Food And Drug Administration Research Articles

An Analysis of the Complication Reports of Expandable Lumbar Interbody Cages in the Food and Drug Administration Manufacturer and User Facility Device Experience Database.

Expandable lumbar interbody cages (ELICs) are commonly used for interbody fusion and provide lordotic correction by lengthening the anterior column of the vertebral spine. We sought to identify unique failure mechanisms and significant differences in the types of complications associated with ELICs as reported to the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) Database. The MAUDE Database was analyzed for complication reports submitted for ELIC systems between January 2013 and July 2023. Reports were categorized by manufacturer, brand name, type of expandable cage, type of complication, year of complication, and reporter identity. Reports that were duplicated or had insufficient information were excluded from analysis. The top 5 manufacturers with the most implant-related complications were independently analyzed and compared. A total of 821 reports were analyzed. The top 5 complications reported across all manufacturers were cage breakage during insertion (25.7%), postoperative migration without collapse (16.0%), postoperative collapse (15.6%), inserter breakage (11.1%), and tubing problems (3.0%). A significant difference was detected in complication type between manufacturers (χ2=557, P<.001). The largest number of reports (120, 14.6%) was in 2016. With FDA approval of novel ELIC systems and the adoption of newer surgical techniques, understanding the range of potential complications is paramount in ensuring patient safety. This study of the MAUDE Database provides a comprehensive summary of adverse reported events associated with ELICs during the past decade. [Orthopedics. 202x;4x(x):xx-xx.].

Benchmarking the medication efficiency and technological progress of diabetes drugs

BackgroundDiabetes poses a serious global challenge, given its increasing prevalence, detrimental effects on public health, and substantial economic burden. Since 1950s, tens of drugs have been approved by the United States (US) Food and Drug Administration (FDA). In the past decade, the medical community and regulatory agencies have moved away from the glucose-centric paradigm and increasingly call for a holistic approach to assess different treatments’ benefits and harms.ObjectiveThis study aimed to assess the medication efficiency and technological progress of Type 2 Diabetes (T2D) drugs, by considering their physiological outcomes, including both benefits (i.e., glucose lowering and weight loss) and adverse effects (mortality), relative to dosing frequency.MethodsTo derive medication efficiency, this study utilized data from the US FDA and prominent meta-analyses. Given that both the benefits and adverse effects of medications are multidimensional, this study employed a nonparametric frontier method, the data envelopment analysis (DEA) model, to integrate these factors into a measure of medication efficiency. Physiological outcomes could assume both positive and negative values. Adverse effects were regarded undesirable outputs. The DEA model was built under the framework of directional distance function and was able to handle negative and undesirable values which naturally arose in the case of T2D medications.ResultsThe paper presented a ranking of 20 T2D drugs in terms of medication efficiency. Three of them were able to attain the highest medication efficiency, all of which were in the GLP-1 class, including oral Semaglutide, subcutaneous Semaglutide and Dulaglutide. However, the other two GLP-1 drugs, Lixisenatide and Liraglutide, were less efficient. The average medication efficiency of drugs approved post-2010 was significantly higher than pre-2010 drugs. High dose frequency, low HbA1c reduction and insignificant weight loss were the main driving factors behind inefficiencies. Overall, medication efficiency provided an alternative perspective on treatment effectiveness other than conventional measures such as cost-effectiveness.

Caffeine: A Multifunctional Efficacious Molecule with Diverse Health Implications and Emerging Delivery Systems

Natural caffeine is found in many plants, including coffee beans, cacao beans, and tea leaves. Around the world, many beverages, including coffee, tea, energy drinks, and some soft drinks, have this natural caffeine compound. This paper reviewed the results of meta-studies on caffeine’s effects on chronic diseases. Of importance, many meta-studies have shown that regularly drinking caffeine or caffeinated coffee significantly reduces the risk of developing Alzheimer’s disease, epilepsy, and Parkinson’s disease. Based on the health supplements of caffeine, this review summarizes various aspects related to the application of caffeine, including its pharmacokinetics, and various functional health benefits of caffeine, such as its effects on the central nervous system. The importance of caffeine and its use in alleviating or treating cancer, diabetes, eye diseases, autoimmune diseases, and cardiovascular diseases is also discussed. Overall, consuming caffeine daily in drinks containing antioxidant and neuroprotective properties, such as coffee, prevents progressive neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Furthermore, to effectively deliver caffeine to the body, recently developed nanoformulations using caffeine, for instance, nanoparticles, liposomes, etc., are summarized along with regulatory and safety considerations for caffeine. The U.S. Department of Agriculture (USDA) and the Food and Drug Administration (FDA) recommended that healthy adults consume up to 400 mg of caffeine per day or 5~6 mg/kg body weight. Since a cup of coffee contains, on average, 100 to 150 mg of coffee, 1 to 3 cups of coffee may help prevent chronic diseases. Furthermore, this review summarizes various interesting and important areas of research on caffeine and its applications related to human health.

Safety of the contrast enhancement agent sulfur hexafluoride in ultrasound: Analysis of the Federal Drug Administration Adverse Event Reporting System database

ABSTRACT Background and Objectives Sulfur hexafluoride is an inert gas that creates microbubbles to enhance diagnostic accuracy in a variety of ultrasound (US) studies and is widely used in EUS. We analyzed the reported adverse events (AEs) of the US contrast agent, sulfur hexafluoride, extensively used during EUS procedures using a US national database. Methods From December 2008 to January 2024, AEs reported in the Federal Drug Administration Adverse Event Reporting System database for sulfur hexafluoride were examined. Results There were 1069 individual reports analyzed. Reports were excluded if they contained drugs other than sulfur hexafluoride. Echocardiogram (70.9%) was the common diagnostic study in which sulfur hexafluoride was administered. The most common AE reported was anaphylactic reaction (n = 179, 16.7%), followed by hypotension (n = 162, 15.2%), cardiac arrest (n = 161, 15.1%), and dyspnea (n = 159, 14.9%). The most common gastrointestinal AE was nausea (n = 135, 12.6%). Severity of AEs ranged from nonserious to death. Death associated with sulfur hexafluoride use was reported in 58 patients (5.4% of AE reports). Conclusions Anaphylactic reaction was the most common AE reported with sulfur hexafluoride use, and severe AEs including death may be more common than prior large, retrospective, observational studies to date have suggested.

Anticancer Effects of New Disulfiram Analogs.

Disulfiram (DSF), an irreversible aldehyde dehydrogenase 2 (ALDH2) inhibitor, is an U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism. Recent studies have reported an interesting antitumor activity of DSF against a wide range of human malignancies, while a growing number of ongoing and completed clinical trials have provided evidence supporting the repurposing of DSF as an anticancer treatment. Nevertheless, despite its current clinical indications and potential future therapeutic applications for treating various diseases, DSF is associated with serious side effects attributed to the inhibition of ALDH2. We have recently synthesized DSF analogs (2a-v) with limited inhibition of ALDH2. Here, we report the anticancer activity of these molecules by highlighting their effects on cell signaling in Jurkat cells. DSF and two DSF analogs, 2g and 2r, all stimulated apoptotic signaling pathways, although the 2g analog activated more apoptosis-related genes and induced higher levels of apoptosis in vitro. Differential gene expression data suggested that compounds 2g and 2r specifically reprogram target cells to downregulate pathways related to cell growth and division, while upregulating pathways related to apoptosis or differentiation. Interestingly, both compounds 2g and 2r had more differentially expressed genes related to DNA damage pathways (including those related to apoptosis) when compared to DSF, which may offer insights into their mechanisms of action.

Drug risks associated with sarcopenia: a real-world and GWAS study

IntroductionDrug-induced sarcopenia has not received adequate attention. Meanwhile, there is growing recognition of the importance of effective pharmacovigilance in evaluating the benefits and risks of medications.AimsThe primary aim of this study is to investigate the potential association between drug use and sarcopenia through an analysis of adverse event reports from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and to evaluate the genetic factors contributing to drug-induced sarcopenia using summary-data-based Mendelian randomization (SMR).MethodsWe obtained reports of adverse drug reactions from FAERS. Primary outcomes included sarcopenia and potential sarcopenia. We calculated the Proportional reporting ratio (PRR) to assess the risk of specific adverse events associated with various drugs, applying chi-square tests for statistical significance. Additionally, we used SMR based on Genome-wide association study (GWAS) to evaluate the potential associations between drug target genes of some significant medications and sarcopenia outcomes. The outcome data for sarcopenia included metrics as hand grip strength and appendicular lean mass (ALM).ResultsA total of 55 drugs were identified as inducing potential sarcopenia, and 3 drugs were identified as inducing sarcopenia. The top 5 drugs causing a potential risk of sarcopenia were levofloxacin (PRR = 9.96, χ2 = 1057), pregabalin (PRR = 7.20, χ2 = 1023), atorvastatin (PRR = 4.68, χ2 = 903), duloxetine (PRR = 4.76, χ2 = 527) and venlafaxine (PRR = 5.56, χ2 = 504), and the 3 drugs that had been proved to induced sarcopenia included metformin (PRR = 7.41, χ2 = 58), aspirin (PRR = 5.93, χ2 = 35), and acetaminophen (PRR = 4.73, χ2 = 25). We identified electron-transfer flavoprotein dehydrogenase (ETFDH) and protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (PRKAB1) as the primary drug target genes for metformin, while Prostaglandin-endoperoxide Synthase 1 (PTGS1) and Prostaglandin-endoperoxide Synthase 2 (PTGS2) were considered the primary action target genes for aspirin and acetaminophen according to DrugBank database. SMR showed that the expression abundance of ETFDH was negatively correlated with right hand grip strength (blood: OR = 1.01, p-value = 1.27e-02; muscle: OR = 1.01, p-value = 1.42e-02) and negatively correlated with appendicular lean mass (blood: OR = 1.03, p-value = 7.73e-08; muscle: OR = 1.03, p-value = 1.67e-07).ConclusionsWe find that metformin, aspirin, and acetaminophen are specifically noted for their potential to induce sarcopenia based on the analyses conducted. We perform signal mining for drug-associated sarcopenia events based on real-world data and provides certain guidance for the safe use of medications to prevent sarcopenia.

A real-world study of adverse drug reactions of two isocitrate dehydrogenase inhibitor based on the US FDA adverse event reporting system and VigiAccess databases

A real-world study of adverse drug reactions of two isocitrate dehydrogenase inhibitor based on the US FDA adverse event reporting system and VigiAccess databases

How improvements in US FDA regulatory process and procedures led to the drug approval for first ever treatment of a common liver disease.

Metabolic-associated liver disease is a growing public health crisis, with phenotypes from fatty liver to steatohepatitis, previously known as NASH (Non-Alcoholic SteatoHepatitis) and currently rebranded as MASH (Metabolic dysfunction-Associated SteatoHepatitis). Dysfunction in liver metabolism can progress to liver fibrosis, end stage cirrhosis and death. MASH (NASH) is associated with an increased risk of cardiovascular disease, elevation in serum lipids and Type 2 Diabetes Mellitus. There is now a US-approved drug to treat patients with NASH (MASH) under the FDA Accelerated Approval Pathway, which requires follow-up outcome studies to confirm clinical benefit or risk drug withdrawal by the agency. Despite extra-hepatic factors that contribute to MASH and complicate clinical trial design, reorganization of the FDA drug premarket review divisions, improvements to agency policies and procedures, as well as updates to the US Food, Drug & Cosmetic Act (FD&C Act) upon which FDA regulation is based, have provided new agency tools that facilitated such a drug approval to address the profound unmet medical need for patients with this metabolic-based liver disease. There is reason for hope that continued evolution of the regulatory process will lead to additional drug approvals, as well as the ability for clinical trial endpoints studying MASH treatments to include both liver-based and traditional metabolic measures, independent of the specific FDA review division. This initial NASH/MASH FDA approval has also opened the door for initiation of Combination Clinical Trials, where the approved drug is paired with an experimental drug with a different mechanism of action, to increase overall efficacy and potentially minimize risks. It is envisioned that future treatment of NASH/MASH will mirror what is currently observed with Type 2 Diabetes Mellitus practice patterns, where multiple drugs with different mechanisms of actions are used to optimize treatment benefit/risk in the selected patient populations.

Conflicting interpretations and FDA reputation: the case of post-market surveillance of breast implants

Conflicting interpretations regarding the severity of the adverse effects associated with FDA-approved drugs and therapies are common among the United States Food and Drug Administration (FDA), the medical community, patients, and the general public. However, scholars have paid little attention to how these conflicting interpretations may affect the FDA’s reputation for facilitating inclusive dialogue between competing policy actors. Focusing on breast implants, a medical device characterized by a stormy regulatory past, we observe that the design properties of post-market surveillance are adjusted to low-quality information. Such information-gathering mechanisms likely lead to underreporting by medical practitioners and patients, thus resulting in low-quality data. Given that the FDA cannot rely on congressional appropriations to ensure a stable flow of funding, the confusion and uncertainty created by conflicting interpretations enhance the FDA’s ability to appeal to different audiences simultaneously and thereby secure funding from industry-based user fees. This strategy may persist until the FDA’s reputation is challenged by critical information regarding adverse effects and the ensuing potentially negative media coverage. A stable appropriation-based funding model will likely encourage stronger post-market surveillance of medical devices.

Shifting the paradigm of type 1 diabetes: a narrative review of disease modifying therapies

A new diagnosis of type 1 diabetes (T1D) may be accompanied by numerous lifelong financial, emotional, and physical challenges, thus advancements in therapies that can delay the onset of clinical disease are crucial. T1D is an autoimmune condition involving destruction of pancreatic beta cells leading to insulin deficiency, hyperglycemia, and long-term insulin dependence. The pathogenesis of T1D is classified into stages, with the first signal being the detection of autoantibodies without any glycemic changes. In the second stage, dysglycemia develops without symptoms, and in stage 3, symptoms of hyperglycemia become apparent, and at this time a clinical diagnosis of T1D is made. As a greater understanding of these stages of T1D have evolved, research efforts have been devoted to delaying the onset of clinical disease. To date, only one medication, teplizumab, has been approved by the Food and Drug Administration (FDA) for the treatment of stage 2 T1D. This narrative review present published trials and ongoing research on disease modifying therapies (DMT) in T1D, the mechanisms of action for each therapy, and the stages of T1D that these interventions are being studied.

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease.

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies.

Analysis of tirzepatide in the US FDA adverse event reporting system (FAERS): a focus on overall patient population and sex-specific subgroups

ObjectiveTirzepatide, a novel GIP and GLP1 agonist, has been extensively examined in clinical trials. However, specific data on its adverse drug events (ADEs) remain limited. This study aims to comprehensively assess real-world ADEs associated with tirzepatide by mining data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.MethodsADE reports from the FAERS database were retrieved for the second quarter of 2022 through the first quarter of 2024. Significant associations between ADEs and tirzepatide were evaluated using proportional disproportionality analyses, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS).ResultsA total of 37,827 ADE reports associated with tirzepatide were identified, with 100 significantly disproportionate preferred terms (PTs) recognized by all four algorithms. The top five PTs with the highest reporting rates were incorrect dose administered, injection site pain, off-label use, nausea, and injection site hemorrhage. Additionally, unexpected signals such as starvation ketoacidosis were identified. The median time to onset for all ADEs was 23 days. Furthermore, sex-specific high-intensity signals were found, with males primarily experiencing gastrointestinal disorders and females experiencing general disorders and administration site conditions.ConclusionThis study provides valuable insights into the occurrence of ADEs following tirzepatide administration, potentially supporting clinical monitoring and risk identification efforts.

Update on Mpox Management: Epidemiology, Vaccines and Therapeutics, and Regulatory Changes.

Mpox, caused by the monkeypox virus (MPXV), is categorized into two primary clades: Clade I and Clade II, with notable outbreaks linked to Clade IIb. Historically endemic in Africa, recent years have seen significant global spread. The World Health Organization (WHO) declared mpox a Public Health Emergency of International Concern in August 2024, highlighting the emergence of Clade Ib outside Africa and the broadening demographic impact of the outbreak. This review updates the current status of mpox vaccines and treatments, including their safety and effectiveness. There are two US Food and Drug Administration (FDA)-approved vaccines for the prevention of mpox disease, JynneosTM and ACAM2000®. The JynneosTM vaccine, recommended for high-risk individuals, has seen limited uptake despite its efficacy in preventing disease. Tecovirimat, while FDA-approved for smallpox and available in the European Union for mpox, has shown mixed results in recent trials, with new data suggesting limited effectiveness in Clade I infections and emergence of new mutations with resistance to this drug. Brincidofovir and Vaccinia Immune Globulin Intravenous offer additional treatment options, particularly for severe cases, although their use is constrained by regulatory and logistical challenges. Furthermore, the WHO recently approved the first commercial molecular assay, the Alinity m MPXV assay by Abbott Molecular Inc., for emergency use-an essential step in expanding testing capacity in regions experiencing mpox outbreaks. These updates underscore the critical need for continued research to enhance therapeutic outcomes and adapt public health strategies. Ensuring equitable access to vaccines, treatments, and diagnostics remains a significant challenge as the global community responds to the evolving mpox situation.

Patient-Derived Organoids on a Microarray for Drug Resistance Study in Breast Cancer.

Drug resistance is always a challenge in cancer treatment, whether for chemotherapy, targeting, or immunotherapy. Although tumor cell lines are derived from cancer patients, they gradually lost the original characteristics, including heterogeneity and tumor microenvironment (TME), during the long period of in vitro culturing. Therefore, it is urgent to use patient-derived tumor models instead of cancer cell lines to study tumor drug resistance. Herein, we developed a microarray device that serves as a platform for high-throughput and three-dimensional culture of breast cancer patient-derived organoids (BCOs) and investigated their resistance to adriamycin (ADM). Coupled with fluorescence microscopy, this system enabled on-chip drug response monitoring and cell viability assessment without the consumption of a large number of tumor cells. The organoids were divided into a resistant BCO group (RBCO) and a sensitive BCO group (SBCO) according to their half-inhibitory concentration (IC50). Different from cancer cell lines, BCOs demonstrated obvious heterogeneity in drug treatment. Ivermectin (IVM), a broad-spectrum antiparasitic agent approved by the Food and Drug Administration (FDA), was observed to synergistically augment ADM-induced cytotoxicity in organoids. The BCO chip provides a promising platform for investigation of drug resistance and preclinical drug screening based on clinical samples.

An update on the pharmacotherapy of postpartum depression.

Extensive research has been conducted on postpartum depression (PPD) over the past century, and yet no definitive answer regarding its etiopathogenesis, risk factors, genetic predilection, and treatment has been found. The few preclinical and clinical studies propose that maternal brain adaptations to the endocrinological, immunological, and behavioral changes and external sociodemographic risk factors in the perinatal period make women more vulnerable to anxiety and depression. Irrespective of the cause, a dilemma exists regarding the type of help to provide postpartum mothers. With very few treatment options at our disposal, deciding between psychotherapy, pharmacological, and non-pharmacological therapy on a case-by-case basis is unproductive because in developing countries infrastructure is limited and the availability of medications, especially for psychiatric illnesses, is still evolving. Hence, regardless of psychotherapy, antidepressants remain the first line of treatment with selective serotonin reuptake inhibitors (SSRIs); sertraline has the best efficacy and safety profile in breastfeeding women. As endocrine factors play a significant role in etiopathogenesis, hormonal therapy with oxytocin has been shown to be efficacious, and studies investigating the role of testosterone in treating PPD are also under way. In 2019, the US Food and Drug Administration (FDA) approved the first and only drug for the sole purpose of treating PPD, brexanolone. Zuranolone, a drug recently approved by the FDA, has a similar mechanism of action to brexanolone. For breastfeeding mothers reluctant to use pharmacotherapy, somatic therapy has been studied, including bright light therapy, vagal nerve stimulation, and newer noninvasive interventions. This article encompasses a short note on PPD, including its etiopathogenesis and clinical characteristics, and recapitulates the various available and evolving pharmacological and nonpharmacological therapies.

FDA recalls thousands of bottles of antidepressants over toxic chemical

In late October, the Food and Drug Administration (FDA) recalled more than 7,000 bottles of the popular antidepressant duloxetine, sold under the brand name Cymbalta, Consumer Affairs reported on Oct. 24. The agency found that the affected bottles of the drug, which is used to treat depression, anxiety and mood disorders, contained toxic levels of the chemical nitrosamine. While the FDA says that the chemical isn't likely to cause harm in low levels and that consumers can handle low levels of the chemical for 70 years without health risks, it can increase the risk of cancer and become toxic to humans when ingested at higher‐than‐acceptable levels over an extended period of time. “FDA, in collaboration with regulatory counterparts around the world, has set internationally recognized acceptable daily intake limits for nitrosamines,” the agency said. “If drugs contain levels of nitrosamines above the acceptable daily intake limits, FDA recommends these drugs be recalled by the manufacturer as appropriate.” Currently, this recall is classified as a Class II recall, which the FDA defines as “a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.” Towa Pharmaceutical Europe manufactured the contaminated pills, which were distributed across the United States. In total, there are 7,107 bottles of duloxetine that have higher‐than‐normal levels of nitrosamines. The affected medications are 20 mg pills that come in bottles of 500 pills and have an expiration date of December 2024 with a lot number of 220128.

The Food and Drug Administration’s Safety Surveillance of Adverse Event Cases Involving Cannabinoid Hemp Products, 2019–2023

Objective. To characterize adverse event (AE) cases received by the US Food and Drug Administration (FDA) reportedly involving cannabinoid hemp products (CHPs). Methods. We searched the FDA Adverse Event Reporting System and Center for Food Safety and Applied Nutrition Adverse Event Reporting System for cases reported directly to the FDA from 2019–2023 involving CHPs, which are defined as products containing 1 or more of the following: cannabidiol, delta-8 tetrahydrocannabinol, and emerging cannabinoids (i.e., other intoxicating cannabinoids often synthesized from hemp-derived cannabidiol). We abstracted and summarized information on reporting trends, consumer demographics, reporter information, product information, and AEs. Results. We identified 610 AE cases reportedly involving CHPs containing 1 or more of the following: delta-8 tetrahydrocannabinol (n=355), cannabidiol (n=253), and emerging cannabinoids (n=36). Multiple trends and safety issues were identified, including an annual increase in the number of cases involving intoxicating cannabinoids since 2021, potential quality issues, and the occurrence of fatalities and pediatric exposures. Conclusions. Our findings emphasize the importance of monitoring AE cases received by the FDA involving CHPs as part of a comprehensive surveillance strategy to identify trends and safety issues with these products. ( Am J Public Health. 2024;114(S8):S664–S672. https://doi.org/10.2105/AJPH.2024.307712 )

Medical Devices Applying for Outpatient Medicare Supplemental Payments.

Medicare transitional pass-through payments (TPTPs) provide supplemental reimbursement that is intended to facilitate adoption of new devices in the outpatient setting. The US Centers for Medicare & Medicaid Services (CMS) have historically evaluated manufacturer applications for TPTPs based on newness, cost, and evidence of substantial clinical improvement, ie, the traditional pathway. In 2020, CMS introduced an alternative pathway to allow US Food and Drug Administration (FDA)-designated breakthrough devices to qualify for supplemental reimbursement without demonstrating substantial clinical improvement. To characterize CMS TPTP approval rates and the premarket evidence used by FDA to support authorization of new outpatient medical devices considered for CMS TPTP. This was a cross-sectional study of TPTP applications for new outpatient medical devices from 2017 to 2023. Using the Federal Register, CMS Outpatient Prospective Payment System final rules for fiscal years 2017 through 2023 were obtained, from which all manufacturer applications for TPTPs were identified. For each application, the CMS TPTP review pathway (traditional/alternative), CMS final decision (award/deny), and FDA authorization pathway were assessed. Characteristics of devices considered for CMS TPTPs and design, effectiveness end points, and patient demographic characteristics of premarket clinical studies used to support FDA authorization. CMS approved 17 of 43 (40%) applications for TPTPs, including all 8 (100%) alternative pathway applications for breakthrough devices and 9 of 35 applications (26%) using the traditional pathway. Devices approved for TPTPs were more likely to have been assessed in premarket clinical studies than devices denied TPTPs (12/17 [71%] vs 2/26 [8%]). Among the 14 premarket studies of TPTP-approved devices, 8 (57%) used surrogate markers as primary effectiveness end points and 5 (42%) did not meet all primary end points. The median (IQR) percentage of female, Black, and Hispanic patients among the trials that reported demographic data was 26% (17%-36%), 6% (2%-17%), and 4% (3%-5%), respectively. The findings of this cross-sectional analysis indicated that CMS more commonly awarded supplemental outpatient payment through TPTPs for devices assessed in premarket clinical studies to support FDA authorization. However, these studies often lacked generalizability to Medicare beneficiaries, used surrogate markers of effectiveness, or did not meet all primary end points. As more breakthrough devices receive FDA authorization and effectively qualify for automatic supplemental payments, strengthening premarket clinical evidence requirements for CMS TPTP approvals would provide better information to guide clinical decision-making and ensure that supplemental reimbursement enhances care for Medicare beneficiaries.

Small-Molecule Drugs Offer Comparable Health Benefits To Biologics At Lower Costs.

The Inflation Reduction Act of 2022 requires that Medicare negotiate a Maximum Fair Price for selected small-molecule drugs nine years after their Food and Drug Administration (FDA) approval and thirteen years postapproval for selected biologics. The discrepancy between these time frames raises questions about the relative value of small-molecule drugs versus biologics. We compared the incremental quality-adjusted life-year (QALY) gains, incremental costs, and incremental cost-effectiveness ratios (ICERs) of small-molecule drugs and biologics approved by the FDA during the period 1999-2018. We used the Mann-Whitney U test (to compare medians) and Kolmogorov-Smirnov test (to compare the distributions). We found that small-molecule drugs and biologics offer similar magnitudes of incremental QALY gains (0.08 versus 0.10). Small-molecule drugs tend to be associated with lower additional costs ($4,738 versus $16,020) and more favorable cost-effectiveness ($108,314 per QALY versus $228,286 per QALY). Creating parity regarding time to Medicare price negotiation may be appropriate.

Administrative Aspects of Molecular Diagnostics-Oversight, Regulatory Approval Process, Clinical and Operational Workflows, and Payment Models.

This paper discusses the administrative aspects of molecular diagnostics in oncology, including US Food and Drug Administration (FDA) oversight, the regulatory approval process, clinical, and operational workflows, and payment models. Comprehensive molecular testing is important to deliver optimal oncology care and improve patient outcomes. Despite the potential benefits of testing, utilization remains low. The FDA regulatory approval process is reviewed for in vitro diagnostic products, which includes classification into three regulatory classes on the basis of risk. Companion diagnostic devices are used to guide treatment decisions. The clinical and operational challenges associated with molecular testing in oncology are also discussed, including the rapidly evolving landscape of precision oncology, the wide range of biomarker testing options, and complexities of test ordering, interpretation, and result delivery. There is a need for a multifaceted support approach involving education, technology enhancements, and workflow support to overcome these challenges. In terms of payment models, coverage policies between Medicare and commercial payers are compared with differences in coverage criteria, with Medicare focusing on FDA approval or clearance, whereas commercial payers consider additional factors such as National Comprehensive Cancer Network and ASCO guidelines. Commercial payers tend to cover smaller panels on the basis of guideline-recommended biomarkers, whereas coverage for broad tumor profiling is limited. Several strategies can increase the utilization of molecular testing, including integrating test results into electronic medical record platforms, standardizing billing practices, increasing clinical trials, and primary literature supporting the use of molecular testing, educating physicians, and using tumor boards for result interpretation and treatment discussions.