Food And Drug Administration Drug Research Articles

Trends in COA Use and Regulatory Acceptance for Epileptic Encephalopathy and Developmental Epileptic Encephalopathy Indications (P13-1.006)

<h3>Objective:</h3> To investigate the landscape of clinical outcome assessments (COAs) used in epileptic encephalopathies (EEs) and developmental epileptic encephalopathies (DEEs). <h3>Background:</h3> EEs and DEEs are rare conditions characterized by difficult-to-treat seizures and intellectual or developmental disability. The heterogeneity of these conditions creates unique challenges for outcome measurement, particularly in clinical trials. To assess trends in the COA landscape, a targeted literature review was conducted to identify COAs used in EE and DEE clinical trials. <h3>Design/Methods:</h3> A search was conducted in ClinicalTrials.gov to identify interventional studies in EEs and DEEs. Findings were supplemented by searches in PubMed (titles/abstracts only), PROLABELS, and Food and Drug Administration (FDA) COA guidance materials, pairing EE/DEE and COA search terms when applicable. No limits on year of publication were applied. All results were reviewed, and relevant data were extracted and analyzed to identify trends in COA use. <h3>Results:</h3> The search identified 153 trials (ClinicalTrials.gov), 405 articles (PubMed), and 92 FDA drug labels (PROLABELS). Following screening, 105 trials, 26 article abstracts, and 19 labels met the criteria for data extraction. Excluding safety measures, 113 COAs were identified. Consistent with FDA guidance, seizure assessments and diaries were utilized most frequently, followed by clinician- or caregiver-rated global impression measures. Observer-reported outcomes and clinician-reported outcomes were more common than patient-reported outcomes. Approximately 25% of COAs were disease-specific. Additionally, common domains in COAs reviewed included cognition (n=22), motor functioning (n=14), multi-domains or quality of life (n=14), or communication (n=6). Several COAs utilized a global impression approach to assess within-patient change in domains, such as seizure severity or non-seizure concepts. <h3>Conclusions:</h3> Importantly, disease-specific measures, including global impression items intended to capture change in multiple domains, were identified. These findings may suggest that a disease-specific global impression approach is becoming increasingly common in these heterogeneous conditions to accompany seizure assessments and diaries. <b>Disclosure:</b> Ms. Graham has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of IQVIA. Dr. Batchelder has received personal compensation for serving as an employee of IQVIA. Dr. Gleeson has nothing to disclose. Ms. Buenfil has received personal compensation for serving as an employee of IQVIA. Ms. Kim has received personal compensation for serving as an employee of IQVIA. Dr. Meyers has received personal compensation for serving as an employee of IQVIA. Dr. Williams has received personal compensation for serving as an employee of IQVIA.

Data visualization explorer: A tool for participant representation in pivotal trials of FDA-approved medicinal products

This paper presents a 2015-2021US Food and Drug Administration (FDA) Drug Trials Snapshots (DTS) Data Visualization Explorer-an interactive data visualization web-based tool (https://arielcarmeli.shinyapps.io/fda-drug-trial-snapshots-data-explorer) built in R and based on publicly available FDA clinical trial participation data and disease incidence data from the National Cancer Institute and Centers for Disease Control and Prevention. FDA data can be explored by race, ethnicity, sex, age group, therapeutic area, pharmaceutical sponsor, and approval year for clinical trials that supported each of the 339 FDA drug and biologic approvals between 2015 and 2021. This work provides several advantages relative to past literature and DTS reports: a dynamic data visualization tool; race, ethnicity, sex, and age group data presented in one place; data on sponsor; and emphasis on data distributions instead of averages. We present recommendations for improved data access, reporting, and communication to assist leaders in making evidence-based decisions to improve trial representation to enhance health equity.

The Pharmaceutical Industry in 2022: An Analysis of FDA Drug Approvals from the Perspective of Molecules.

While 2021 ended with the world engulfed in the COVID-19 Omicron wave, 2022 has ended in almost all countries, except China, with COVID-19 being likened to the flu. In this context, the U.S. Food and Drug Administration (FDA) has authorized only 37 new drugs this year compared to an average of 52 in the last four years. Thus 2022 is the second lowest harvest after 2016 in the last six years. This ranking may be transient and will be confirmed in the coming years. In this regard, the reduction in the number of drugs accepted by the FDA this year applies only to the so-called small molecules as there has been no variation in the respective numbers of biologics or TIDES (peptides and oligonucleotides). Monoclonal antibodies (mAbs) continue to be the class with the most drugs authorized (9), while proteins/enzymes (5) and an antibody-drug conjugate complete the biologics harvest. In 2022, five TIDES and seven drugs inspired by natural products have received the green light, thus showing the same tendency as in previous years. Finally, pharmaceutical agents with nitrogen aromatic heterocycles and/or fluorine atoms continue to be predominant among small molecules this year. Furthermore, three drugs have been approved for imaging, reinforcing the trend in recent years for this class of treatments. A keyword in 2022 is bispecificity since four drugs have this property (two mAbs, one protein, and one peptide). Herein, the 37 new drugs approved by the FDA in 2022 are analyzed. On the basis of chemical structure alone, these drugs are classified as the following: biologics (antibodies, antibody-drug conjugates, proteins/enzymes), TIDES (peptide and oligonucleotides), combined drugs, natural products; nitrogen aromatic heterocycles, fluorine-containing molecules, and other small molecules.

Fine-tuning BERT for automatic ADME semantic labeling in FDA drug labeling to enhance product-specific guidance assessment

Product-specific guidances (PSGs) recommended by the United States Food and Drug Administration (FDA) are instrumental to promote and guide generic drug product development. To assess a PSG, the FDA assessor needs to take extensive time and effort to manually retrieve supportive drug information of absorption, distribution, metabolism, and excretion (ADME) from the reference listed drug labeling. In this work, we leveraged the state-of-the-art pre-trained language models to automatically label the ADME paragraphs in the pharmacokinetics section from the FDA-approved drug labeling to facilitate PSG assessment. We applied a transfer learning approach by fine-tuning the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model to develop a novel application of ADME semantic labeling, which can automatically retrieve ADME paragraphs from drug labeling instead of manual work. We demonstrate that fine-tuning the pre-trained BERT model can outperform conventional machine learning techniques, achieving up to 12.5% absolute F1 improvement. To our knowledge, we were the first to successfully apply BERT to solve the ADME semantic labeling task. We further assessed the relative contribution of pre-training and fine-tuning to the overall performance of the BERT model in the ADME semantic labeling task using a series of analysis methods, such as attention similarity and layer-based ablations. Our analysis revealed that the information learned via fine-tuning is focused on task-specific knowledge in the top layers of the BERT, whereas the benefit from the pre-trained BERT model is from the bottom layers.

Risk of Poor Neonatal Adaptation Syndrome Among Infants Exposed to Second-Generation Atypical Antipsychotics Compared to Antidepressants: Results From the National Pregnancy Registry for Psychiatric Medications.

Objective: While poor neonatal adaptation syndrome (PNAS) has been particularly well described among infants exposed to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), this is not the case for second-generation antipsychotics (SGAs). In 2011, the US Food and Drug Administration (FDA) issued a drug safety warning regarding fetal antipsychotic exposure and risk for PNAS and extrapyramidal symptoms (EPS). The primary objective of this study was to examine the risk for PNAS among infants exposed to SGAs compared to SSRI/SNRI-exposed infants, leveraging the prospective, longitudinal design of the National Pregnancy Registry for Psychiatric Medications (NPRPM). Methods: The NPRPM is a prospective pharmacovigilance program in which pregnant women, aged 18–45 years, are enrolled and followed prospectively. Medical records were systematically reviewed and data abstracted using a checklist of PNAS and EPS symptoms specifically outlined in the FDA drug safety warning. The two study groups included infants exposed to an SGA during pregnancy and infants exposed to an SSRI/SNRI during pregnancy. The primary outcome was the presence of at least one or more PNAS symptoms during the first month of life. Other neonatal outcomes following exposure to the medication of interest, including preterm birth, neonatal intensive care unit (NICU) admission, rates of EPS, and whether infants were discharged home with their mothers, are also reported. Results: Of the 2,145 women enrolled in this study as of December 16, 2020, a total of 373 women and their infants (n = 384) were eligible for inclusion (n = 193 SGA-exposed infants and 191 SSRI/SNRI-exposed infants). Among SGA-exposed infants, 32.6% (63/193) experienced at least 1 PNAS sign compared to 34.6% of infants (66/191) in the SSRI/SNRI-exposed group. The majority of infants in each group showed no symptoms of PNAS. No differences were observed between the two groups with respect to rates of preterm birth, NICU admission, prevalence of EPS, and timing of infants being discharged home with their mothers. Conclusions: PNAS symptomatology was comparable among infants exposed prenatally to an SGA or to an SSRI/SNRI. These preliminary findings provide an estimated risk of PNAS among infants exposed to SGAs of roughly 30%. Interestingly, these findings are also consistent with estimates in the literature of PNAS in SSRI/SNRI-exposed infants, suggesting a possible common pathway underlying this phenomenon. Trial Registration: ClinicalTrials.gov identifier: NCT01246765

USING REAL-WORLD EVIDENCE TO SUPPORT THE FDA REGULATORY APPROVAL: METHODOLOGICAL CONSIDERATIONS

Abstract Evidence from clinical trials has traditionally been used to support regulatory drug approval, whereas real-world evidence (RWE) has been used for post-marketing surveillance studies. With the enaction of the 21st Century Cures Act, the Food and Drug Administration (FDA) is evaluating the potential use of RWE to support new indications for an approved product or to satisfy post-approval study requirements. Yet the substantial evidence standard remains unchanged for FDA approval. To date, the FDA has issued guidelines or frameworks for using RWE for regulatory decisions. However, many methodological challenges remain unanswered when using RWE in gerontology research. This Pharmaceutical Care and Outcomes Research Interest Group-sponsored symposium consists of leading experts in the country to address these problems. The four papers in this symposium will address methodological challenges that are unique in gerontology research. Specifically, The first paper will introduce the FDA drug evaluation process, focusing on the key considerations for evaluating RWE in regulatory decision making; the second paper will discuss possible challenges related to data sources from which RWE are generated in aging research; the third paper will provide a case example of some of the challenges in using RWD sources to generate RWE in the Alzheimer’s Disease setting; and the fourth paper will provide recommendations for improving gerontology research based on RWE going forward.

Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs

ObjectiveTo review the clinical evidence, regulatory background, and cost of antibiotics approved by the US Food and Drug Administration (FDA), 2016-19.DesignCohort study of FDA approved drugs.Data sourcesFDA databases, ClinicalTrials.gov, and...

Overview of FDA Drug Approval and Labeling

The U.S. Food and Drug Administration (FDA) regulates a variety of products, including medical, food, and tobacco products. Prior to the creation of the FDA, there were few protections to the public around the contents and sale of food and pharmaceuticals. Over time, legislation was passed and amended that ensured drugs and biologics undergo extensive review by multidisciplinary teams to provide assurance that marketed products are safe and effective for their intended use. The FDA-approved drug labeling is the primary tool for communicating essential information regarding the safe and effective use of a drug product. As such, providers should be familiar with the format of the prescribing information because it is a valuable source of information, particularly prior to prescribing a new drug for the first time. Although there are clinical circumstances in which off-label drug use may be warranted, prescribing drugs off-label involves a context of use that has not undergone the FDA's rigorous evaluation of the benefit-risk assessment.

The Financial Toxicity of FDA-Drugs Approved for Malignant Hematology

Background: Many Food and Drug Administration (FDA) drugs (FDADs) are available now for patients with malignant hematology (MH). Still,the high prices of FDADs for MH affect the care of these patients and our health care system. Here, we estimated one monthly supply price (OMSP) for FDADs for MH approved between 2011 and 2021. Also, we reported the total cost (TC) of FDADs by multiplying OMSP times the assumed duration of therapy based on the available overall survival (OS) (OMSP x OS (months)). Methods: We performed a retrospective review of clinical trials (CTs) published from January 2011 to May 2021 that led to FDA approval of hematological malignancy drugs (Leukemias, lymphomas, Multiple Myeloma (MM), Myelodysplastic Syndrome (MDS), and Myeloproliferative Neoplasm (MPN)). The drugs investigated were selected using FDA Databases, 'Oncology (Cancer) / Hematologic Malignancies Approval Notifications' and 'Novel Drug Approvals'. CTs were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature on drug approval. FDADs were divided into disease groups: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), MDS+MPN, MM, and lymphoma. We compared prices between drug.com and UpToDate using the lowest price for each drug (the percentage change was low 0.18). We calculated the median of OMSP for each group, compared the median of OMSP between oral (PO), subcutaneous (SQ), and intravenous (IV) FDADs, and calculated TC for each group. For non-reached OS, we used 60 months to calculate TC. Results: Sixty-one FDADs were identified; 9,4,4,7 and 4 for AML, CML, ALL, CLL, and MDS+MPN, respectively. For MM and lymphoma, we identified 11 and 22, FDADs, respectively. The median of PO, SQ, and IV FDADs were 29, 4, and 30, respectively (some drugs were approved for more than one group). The median of OMSP for AML, CML, ALL, CLL, and MDS+MPN were $30,923 [range, $5,989-36,099], $19,343 [range, $20,834-22,570], $75,839 [range, $48,917-93,660] (excluding chimeric antigen receptor-T cell (CAR-T) therapy), $15,263 [range, $3,532- 23,091], and $15,284 [range, $8,060- 24,157], respectively. The median of OMSP for MM and lymphoma excluding CAR-T were $20,514 [range, $2,090-35,276 ] and $18,434 [range, $6,834-34,351], respectively. The median of OMSP for PO, SQ, and IV FDADs were $18,291 [range, $2,628-31,686], $18,370 [range, $6,934-22,583] and $24,691 [range, $2,090-93,660] (excluding CAR-T cell therapy), respectively. All FDADs for ALL patients were IV. The median OMSP for FDADs approved from (2011 to 2016) and (2016 to 2021) were $22,233 (range, $8,300-23,091) and $24,517 (range, $2,352-86,253), respectively. The median TC for AML, CML, ALL, CLL, and MDS+MPN were $351,327 (range, $196,380-791,041), $1,160,597 (range, $1,097,482-1,354,993), $547,091 (range, $244,587-$985,915), $971,160 (range, $564,720-3,456,000), and $1,114,038 (range, $255,502-1,449,447), respectively. OS was not reached for all CML drugs, in 5/7 (71%) of CLL drugs and 12/61 (34%) of all FDADs. The median TC for MM and lymphoma were $607,031 [range, $18,813-1,743,706 ] and $884,900 [range, $183,817-9,116,360], respectively. Excluding CAR-T drugs, The highest OMSP was for ALL but not TC due to the short median OS (10 months) (Figure 1). There were 5 CAR-T products approved between August 2017 and March 2021 (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, brexucabtagene autoleucel and idecabtagene vicleucel). The median cost was $432,055 (range, $373,000-475,000), and the estimated OMSP was $21,635 (range,$6,216-39,583). The median household monthly income was $6,558 in 2020 in the United States (US). In 2020, 8.6% of US population (28 million) did not have helath insurance at any point during the year. There are currently no generic drug products of these FDADs available in the US. Conclusion: The cost-effectiveness of CAR-T products is relatively similar to other FDADs. Patients with malignant hematologic disorders are affected by treatment-related financial harm. Although the costs used for this analyses may be modulated by many factors where the actual cost may not be what is reported in the sources used, the financial impact is still significant for many patients. There is a need for strategies to lower the costs. The value of drugs should be considered in formulating treatment guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IBCL-015 The Financial Toxicity of FDA-Drugs Approved for Malignant Hematology

The high prices of cancer drugs affect the care of cancer patients and our health care system. Many Food and Drug Administration (FDA) drugs (FDADs) are available now for patients with malignant hematology (MH). We reviewed one monthly supply price (OMSP) for FDADs for MH approved between 2011 and 2021. We performed a retrospective review of randomized clinical trials that led to FDAs approval for MH. Sixty-three FDADs were identified. FDADs were divided into disease groups: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome + myeloproliferative neoplasms (MDS+MPN), and lymphoma. We compared prices between drug.com and UpToDate. The percentage change was low (0.18). We calculated the median of OMSP for FDADs for each group. We compared the median of OMSP between oral (PO), subcutaneous (SQ), and intravenous (IV) FDADs. The median of OMSP for AML, CML, ALL, CLL, and MDS+MPN were $30923 [range, 5989 to 36099], $19343 [range, 20834 to 22570], $84749 [range, 75839 to 373000], $15263 [range, 3532 to 23091], and $15284 [range, 8060 to 24157], respectively. All FDADs for ALL patients were IV. The median of OMSP for MM and lymphoma were $20982 [range, 12054 to 441,743] and $23091 [range, 6834 to 475000], respectively. The median of OMSP for PO, SQ, and IV FDADs were $18291 [range, 2628 to 31,686], $18370 [range, 6934 to 22583] and $24691 [range, 2090 to 93660] (discounting CAR-T cell therapy), respectively. The median of OMSP for FDADs approved from (2011 to 2016) and (2016 to 2021) were $22233 (range, 8300 to 23091) and $24517 (range, 2352 to 475000), respectively. The median household monthly income was $6,558 in 2020 in the United States (US). There are currently no generic drug products of FDADs available in the US. MH patients are affected by treatment-related financial harm. The need for generic versions to lower the price is urgent. IV FDADs are more expensive than PO or SQ. The value of drugs should be considered in formulating treatment guidelines.

Identification of a potential inhibitor for New Delhi metallo-β-lactamase 1 (NDM-1) from FDA approved chemical library- a drug repurposing approach to combat carbapenem resistance

Superbugs producing New Delhi metallo-β-lactamase 1 (NDM-1) enzyme is a growing crisis, that is adversely affecting the global health care system. NDM-1 empowers the bacteria to inactivate entire arsenal of β-lactam antibiotics including carbapenem (the last resort antibiotic) and remains ineffective to all the available β lactamase inhibitors used in the clinics. Limited therapeutic option available for rapidly disseminating NDM-1 producing bacteria makes it imperative to identify a potential inhibitor for NDM-1 enzyme. With drug repurposing approach, in this study, we used virtual screening of available Food and Drug Administration (FDA) approved chemical library (ZINC12 database) and captured ‘adapalene’ (FDA drug) as a potent inhibitor candidate for NDM-1 enzyme. Active site docking with NDM-1, showed adapalene with binding energy −9.21 kcal/mol and interacting with key amino acid residues (Asp124, His122, His189, His250, Cys208) in the active site of NDM-1. Further, molecular dynamic simulation of NDM-1 docked with the adapalene at 100 ns displayed a stable conformation dynamic, with relative RMSD and RMSF in the acceptable range. Subsequently, in vitro enzyme assays using recombinant NDM-1 protein demonstrated inhibition of NDM-1 by adapalene. Further, the combination of adapalene plus meropenem (carbapenem antibiotic) showed synergistic effect against the NDM-1 producing carbapenem (meropenem) resistant clinical isolates (Escherichia coli and Klebsiella pneumoniae). Overall, our data indicated that adapalene can be a potential inhibitor candidate for NDM-1 enzyme that can contribute to the development of a suitable adjuvant to save the activity of carbapenem antibiotic against infections caused by NDM-1 positive gram-negative bacteria. Communicated by Ramaswamy H. Sarma

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.

A review of patient-reported outcome assessments in registration trials of FDA-approved new oncology drugs (2014–2018)

The Food and Drug Administration (FDA) encourages the assessment of patient-reported outcomes (PROs) in oncology clinical trials. A 2015 review showed that approximately 26% of industry-sponsored oncology trials included assessment of PROs. However, the proportion of recent trials that supported new oncology drug approvals and assessed PROs is unknown. This review found that assessment of PROs was included in about 75% of registration trials that supported 55 new FDA drug approvals during 2014–2018. Patient-reported outcome assessment was included more in randomized controlled trials than in open-label trials (88% vs. 69%, respectively) and more in phase 3 than in phase 2 trials (89% vs. 66%, respectively).

Trends in the Quality of Evidence Supporting FDA Drug Approvals: Results from a Literature Review.

New drug approvals in the United States must be supported by substantial evidence from "adequate and well-controlled" trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. The authors conducted a systematic literature review of studies evaluating the design and outcomes of the key trials supporting new drug approvals in the United States. They extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point toward less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. The characteristics of trials used to approve new drugs have evolved over the past two decades along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high-quality data collection before or after FDA approval.

New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review of 2021.

ObjectiveTo evaluate new medical devices and drugs pertinent to otolaryngology–head and neck surgery that were approved by the Food and Drug Administration (FDA) in 2021.Data SourcesPublicly available FDA device and drug approvals from ENT (ear, nose, and throat), anesthesia, neurosurgery, plastic surgery, and general surgery FDA committees.Review MethodsFDA device and therapeutic approvals were identified and reviewed by members of the American Academy of Otolaryngology–Head and Neck Surgery’s Medical Devices and Drugs Committee. Two independent reviewers assessed the relevance of devices and drugs to otolaryngologists. Medical devices and drugs were then allocated to their respective subspecialty fields for critical review based on available scientific literature.ConclusionsThe Medical Devices and Drugs Committee reviewed 1153 devices and 52 novel drugs that received FDA approval in 2021 (67 ENT, 106 anesthesia, 618 general surgery and plastic surgery, 362 neurosurgery). Twenty-three devices and 1 therapeutic agent relevant to otolaryngology were included in the state of the art review. Advances spanned all subspecialties, including over-the-counter hearing aid options in otology, expanding treatment options for rhinitis in rhinology, innovative laser-safe endotracheal tubes in laryngology, novel facial rejuvenation and implant technology in facial plastic surgery, and advances in noninvasive and surgical treatment options for obstructive sleep apnea.Implications for PracticeFDA approvals for new technology and pharmaceuticals present new opportunities across subspecialties in otolaryngology. Clinicians’ nuanced understanding of the safety, advantages, and limitations of these innovations ensures ongoing progress in patient care.

Association Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US

Clinical trials and compassionate use agreements provide selected patients with access to potentially life-saving treatments before approval by the Food and Drug Administration (FDA). Approval from the FDA decreases a number of access barriers; however, it is unknown whether FDA approval is associated with increases in the equitable use of novel therapies and reductions in disparities in use among patients with cancer in the US. To assess the association between FDA drug approval and disparities in the use of immunotherapy across health, sociodemographic, and socioeconomic strata before and after approval of the first checkpoint inhibitors for the treatment of patients with cancer in the US. This cohort study used data from the National Cancer Database to examine the use of immunotherapy across health, sociodemographic, and socioeconomic strata before and after FDA approval of the first checkpoint inhibitor therapies. A total of 402 689 patients 20 years or older who were diagnosed with stage IV non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma of the skin between January 1, 2007, and December 31, 2018 (specific years varied by tumor type), were included. Patient health (Charlson-Deyo comorbidity score and age), sociodemographic characteristics (sex, race, and ethnicity), and socioeconomic (insurance status and household income based on zip code of residence) characteristics. The association of patient characteristics with receipt of immunotherapy was evaluated in the 4 years before and the 3 years immediately after FDA approval using multivariable logistic regression modeling. Among 402 689 patients (median [IQR] age, 68 [60-76 years]; 225 081 men [55.9%]), 347 233 had NSCLC, 43 714 had RCC, and 11 742 patients had melanoma. A total of 47 527 patients (11.8%) were Black, 15 763 (3.9%) were Hispanic, 375 874 (93.3%) were non-Hispanic, 335 833 (83.4%) were White, and 16 553 (4.1%) were of other races. Before FDA approval, 6271 patients (3.2%) with NSCLC, 1155 patients (4.8%) with RCC, and 504 patients (8.6%) with melanoma received immunotherapy compared with 23 908 patients (15.6%) with NSCLC, 3890 patients (19.7%) with RCC, and 1143 patients (19.3%) with melanoma after FDA approval. Before FDA approval, sociodemographic and socioeconomic characteristics were associated with variable immunotherapy administration by tumor type. For example, among those with NSCLC, Black patients were less likely to receive immunotherapy than White patients (odds ratio [OR], 0.78; 95% CI ,0.71-0.85; P < .001); among those with RCC, uninsured patients were less likely to receive immunotherapy than privately insured patients (OR, 0.31; 95% CI, 0.20-0.48; P < .001). After FDA approval, most disparities persisted, but several narrowed (eg, Black patients with NSCLC: OR, 0.87 [95% CI, 0.83-0.91; P < .001]; uninsured patients with RCC: OR, 0.60 [95% CI, 0.48-0.75; P < .001]). Although many disparities remained, some gaps across socioeconomic characteristics appeared to widen (eg, patients with NSCLC in the lowest vs highest income quartile: OR, 0.80; 95% CI, 0.76-0.83; P < .001), and new gaps emerged (eg, Black patients with RCC: OR, 0.82; 95% CI, 0.72-0.93; P = .003). In this cohort study, disparities in immunotherapy use existed across a number of sociodemographic and socioeconomic characteristics among patients with NSCLC, RCC, and melanoma before FDA approval, including during the important period when clinical trials were accruing patients. Although FDA approval was associated with a significant increase in the use of immunotherapy, gaps persisted, suggesting that FDA approval may not eliminate disparities in the use of novel therapies.

Is health-related quality of life (HRQoL) reporting keeping pace with new drug approvals in hematology and oncology: A five-year analysis of 245 drug approvals.

6519 Background: HRQoL data in cancer clinical trials can inform tolerability of new drugs, facilitate informed decision-making, and influence health care and policy decisions, but are frequently underreported. We reviewed all registration trials that informed Food and Drug Administration (FDA) approval between 2015-2020 for latency and quality of HRQoL reporting. Methods: HRQoL data for each clinical trial associated with FDA drug approval between 7/2015-5/2020 was collected retrospectively from multiple sources including the FDA and clinicaltrials.gov website, conference abstracts, and journal manuscripts. The aim of the study was to analyze the proportion of trials reporting HRQoL, quality of HRQoL data, latency between FDA approval and first reporting of HRQoL data, and association between changes in HRQOL and overall survival (OS) and progression-free survival (PFS) outcomes. Results: Of the 259 trials involving 245 drug approvals, majority involved solid tumors (61.4%), were phase III (59.1%), and led to approval based on a non-PFS/OS endpoint (52.9%). HRQoL was a pre-specified endpoint in 55.2% and reported in 49.8% trials. HRQoL data was published by the time of FDA approval in only 41.8% cases, 24.8% reported HRQoL data &gt; 12 mo after approval. Further, among trials reporting HRQoL (n = 129), HRQoL data was first reported in the primary paper in only 34.1%, and either in an ancillary paper in 41.9% or an ancillary abstract in 24% trials. Of the 129 trials with HRQoL data, an improvement in HRQoL was seen in 44.2%, no significant change in 41.9%, mixed results in 11.6%, and worsening in 2.3% of trials. Overall, by the time of FDA approval, OS and PFS data were reported in 59% (152/259) and 65% (168/259) trials respectively with an OS benefit seen in 23.9% (62/259) trials, and PFS benefit in 38.6% (100/259) trials. Of the 84 trials that led to FDA approvals based solely on response rate, HRQoL was reported in only 23.8% (n = 24) with a HRQoL benefit seen in only 9.5% (n = 8) trials. Trials reporting either no significant impact on HRQoL or a mixed impact on HRQoL reported median OS benefit of 4.6 months and 4.2 months respectively. In trials reporting HRQoL data &gt; 6 mo from FDA approval, OS benefit of &lt; 3 mo was seen in 17.8% (8/45) trials. No significant time trends were noted during the study period. Conclusions: There was significant underreporting of HRQoL outcomes in trials ( &lt; 50%) associated with FDA drug approvals between 2015-2020 with majority of trials reporting HRQoL data in an ancillary paper/abstract, and at a much later time than the FDA approval. While it is widely accepted that timely dissemination of HRQoL data from cancer drug trials are vital for clinical and regulatory decisions, no improvement in reporting rates were noted over past 5 years. Only 10% of drugs approved on the basis of response rates showed improvement in HRQoL in the registration trials.

An Evaluation of Sex- and Gender-Based Analyses in Oncology Clinical Trials.

The objective of this study was to evaluate whether sex- and gender-based analyses and proper sex and gender terminology were used in oncology trials leading to regulatory drug approval. The Food and Drug Administration (FDA) Hematology/Oncology Approvals and Safety Notifications page was used to identify all anticancer therapies that received FDA approval between 2012 and 2019. The trials used to support FDA drug approval were collected along with all available supplemental tables and study protocols. Documents were reviewed to determine if there was a plan to analyze results according to sex and gender and to determine if consistent sex and gender terminology were used. We identified 128 randomized, controlled trials corresponding to a cancer medicine, which received FDA approval. No study specified how sex and gender were collected or analyzed. No study reported any information on the gender of participants. Sex and gender terminology were used inconsistently at least once in 76% (97 of 128) of studies. Among the 102 trials for nonsex-specific cancer sites, 89% (91 of 102) presented disaggregated survival outcome data by sex. No study presented disaggregated toxicity data by sex or gender. The majority of pivotal clinical trials in oncology fail to account for the important distinction between sex and gender and conflate sex and gender terminology. More rigor in designing clinical trials to include sex- and gender-based analyses and more care in using sex and gender terms in the cancer literature are needed. These efforts are essential to improve the reproducibility, generalizability, and inclusiveness of cancer research.

Use of Extrapolation in New Drug Approvals by the US Food and Drug Administration

The US Food and Drug Administration (FDA)-approved indications can be factors in prescribing practices and insurance coverage, yet the frequency with which the extrapolation of clinical characteristics from pivotal trial data to the final approved indication occurs is not well understood. To evaluate the frequency of extrapolation beyond pivotal trial data into approved indications in relation to disease severity, disease subtype, and concomitant medication use. In a cross-sectional study, the characteristics of patients in pivotal trials of 105 novel drug approvals from 2015 to 2017 were identified and compared with the FDA-approved indications for the drugs. Main sources analyzed included FDA reviews, published material describing the pivotal trials, and the original drug labeling. The study was conducted from July 4, 2019, to June 1, 2021. Clinical characteristics of pivotal trials used in FDA approval. Main outcomes included the nature and frequency of extrapolation from study populations to the final indications. Extrapolation was defined as the granting of an indication for use in a broader population than was included in the pivotal trials on the basis of disease severity, disease subtype, or concomitant medication use. Among the 105 novel FDA drug approvals studied, 23 extrapolations of trial population characteristics to the approved indication were identified in 21 drugs (20%): 12 times (29%) in 2015, 3 times (15%) in 2016, and 6 times (14%) in 2017. Extrapolation of trial findings to patients with greater disease severity was most common (n = 14 drugs), followed by differences in disease subtype (n = 6) and concomitant medication use (n = 3). The findings of this study suggest that extrapolation from pivotal trial data to FDA-approved indications is common. Although extrapolations may be grounded in reasonable clinical predictions, they can limit the generalizability of such indications to specific prescribing decisions; these findings suggest a greater need for close postapproval monitoring to determine whether new safety issues arise, or effectiveness differs from expectations when these medications are used in broader real-world populations.

Tolerability of duloxetine in elderly and in non-elderly adults: a protocol of a systematic review and individual participant data meta-analysis of randomized placebo-controlled trials

BackgroundDuloxetine is an antidepressant that benefits from a wide range of approval in the elderly population, while its safety for use compared to non-elderly is not clearly assessed. This protocol outlines a systematic review and individual participant data meta-analysis comparing the tolerability of duloxetine between elderly and non-elderly.MethodsSearches will be conducted in PubMed, ClinicalTrials.gov, Clinicaltrialsregister.eu, data sharing platforms, FDA drug approval packages, European public assessment reports and withdrawn applications from the EMA website. The review will be performed on studies available in electronic databases from their date of inception to the 31 March 2022. Only randomized controlled clinical trials, comparing duloxetine to placebo, will be included in this meta-analysis. The studies will be selected if they comprise both elderly and non-elderly adults, in conditions of use of duloxetine approved by the European Medical Agency (EMA) and the Food and Drug Administration (FDA). The primary outcome will be the rate ratio of serious adverse events under duloxetine compared to placebo, between participants at least 65 years old and non-elderly. Second, the number of any adverse events, clinical efficacy and quality of life will be compared between elderly and non-elderly under both interventions. The quality of evidence in the tolerability of duloxetine will be assessed using the GRADE system. A one or two-stage individual participant data random effect meta-analysis will be conducted depending on the availability of the data.DiscussionThis meta-analysis will investigate the tolerability safety of duloxetine in the elderly population across all conditions approved by European and American regulatory authorities. The results from this meta-analysis are intended to help prescribers to provide better care for the elderly population.Systematic review registrationThe protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019130488).