Food And Drug Administration Guidance Research Articles

Individualized medication of venetoclax based on therapeutic drug monitoring in Chinese acute myeloid leukemia patients using an HPLC method.

The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. The analysis required the extraction of a 50 μl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH 2 PO 4 (pH 3.5) (60/40, v/v) on a Diamond C 18 (4.6 mm × 250 mm, 5 μm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). The calibration curve was linear ( R2 = 0.9998) over the range of 75-4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration ( Cmax ) was 1881.19 ± 756.61 ng/ml, while the trough concentration ( Cmin ) was 1212.69 ± 767.92 ng/ml in acute myeloid leukemia patients. Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Staying Out of Trouble: FDA Regulation of Orthobiologics and the Shoulder Surgeon

Food and Drug Administration (FDA) regulation of Orthobiologics can be challenging to interpret for the non-regulatory scientist. However, understanding how regulations apply to clinical use of these orthobiologic products is critical, as there are both ethical and legal ramifications to using orthobiologics in conflict with regulations. Recent FDA guidances have attempted to clarify these issues, although questions still remain regarding nuances in regulatory applications. FDA guidances, industry blogs, and relevant publications were searched for citations regarding recent orthobiologics and regulations. These sources were compiled into a current assessment of FDA regulations regarding the use of orthobiologics in the shoulder. Key to understanding these regulations is the FDA differentiation of human cellular and tissue based products (HCTPs) into 361 and 351 category products. While some controversy still exists, FDA has attempted to clarify these issues with several recent guidances. Of equal importance, FDA has ended enforcement discretion for many biologic products in June of 2021, creating a previously tolerated class of orthobiologics that now requires an Investigational New Drug (IND) application and subsequent Biologic License Application to legally market these orthobiologics. The Same Surgical Procedure Exception was further clarified in 2017 to exempt facilities from regulatory controls when specific guidelines are met. This article attempts to clarify the current thinking on FDA regulations and will allow the shoulder and elbow surgeon to stay within the current bounds of ethical and legal use of these products.

Large language model non-compliance with FDA guidance for clinical decision support devices.

Large language models (LLMs) show considerable promise for clinical decision support (CDS) but none is currently authorized by the Food and Drug Administration (FDA) as a CDS device. We evaluated whether two popular LLMs could be induced to provide unauthorized, devicelike CDS, in violation of FDA's requirements. We found that LLM output readily produced devicelike decision support across a range of scenarios despite instructions to remain compliant with FDA guidelines.

Evaluating the accuracy of Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) responses to United States Food and Drug Administration (FDA) frequently asked questions about dental amalgam

BackgroundThe use of artificial intelligence in the field of health sciences is becoming widespread. It is known that patients benefit from artificial intelligence applications on various health issues, especially after the pandemic period. One of the most important issues in this regard is the accuracy of the information provided by artificial intelligence applications.ObjectiveThe purpose of this study was to the frequently asked questions about dental amalgam, as determined by the United States Food and Drug Administration (FDA), which is one of these information resources, to Chat Generative Pre-trained Transformer version 4 (ChatGPT-4) and to compare the content of the answers given by the application with the answers of the FDA.MethodsThe questions were directed to ChatGPT-4 on May 8th and May 16th, 2023, and the responses were recorded and compared at the word and meaning levels using ChatGPT. The answers from the FDA webpage were also recorded. The responses were compared for content similarity in “Main Idea”, “Quality Analysis”, “Common Ideas”, and “Inconsistent Ideas” between ChatGPT-4’s responses and FDA’s responses.ResultsChatGPT-4 provided similar responses at one-week intervals. In comparison with FDA guidance, it provided answers with similar information content to frequently asked questions. However, although there were some similarities in the general aspects of the recommendation regarding amalgam removal in the question, the two texts are not the same, and they offered different perspectives on the replacement of fillings.ConclusionsThe findings of this study indicate that ChatGPT-4, an artificial intelligence based application, encompasses current and accurate information regarding dental amalgam and its removal, providing it to individuals seeking access to such information. Nevertheless, we believe that numerous studies are required to assess the validity and reliability of ChatGPT-4 across diverse subjects.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Improving Enforcement Measures and Establishing Clear Criteria: A Content Analysis of Tobacco-Brand-Owned Instagram Accounts.

This study examines limitations of the current regulatory framework for tobacco advertising on Instagram. We first investigate compliance with Food and Drug Administration (FDA) warning label requirements for posts by tobacco-owned accounts. Next, we examine the prevalence of content that has been restricted in broadcast or print for its youth appeal, followed by content meeting more expansive criteria for youth appeal set forth in the FDA's guidance document. Posts by tobacco-brand-owned accounts between January 1, 2021, and February 14, 2022, were sampled from Mintel's Comperemedia Omni database. Instagram posts from 15 accounts were examined for violations of FDA warning label requirements and content that has been restricted on other mediums, including cartoons, sports branding, unauthorized claims, and young models (N = 1243). Finally, a subsample of n = 453 unambiguously branded posts was coded for themes that met the FDA's criteria of resonating with younger audiences, particularly that "adolescents rely on external information as they seek to shape their own identities." Only 12.8% of posts had fully compliant warning labels. Content that has been in some way regulated on other mediums, such as cartoons (1.6%), unauthorized health claims (<1%), sports branding (<1%), and young models (4.4%) were infrequent. However, a conservative analysis focusing only on branded posts found that posts frequently highlighted tech elements (45%), device customizability (24.5%), vaper identity (17.7%), stylized product photography (33.6%), social media engagement (32.2%), and memes (5.7%). Enforcement of existing regulations on Instagram is minimal. Explicit content restrictions applying evidence-based guidance on youth-appealing advertising are needed. This research has important implications for enforcing and expanding advertising regulations on social media. First, Instagram's self-imposed regulations are ineffective, permitting tobacco companies to post ads from brand-owned accounts despite claiming to restrict tobacco promotion on the platform. Second, policymakers should seek to apply FDA guidance on youth-appealing advertising informed by decades of research to create explicit enforceable content restrictions that extend beyond cartoons, sports figures, and young models to include content likely to situate tobacco use within the developing self-concept of vulnerable youth such as presenting e-cigarettes as hi-tech devices, highlighting vaper identity, or infiltrating online social media culture. Finally, greater resources for enforcement are needed given the only applicable regulation, warning labels, remains largely ignored.

Patient experiences in ulcerative colitis: conceptual model and review of patient-reported outcome measures

PurposeTo identify symptoms and their impacts on daily functioning and health-related quality of life (HRQoL) experienced by adult patients with ulcerative colitis (UC) and evaluate patient-reported outcome (PRO) measures for UC clinical studies.MethodsA conceptual model of symptoms and impacts of UC were developed from a literature review. PRO measures were identified from the literature, clinical trials databases, health technology assessment submissions, and regulatory label claims, and were selected for conceptual analysis based on disease specificity and use across information sources. PRO measures covering the most concepts when mapped against the conceptual model were assessed for gaps in psychometric properties using Food and Drug Administration (FDA) guidance and consensus-based standards for the selection of health measurement instruments (COSMIN) criteria.ResultsThe conceptual model grouped the 52 symptom concepts and 72 proximal and distal impacts into eight, two, and five dimensions, respectively. Of 65 PRO measures identified, eight underwent conceptual analysis. Measures covering the most concepts and assessed for psychometric properties were the Inflammatory Bowel Disease Questionnaire, Symptoms and Impacts Questionnaire for UC, UC-PRO symptoms modules, UC-PRO impact modules, and Crohn’s and UC Questionnaire; all had good or excellent support for content validity. The UC-PRO Signs and Symptoms fully met FDA guidance and COSMIN criteria for content validity and most psychometric properties.ConclusionExisting PRO measures assess concepts relevant to patients with UC, but all PRO measures reviewed require further psychometric evaluation to demonstrate they are fit for purpose.

Scientific and Regulatory Policy Committee Points to Consider: Review of the United States Food and Drug Administration (FDA) Guidance on Pathology Peer Review in Nonclinical Toxicology Studies.

In December 2021, the United States Food and Drug Administration (FDA) issued the final guidance for industry titled Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers. The stated purpose of the FDA guidance is to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with good laboratory practice (GLP) regulations. On behalf of and in collaboration with global societies of toxicologic pathology and the Society of Quality Assurance, the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) initiated a review of this FDA guidance. The STP has previously published multiple papers related to the scientific conduct of a pathology peer review of nonclinical toxicology studies and appropriate documentation practices. The objectives of this review are to provide an in-depth analysis and summary interpretation of the FDA recommendations and share considerations for the conduct of pathology peer review in nonclinical toxicology studies that claim compliance to GLP regulations. In general, this working group is in agreement with the recommendations from the FDA guidance that has added clear expectations for pathology peer review preparation, conduct, and documentation.

Rapid and simple quantification of belimumab in human plasma using ultra-high performance liquid chromatography with tandem mass spectrometry

ObjectiveBelimumab is a monoclonal antibody against the B-lymphocyte stimulating factor and is approved for the treatment of patients with systemic lupus erythematosus (SLE) not responding adequately to existing therapies. In this study, we established and validated an assay for quantifying belimumab in human plasma. MethodsFrom the peptides generated by trypsin digestion of belimumab, in silico analysis was used to search for unique peptides to determine the surrogate peptides. Samples were trypsin digested, pretreated with solid phase extraction, and analyzed by ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) to quantify the surrogate peptide in the samples. The assay was validated according to the Food and Drug Administration (FDA) bioanalytical method validation guidance. We used the established assay to quantify plasma belimumab concentrations in two SLE patients treated with belimumab. ResultsAmong the unique peptides identified by the in silico analysis, the peptide with the best peak shape when measured by UHPLC-MS/MS was selected as the surrogate peptide. The validation results of this assay met the acceptable criteria recommended by the FDA guidance. The lower limit of quantification (LLOQ) for belimumab was 2 µg/mL. Recovery rates and matrix effects when corrected for internal standards were 91.5–114.3 % and 96.9–108.4 %, respectively. Plasma concentrations of belimumab were measured in 12 samples from two belimumab-treated SLE patients. All concentrations were within the calibration range. ConclusionsWe have established and validated a method for measuring plasma belimumab concentrations using UHPLC/MS-MS. By measuring plasma belimumab concentrations in more patients, this method is expected to contribute to appropriate use of belimumab.

Implementation status of pharmacological studies in the development of orphan drugs

BackgroundThe nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan.ResultsA total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials.ConclusionsIt was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.

Clinical Trial Design in Ulcerative Colitis: Interpreting Evolving Endpoints Based on Post Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1.

The 12-point total Mayo score including a Physician's Global Assessment (PGA) of disease activity has been used to assess outcomes in clinical trials for ulcerative colitis (UC). In 2016, the US Food and Drug Administration (FDA) issued guidance advising the removal of the PGA in future trials. We examined how endpoints in UC trials have evolved and conducted a post hoc analysis of the GEMINI 1 and VISIBLE 1 trials to understand how the use of a 9-point modified Mayo score, excluding PGA, compares with the total Mayo score. Endpoint definitions of clinical remission in phase 3 trials were extracted from published literature and ClinicalTrials.gov. The difference (%Δ) between the proportions of patients in GEMINI 1 and VISIBLE 1 achieving clinical remission with vedolizumab versus placebo at week 52 was measured according to 4 endpoint definitions. Trials completed up to the end of 2019 used the total Mayo score to assess clinical remission. Most trials that were completed or estimated to be completed by June 2020 or later used modified Mayo scores. Post hoc analysis revealed decreasing endpoint stringency was associated with increasing %Δ values. The modified Mayo score definition most like the definition recommended by the FDA produced %Δ values like those reported using the total Mayo score in GEMINI 1 and VISIBLE 1. Endpoint definitions for UC clinical trials have evolved following FDA guidance. The efficacy of vedolizumab, measured using modified Mayo scoring, was comparable to values reported using the total Mayo score.

Quality By Design Pilot Analysis of FDA Regulatory Guidance Web Data Usability for Innovators in Non-Hodgkin Lymphoma: Overcoming Challenges to CAR-T Development

Background: Non-Hodgkin lymphoma (NHL) remains a challenging hematological disease due to varied presentation and etiologies. Historically, cell/gene therapy guidance from the U.S. Food and Drug Administration (FDA) have partial utility in CAR-T development owing to the unique nature of cell-based gene modification but overlap with some key regulatory tenants of broader gene therapy. Inability to identify and apply appropriate guidance poses a challenge for next generation CAR-T immuno- and targeted therapy developers and start-ups, who are situated in a uniquely dynamic regulatory compliance landscape. Methods: A pragmatic Quality by Design (QbD) approach was taken to analyzing the usability and utility of publicly available web-based regulatory guidance via ethnographic observation of an asynchronous industry focus groups ( N = 14) of quality and translational research professionals seeking NHL regulatory guidance and/or regulatory approval information relevant to development of new CAR-T therapeutics (Fig. 1, top) over the course of approximately 10 minutes per observation. Further, a database of innovator and generic approval timelines was created for the 93 currently FDA-approved therapies based on ease of finding corresponding information. Results: Within the focus group, 7% (1/14) rated their team's confidence high in differences between recent specific FDA guidance for early phase CAR-T (Mar 2022) and prior gene and cell therapy guidance agnostic to gene therapy vs CAR-T and 79% (11/14) felt additional CAR-T manufacturing change guidance was needed. QbD stepwise analysis showed experienced users ( N = 9) clicked 10±3 pages before arriving at a desired FDA web-based guidance from the relevant framework (Fig. 1, bottom); remaining inexperienced users were unable to locate the guidance within the test period, primarily due to discrepancies in identifying appropriate classification and center (i.e. FDA CDER/CDER/CDRH) to locate the target guidance. Users had more difficulty locating information on biosimilars and generic drugs, owing in part to confusion between generic terminology on drug vs biologics/vaccines web portals. Conclusions: While current guidance has improved clarity of translational development, additional clarity and ease of access is needed for guidance on manufacturing change and implementation at non-traditional GMP sites for CAR-T to further streamline and scale these therapies. Further, generics developers, in particularly in biosimilars, may face larger hurdles in locating and applying appropriate regulatory guidance using current web-based resources. The research provides a foundation for developing merging web-based aggregation systems to improve the accessibility of regulatory content, utility, and usability of publicly available regulatory information. Such systems have the potential to improve time-to-market for innovator therapeutics and cost-effective biosimilars in NHL. This research provides insight into future web systems and natural language processing (NLP) design that could utilize merging automation to make regulatory information more accessible within key areas.

Use of Single-Arm Trials in FDA Approvals of Treatments in Relapsed or Refractory B-Cell Lymphoma

Background: Single-arm trials are commonly used to evaluate therapies targeting life-threatening or rare diseases (e.g., late-stage cancers that are relapsed or refractory to prior interventions). A number of oncology products supported by single-arm trials have been approved by the United States Food and Drug Administration (FDA). The draft guidance issued by the FDA on 24 March 2023 recommended key considerations for trial design and analysis when a single-arm trial is considered appropriate to support accelerated approval. The objective of this study was to assess how often anticancer drugs approved by the FDA were based on single-arm trials in a typical relapsed or refractory indication and to evaluate the quality of trial design and data leading to approvals. Methods: We reviewed past approvals between 2006 and 2023 listed on the FDA website, focusing on the indication of relapsed or refractory B-cell lymphoma. Of 11 approvals identified, eight were supported by single-arm trials and three were based on randomized controlled trials. Approvals based on single-arm trials were further investigated, and each trial was analyzed for the following criteria as recommended by the draft FDA guidance: 1) if the endpoint was based on response rate assessed using appropriate criteria; 2) if the sample size was sufficient to provide robust estimates of efficacy and safety profile; and 3) if the magnitude and duration of response were adequate. Results: Among the eight approvals based on single-arm trials, one was approved in 2017, one in 2018, and two each in 2020, 2021, and 2023. Three were chimeric antigen receptor T-cell (CAR-T) therapies and were granted regular approval; the other five were non-CAR-T therapies which were granted accelerated approval. The primary endpoints adopted by all the trials were overall response rates (defined as complete and partial responders) and duration of response determined by an independent review committee. The magnitude of overall response rates reported by most trials ranged from 48% to 72% (with more than 50% of them with a complete response); one trial reported an overall response rate of 29% with complete response rate of 13%. A minimal median follow-up of six months after response was achieved in all trials. The estimated median duration of response varied from 10.3 to 21.7 months, with three trials reporting medians not reached. Based on the trial description, the analysis population was pre-specified for the evaluation of efficacy, ranging from 68 to 192 participants. Conclusion: Submissions based on single-arm trials for oncology therapies in the relapsed and refractory setting tended to be well accepted by FDA for accelerated and regular approval when the key criteria of trial design and data quality were adequately met.

A Pragmatic Approach to Navigating FDA Guidance for Therapeutic Product Development in Malignant Hematological Disease

Background: Owing to the unique therapeutic characteristics and diverse etiology of underlying disease, navigating available regulatory guidance can be a challenge for newcomers to therapeutic research and development (R&amp;D). Further, classes of drugs and biologic products are regulated separately by the U.S. Food and Drug Administration (FDA) centers CBER and CDER, respectively. Methods: We provide background on the FDA guidance structure herein and further examine publicly registered clincialtrials.gov data to provide an overview of development status by phases and novel modality (i.e., CAR-T) in context of the regulatory landscape. Results: Therapeutic products developed for malignant hematological disease can be regulated by either CDER or CBER depending on the type of drugs, ranging from small molecules to macromolecules, including cellular and gene therapies. In 2019, CDER of Hematology and Oncology Products (OHOP) has been reorganized and renamed the Office of Oncologic Diseases (OOD). The new OOD structure consists of six divisions including Division of Hematologic Malignancies 1 (DHM1) and Division of Hematologic Malignancies 2 (DHM2) for the review of hematologic malignancies. In 2022, CBER of Office of Tissues and Advanced Therapies (OTAT) was transformed into the Office of Therapeutic Products (OTP) to address the exponential growth in cell and gene therapies. PDUFA VII expanded the INTERACT meeting program to include both centers, a major change that may drive early phase development collaboration. A review on the current state of hematologic malignancies clinical trials in USA shows that, of 301 hematologic malignancies related trails in USA registered to ClinicalTrials.gov (Fig. 1), 4 are in early phase 1(exploratory phase), 126 in phase 1, 120 in phase 2, 18 in phase 3, and 1 in phase 4. Most of the trials are still in early phases 1 or 2. Among the 301 registered clinical trials, 21 of clinical trials (Fig. 2) are CAR-T related, and 10 of the trials are gene modified cell products related. Conclusions: Compared with traditional treatment on malignant hematological disease, immunotherapy is the upcoming trend in cancer treatment. Chimeric antigen receptor (CAR) therapy is at the forefront of cellular/adoptive immunotherapy for cancer treatment due to its sustained remission and better quality of life. Much research and clinical trials have been undertaken in recent years which led to several successful outcomes in CAR therapy. Despite tremendous progress, CAR-T are still faced with many challenges, including evolving regulatory framework along the road. We summarize the regulatory landscape to assist therapy developers to align with FDA expectations.

Analyzing FDA's approaches to using electronic health record and medical claims data to support regulatory decision making

In 2021, the U.S. Food and Drug Administration (FDA) issued draft guidance on the use of electronic health records and medical claims data for regulatory decisions. The draft guidance provides recommendations for sponsors regarding the use of real-world data in conducting studies. It also addresses the challenges and limitations associated with the use of these data and provides recommendations to overcome them. The purpose of this article is to provide a brief overview of key aspects of the FDA's guidance on the use of electronic health record data in regulatory decision making.

SURF: A Screening tool (for sponsors) to evaluate whether Using real-world data to support an effectiveness claim in an FDA application has Regulatory Feasibility.

Based on recent guidance and publicly available approvals, FDA has demonstrated its openness to considering evidence of effectiveness from real-world data (RWD) and non-randomized studies (or "real-world evidence (RWE)") in its decision-making. Through analysis of FDA approvals, several authors have identified methodologic issues commonly discussed by FDA reviewers. However, in our analysis of FDA guidance and use cases, acceptability of RWE also critically depends on whether the characteristics of the clinical development program align with circumstances in which FDA may have flexibility in considering evidence from real-world (RW) study designs relative to more robust designs. Successful use of RWD requires advance planning to allocate the necessary resources and time to undertake principled epidemiology approaches to study design, data selection, and implementation of analyses as well as address regulatory feedback. Thus, sponsors benefit from early identification of programs in which successful RWD use is more likely, to ensure efficient use of resources required for the next steps of scientific feasibility assessment. We developed SURF, a screening tool intended to help a sponsor decide whether to prioritize resources for further exploring the feasibility of using an RWD approach to meet FDA's effectiveness evidentiary standards for a particular clinical development program. Here we provide an analysis of FDA guidance, highlighting the circumstances in which RWD approaches may be most acceptable, and demonstrate the use of this screening tool, including the rationale for its construction, types of evidence needed, and application to publicly available approvals as support of concept.

Poster 378: The Availability and Price of Orthobiologic Injections in the Chicagoland Area: A Market Assessment Study

Objectives: Orthobiologic therapies have recently gained popularity in orthopaedic surgery as potential treatment options that can be used to manage the symptoms of musculoskeletal conditions. However, the market for these products remains unregulated by the Food and Drug Administration (FDA), giving rise to a wide range of available yet untested products. There are growing concerns related to patient safety and product efficacy, but also in regard to the amount of money being charged by providers for these treatments Thus, the purpose of this study was to investigate the current market for orthobiologic injections for knee osteoarthritis in a large, metropolitan city and determine 1) the willingness of providers to disclose the cost of an injection prior to an appointment; 2) the cost of injections if disclosed; 3) the cellular source of injections being advertised as “stem cell” products; and 4) whether there are differences in the market for orthobiologics within and outside of orthopaedic sports medicine practices. Methods: Orthopaedic sports medicine providers in the Chicagoland area were identified through the American Orthopaedic Society for Sports Medicine (AOSSM) and Arthroscopy Association of North America (AANA) registries of sports medicine physicians seeing patients in at least one location within the Chicagoland area. Non orthopaedic clinics (including chiropractors, pain management physicians, and self-advertised “regenerative medicine” clinics) offering orthobiologic injections were compiled using Yelp! and Google search for listings and reviews containing the following key words: “PRP” or “platelet-rich plasma” or “platelet rich plasma,” “SCT” or “stem cells” or “amniotic tissue injections” or “adipose stem cell injections,” and “BMAC” or “bone marrow aspirate concentrate.” A single author [BLINDED] contacted every clinic via a common telephone script, which was modified from an existing study. Data was collected for each site on the types of injections offered, whether price was disclosed over the phone, the price of injections offered, and the source of alternative “stem cell” injections if they were provided. Prices were explicitly specified as being for one injection of one joint. Results: A total of 25 orthopaedic sports medicine practices (comprising 80 AOSSM/AANA surgeons) and 40 non orthopaedic clinics offered at least one of either PRP, “stem cell,” and/or BMAC injections over the phone (Table 1). There was no difference in the likelihood of providing PRP injections (p = 0.698) or BMAC injections (p = 0.340). However, non orthopaedic clinics were significantly more likely to offer “stem cell” injections (p &lt; 0.001). There was no difference in the willingness to disclose the price of PRP without an appointment (p = 0.269), willingness to disclose the price of “stem cell” injections (p = 0.302), willingness to disclose price of BMAC (p = 0.528), or willingness to disclose the source of what each clinic advertised as “stem cell” injections (p = 0.302). While the average price of a BMAC injection was not different between provider types (p = 0.238), the average price of a single PRP injection was significantly higher (p = 0.011) and significantly more variable (F statistic = 0.139; p &lt; 0.001) at non orthopaedic clinics (Figure 1). Similarly, the average price of a single “stem cell” injection was significantly higher (p &lt; 0.001) and significantly more variable (F statistic = 0.080; p = 0.025) at non orthopaedic clinics. Most commonly, alternative “stem cell” products included amniotic-based injections, which are currently discouraged for distribution or use based upon the most recent FDA guidance document. Conclusions: When compared to orthopaedic sports medicine providers, non orthopaedic clinics providing orthobiologic treatments in the Chicagoland area are more likely to offer alternative “stem cell” injections and charge a significantly greater and more variable amount per PRP and “stem cell” injection. Unfortunately, there was liberal use of the terms “regenerative medicine” and “stem cell” therapies in the face of increased scrutiny related to the FDA’s current position on cell-based therapies. Future studies should examine these trends on a national scale to assess compliance with FDA regulations on orthobiologics, as well as establish standards of price for these treatments. [Table: see text]

Optical performance measurement methods for whole slide imaging devices employing a Bayer color imager

Whole slide imaging (WSI) is a widely used digitalization technique to record microscopic images of a whole-stained tissue sample on a glass slide. The US Food and Drug Administration (FDA) provides guidelines for methods used to evaluate various WSI devices. However, the designated evaluation methods for guidance are not always optimal. To this end, novel inspection methods are proposed, which fulfill the requirements of FDA guidance, and then deployed to evaluate the measurement accuracy of our laboratory-built WSI device that employs a 2D Bayer imager. The proposed methods demonstrably evaluate distortion, chromatic aberration, and field curvature with the required precision.

Early evaluation of the Food and Drug Administration (FDA) guidance on antimicrobial use in food animals on antimicrobial resistance trends reported by the National Antimicrobial Resistance Monitoring System (2012–2019)

Antimicrobial resistance (AMR) is one of the biggest challenges to global public health. To address this issue in the US, governmental agencies have implemented system-wide guidance frameworks and recommendations aimed at reducing antimicrobial use. In particular, the Food and Drug Administration (FDA) prohibited the extra-label use of cephalosporins in food animals in 2012 and issued the guidance for industry (GFI) #213 about establishing a framework to phase out the use of all medically relevant drugs for growth promotion in 2012. Also in 2015, the FDA implemented veterinary feed directive (VFD) drug regulations (GFI# 120) to control the use of certain antimicrobials. To assess the potential early effects of these FDA actions and other concurrent antimicrobial stewardship actions on AMR in the food chain, we compared the patterns of the phenotypic (minimum inhibitory concentration (MIC) and percentage of resistance) and genotypic resistances for selected antimicrobials before and after 2016 across different enteric pathogen species, as reported by the National Antimicrobial Resistance Monitoring System (NARMS). Most of the antimicrobials analyzed at the phenotypic level followed a downward trend in MIC after implementing the guidance. Although, most of those changes were less than one 1-fold dilution. On the other hand, compared to MIC results, the results based on phenotypic resistance prevalence evidenced higher differences in both directions between the pre- and post-guidance implementation period. Also, we did not find relevant differences in the presence of AMR genes between pre- and post-VFD drug regulations. We concluded that the FDA guidance on antimicrobial use has not led to substantial reductions in antimicrobial drug resistance yet.

Bridging the gap: FDA diversity-related postmarketing requirements.

e13608 Background: Historically, pre-market clinical trials have lacked enrollment of racial and ethnic minority patients that represent the population intended to be treated with the approved drug in the US. The Food and Drug Administration (FDA) has several programs and initiatives designed to enhance diversity in oncology clinical trials, such as the Oncology Center of Excellence’s (OCE) Project Equity, FDA Guidance documents, and submission of Diversity Plans from industry. Under the code of federal regulations and/or statute, the FDA can issue post-marketing requirements (PMR) to fulfill accelerated approval requirements for confirmatory studies; for assessing safety signals; or for conducting dedicated studies in pediatric patients. FDA may also issue post-marketing commitments (PMC) to generate additional clinical evidence. PMRs and PMCs have been used to obtain additional information on under-represented populations. The objectives of this analysis were to identify oncology PMRs/PMCs issued with a specific focus on racial and ethnic minority populations and examine the trend over the 10-year period. Methods: We searched FDA’s publicly available database of PMR/PMCs, inclusive of drugs and biologic products, and internal agency databases for PMR/PMCs issued between 2012-2022. The PMR/PMC search was further narrowed down by keywords to capture all PMRs/PMCs relevant to races and ethnicity. The PMRs/PMCs were then manually reviewed for duplication and applicability to malignant indications. Results: In a 10-year period, 34 PMR/PMCs focused on race and ethnicity were issued across 461 oncology approvals (initial marketing approvals = 164, new indications = 297). Twenty-two were issued with the initial marketing approval and 12 with supplemental efficacy approvals. All PMR/PMCs were issued in the last 3 years (2019-2022). PMCs accounted for 55.9% (n = 19) and PMRs 44.1% (n = 15). Nine of the 15 PMRs requesting additional information on underrepresented populations were included with the accelerated approval PMRs. Six of the 34 PMR/PMCs were issued to obtain additional PK or dosing information in the underrepresented population. The most common PMR/PMC indications issued were lymphoma (n = 13, 38.2%), multiple myeloma (n = 8, 23.5%), and non-small cell lung cancer (n = 4, 11.8%). Although PMR/PMCs that mentioned a specific race were limited, African American/Black (n = 8) and Asian (n = 1) were occasionally identified. All studies identified in this analysis are ongoing except for one, for which the product was withdrawn. Conclusions: Our analysis highlights the trend and increased emphasis on race and ethnicity in post approval oncology studies. While progress has been made to promote studies that are representative of the US population through these PMRs/PMCs, diversity plans, and FDA guidance over the course of the past 10 years, more efforts are needed to better enhance diversity in clinical trials moving forward.