FDA Guidance Research Articles

Analytical Studies on Ciguateric Fish in Okinawa, Japan (II): The Grouper Variola albimarginata

Ciguatera fish poisoning (CFP) refers to an illness caused by ingesting fish that have accumulated ciguatoxins (CTXs). CFP frequently occurs in the tropical and subtropical Indo-Pacific Ocean and the Caribbean Sea. In Japan, CFP occurs sporadically but constantly in Okinawa and the Amami Islands. The grouper Variola albimarginata is regarded to be safe for consumption. To assess the real risk of V. albimarginata, we analyzed 133 specimens of the fish in Okinawa using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Ciguatoxin-1B, 54-deoxyciguatoxin-1B, and 52-epi-54-deoxyciguatoxin-1B were detected in 28 specimens (21%). In 11 of these specimens (8%), the CTX levels exceeded the US FDA guidance level (0.01 µg/kg CTX1B equivalent). However, only one fish (<1%) was found to have levels above the recommended level in Japan (0.175 μg/kg CTX1B equivalent). The amount of CTXs in the flesh (280 g) of the most toxic specimen (0.225 μg/kg) did not reach the level needed to cause illness. The CFP risk due to the consumption of this species was thus considered to be low in Okinawa, supporting local belief. The CTX levels in the flesh were positively correlated with standard length, body weight, and age. The total CTX levels significantly fluctuated between the male and the female of the species. The estimated annual catch of V. albimarginata in Okinawa and Yaeyama Islands was 4909 kg or 13,636 fish. As many as 1227 fish had levels over the US FDA guidance level, but only 136 fish had levels above the Japanese recommendation. Risk management based on the Japanese recommendation level seems to be effective in protecting public health and enabling appropriate exploitation of fishery resources.

227. Impact of Asymptomatic Bacteriuria on Primary Efficacy Analyses in the Evaluation of Novel Antimicrobials for the Treatment of Patients with Urinary Tract Infection

Abstract Background Per FDA Guidance, the primary efficacy endpoint for trials evaluating antimicrobials for treatment of uncomplicated urinary tract infection (uUTI) and complicated urinary tract infection (cUTI) is a combined clinical/microbiologic outcome response. Overall success requires both resolution of UTI symptoms and demonstration that the causative uropathogen is reduced to < 103 CFU/mL at a fixed time point after randomization, regardless of whether the patient is symptomatic. In clinical practice, it is not standard of care to routinely screen for or treat asymptomatic bacteriuria (ASB), nor to obtain ‘proof of cure’ cultures. In the clinical trial setting, the impact of post-treatment asymptomatic bladder recolonization on the rates of microbiologic response, re-infection, or emergence of resistance is unknown. Methods Study IT001-301 and -302 are double blind, double-dummy, Phase 3 randomized trials comparing sulopenem to comparator for patients with pyuria, bacteriuria, and clinical signs/symptoms of uUTI and cUTI, respectively. In Study 301, 1671 ambulatory female adults with uUTI were randomized to oral sulopenem bid x 5d or oral ciprofloxacin bid x 3d. In Study 302, 1395 hospitalized adults with cUTI were randomized to sulopenem IV once daily x 5d followed by oral sulopenem bid or ertapenem IV once daily x 5d followed by either oral ciprofloxacin or amoxicillin-clavulanate bid, depending on baseline uropathogen susceptibility. The primary endpoint was overall (clinical + microbiologic) response in micro-MITT population at TOC visit (D12 in uUTI study and D21 in cUTI study). Results Figure 1 Conclusion Different classes of antibiotics appear to have a differential effect on the frequency of post-treatment ASB with quinolones having a lower rate relative to beta-lactams. The presence of ASB a week or more after completing UTI therapy was not associated with a higher rate of clinical relapse for UTI patients; treatment with ciprofloxacin was associated with the selection of resistant pathogens in the post-treatment flora. Inclusion of ASB in the primary endpoint for studies of UTI should be reconsidered as it implies that a post-treatment culture should be obtained to document resolution of infection, a practice inconsistent with available treatment recommendations. Disclosures Steven I. Aronin, MD, Iterum Therapeutics: Stocks/Bonds Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Sailaja Puttagunta, MD, Iterum Therapeutics: Stocks/Bonds.

The parent–child IND approach: an interpretation of FDA’s guidance on studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial

Advancements in cell and gene therapies are occurring at a rapid pace resulting in the opportunity for multiple versions of a product to advance quickly to clinical readiness. To translate these rapid advances into clinical benefit for patients, sponsors desire opportunities to progress these versions more efficiently through early phase clinical studies. The parent–child approach to the study of multiple versions described in recent FDA guidance has the potential to offer sponsors this pathway. However, this approach may be most advantageous to companies seeking to accelerate selection of a lead candidate, rather than companies prioritizing speed to market. Additionally, alternative use cases for parent–child INDs such as a staggered introduction of new versions are not discussed in FDA’s guidance. Although questions remain regarding how FDA will implement aspects of the guidance, the Agency has provided sponsors with a well-reasoned roadmap for the study of these versions in early phase trials.

2235. Discordance of Clinical and Microbiological Endpoints in Clinical Trials for Complicated Urinary Tract Infection (cUTI)

Abstract Background Complicated urinary tract infections (cUTI) are a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine or blood culture, accompanied by local and systemic signs and symptoms, in the presence of urinary tract abnormalities or acute pyelonephritis. Current FDA guidance recommends that the primary endpoint for cUTI clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed time after therapy. In recent trials, it has been noted that while some patients have clinical resolution of symptoms, they are considered failures due to positive urine cultures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. Methods We analyzed patient data from 13 phase 3 clinical trials submitted to the FDA. We focused on the microbiological modified intent-to-treat (m-MITT) population, including patients who have at least 1 bacterial pathogen known to cause cUTI and received at least one dose of study drug (N=4842). Outcomes were determined at the Test of Cure (TOC) visit 7-10 days after therapy, and the Late Follow Up (LFU) visit 3-4 weeks after therapy. Clinical and microbiological success were defined as the resolution of cUTI symptoms present at entry, with no new symptoms (clinical cure), and reduction of the pathogen at entry to ≤ 103 CFU/mL on urine culture (microbiological eradication). Results Among all included patients, 70.7% were overall successes at the TOC, exhibiting clinical and microbiological success. 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). In a multivariate logistic regression model, discordance was associated with obesity, lithiasis, use of analgesics, and receipt of carbapenem antibiotics. Discordant patients were at an increased risk for clinical failure at the LFU visit, and the risk of late clinical failure increased with longer time between the TOC and LFU visits. Conclusion Microbiological persistence at the TOC visit despite resolution of symptoms was associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component in the composite endpoint. Disclosures All Authors: No reported disclosures.

Review on: Preparation and Evaluation of Paracetamol Emulsion dosage Form

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

BCS Class II Drug & Its Solubility Enhancement: A Review

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Lecanemab (BAN2401) Infusion Reactions and Immunogenicity: Results from Randomized Phase 2 Study and an Open‐Label Extension (OLE).

AbstractBackgroundTreatment with 10 mg/kg lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species, has been shown to reduce amyloid PET standard uptake value ratio (SUVr) and slow clinical decline in an 18‐month, phase 2 proof‐of‐concept study (Study 201 Core) in early Alzheimer’s disease with an OLE. The present analysis aimed to review infusion related reactions from Study 201 and the results of immunogenicity assessments from the completed lecanemab clinical trial.MethodsInfusion related reactions were summarized by treatment group using descriptive statistics. All adverse events were coded using MedDRA version 24.0 and graded based on CTCAE guidelines.Analysis of anti‐drug antibodies (ADA) and its impact on pharmacokinetics, pharmacodynamics, efficacy, and safety during Study 201 were undertaken. All ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach.ResultsIn Study 201 Core, 854 treated subjects (lecanemab:609; placebo:245) were randomized across 6 treatment groups. In the OLE phase a total of 180 subjects were treated with lecanemab 10 mg/kg biweekly (LEC10BW). Infusion‐related reactions were the most common adverse event associated with LEC10BW treatment, with 19.9% (32/161) of subjects compared to 3.3% (8/245) of placebo subjects. All events were mild/moderate in severity, most occurred with the first infusion, resulted in a low rate of discontinuations (LEC10BW:2.5%; placebo:0.8%). Over 70% of patients who initially experienced infusion‐related reactions had no further reactions with preventative medications. Infusion reaction data from the OLE were consistent with the Core study. The incidences of ADA for LEC10BW in the Core and OLE were 40.9% and 11.1% (Core placebo‐treated subjects), respectively; titers were very low (most ≤125). Detailed analysis of lecanemab ADA demonstrated no meaningful impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.ConclusionsIn the lecanemab Study 201 Core and OLE, infusion‐related reactions were the most common adverse event, however were readily manageable with preventative medication, were of low severity, and resulted in minimal discontinuations. Lecanemab is a low‐risk molecule for immunogenicity based on ADA profile and minimal impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.

Feasibility of Real-World Assessment of Patient-Reported Outcomes in Acute Myeloid Leukemia By Cytogenetic Risk and Treatment Status

Background Prior research has demonstrated the benefit of gathering patient-reported-outcomes (PRO's) in oncology practice for clinical outcomes, health resource utilization and quality of life. The FDA guidance on Core Patient Reported Outcomes in Cancer Clinical Trials further highlights the importance of PRO's for capturing disease, treatment, and functional impacts of oncology therapy. For patients with Acute Myeloid Leukemia (AML), disease mortality and survey compliance pose particular challenges to gathering PRO data. Methods The study cohort was derived from users of Patient Reported Outcomes mobile platform (PROmpt®), an application for remote patient reporting and provider symptom management that is employed in routine care in 30+ integrated cancer treatment centers in the United States. Patients age 18+, with confirmed AML diagnosis from March, 2021 to May, 2022 were enrolled in the platform at treatment initiation and provided with weekly surveys. Weekly assessments included symptom burden (PRO-CTCAE), function impact (PROMIS 4A), and overall quality of life (EORTC QLQ C29, C30). Clinical, biomarker, and treatment data were obtained from electronic medical record structured data. Patients were stratified by cytogenetic risk (Poor vs Favorable/Intermediate/Unknown) and treatment type (Curative Therapy vs Maintenance Therapy). Baseline demographics and characteristics were assessed. Symptom burden, functional impact and quality-of-life impact were described longitudinally Results The overall cohort (n=65) had a median age of 69 (range 20-87). Among the persons with reported frailty status (n=42), there were 11 (26%) Fit, 21 (50%) (Intermediate Fit) and 10 (24%) Frail. Across all unique patient-weeks, the most frequent symptoms reported were fatigue (19%), decreased appetite (15%), general pain (14%) and nausea (13%). From Weeks 1 to 12, the average number of symptoms reported per patient per week ranged from 1.3 to 2.7, the averages collectively decreasing over time. Patients receiving Maintenance Therapy were directionally older and less fit than patients receiving Curative Therapy, mean age 72 vs 67 years and Intermediate-Fit/Frail 72 vs 50%, respectively. Over 12 weeks of treatment, PROMIS 4A Composite Function Scores were also consistently higher among patients receiving Maintenance Therapy compared to patients receiving Curative Therapy (Figure 1). In contrast, patients with Poor Cytogenetic Risk showed similar age and fitness status compared to patients with Favorable, Intermediate or Unknown Cytogenetic Risk. However, patients with Poor Cytogenetic Risk consistently reported higher PROMIS 4A Composite Function Scores over the 12 weeks of treatment compared to those with Favorable, Intermediate, or Unknown Cytogenetic Risk (Figure 2). Conclusion This study demonstrates the feasibility of gathering PRO's with real-world data among a cohort of patients with AML using a remote symptom monitoring platform, across baseline prognostic and therapeutic factors. Although results are limited due to small sample sizes, higher levels in overall function for patients on Maintenance Therapy and those with Poor Cytogenetic Risk underscore the value of routine follow-up, which should include PRO assessment throughout the entire therapeutic process. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1 Trial of AUC-Targeted Melphalan in Myeloma Patients Undergoing Autologous Transplant (The MyMel Study)

Standard 200 mg/m2 high dose melphalan (HDM) yields a 500% variation in plasma melphalan exposure, i.e. area under the curve (AUC), leading to unpredictable DNA damage and widely variable clinical responses. Strategies to predict melphalan AUC have been unsuccessful given population PK models (Nath, Br J Clin Pharmacol 2010 & Cho Clin Pharmacol Ther 2017) are ineffective on an individual patient level and only explain ~20% of the variability observed, and test dose predictions have failed to accurately represent melphalan AUC for doses >100 mg/m2. PK directed dose adjustment of HDM would require a 24-hour turnaround for sample collection, shipping, processing and data analysis. Previously we described methods for measuring melphalan PK after the Day -2 HDM dose, allowing for real-time dose adjustments (Sweiss, Br J Clin Pharmacol 2020). Here, we set out to perform the first phase 1 study of AUC-targeted HDM in ASCT (NCT04483206). This multicenter phase 1 trial (Fig 1) is designed to test 7 AUC ranges (13-21 mg*h/L) to determine the maximum tolerated systemic exposure (MTSE). The feasibility portion focuses on the first 2 AUCs (phase A, n=20) in patients with ≥2L therapy, where we measure accuracy of achieving target AUCs of 13.5 and 14.5 mg∗h/L, respectively. Patients receive HDM 100 mg/m2 on day -3 with PK measurement and subsequent dose-adjustment on day -1 to achieve the total target AUC. 7 blood samples are drawn, processed and shipped frozen for LC-MS/MS analysis. PK parameter estimations are determined from noncompartmental analysis (NCA) and per FDA guidance used to adjust doses. Nonlinear mixed effects modeling (NONMEM) is performed in parallel to compare PK estimations. Using observed first-dose HDM clearance (Clobs) from NCA and assuming that Cl is consistent between doses, linear dose-proportional adjustments are performed to achieve the target AUC0-inf. After a planned FDA review of these cohorts, we will begin to dose escalate to determine the MTSE with up to 5 AUC levels (15.5-19.5 mg∗h/L). Bone marrow (BM) MRD status will be assessed at Day 90 as part of the Phase B primary objective. Correlatives include measuring DNA damage in circulating PBMCs post-HDM to correlate with AUC, piloting a DNA fiber combing assay on primary MM cells from patient BM samples to quantify DNA replicative stress, and assessing PROs using NCI PRO-CTCAE v.1.0. We have enrolled 8 patients into the first AUC cohort with 110 blood samples collected. Median age was 69 (56-75) years, with 7 (87.5%) males, and 4 (50%) Blacks. The median day -3 HDM Clobs and AUC0-inf were 22.05 (16.3-38.2) L/hr and 9.53 (6.97-11.82) mg∗h/L, respectively. All shipped blood samples were received in suitable frozen condition, and in 7 (87.5%) of 8 patients, LC-MS/MS run with NCA estimation and dose reporting was done within 12 hours of receiving samples. One patient whose samples were delayed from shipping had the dose reported on day-1 resulting in 5 of 7 day-1 samples collected. Covariates of HDM PK (i.e., FFM, hematocrit) were entered into our developed PK model to further enrich our data prediction. All 8 day -1 doses were adjusted, with a resulting median total BSA-based HDM dose of 139.6 (110.93-192.6) mg/m2. After adjustment, median day -1 Clobs and AUC0-inf were 24.48 (19.3-35.8) L/hr and 3.84 (1.7-7) mg∗h/L, respectively. For accuracy of dose adjustment, 107 (97.3%) samples were evaluable for PK parameter estimation, with 3 concentrations excluded (n=3 patients). One subject whose last 2 day -1 samples were not collected was removed from analysis as it resulted in 19% AUC extrapolation and 33% variance between day -3 and -1 Cl values. Of 7 patients, 6 (85.7%) achieved the target AUC, with less than 10% variance in Cl between doses. (Fig 2). In the one patient, it was assessed that the day -1 Cl deviated by 24% as a result of prolonged time from drug admixture to completion of infusion leading to drug degradation. Estimated melphalan Cl generated from NCA and NONMEM correlated well (r=0.99). This is the first trial in MM implementing a novel personalized dosing approach using drug exposure as the target to define each cohort. We demonstrate feasibility of real-time PK sampling, shipping, processing, NCA PK parameter estimation, and dose adjustment of HDM. So far we report a high rate of accuracy in achieving the target AUC which we hypothesize will deliver reliable DNA damage to MM cells. Enrollment is active and mature data will be presented at the conference. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bacterial culture time to detection in platelet components: An evidence synthesis and estimation of detection failures.

Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized. We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice. The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2h while it was 24.9h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms. TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

Simultaneous determination of multiple constituents of Qi-Lin pill by UPLC-MS/MS: Applications to pharmacokinetics and testicular tissue distribution in rats

Qi-Lin pill (QLP) is an effective traditional Chinese medicine prescription (TCMP) that has been used for the treatment of the oligoasthenozoospermia in China. Recently, some articles described the pharmacological effects of QLP and multiple ingredients in QLP contribute to its effects. However, the pharmacokinetic and target tissue distribution data of QLP are still unknown. In the present study, according to the Bioanalytical Method Validation Guidance of FDA, a sensitive and selective UPLC-MS/MS method was developed and validated for simultaneous determination of multiple constituents in rat plasma and testicular tissue, including morusimic acid A, codonopyrridium B, magnoflorine, emodin, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), ecliptasaponin A, paeoniflorin, albiflorin, gallic acid, danshensu, salvianolic acid A, catechin, isosinensetin, nobiletin, formononetin, calycosin, icariside II, icariin and epimedin C. For 19 analytes, the LLOQs reached 0.01–4 ng/mL. And all calibration curves showed favorable linearity (r ≥ 0.9903) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.92 %, and the accuracies (as relative error) were in the range of − 6.44 % to 6.22 %. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The method was successfully applied for the pharmacokinetics and testis distribution of multiple chemical constituents in QLP after a single oral dose. As a result, high exposure of danshensu, gallic acid, paeoniflorin and albiflorin were observed in rat plasma and testicular tissue. Among the flavonoids, isosinensetin and nobiletin had high exposure in testicular tissue. Moreover, alleviation of progesterone reduction was evaluated in H2O2-induced R2C leydig cells, and danshensu, gallic acid, paeoniflorin, albiflorin and nobiletin showed potent activity. Therefore, these five components were considered to be the effective components of QLP due to their relatively high exposure in vivo and biological activity. This finding also provided relevant information on action mechanism of QLP in the treatment of oligoasthenozoospermia.

LBSUN214 Accuracy Of A Continuous Glucose Monitor In The Intensive Care Unit

Abstract Studies have shown that hyper/hypoglycemia and glycemic variation are associated with adverse outcomes in critically ill patients. Currently, frequent blood point-of-care (POC) glucose measurements from an arterial or capillary sample is the only technology available to minimize glycemic excursions in the ICU. Continuous glucose monitoring (CGM) is becoming the standard of care for outpatient diabetes care and has shown improved glycemic control in the non-ICU inpatient setting. The Dexcom G6 sensor (G6) is the first CGM device approved by Health Canada for outpatient diabetes management without the need for calibration, but it has not yet been approved for inpatient use. We collected data from 23 adults who were on an insulin infusion in a medical-surgical ICU in Vancouver, British Columbia to evaluate the accuracy of uncalibrated CGM in the ICU. A blinded G6 was attached to the patient's arm and collected glucose measurements every five minutes without calibration. Nursing staff continued POC arterial glucose measurements using the AccuChek Inform II machine per standard of care. Excluding four outliers (with mean absolute relative difference (MARD) ≥ 25%), the overall MARD was 13.24% (SE 0.43) over 649 matched CGM and arterial glucose values. A Clarke Error Grid demonstrated 99.1% of CGM measurements within zones A and B. The MARD using three-point rolling averages of CGM measurements in five-minute intervals was 13.49% (SE 0.68). There were 573 matched pairs between glucose ranges of 3.9-13.9 mmol/L with two pairs <3.9 and 74 pairs >13.9 mmol/L. Eleven patients had renal replacement therapy and twelve had vasopressor use. There was no significant difference in MARD with renal replacement or across glycemic ranges ≥3.9. The MARD for patients with vasopressors was lower than for patients without (13% vs 13.55%, p<0. 01), a finding of doubtful clinical relevance. There is no expert agreement yet about the acceptable accuracy for CGM use in hospital. Our overall MARD meets the 2013 Critical Care expert consensus recommendations for MARD <14%. The FDA guidance on standard of accuracy for conventional POC glucometers require 98% of values within 15% for BG ≥ 75mg/dL. Our data showed 65.18% of values were within 15%. Previous studies using CGM in the ICU, even those using G6, all used calibration. The majority were non-blinded, and none met FDA criteria for inpatient use. Our study is the first uncalibrated and blinded study that was able to demonstrate acceptable accuracy in a large sample size. Since CGM accuracy may be affected by various factors, our comprehensive data can potentially identify specific interferences and quantify a calibration or correction criteria to improve CGM accuracy in critically ill patients. Overall, our results show that CGM shows strong potential to be an accurate, resource-efficient, and intuitive alternative to POC glucose monitoring to meet glycemic targets in the ICU. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Determination of five positive control drugs in hERG external solution (buffer) by LC-MS/MS to support in vitro hERG assay as recommended by ICH S7B

ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QTC prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to molecule-specific properties (such as non-specific binding), thereby introducing error when assessing drug potency. To account for this potential source of error, both the original ICH S7B and the newly released ICH E14/S7B Q&As guidelines call for verifying drug solutions' concentrations. Dofetilide, cisapride, terfenadine, sotalol and E-4031 are hERG blockers commonly used as positive controls to illustrate hERG assay sensitivity. The first four compounds are also clinical drugs associated with high TdP risk; therefore, their safety margins may be useful comparators to better understand an investigational product's TdP risk. Having analytical methods to quantify these five compounds in the hERG external solution that will be used for patch clamp recordings is important from a regulatory science research perspective. However, a literature search revealed no analytical methods or stability information for these molecules in the high salt, serum-free matrix that constitutes the hERG external solution. This study was conducted to develop and validate LC-MS/MS methods to quantify these 5 molecules in hERG external solution. The bioanalytical methods for these positive controls were validated as per the FDA's bioanalytical method validation guidance along with various stabilities.

日本沿岸産イシガキダイのシガトキシン分析

Ciguatera fish poisoning (CFP) is recognized as the most frequent seafood poisoning due to the consumption of fish containing the principal toxins, ciguatoxins (CTXs). In Japan, CFP events have been reported annually from Okinawa and Amami Islands, locating subtropical regions. In addition, there have been reported several outbreaks due to consumption of the fish caught from the Pacific coast of the Mainland and they were often caused by the matured spotted knifejaw, Oplegnathus punctatus. As part of our research on CFP in Japan, we investigated CTXs analysis by LC-MS/MS on 176 individuals of O. punctatus (weight: 100-6,350 g, standard length: 13-60 cm) from the coast of the Mainland (Honshu, Shikoku, and Kyushu), Amami, Okinawa, and Ogasawara (Bonin) Islands. CTXs were detected from only two specimens collected from Okinawa. Total CTXs levels of the two specimens were at 0.014 and 0.040 μg/kg, respectively, exceeding FDA guidance level at 0.01 μg CTX1B equivalent/kg. However, they might be little risk of CFP because consuming over 1.5 kg of flesh is needed to develop intoxication. The toxins consisted of CTX1B analogs including CTX1B, 52-epi-54-deoxyCTX1B, CTX4A, and CTX4B, and no CTX3C analogs, supporting the finding that ciguatoxic fishes in Okinawan Waters containing only CTX1B analogs.

Emerging Trends in Abuse-Deterrent Formulations: Technological Insights and Regulatory Considerations.

Opioid medications are an integral part of the management of acute and chronic severe pain. However, non-medical practice of these prescription drug products is emerging as a serious public health problem. To control this opioid epidemic, USFDA is encouraging pharmaceutical companies to develop Abuse Deterrent Formulations (ADFs). ADF's are much more difficult to manipulate and abuse when compared to their conventional formulations. This feature of ADFs is due to their ability to incumber extraction of active ingredients, to prevent administration through alternative routes, making abuse of altered product less rewarding. The main objective of this review is to abridge different ADFs and various laboratory- based in vitro manipulation and extraction studies, demonstrating that these approved ADFs have the capabilities to deter abuse. The method includes the collection of data from different search engines like PubMed, FDA guidance documents, ScienceDirect, Google Patents to get coverage of literature in order to get appropriate information regarding ADFs. Various in vitro studies demonstrate that ADFs are effective in minimizing opioid drug abuse, including opioid overdose. However, real impact of these ADFs on reducing the drug abuse can be concluded only after receiving the post marketing data. ADFs are embracing fundamentally different paradigms in the management of severe pain. We believe that the development of abuse deterrent technologies would shift the architype, deterring multipill abuse and can prove as a breakthrough strategy in controlling this opioid epidemic menace.

Key Points from the FDA's Guidance for CAR T-Cell Products

Key Points from the FDA's Guidance for CAR T-Cell Products

Clinical grade manufacture of 3D printed patient specific biodegradable devices for pediatric airway support

Implantable patient-specific devices are the next frontier of personalized medicine, positioned to improve the quality of care across multiple clinical disciplines. Translation of patient-specific devices requires time- and cost-effective processes to design, verify and validate in adherence to FDA guidance for medical device manufacture. In this study, we present a generalized strategy for selective laser sintering (SLS) of patient-specific medical devices following the prescribed guidance for additive manufacturing of medical devices issued by the FDA in 2018. We contextualize this process for manufacturing an Airway Support Device, a life-saving tracheal and bronchial implant restoring airway patency for pediatric patients diagnosed with tracheobronchomalacia and exhibiting partial or complete airway collapse. The process covers image-based modeling, design inputs, design verification, material inputs and verification, device verification, and device validation, including clinical results. We demonstrate how design and material assessment lead to verified Airway Support Devices that achieve desired airway patency and reduction in required Positive End-Expiratory Pressure (PEEP) after patient implantation. We propose this process as a template for general quality control of patient-specific, 3D printed implants.

Validation of an LC-MS/MS assay for the simultaneous determination of bictegravir, doravirine, and raltegravir in human plasma

Bictegravir (BIC), an integrase inhibitor, and doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor, were recently approved by the US FDA for HIV treatment and are recommended first line treatment options. Because certain clinical scenarios warrant using them in combination, we developed a fully validated LC-MS/MS method for simultaneous measurement of BIC and DOR, along with a legacy integrase inhibitor, raltegravir (RAL), in human plasma over a clinically relevant 1000-fold range for each analyte. These analytes were extracted from the plasma by protein precipitation with their stable, isotopically labeled internal standards (BIC-d5, 13C6-DOR, and RAL-d6). Following extraction, samples were analyzed by reverse phase chromatography on a Waters Atlantis T3 C18 (50 ×2.1 mm, 3 µm particle size) column with subsequent detection by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The assay was linear (R2 >0.994) over the selected calibration ranges (20.0–20,000 ng/mL (BIC), 3.00–3000 ng/mL (DOR), and 10.0–10,000 (RAL)). The assay was accurate (inter-assay %Bias ≤ ± 8.5) and precise (inter-assay %CV ≤11.4). This method was validated according to FDA guidance for industry and can be used to assess the pharmacokinetics of two newly approved antiretrovirals, or to support therapeutic drug monitoring for modern antiretroviral therapy.

Noncompartmental pharmacokinetics of three intravenous mycophenolate mofetil concentrations in healthy Standardbred mares.

Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed. To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses. Six healthy Standardbred mares. Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation. Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in Cmax and AUCinf _obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in Cmax and AUCinf _obs for MMF and its metabolites was nonlinear. Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.

Character-space-limited online prescription drug communications: Four experimental studies

BackgroundCharacter-space-limited (CSL) communications (e.g., tweets) present a challenge for maintaining fair balance between risks and benefits in direct-to-consumer prescription drug promotion. Current FDA guidance advises incorporating risk information within the CSL communication. Because space is limited, others suggest only linking to risk information. ObjectivesThe primary objectives were to examine the effects of (1) including substantive risk information in CSL communications versus only providing a link to risk information and (2) including risks and benefits versus only risks on the linked landing page. MethodsFour experimental studies (N = 469 per study) were conducted. Participants self-reported migraine (Studies 1 and 2) or being overweight (Studies 3 and 4). Participants were instructed to either browse or search a mock Google (Studies 1 and 3) or Twitter (Studies 2 and 4) search page that included the study CSL communication. The CSL communication either did or did not include risk information, and its linked landing page either did or did not include benefit information. Half the participants used a mobile device and half used a desktop/laptop. Participants viewed the search page once without prompting to pay attention to the CSL communication and a second time with prompting. ResultsIncluding the risk in the CSL communication increased the likelihood that participants would recognize the risk after the first viewing (three studies) and second viewing (four studies). However, after the second viewing, including the risk decreased the likelihood that participants would click the landing-page link (three studies), and decreased the number of landing-page-only risks recognized (three studies). Including the drug's benefit on the landing page increased benefit recognition (four studies) without negatively affecting risk recognition or risk perceptions (three studies). ConclusionsThe results provide a first look at the tradeoffs for consumer understanding of drug risks and benefits when drugs are promoted in CSL communications.