Food And Drug Administration Label Research Articles

Automatic text classification of drug-induced liver injury using document-term matrix and XGBoost.

Regulatory agencies generate a vast amount of textual data in the review process. For example, drug labeling serves as a valuable resource for regulatory agencies, such as U.S. Food and Drug Administration (FDA) and Europe Medical Agency (EMA), to communicate drug safety and effectiveness information to healthcare professionals and patients. Drug labeling also serves as a resource for pharmacovigilance and drug safety research. Automated text classification would significantly improve the analysis of drug labeling documents and conserve reviewer resources. We utilized artificial intelligence in this study to classify drug-induced liver injury (DILI)-related content from drug labeling documents based on FDA's DILIrank dataset. We employed text mining and XGBoost models and utilized the Preferred Terms of Medical queries for adverse event standards to simplify the elimination of common words and phrases while retaining medical standard terms for FDA and EMA drug label datasets. Then, we constructed a document term matrix using weights computed by Term Frequency-Inverse Document Frequency (TF-IDF) for each included word/term/token. The automatic text classification model exhibited robust performance in predicting DILI, achieving cross-validation AUC scores exceeding 0.90 for both drug labels from FDA and EMA and literature abstracts from the Critical Assessment of Massive Data Analysis (CAMDA). Moreover, the text mining and XGBoost functions demonstrated in this study can be applied to other text processing and classification tasks.

US adolescents’ response to nicotine warning labels in influencer e-cigarette marketing social media posts: a survey-based randomised between-subject experiment

BackgroundE-cigarette promotional posts with misleading nicotine warning labels on social media may lower adolescents’ risk perceptions of e-cigarettes. A between-subject experiment assessed effects of influencers’ e-cigarette promotional posts with different...

338. ChatGPT Conveys Incorrect Information about the FDA’s Antibiotic Boxed Warnings

Abstract Background Chat Generative Pre-training Transformer (ChatGPT) is a popular artificial intelligence-based chatbot that rapidly provides responses to online inquiries. As a language-processing – rather than a scientific – tool, ChatGPT does not guarantee accuracy. The United States Food and Drug Administration (FDA) labels medications with significant risk of serious or life-threatening adverse effects with boxed warnings (BW). We sought to assess the accuracy of ChatGPT regarding FDA BW for antibiotics. Methods FDA labels for commonly-used antibiotics were categorized through the DailyMed database of the National Library of Medicine (Table 1). ChatGPT-3.5 was then queried regarding FDA BWs using the following query: “Are there any boxed warnings on the FDA label for XX [medication] and if so, what are they?” Responses were sorted into 3 categories:(1) “Matching”: ChatGPT accurately reported both existence and content of BW or its absence;(2) “Inaccurate”: ChatGPT accurately reported a BW but erred on some aspects of the content; and(3) “Incorrect”: ChatGPT misidentified existence of BW, or listed incorrect adverse effects (AE)Table 1:FDA Boxed Warnings for Commonly Used Antibiotics Results Of the 41 antibiotics queried, 9 have FDA BWs and ChatGPT correctly identified the existence of all 9. However, ChatGPT correctly matched the AE of the FDA BW in only 3 instances (33%); in five instances (56%), ChatGPT listed inaccurate AEs (either under- or overinclusive) and in one (11%), ChatGPT listed an incorrect AE. For the 32 antibiotics without an FDA BW, ChatGPT reported that 23 (72%) had a BW (Figure 1). Figure 2 provides some examples of incorrect ChatGPT claims regarding AEs.Figure 1:ChatGPT Responses about FDA Boxed WarningsFigure 2:Examples of Incorrect ChatGPT claims Conclusion ChatGPT reported inaccurate and incorrect information about FDA BW for antibiotics. Clinicians should be aware of this new source of information for patients. Disclosures All Authors: No reported disclosures

Prescribing cascades in ambulatory care: A structured synthesis of evidence.

The strength of evidence for specific ambulatory care prescribing cascades, in which a marker drug is used to treat an adverse event caused by an index drug, has not been well characterized. To perform a structured, systematic, and transparent review of the evidence supporting ambulatory care prescribing cascades. Ninety-four potential prescribing cascades identified through a previously published systematic review. Systematic search of the literature to further characterize prescribing cascades. (1) Grading of evidence based on observational studies investigating associations between index and marker drugs, including: Level I-strong evidence [i.e. multiple high-quality studies]; Level II-moderate evidence [i.e. single high-quality study]; Level III-fair evidence [no high-quality studies but one or more moderate-quality studies]; and Level IV-poor evidence [other]. (2) Listing of the adverse event associated with the index drug in the product's United States Food and Drug Administration (FDA) label. (3) Synthesis of the evidence supporting mechanisms linking index drugs and associated adverse events. Of 99 potential cascades, 94 were supported by one or more confirmatory observational studies and were therefore included in this review. The 94 cascades related to 30 types of adverse drug reactions affecting 10 different anatomic/physiologic systems and were investigated by a total of 88 confirmatory studies, including prescription sequential symmetry analysis (n = 51), cohort (n = 30), and case-control (n = 7) studies. Overall, the evidence from observational studies was strong for 18 (19.1%) prescribing cascades, moderate for 61 (64.9%), fair for 13 (13.8%), and poor for 2 (2.1%). Although the evidence supporting mechanisms that link index drugs and associated adverse events was variable, FDA labels included information about the adverse event associated with the index drug for most (n = 86) but not all of the 94 prescribing cascades. Although we identified 18 of 94 prescribing cascades supported by strong clinical evidence and most adverse events associated with index drugs are included in FDA label, the evidentiary basis for prescribing cascades varies, with many requiring further evidence of clinical relevance.

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

Commercial coverage of specialty drugs, 2017-2021.

Health plans guide their enrollees' access to specialty drugs through coverage policies. We examined a set of health plan policies to determine if they have become more or less stringent over time. We did so by comparing the consistency of policies with Food and Drug Administration (FDA) label indications. We considered coverage policies for the same 187 specialty drugs issued by 17 large US commercial health plans from 2017 through 2021. Overall, the proportion of policies that were consistent with the FDA label declined from 57.1% in 2017 to 45.1% in 2021; the proportion of policies that were more restrictive than the FDA label increased from 39.5% to 51.7%. The proportion of policies excluding drug coverage remained approximately constant (3.4% in 2017; 3.2% in 2021). Trends in coverage restrictiveness varied across plans. For 13 plans, the proportion of policies with restrictions increased over time, while for 4 plans it declined.

Commercial health plans use of patient subgroup restrictions: An analysis of orphan and US Food and Drug Administration-expedited programs.

BACKGROUND: Health plans apply utilization management criteria to guide their enrollees' access to prescription drugs. Patient subgroup restrictions (ie, clinical prerequisites for drug coverage) are a form of utilization management that have not been thoroughly investigated. OBJECTIVE: To examine the frequency with which large US commercial health plans impose patient subgroup restrictions beyond the US Food and Drug Administration (FDA) label in their coverage policies for orphan drugs and for drugs included in 1 or more FDA-expedited programs. To determine how consistently these patient subgroup restrictions align with eligibility criteria specified in each drug's pivotal clinical trial(s). METHODS: The Tufts Medical Center Specialty Drug Evidence and Coverage (SPEC) database was used, which includes coverage policies issued by 17 large US commercial health plans. SPEC contained 3,786 orphan drug policies and 4,027 FDA-expedited drug policies (current as of December 2020). SPEC data on plans' patient subgroup restrictions were assessed for the first objective. Each patient subgroup restriction was benchmarked against the corresponding eligibility criteria for a drug's pivotal clinical trial(s) for the second objective. To do so, the "Clinical Studies" section of the drug's FDA label was reviewed or, if necessary, the published manuscript describing the drug's pivotal trial(s). Patient subgroup restrictions were categorized as follows: (1) "consistent," the restriction and trial eligibility criterion are equivalent; (2) "same measure, more stringent," the restriction and trial eligibility criteria depend on the same measure, but the plan coverage is more restrictive; (3) "same measure, less stringent," the restriction and trial eligibility criteria depend on the same measure, but the plan coverage is less restrictive; and (4) "not consistent," the restriction and trial eligibility criteria depend on different measures. RESULTS: Health plans imposed patient subgroup restrictions in 20.2% of orphan drug policies (frequency varied by health plan, 11.7%-36.6%), and in 21.8% of FDA-expedited drug policies (frequency varied by health plan, 11.1%-47.9%). Of the 936 patient subgroup restrictions in orphan drug policies, 60.3% were categorized as consistent; 7.3% as same measure, more stringent; 12.0% as same measure, less stringent; and 20.5% as not consistent. Of the 1,070 patient subgroup restrictions in FDA-expedited drug policies, 57.5% were categorized as consistent; 6.7% as same measure, more stringent; 16.0% as same measure, less stringent; and 19.8% as not consistent. CONCLUSIONS: Patient subgroup restrictions for orphan drugs and FDA-expedited programs varied substantially across health plans, potentially resulting in inconsistent access to a given therapy across the approved patient population. Patient subgroup restrictions tend to be consistent with eligibility criteria specified in pivotal clinical trials. DISCLOSURES: This study was funded by Sarepta Therapeutics, Inc. Alexa C Klimchak and Lauren E Sedita are employees of Sarepta Therapeutics, Inc., and may own stock/options in the company.

Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, "No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time". The panelists' assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.

Using real-world data from health systems to evaluate the safety and effectiveness of a catheter to treat ischemic ventricular tachycardia.

The ThermoCool STSF catheter is used for ablation of ischemic ventricular tachycardia (VT) in routine clinical practice, although outcomes have not been studied and the catheter does not have Food and Drug Administration (FDA) approval for this indication. We used real-world health system data to evaluate its safety and effectiveness for this indication. Among patients undergoing ischemic VT ablation with the ThermoCool STSF catheter pooled across two health systems (Mercy Health and Mayo Clinic), the primary safety composite outcome of death, thromboembolic events, and procedural complications within 7days was compared to a performance goal of 15%, which is twice the expected proportion of the primary composite safety outcome based on prior studies. The exploratory effectiveness outcome of rehospitalization for VT or heart failure or repeat VT ablation at up to 1year was averaged across health systems among patients treated with the ThermoCool STSF vs. ST catheters. Seventy total patients received ablation for ischemic VT using the ThermoCool STSF catheter. The primary safety composite outcome occurred in 3/70 (4.3%; 90% CI, 1.2-10.7%) patients, meeting the pre-specified performance goal, p = 0.0045. At 1year, the effectiveness outcome risk difference (STSF-ST) at Mercy was - 0.4% (90% CI: - 25.2%, 24.3%) and at Mayo Clinic was 12.6% (90% CI: - 13.0%, 38.4%); the average risk difference across both institutions was 5.8% (90% CI: - 12.0, 23.7). The ThermoCool STSF catheter was safe and appeared effective for ischemic VT ablation, supporting continued use of the catheter and informing possible FDA label expansion. Health system data hold promise for real-world safety and effectiveness evaluation of cardiovascular devices.

Applicability of Vericiguat to Patients Hospitalized for Heart Failure in the United States

BackgroundIn January 2021, vericiguat, a soluble guanylate cyclase stimulator, was approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and heart failure (HF) hospitalization among patients with a recent worsening HF event based on the VICTORIA (VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. ObjectivesThis study sought to leverage a contemporary U.S. registry of patients hospitalized for heart failure (HF) to characterize patients who may be candidates for vericiguat based on FDA label and the VICTORIA trial eligibility criteria. MethodsThe authors studied patients hospitalized for HF with ejection fraction (EF) <45% across 525 sites in the GWTG-HF (Get With The Guidelines–Heart Failure) registry between January 2014 and December 2020. Approximate FDA label criteria (excluding estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, dialysis, or patients with heart transplantation or durable mechanical circulatory support) and eligibility criteria for the VICTORIA trial were applied to the GWTG-HF cohort. ResultsAmong 241,057 patients with EF <45% in the GWTG-HF registry, 221,730 (92%) could be candidates for vericiguat under the FDA label and 92,249 (38%) would have been eligible for the VICTORIA trial. The most frequent reasons for ineligibility for the FDA label were eGFR <15 mL/min/1.73 m2 (5.7%) and dialysis (1.6%). Although there were greater proportions of women and Black patients in the GWTG-HF registry, most clinical characteristics were qualitatively similar with patients enrolled in the VICTORIA trial. Among Medicare beneficiaries in the GWTG-HF registry eligible for vericiguat by either FDA label or VICTORIA trial criteria, 12-month postdischarge rates of mortality (36%-37%), HF hospitalization (33%-35%), all-cause hospitalization (64%-66%), and mean health care expenditure (U.S. $25,106-$25,428) were high. ConclusionsData from a large, contemporary U.S. registry of patients actively hospitalized for HF with EF <45% suggest that approximately 4 in 10 patients meet the criteria of the VICTORIA trial and that more than 9 in 10 patients are potential candidates for vericiguat based on the FDA label. Contemporary Medicare beneficiaries hospitalized for HF with EF <45% and eligible for vericiguat face high rates of postdischarge mortality and readmission and accrue substantial health care costs.

1153 SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS ELIGIBILITY IN PATIENTS WITH HEART FAILURE ACROSS THE SPECTRUM OF EJECTION FRACTION

Abstract Background Large randomized clinical trials demonstrated that sodium–glucose co-transporter-2 (SGLT2) inhibitors reduced adverse cardiovascular outcomes in patients with heart failure (HF) with both reduced (HFrEF) and preserved (HFpEF) ejection fraction. Despite the high potential to change clinical practice, the strict trial selection criteria might reduce external validity of these findings. Purpose The aim of the study was to evaluate the proportion of outpatients with HF that would be eligible for SGLT2 inhibitors across the spectrum of left ventricular ejection fraction (LVEF) in a contemporary real-world population. Methods We retrospectively evaluated patients with chronic stable HF followed-up at the outpatient clinic of our institution. HFrEF (LVEF &amp;lt;40%) patients’ eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin). In HFpEF group (LVEF&amp;gt;40%), Eligibility to SGLT2 inhibitors was based both strict and pragmatic (most likely influencing treatment decisions in clinical practice) EMPEROR- Preserved inclusion/exclusion criteria (empagliflozin). Results A total of 642 HF patients (441 HFrEF; 201 HFpEF) was studied. Among HFrEF patients, according to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, On the other hand, in HFpEF patients, 125 (62%) patients would be candidates for initiation of empagliflozin based on the EMPEROR-Preserved trial selection criteria. No significant differences were found between diabetic and non-diabetic patients in both HFrEF (p=0.23) and HFpEF (p=0.37). In patients not suitable for gliflozins treatment the major determinant of ineligibility was the failure to achieve the predefined NTproBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%. Similarly, applying EMPEROR-Preserved criteria most likely influencing treatment decisions in clinical practice (symptomatic HF; eGFR &amp;lt;20 mL/min/1.73 m2; symptomatic hypotension; history of ketoacidosis) the proportion of HFpEF patients potentially eligible to empagliflozin rose to 85%. Conclusions In our real-world analysis the proportion of HF patients potentially candidate for initiation of SGLT2 inhibitors is consistent across the entire spectrum of LVEF. Our findings might herald an extensive use of gliflozins in HF treatment, with a consequent strong beneficial impact on cardiovascular outcomes in eligible patients.

Good news for the mdx mouse community: Improved dystrophin restoration after skipping mouse dystrophin exon 23

Good news for the mdx mouse community: Improved dystrophin restoration after skipping mouse dystrophin exon 23

Real-world eligibility and cost-effectiveness analysis for empagliflozin in patients with heart failure

Abstract Background/Introduction Empagliflozin was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for reducing cardiovascular mortality and heart failure (HF) hospitalization in both patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Purpose Limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and cost-effectiveness based on a nationwide prospective HF registry. Methods For the study, 3108 HFrEF and 2070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analysed. Eligibility was estimated by FDA and EMA label criteria and by inclusion and exclusion criteria of EMPEROR-Reduced and EMPEROR-Preserved trials. The cost-effectiveness analysis was performed using the decision tree model, where effectiveness was the avoidance of the first hospitalization. Results Among the KorAHF patients, 91.4% met FDA &amp; EMA label criteria, while 44.7% met the clinical trial criteria. The main factor for exclusion in the clinical trial-based empagliflozin eligibility was low systolic blood pressure, including 18.7% of HFrEF and 11.0% of HFpEF patients. Other factors were acute (&amp;lt;4 weeks) myocardial infarction and impaired renal function (eGFR &amp;lt;20 mL/min/1.73 m2 or requiring dialysis). The overall expected hospitalization rate and cost reduction were 3.6 and US$ 14,885 per 100 eligible HF patients per year. In HFrEF patients, hospitalization rate and cost reduction were 4.8 and US$ 28,442. However, in HFpEF, the cost was increased by US$ 7,576, while hospitalization reduction was 1.7. Conclusion(s) There is a large discrepancy of real-world eligibility for empagliflozin between FDA &amp; EMA labels and clinical trial criteria. The cost-effectiveness benefit was more evident in patients with HFrEF than HFpEF. The efficacy and safety of empagliflozin in real-world patients should be further investigated for a broader range of clinical applications. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Minister of Science and Information and Communication Technologies (NRF-2021R1F1A1063430), by the Catholic Medical Center Research Foundation (2022), and by the Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E6300300, 2014-E63003-01, 2015-E63003-02, 2016-ER6303-00, and 2017-ER6303-01).

Global online interest in finasteride sexual side effects.

Prior literature has suggested that finasteride may negatively impact men's sexual health. In 2011, the Food and Drug Administration(FDA) provided a warning on finasteride drug labels to incorporate sexual side effects such as reduced libido and erectile dysfunction. We aimed to evaluate global online interest in finasteride sexual side effects, their penetrance and variation, and how they compared overtime. We also aimed to evaluate the influence of the FDA label warnings on web-based searches for finasteride side effects. We utilized Google search engine from January 2004 to December 2020 to include separate trends from web searches of "Propecia," "Propecia side effects," "finasteride", "finasteride side effects", and "post-finasteride syndrome" compared amongst the United States, United Kingdom, and Australia. We performed join-point regression analysis. We compared the annual relative search volume (ARSV) and annual percentage change (APC) to evaluate for loss or gain of interest in the respective key terms. We determined thatthe average ARSV for "finasteride" was 14.8% in 2004 and increased significantly to 57.3% in 2020 (APC: +9.25%, 95% CI 8 to 10.5, p < 0.001). Likewise, there was significant increased interest in "finasteride side effects" (APC: +20.7, p < 0.001) and "post-finasteride syndrome" (APC: +29.2; p < 0.001) in the United States overtime. Finally, when we compared trends before and after the FDA warnings, the average ASRV of "finasteride", "finasteride side effects", and "post-finasteride syndrome" all increased significantly (p = 0.001, p = 0.014, p < 0.001), respectively. Thus, it is evident that there is a global web-based interest in finasteride and its sexual health side effects, particularly after the FDA warning in 2011. There is boosted public awareness, and thus providers should have more detailed and careful conversations with patients prior to starting a 5α-reductase inhibitor such as finasteride.

Evaluation of US Food and Drug Administration Drug Label Recommendations for Coadministration of Antivirals and Acid-Reducing Agents.

Coadministration with acid-reducing agents (ARAs), including proton pump inhibitors (PPIs), histamine H2 -receptor antagonists (H2 blockers), and antacids has been demonstrated to reduce antiviral exposure and efficacy. Therefore, it is essential that US Food and Drug Administration (FDA) drug labels include recommendations to manage these drug-drug interactions (DDIs). This investigation analyzed information in FDA drug labels to manage DDIs between ARAs and antivirals approved from 1998 to 2019. To ascertain clinical adoption, we assessed whether FDA label recommendations were incorporated into current antiviral clinical practice guidelines. We identified 82 label recommendations for 43 antiviral approvals. Overall, 56.1% of recommendations were deemed clinically actionable, with the most common actionable management strategies being dose adjustment during coadministration (40.2%) and coadministration not recommended (9.8%). The sources informing DDI recommendations were clinical DDI studies (59.8%) and predictions of altered exposure (40.2%). Antivirals with low aqueous solubility were more likely to have label recommendations and were more commonly investigated using clinical DDI studies (P < 0.01). For recommendations informed by clinical DDI studies, changes in drug exposure were associated with actionable label recommendations (P < 0.01). The frequency of exposure changes in clinical DDI studies was similar across antiviral indications, but exposure changes were numerically higher for antacids (71.4%) relative to PPIs (42.9%) and H2 blockers (28.6%). Of DDI pairs identified within drug labels, 76.8% were included in guidelines, and recommended management strategies were concordant in 90.5% of cases. Our findings demonstrate that current regulatory oversight mostly (but not completely) results in actionable label recommendations to manage DDIs for high-risk antivirals.

Impact of Label Restriction on Checkpoint-Inhibitor Use in Bladder Cancer and Changes in Mortality.

In 2018, the US Food and Drug Administration (FDA) limited the indication for immune checkpoint inhibitors (ICI) in metastatic bladder cancer to patients with programmed cell death protein ligand-1 (PD-L1)–positive tumors. The impact of the label change on survival outcomes remains unknown. We conducted a controlled interrupted time series analysis using a nationwide electronic health record–derived oncology dataset. We used Cox regression to compare mortality in the post- vs prelabel change periods among affected (initiators of ICI or carboplatin-based chemotherapy) vs unaffected (initiators of cisplatin-based chemotherapy) patients. The use of ICI, carboplatin, and cisplatin was similar pre- and postlabel change, but PD-L1 testing increased postlabel change. In adjusted models, survival did not differ after the FDA label change policy compared with prior to the label change in any of the groups. The FDA label restriction on immunotherapy was associated with increased PD-L1 testing but not with changes in treatment patterns or mortality among patients with metastatic bladder cancer.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Patients\u2019 access to rare neuromuscular disease therapies varies across US private insurers

BackgroundThe extent to which different US private insurers require their enrollees to meet the same coverage criteria before gaining access to treatment is unclear. Our objective was to scrutinize the patient access criteria imposed by US private insurers for a set of rare neuromuscular disease (NMD) disease-modifying therapies (DMTs).MethodsWe examined coverage policies issued by 17 large US private insurers for the following NMD treatments: nusinersen and onasemnogene abeparvovec for spinal muscular atrophy, edaravone for amyotrophic lateral sclerosis, and eteplirsen for Duchenne muscular dystrophy. We reviewed the plans’ coverage policies and identified the patient access criteria, including clinical prerequisites, step therapy protocols, and prescriber requirements. We compared the plans’ patient access criteria with the therapies’ US Food and Drug Administration (FDA)-labeled indications.ResultsThe included insurers issued 65 coverage policies for the included therapies. Plans imposed coverage restrictions beyond the FDA-approved indications in 60 coverage policies; plans did not cover eteplirsen in five policies. No therapy was covered the same way by all insurers. Plans applied clinical criteria beyond the FDA label indication in 56 policies and step therapy protocols in three policies. Plans required that a neurologist prescribe the therapy in 37 policies, 22 of which required the neurologist to have expertise in the particular disease. Plans often required patients to suffer from symptoms of particular severity; e.g. for eteplirsen, plans differed in their 6-min walk test requirements; for edaravone, some plans required that patients had normal respiratory function, while others required only that patients did not require ventilation; for nusinersen and onasemnogene abeparvovec, plans differed in the number of SMN2 gene copies they required patients to have (SMN2 copy number is correlated with disease severity).ConclusionsThe evaluated large US private insurers tended to impose coverage restrictions beyond the FDA label indication for the included set of rare NMD DMTs. Plans rarely applied the same patient access criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies across insurers.

257 Sodium-glucose CO-transporter-2 inhibitors eligibility in patients with heart failure with reduced ejection fraction

Abstract Aims The sodium–glucose co-transporter-2 (SGLT2) inhibitors dapagliflozin and empagliflozin have been demonstrated to reduce adverse cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Limited data are available characterizing the generalizability of SGLT2 inhibitors treatment in the clinical practice. The aim of the study was to evaluate the proportion of outpatients with HFrEF that would be eligible for SGLT2 inhibitors in a contemporary real-world population. Methods and results We retrospectively evaluated patients with chronic stable HFrEF followed-up at the HF outpatient clinic of our institution. Patients’ eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin). A total of 441 HFrEF patients was enrolled. According to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, without significant differences between diabetic and non-diabetic patients (P = 0.23). Among patients not suitable for gliflozins treatment (159 patients; 36%), the major determinant of ineligibility was the failure to achieve the predefined NT-proBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%. Conclusions In our real-world analysis a large proportion of HFrEF patients would be candidates for initiation of SGLT2 inhibitors, supporting its broad generalizability in clinical practice. This would be expected to reduce morbidity and mortality in eligible patients.

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US

The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%). The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.