Food And Drug Administration For Use Research Articles

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

First Food and Drug Administration Cleared Thin-Film Electrode for Intracranial Stimulation, Recording, and Monitoring of Brain Activity-Part 1: Biocompatibility Testing.

Subdural strip and grid invasive electroencephalography electrodes are routinely used for surgical evaluation of patients with drug-resistant epilepsy (DRE). Although these electrodes have been in the United States market for decades (first FDA clearance 1985), their fabrication, materials, and properties have hardly changed. Existing commercially available electrodes are made of silicone, are thick (>0.5 mm), and do not optimally conform to brain convolutions. New thin-film polyimide electrodes (0.08 mm) have been manufactured to address these issues. While different thin-film electrodes are available for research use, to date, only one electrode is cleared by Food and Drug Administration (FDA) for use in clinical practice. This study describes the biocompatibility tests that led to this clearance. Biocompatibility was tested using standard methods according to International Organization for Standardization (ISO) 10993. Electrodes and appropriate control materials were bent, folded, and placed in the appropriate extraction vehicles, or implanted. The extracts were used for in vitro and in vivo tests, to assess the effects of any potential extractable and leachable materials that may be toxic to the body. In vitro studies included cytotoxicity tested in L929 cell line, genotoxicity tested using mouse lymphoma assay (MLA) and Ames assay, and hemolysis tested in rabbit whole blood samples. The results indicated that the electrodes were non-cytotoxic, non-mutagenic, non-clastogenic, and non-hemolytic. In vivo studies included sensitization tested in guinea pigs, irritation tested in rabbits, acute systemic toxicity testing in mice, pyrogenicity tested in rabbits, and a prolonged 28-day subdural implant in sheep. The results indicated that the electrodes induced no sensitization and irritation, no weight loss, and no temperature increase. Histological examination of the sheep brain tissue showed no or minimal immune cell accumulation, necrosis, neovascularization, fibrosis, and astrocyte infiltration, with no differences from the control material. In summary, biocompatibility studies indicated that these new thin-film electrodes are appropriate for human use. As a result, the electrodes were cleared by the FDA for use in clinical practice [510(k) K192764], making it the first thin-film subdural electrode to progress from research to clinic. Its readiness as a commercial product ensures availability to all patients undergoing surgical evaluation for DRE.

Management of Type 1 Diabetes in Children in the Outpatient Setting.

Management of Type 1 Diabetes in Children in the Outpatient Setting.

Metformin Treatment of Pediatric Obesity.

* Abbreviations: FDA — : US Food and Drug Administration RCT — : randomized controlled trial T2DM — : type 2 diabetes mellitus Childhood obesity has steadily become a contemporary epidemic with serious public health implications.1 Approximately 70% of children with obesity will remain obese in adulthood.2 Obesity is a risk factor for development of atherosclerosis and type 2 diabetes mellitus (T2DM),3 and its prevention and management represents a priority for pediatric primary care providers. This underscores the need for evidence-based interventions for children and adolescents with obesity, including pharmacotherapy.4 Metformin is US Food and Drug Administration (FDA) approved for use in children 10 years of age and older with T2DM and has been used off label to achieve weight loss in children. In the current issue of Pediatrics , Masarwa et al5 present a systematic review of the safety and efficacy of metformin use from randomized controlled trials (RCTs) in children and adolescents. The authors demonstrated that metformin therapy resulted in modest benefits in reduction of BMI in those with obesity. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (−1.12 to 1.90). As pointed out by the authors, the results across the studies were heterogeneous, with 11 RCTs suggesting that it decreased BMI, whereas 3 RCTs revealed an increase in BMI. Among the 7 RCTs in which a BMI z score was reported, metformin consistently resulted in a decrease … Address correspondence to Vandana Raman, MD, Division of Endocrinology, Department of Pediatrics, University of Utah School of Medicine, 81 N Mario Capecchi Dr, Salt Lake City, UT 84113. E-mail: vana.raman{at}hsc.utah.edu

Practicing With Uncertainty: Kidney Transplantation During the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic required transplant nephrologists, surgeons, and care teams to make decisions about the full spectrum of transplant program operations and clinical practices in the absence of experience or data. Initially, across the country, there was a reduction in kidney transplant procedures and a striking pause in the conduct of living donation and living-donor transplant surgeries. Aspects of candidate evaluation and follow-up rapidly converted to telehealth. Months into the pandemic, much has been learned from experiences worldwide, yet many questions remain. In this Perspective, we reflect on some of the practice decisions made by the transplant community in the initial response to the pandemic and consider lessons learned, including those related to the risks, benefits, and logistical considerations of proceeding with versus delaying deceased-donor transplantation, living donation, and living-donor transplantation during the pandemic. We review the evolution of therapeutic strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their use in transplant recipients, current consensus related to immunosuppression management in infected transplant recipients, and emerging information on vaccination against SARS-CoV-2. We share our thoughts on research priorities, discuss the areas in which we are still practicing with uncertainty, and look ahead to the next phase of the pandemic response.

The case for cochlear implantation in unilateral and asymmetric sensorineural hearing loss.

Cochlear implants have been used to treat bilateral deafness for over 40 years. A more recent development has been the application of this technology toward single-sided deafness (SSD) and asymmetric hearing loss (AHL), culminating in the Food and Drug Administration (FDA) approval in the United States for this indication in July of 2019. This review examines the recent literature on cochlear implants for SSD and AHL, focusing on speech perception, sound localization, tinnitus, and quality of life. There is an expanding body of literature supporting the use of cochlear implant in SSD/AHL patients. The cochlear implant offers a unique rehabilitation option for this subset of patients as it potentially restores binaural hearing (direct stimulation of both ears). A review of the literature reveals significant improvements with the cochlear implant in speech perception in quiet and noise, sound localization, tinnitus, and quality of life. In addition, these improvements appear to be greater than what conventional options such as a contralateral routing of signal (CROS) hearing aid and bone conduction device (BCD) are able to achieve. Cochlear implants offer additional benefits over previously available options of CROS and BCDs and have recently been approved by the FDA for use in patient with SSD/AHL. Given the growing body of literature demonstrating the benefit of cochlear implant over other devices, it is important to offer cochlear implant as an option to these patients.

SMA – THERAPY: P.272 Combination therapy with nusinersen and AVXS-101 in patients with SMA Type 1

The Food and Drug Administration (FDA) have approved disease modifying therapies that are changing the management of Spinal Muscular Atrophy (SMA). Nusinersen is an antisense oligonucleotide that increases production of SMN protein by splicing SMN2 pre-mRNA. It was approved by the FDA for use in all types of SMA in December of 2016. AVXS-101 is a gene replacement strategy with AAV9 and was approved in May of 2019 for use in children younger than two years of age. We describe four patients with SMA type 1 who have been treated in our facility with Nusinersen followed by AVXS-101.

Value and affordability of CAR T-cell therapy in the United States.

In the United States the increasing number of Food and Drug Administration (FDA)-approved, innovative, and potentially effective commercial cancer therapies pose a significant financial burden on public and private payers. Chimeric antigen receptor (CAR) T cells are prototypical of this challenge. In 2017 and 2018, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite) were approved by the FDA for use after showing groundbreaking results in relapsed/refractory B-cell malignancies. In 2020 and 2021, four further submissions to the FDA are expected for CAR T-cell therapies for indolent and aggressive B-cell malignancies and plasma cell myeloma. Yet, with marketed prices of over $350,000 per infusion for the two FDA-approved therapies and similar price tags expected for the coming products, serious concerns are raised over value and affordability. In this review we summarize recent, peer-reviewed cost-effectiveness studies of tisagenlecleucel and axicabtagene ciloleucel in the United States; discuss key issues concerning the health plan budget impact of CAR T-cell therapy; and review policy, payment and scientific approaches that may improve the value and affordability of CAR T-cell therapy.

Proceedings of the Food and Drug Administration public workshop on pathogen reduction technologies for blood safety 2018 (Commentary, p. 3026).

On November 29, 2018, experts in the field of infectious diseases, pathogen reduction technologies (PRTs) and other participants from blood centers, academia, and industry gathered at the Food and Drug Administration (FDA) White Oak Campus in Silver Spring, Maryland, for a 2‐day public workshop entitled “Pathogen Reduction Technologies for Blood Safety.” The workshop opened with welcome remarks from Dr. Nicole Verdun, Director, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA, followed by introductory remarks from Dr. Peter Marks, Director, CBER, FDA. The first day of the workshop focused on blood‐borne infectious agents and their impact on blood safety, experiences of the American Red Cross, and other blood establishments in implementing FDA‐approved pathogen inactivation (PI) technology for plasma and platelets (PLTs) in the United States and novel PRTs under consideration for whole blood (WB) and red blood cells (RBCs). The second day opened with welcome remarks from Dr. Chintamani Atreya, Associate Director for Research, OBRR, CBER, FDA. The focus was on emerging innovations relevant to PRTs and potential alternatives to PRTs. The workshop concluded with remarks on insights for future research and development in this area for blood and blood product safety from infectious agents. A brief introduction of each session by the session moderator followed by a summary of the speaker presentation as submitted by the moderator and speaker are reported here.

Update on Microinvasive Glaucoma Surgery.

Update on Microinvasive Glaucoma Surgery.

The Amigo™ Remote Catheter System: From Concept to Bedside.

Radiation exposure is a serious concern during fluoroscopic procedures, including electrophysiology (EP) studies and radiofrequency catheter ablation of arrhythmias. Operators typically don lead aprons to protect themselves from radiation, but wearing lead can result in greater fatigue and orthopedic injury during long procedures. To address this problem, two robotic catheter systems (RCS) have previously been introduced on the market, the Niobe® (Stereotaxis Inc., St. Louis, MO, USA) and Sensei® X (Hansen Medical, Inc., Mountain View, CA, USA) systems. However, the widespread adoption of these systems has been limited by both cost and ease of use. In contrast, the Amigo™ RCS (Catheter Precision, Inc., Mount Olive, NJ, USA) was developed to provide a simple, lower profile, and less expensive remote catheter manipulation solution. Approved by the United States Food and Drug Administration (FDA), this technology allows for operators to remotely manipulate electrophysiology (EP) catheters from outside the fluoroscopy field. Notably, the Amigo™ RCS (Catheter Precision, Inc., Mount Olive, NJ, USA) first underwent an early study in dogs in 2008 to demonstrate its safety and efficacy in an animal model. After a clinical trial evaluating its safety and mapping capabilities in humans was completed in 2010, the Amigo™ RCS (Catheter Precision, Inc., Mount Olive, NJ, USA) underwent several scientific studies to examine its ability to assist in the mapping and ablation of various arrhythmias in comparison with the conventional manual approach. The Amigo™ RCS (Catheter Precision, Inc., Mount Olive, NJ, USA) achieved mapping and ablation success rates that were similar to those achieved with manual catheter manipulation, and no complications due to its use were observed. It was approved by the FDA for use in diagnostic EP studies of the right atrium and ventricle in 2012, with this indication later expanded in 2014 to include radiofrequency ablations. The device is currently compatible with the Blazer™ (Boston Scientific, Natick, MA, USA) and EZ STEER™ (Biosense Webster, Inc., Diamond Bar, CA, USA) catheter handles. Here, we present a clinical report in which the Amigo™ RCS (Catheter Precision, Inc., Mount Olive, NJ, USA) was employed to map and ablate symptomatic supraventricular tachycardia. Dr. Cohen’s clinical experience with this robotic system is also reviewed.

PCSK9 inhibition: A promise fulfilled?

The association of reduced proprotein convertase subtilisin/kexin type 9 (PCSK9) activity with reduced cardiovascular disease (CVD) events--and the need for add-ons to statin therapy to achieve treatment goals--has led to the rapid development and US Food and Drug Administration (FDA) approval of monoclonal antibody therapies to inhibit PCSK9. Now that PCSK9 inhibitors are approved by the FDA for use in certain patients, data from ongoing long-term clinical trials addressing tolerability, safety, and proof of additional reduction in CVD events are eagerly awaited.

Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.

Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

Pediatric severe obesity: time to establish serious treatments for a serious disease.

Pediatric severe obesity: time to establish serious treatments for a serious disease.

Chlamydia Infections in Children and Adolescents

1. Lorena M. Siqueira, MD, MSPH* 1. *Division of Adolescent Medicine, Miami Children’s Hospital, Miami, FL. * Abbreviations: CDC: : Centers for Disease Control and Prevention FDA: : Food and Drug Administration HIV: : human immunodeficiency virus LGV: : lymphogranuloma venereum MIF: : microimmunofluorescent MSM: : men who have sex with men NAAT: : nucleic acid amplification tests PID: : pelvic inflammatory disease STI: : sexually transmitted infection 1. The need for annual screening for chlamydia in sexually active adolescents and young adults is underrecognized because this infection is asymptomatic in most females (75%) and males (50%). 2. Difficulty in diagnosis arises from the range of possible symptoms at presentation of symptomatic infections and the type of testing that can be used in each situation. After completing this article the reader should be able to: 1. Recognize the spectrum of clinical manifestations of chlamydia infection in neonates, children, and adolescents. 2. Discuss the appropriate use of culture and nonculture diagnostic tests for chlamydia infections in various age groups. 3. List the current recommendations for screening and treatment of chlamydia infections. A 17-year-old girl presents with prolonged menstrual bleeding associated with severe menstrual cramping pain. Her menarche was at age 13 years. Subsequent menstrual cycles were monthly, lasting 5 days, with average flow associated with mild to moderate pain relieved by over-the-counter pain medications. The current cycle began a month ago and is associated with severe lower abdominal pain. She admits to sexual activity with one partner and uses condoms intermittently. On examination she is afebrile and in discomfort, with a heart rate of 120 beats per minute. She does not appear anemic and has good capillary refill. She has diffuse abdominal pain with significant tenderness in both the right lower and upper quadrants. Chlamydiae are small obligate, gram-negative, intracellular bacteria that contain both DNA and RNA and were formerly considered to be viruses. There are 3 species that are pathogenic to humans: Chlamydia trachomatis , Chlamydophilia pneumoniae, and Chlamydophilia psittaci . They fall within 2 genera in the family Chlamydiaceae . C trachomatis is in …

Improving sleep for patients with restless legs syndrome. Part II: meta-analysis of vibration therapy and drugs approved by the FDA for treatment of restless legs syndrome

Improving sleep for patients with restless legs syndrome. Part II: meta-analysis of vibration therapy and drugs approved by the FDA for treatment of restless legs syndrome Fred Burbank,1 Mark J Buchfuhrer,2 Branko Kopjar3 1Salt Creek International Women's Health Foundation, San Clemente, CA, 2Stanford University Center for Sleep Sciences, Downey, CA, 3Department of Health Services, University of Washington, Seattle, WA, USA Background: Vibratory stimulation pads have been shown to improve sleep in patients with restless legs syndrome (RLS) to a greater extent than sham therapy. The current gold standard of treatment is drugs approved by the US Food and Drug Administration (FDA) for use in RLS. The aim of this meta-analysis was to compare the efficacy and safety of vibratory stimulation pads, sham pads, and drugs approved by the FDA for use in RLS. Methods: We searched the PubMed, Embase, and clinical trial websites to identify the relevant randomized, double-blind, and placebo-controlled or sham-controlled studies. Fifteen studies including a combined total of 3455 patients with at least moderately severe primary RLS met our search criteria. Efficacy was defined as the standardized mean difference in sleep improvement between treatment and controls. Safety was assessed by comparing the odds ratios of any adverse events and adverse events leading to study withdrawal between treatment and control subjects. Results: Improvement in Medical Outcomes Study (MOS) sleep inventory scores from baseline was significantly greater in patients treated with vibratory stimulation pads than in those receiving sham pads (Hedges's g, standardized mean difference −0.39, P ≤ 0.02). There was no difference in improvement in sleep scores between patients treated with vibratory stimulation pads (−0.39) and those receiving an approved RLS drug (−0.44, P > 0.70). The risk of any adverse event or withdrawal because of an adverse event was not significantly different between patients treated with vibratory stimulation pads and those assigned to sham pads (Mantel-Haenszel odds ratio 2.16 [P > 0.14] and 1.39 [P > 0.80], respectively). The odds ratios for patients reporting any adverse events and adverse events leading to withdrawal were not significantly different between patients treated with vibratory stimulation pads (2.16 and 1.39, respectively) and those who received approved RLS drugs (2.11 [P > 0.89] and 2.07 [P > 0.82], respectively, mixed-effects model). Conclusion: For patients with moderately severe RLS, vibratory stimulation pads were more effective than sham pads for improving sleep, as effective as FDA-approved RLS drugs, and as safe as both sham pads and FDA-approved RLS drugs. Keywords: meta-analysis, restless legs syndrome, sleep, vibration, counterstimulation, drug therapy

Management of advanced colorectal cancer, part 2

Important developments in chemotherapy for advanced colorectal cancer over the past 15 years are reviewed, with an emphasis on the most recently published data from clinical trials of newer multidrug regimens, administration techniques, and dosing schedules. Eight agents are approved by the Food and Drug Administration (FDA) for use in treating patients with advanced colorectal cancer. Fluorouracil and leucovorin still constitute the foundation of most chemotherapy regimens for this population; combination fluorouracil-leucovorin therapy plus either irinotecan (the FOLFIRI regimen) or oxaliplatin (the FOLFOX regimen) are two firmly established first-line treatments shown to produce similar outcomes. In Phase III trials conducted over the past six to seven years, regimens of capecitabine plus oxaliplatin (CapeOx) were demonstrated to have clinical effectiveness comparable to that of FOLFOX therapy. Response rates of 35-55% and median overall survival of ≥20 months have been documented with some of the newer regimens. Research to define the optimal role of the three monoclonal antibody agents approved by FDA for use in managing advanced colorectal cancer is ongoing; bevacizumab has been shown to confer significant survival benefits when added to certain chemotherapy regimens, and other monoclonal antibodies (cetuximab and panitumumab) also appear to offer significant benefits in select patients as first- or second-line therapies. Over the past 15 years, a shift toward multiagent treatment strategies including a variety of chemotherapy agents and monoclonal antibodies has yielded improved rates of response and prolonged survival among patients with advanced colorectal cancer. The CapeOx, FOLFOX, and FOLFIRI regimens are currently among the most widely used first-line treatments.

Management of advanced colorectal cancer, part 1

Important developments in chemotherapy for advanced colorectal cancer over the past 15 years are reviewed, with an emphasis on the most recently published data from clinical trials of newer multidrug regimens, administration techniques, and dosing schedules. Eight agents are approved by the Food and Drug Administration (FDA) for use in treating patients with advanced colorectal cancer. Fluorouracil and leucovorin still constitute the foundation of most chemotherapy regimens for this population; combination fluorouracil-leucovorin therapy plus either irinotecan (the FOLFIRI regimen) or oxaliplatin (the FOLFOX regimen) are two firmly established first-line treatments shown to produce similar outcomes. In Phase III trials conducted over the past six to seven years, regimens of capecitabine plus oxaliplatin (CapeOx) were demonstrated to have clinical effectiveness comparable to that of FOLFOX therapy. Response rates of 35-55% and median overall survival of ≥20 months have been documented with some of the newer regimens. Research to define the optimal role of the three monoclonal antibody agents approved by FDA for use in managing advanced colorectal cancer is ongoing; bevacizumab has been shown to confer significant survival benefits when added to certain chemotherapy regimens, and other monoclonal antibodies (cetuximab and panitumumab) also appear to offer significant benefits in select patients as first- or second-line therapies. Over the past 15 years, a shift toward multiagent treatment strategies including a variety of chemotherapy agents and monoclonal antibodies has yielded improved rates of response and prolonged survival among patients with advanced colorectal cancer. The CapeOx, FOLFOX, and FOLFIRI regimens are currently among the most widely used first-line treatments.

‘FREEDOM’ trial: Have the interventional cardiologists lost their freedom?

‘FREEDOM’ trial: Have the interventional cardiologists lost their freedom?