United States Federal Drug Administration Research Articles

Can capillary microsampling facilitate a clinical pharmacokinetics study of cefazolin in critically ill children?

Aim: Pharmacokinetic studies in children are limited, in part due to challenges in blood sampling. We compare the use of capillary microsampling and conventional sampling techniques in pediatric patients to show results that can be used in the pharmacokinetic analysis of Cefazolin.Patients & Methods: Paired blood samples (n=48) were collected from 12 patients (median age/weight 49months/18kg).Results: The United States Federal Drug Administration incurred sample reanalysis acceptance criteria was used and identified 79% of paired samples achieved a difference of less than 20% in magnitude with a capillary microsampling bias of -10% (SD 20%). With exclusion of PK outliers, this rose to 88%.Conclusion: Capillary microsampling is reliable, meets acceptance criteria and can be used in pharmacokinetic studies.ACTRN: 12618001469202.

A scoping review of heart failure transitional care quality indicators and outcomes for use in clinical care and research.

There are no accepted quality indicators for transitional care following hospitalization for heart failure (HF). Current quality measures focus on 30-day readmissions without accounting for competing risks such as death. In this scoping review of clinical trials, we aimed to develop a set of HF transitional care quality indicators for clinical or research applications following hospitalization for HF. We performed a scoping review using MEDLINE, Embase, CINAHL, HealthSTAR, reference lists and grey literature from January 1990 to November 2022. We included randomized controlled trials (RCTs) of adults hospitalized for HF who received a healthcare service or strategy intervention that aimed to improve patient-reported or clinical outcomes. We independently extracted data and performed a qualitative synthesis of the results. We generated a list of process, structure, patient-reported, and clinical measures that could be used as quality indicators. We highlighted process indicators that were associated with improved clinical outcomes and patient-reported outcomes that had high adherence to COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and United States Federal Drug Administration (FDA) standards. From 42 RCTs included in the study, we identified a set of process, structure, patient-reported, and clinical indicators that could be used as transitional care measures in clinical or research settings. In this scoping review, we developed a list of quality indicators that could guide clinical efforts or serve as research endpoints in transitional care in HF. Clinicians, researchers, institutions, and policymakers can use the indicators to guide management, design research, allocate resources, and fund services that improve clinical outcomes.

Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review.

Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approvalby the FDA, tianeptine has been distributed online and at small retail locations. The term "gas station drugs" refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as "Zaza" and "Tianna Red." It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

Patients prefer free drug disposal options delivered by pharmacists at the point of care: Results of a decision tree analysis of a national factorial vignette panel survey.

Unused opioid medication in the home increases risk of medication diversion, misuse, and unintended harm. The United States Federal Food and Drug Administration is currently considering the implementation of a risk evaluation and mitigation strategy (REMS) program that would require US pharmacists to provide drug disposal products with opioid prescriptions. Still, little is known about consumer preference for drug disposal method. The objective of this study was to identify product and program characteristics associated with consumer preference for at-home drug disposal products. A 2x2x3x3 full-factorial design was employed to text-based vignettes representing opioid analgesic disposal scenarios. Each vignette varied on four characteristics: product cost (free vs paid), ease of use (a mail back envelope, bringing medication to a takeback site, and an at-home drug deactivation pouch), potential environmental impact (incineration), and point of access (pharmacy, community organization, and prescriber). Of the 36 possible vignettes, 12 were removed as they represented a non-realistic combination of vignette characteristics. The remaining 24 were administered to a panel of patients with controlled-substance use in the past six-months. Decision tree modeling and general linear mixed (GLM) models were used sequentially to identify product characteristics associated with patient drug preferences RESULTS: A total of 1,006 participants completed all vignette drug disposal scenarios. Regression tree analysis found that the most important predictor of use was cost followed by ease of access and product design. GLM showed that takeback programs offered at a pharmacy were the most preferred disposal option followed by at-home products (mailed envelope or deactivation system) dispensed with the prescription. Programs that provide disposal resources directly to the patient at no cost with their prescription are likely to optimize willingness to dispose. Findings support the FDA's plan for a REMS program requiring pharmacies to distribute mail-back envelopes to patients when dispensed opioids.

Tezepelumab for Patients with Severe Uncontrolled Asthma: A Systematic Review and Meta-Analysis.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. It was approved by the United States Federal Drug Administration (US FDA) as an add-on maintenance treatment for patients with severe uncontrolled asthma in December 2021. We conducted a systematic review and meta-analysis to investigate the safety and efficacy of tezepelumab on forced expiratory volume (FEV1) (L), the rate of asthma exacerbations, health-related quality of life, fractional exhaled nitric oxide (FeNO) (ppb), and blood eosinophil count (cells/mL) in patients with severe, uncontrolled asthma. Mean changes for efficacy and proportions (safety) with their corresponding 95% confidence intervals (CIs) were used to provide pooled estimates. A total of six randomized controlled trials comprising 2667 patients were included, of whom 1610 were treated with tezepelumab and 1057 received placebo. The pooled analysis showed that tezepelumab treatment resulted in an improvement in FEV1 of 0.15 L (95% CI: 0.12 to 0.17), a reduction in the asthma exacerbation rate per year of 0.60 (95% CI: 0.51 to 0.70), and a reduction in FeNO of -12.41 ppb (95% CI: -14.28 to -10.53) when compared to placebo. Improvements in FEV1 and FeNO levels were maintained at 24 and 52 weeks. As for safety, patients did not experience a higher incidence of adverse drug reactions with tezepelumab (0.79 (95% CI: 0.55 to 1.12)) as compared to placebo. As for quality of life, different doses of the tezepelumab intervention group depicted non-significant improvement in the QoL, from 0.15 (95% CI: -0.09 to 0.38) for 70 mg, 0.18 (95% CI: -0.10 to 0.46) for 210 mg, 0.08 (95% CI: -0.16 to 0.32) for 280 mg as compared to the placebo. Tezepelumab significantly reduced exacerbation rates and improved FEV1 with an acceptable safety profile.

Identification of Barriers Preventing Biosimiliar Oncology Medication Adoption.

(1) Background: A biosimilar is a biologic medical product that has been approved by the United States Food and Federal Drug Administration (FDA) and is an almost identical copy of an original biologic product yet manufactured by a different company. Biosimilars are often assumed to be the same as generic medications, while often made from living organisms. Through clinical trials, biosimilars have been shown to be both as safe and as effective as their originator products. Biosimilars have also proven they can reduce the costs to both insurance companies and patients in many circumstances. However, despite their cost savings, biosimilar manufacturers continue to face barriers in having oncologists and cancer centers prescribe them for their patients. This review aims to identify barriers associated with medical provider prescriptive behaviors related to biosimilars for patients. (2) Methods: Reviewers analyzed 27 articles and identified common themes. (3) Results: After a thorough literature review, the researchers identified seven barriers to prescribing of biosimilars: physician comfort in originators instead of biosimilars, patient reluctance to switch from a current biologic to a biosimilar, provider profits associated with an originator biologic, lack of stakeholder education on biosimilars, lack of provider team knowledge of biosimilars, lack of knowledge surrounding the biosimilar FDA approval process, and hesitancy to stock multiple drugs for a specific indication. (4) Conclusions: This review's findings of identified barriers to use of biosimilars provides insight for healthcare providers and organizations surrounding prescribing practices and potential treatment benefits for cancer patients who may benefit from biosimilar treatment medications.

The role of JAK inhibitors in hematopoietic cell transplantation.

The Janus Kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) pathway is essential for both the regulation of hematopoiesis and the control of inflammation. Disruption of this pathway can lead to inflammatory and malignant disease processes. JAK inhibitors, designed to control the downstream effects of pro-inflammatory and pro-angiogenic cytokines, have been successfully used in pre-clinical models and clinical studies of patients with autoimmune diseases, hematologic malignancies, and the hematopoietic cell transplantation (HCT) complication graft versus host disease (GVHD). In the last decade, JAK inhibitors Ruxolitinib, Fedratinib, and most recently Pacritinib have been United States Federal Drug Administration (FDA) approved for the treatment of myelofibrosis (MF). Ruxolitinib was also recently approved for the treatment of steroid refractory acute as well as chronic GVHD; JAK inhibitors are currently under evaluation in the pre-HCT setting in MF and for the prevention of GVHD. This review will focus on the role of JAK inhibitors in the treatment of hematologic malignancies, the potential function of pre-HCT JAK inhibitors in patients with MF, and the role of JAK inhibitors in the prevention and treatment of acute and chronic GVHD.

Longevity and reliability of chronic unit recordings using the Utah, intracortical multi-electrode arrays

Objective. Microelectrode arrays are standard tools for conducting chronic electrophysiological experiments, allowing researchers to simultaneously record from large numbers of neurons. Specifically, Utah electrode arrays (UEAs) have been utilized by scientists in many species, including rodents, rhesus macaques, marmosets, and human participants. The field of clinical human brain-computer interfaces currently relies on the UEA as a number of research groups have clearance from the United States Federal Drug Administration (FDA) for this device through the investigational device exemption pathway. Despite its widespread usage in systems neuroscience, few studies have comprehensively evaluated the reliability and signal quality of the Utah array over long periods of time in a large dataset. Approach. We collected and analyzed over 6000 recorded datasets from various cortical areas spanning almost nine years of experiments, totaling 17 rhesus macaques (Macaca mulatta) and 2 human subjects, and 55 separate microelectrode Utah arrays. The scale of this dataset allowed us to evaluate the average life of these arrays, based primarily on the signal-to-noise ratio of each electrode over time. Main results. Using implants in primary motor, premotor, prefrontal, and somatosensory cortices, we found that the average lifespan of available recordings from UEAs was 622 days, although we provide several examples of these UEAs lasting over 1000 days and one up to 9 years; human implants were also shown to last longer than non-human primate implants. We also found that electrode length did not affect longevity and quality, but iridium oxide metallization on the electrode tip exhibited superior yield as compared to platinum metallization. Significance. Understanding longevity and reliability of microelectrode array recordings allows researchers to set expectations and plan experiments accordingly and maximize the amount of high-quality data gathered. Our results suggest that one can expect chronic unit recordings to last at least two years, with the possibility for arrays to last the better part of a decade.

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both invitro and invivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in invitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma

ABSTRACTIntroduction: In September of 2018, the United States Federal Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an intravenous human monoclonal antibody directed against programmed cell death-1 receptor (PD-1). Cemiplimab blocks T-cell inactivation and enhances the immune system’s anti-tumor response.Areas Covered: We review CSCC and the studies leading to cemiplimab’s approval, including common side effects and safety issues experienced during the clinical trials.Expert Opinion: Immunotherapy, specifically checkpoint inhibitors, represents an increasingly utilized class of medications that is proving to be an effective treatment option for those with certain cancers. Over time, immunotherapy is likely to be the standard of care for immune-sensitive tumors. There are many challenges that the field faces, including the identification of reliable biomarkers to better predict response, decreasing toxicity, and the potential treatment of organ transplant patients.

Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm.

To critically assess the current landscape of disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will be discussed and studies for new agents in late development or recently approved are analyzed in terms of their impact on current treatment strategies. A real-world study from Wales suggests that early initiation of highly effective therapy may provide more benefit that an escalation approach in relapsing MS. A study from the MSBase dataset found evidence that early treatment with highly effective therapies decreased the risk of developing secondary progressive MS. Ocrelizumab is highly efficacious in relapsing MS and in a group of patients with primary progressive MS. Another CD20 directed mAb, ofatumumab, is in phase 3. A large study examining extended interval dosing of natalizumab in an attempt to decrease the risk of developing progressive multifocal leukoencephalopathy is underway. Cladribine and alemtuzumab may work by immune reconstitution. Siponimod was recently approved by United States Federal Drug Administration for relapsing MS and active secondary progressive MS. Other S1P receptor modulators are being studied in phase 3 trials for relapsing MS. Cladribine received FDA approval as treatment for relapsing and active secondary progressive MS. Autologous hematopoetic stem-cell transplantation may be an option for treatment-refractory MS. Development of disease-modifying agents in MS continues to be successful. Treatment algorithms need to take new developments into account.

The Latest "Federal Movement" in the Food and Drug Law Arena: The Federal Right-to-Try or Rather Right-to-Know and Thus Request Investigational Therapies for Individuals with a Life-Threatening Disease or Condition

Does the recently enacted Federal Right-to-Try Act provide improved access for the desperately ill? Will insurance companies provide reimbursement for a patient to undergo such investigational therapies? Is the manufacturer protected in terms of lawsuits? That is, does the patient relinquish the right to bring a legal action? Will physicians comprehend the pathway and advocate for their patients? Does this new law guarantee “any novel federal right”? The national state movement regarding Right-to-Try state legislation spurred the enactment of the Federal Right-to-Try (Federal Right-to-Try Act) legislation passed in 2018. Yet, even prior to the enactment of the Federal Right-to-Try law, the United States Federal Food and Drug Administration (FDA) has had mechanisms in place for those terminally ill who do not qualify for a clinical trial. This article provides a Federal Primer on the Investigational Drug, Biologic and Device Process, details a similar national right-to-know movement in the food and drug law arena that led to federal legislation perhaps comparable to how the Federal Right-to-Try Act was enacted and includes a discussion about the state right to try movement which conceivably led to the enactment of the Federal Right-to-Try Act. There are more queries than unambiguous answers regarding the recently enacted Federal Right-to-Try Act. The federal law in essence could prove troublesome and confusing with both the state Right-to-Try measures due to, for instance, issues of national uniformity and preemption. Further, could the recently enacted Federal Right-to-Try Act ultimately be detrimental to the patient in terms of lack of adequate safeguards and perhaps a false unrealistic sense of hope?

Enasidenib for the treatment of acute myeloid leukemia

ABSTRACTIntroduction: In August 2017, the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2.Areas covered: We review the studies leading to enasidenib’s approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome.Expert commentary: We are experiencing a revolution in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.

Production of pharmaceutical proteins by transgenic animals.

Proteins are involved in a majority of the biochemical events that take place in all living organisms. Protein synthesis is directed by genes. All genes contain two major DNA regions. The region containing the genetic message proper (the 'coding region') is preceded by a regulatory region ('the promoter'), which determines when and in which organs a given gene must produce the corresponding protein. The techniques of genetic engineering allow the association of the coding region from one gene with the regulatory region from another gene. The expression of these recombinant genes may be achieved in cultured cells, in transgenic animals or in plants. This leads to the production of the corresponding proteins, including pharmaceutical proteins. Milk from transgenic animals is one potential source of pharmaceutical proteins. To achieve this, the promoters from milk protein genes are bound to DNA fragments containing the coding region of the genes of interest. The desired proteins are then taken from the milk and purified. Two human pharmaceutical proteins are on the market and about 20 projects are in development. One of the proteins produced in milk, antithrombin III, is an anticoagulant and the other, human C1-esterase inhibitor, is an anti-inflammatory. Several human proteins have been produced in the egg white of transgenic chickens and one has been approved by the United States Federal Drug Administration. This process has also been used to modify antibodies in cows. The genes that code for antibodies in the cow were deleted and replaced by human antibody genes. These cows, immunised by various antigens, then secreted purely human antibodies in their blood. Antibodies from such cows were able to attenuate the effects of Ebola virus in human patients.

Still sour about lactic acidosis years later: role of metformin in heart failure.

Metformin remains a widely-used, first-line pharmacotherapy agent for patients with type 2 diabetes mellitus because of its efficacy, mild side effects, and affordability.However, use of this medication has traditionally been shunned by clinicians in patient populations that are considered at risk of lactic acidosis, such as those with heart failure. The underutilization of metformin can largely be attributed to the historical stigma of its biguanide predecessor, phenformin, and its association with lactic acidosis. Despite various studies finding low rates of lactic acidosis and the United States Federal Drug Administration's subsequent removal of heart failure from metformin's contraindication labeling in 2006, this oral hypoglycemic remains underutilized in this patient population. In addition to reports of the safe use of metformin in the heart failure population, a multitude of studies have also additionally suggested a modest reduction in mortality and morbidity. Metformin's role should be strongly reconsidered in the armamentarium of diabetes management in heart failure patients.

M.C. Chang as a Mentor: A Memoir.

M.C. Chang as a Mentor: A Memoir.

A study of HLA-B∗15:02 in a Sri Lankan population: Implications for pharmacogenomic testing

HLA-B∗15:02 is known as a biomarker for carbamazepine (CBZ) induced Steven-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) in some Asian populations. Hence United States Federal Drug Administration (USFDA) recommends HLA-B∗15:02 screening for Asian and other populations with a high prevalence of HLA-B∗15:02, prior to the administration of carbamazepine. This study was conducted to estimate the prevalence of HLA-B∗15:02 in a cohort of Sri Lankans. We observed an overall prevalence of 4.3% (4/93) among 93 Sri Lankans comprising 32 Sinhalese, 30 Sri Lankan Tamils and 31 Moors. The allele was detected in 3 [9.3%; 3/32] Sinhalese, 0 [0%; 0/30] Sri Lankan Tamils and in 1 [3%; 1/31] Moor. The overall prevalence of HLA-B∗15:02 in this population was close to that of other populations where the USFDA has recommended HLA-B∗15:02 screening. A larger study is required to confirm these findings, especially among the Sinhalese where the frequency appears to be high.

An in silico approach to treating “the right patient with the right drug at the right dose at the right time”

Biomarkers that predict responses to anti-cancer drugs are required to establish personalized cancer medicine, which is defined by the United States Federal Drug Administration as treating “ the right patient with the right drug at the right dose at the right time ” (1). In this issue, Dr. Wang and colleagues report a gene expression signature that predicts the efficacy of ZD-6474 (vandetanib) in 89 lung cancer cell lines (2) using a data set deposited in the cancer cell line encyclopedia (3). This was an in silico study; therefore, the results require validation in tumor samples from lung cancer patients treated with ZD-6474. However, the study provides a good example of a method of identifying candidate biomarkers that predict responses to anti-cancer drugs.

Statin associated hepatic adverse effects: a retrospective review from a regional hospital in sultanate of oman.

This study aimed at evaluating the prevalence, pattern and predisposing factors for hepatic adverse effects with statins in a regional hospital in Sultanate of Oman. A retrospective review of the patient files in Department of Medicine during the year 2011 was done to evaluate any hepatic dysfunction possibly related to statins among the patients. For each case of suspected statin induced hepatic effect, additional details on temporal relationship, pattern of presentation, management, final outcome and any contributing factors were obtained. Difference in the occurrence of hepatic effects based on the patient demographics and drug characteristics was additionally evaluated. A total of 927 patients meeting the inclusion criteria were included for the study. Mean age of the evaluated patients was 63.1 ± 11.37 and median duration of use of statin in months was 22 (IQR, 43.25). In 40 (4%) of the 927 patients, there was presence of a hepatic effect considered to be statin related and only in 12 (1%) patients a significant transaminase rise (>3 times) was observed. Median duration of use of statin among those patients who developed suspected statin induced hepatic effects and those who did not was 45 (IQR,52) and 21 (IQR, 43) months, respectively and the difference observed was statistically significant. A significant difference in the prevalence of hepatic effects was observed only based on the duration of statin use. There was an infrequent occurrence of significant hepatic effects associated with statins in the study population. Our results support the latest recommendations including from United States Federal Drug Administration (US FDA) that statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of transaminases does not appear to detect or prevent serious liver injury in association with statins.