poor prognosis regardless of AS severity. CONCLUSIONS: ACS patients with concomitant moderate or severe AS have similar high long-term mortality, regardless of ACS type. The high early mortality in moderate and severe AS emphasises the imperative to attempt to mitigate this risk urgently.

Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors: A Systematic Review.

Importance: Chiral switching, a strategy in which drug manufacturers develop a single-enantiomer formulation of a drug to be substituted for a racemic formulation, allows manufacturers to maintain market exclusivity for drugs losing patent protection, even without demonstrating superior efficacy or safety. Objective: To identify and characterize all randomized clinical trials (RCTs) directly comparing a Food and Drug Administration (FDA)-approved single-enantiomer drug against a previously approved racemic drug for 1 or more efficacy or safety end points. Evidence Review: Drugs were identified using the Drugs@FDA database. Randomized clinical trials were identified using Ovid MEDLINE (1949 to October 22, 2019), Ovid Embase (1974 to October 22, 2019), Web of Science Core Collection (all years), ClinicalTrials.gov, and Cochrane Central Registry of Controlled Trials (CENTRAL, Wiley, Issue 8 of 12, October 22, 2019). Trials were characterized as favoring the single-enantiomer or racemic drugs based on whether the primary efficacy, secondary efficacy, and safety end points achieved each study's defined significance level (eg, P < .05). Trials were characterized as favoring neither drug if no statistically significant differences were reported for any end point or if both drugs were found to be superior for 1 or more separate end points. Findings: Fifteen FDA-approved single-enantiomer drugs were identified with racemic precursors approved in the US or Europe. For 3 single-enantiomer racemic drug pairs, no RCTs directly comparing the drugs were identified. For the remaining 12 pairs, 185 RCTs comparing efficacy or safety of the drug pairs were identified, 124 (67.0%) of which studied 1 pair (levobupivacaine/bupivacaine). There were 179 RCTs directly comparing drug pairs using efficacy end points, of which 23 (12.8%) favored the single enantiomer based on primary efficacy end point results. There were 124 RCTs directly comparing drug pairs using safety end points, of which 17 (13.7%) favored the single-enantiomer drug. For 9 of the 15 single-enantiomer drugs (60.0%), no RCTs were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors. Conclusions and Relevance: The results of this systematic review suggest that most newly marketed FDA-approved single-enantiomer drugs are infrequently directly compared with their racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.