Drug Administration Center Research Articles

Facilitating the Approval Process of Anti-Infective Technologies and Advancing Them to the Market: Insights from an FDA Workshop on Orthopaedic Device-Related Infections.

Orthopaedic device-related infection is one of the most devastating complications in orthopaedic and trauma surgery. With increasing life expectancies as well as the lifelong risk of bacterial seeding on an implant, the prevention and treatment of device-related infection remains an important area for research and development. To facilitate information exchange and enhance collaboration among various stakeholders in the orthopaedic community, the U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) organized an inaugural workshop on orthopaedic device-related infections, exploring the regulatory challenges that are faced when proceeding from the bench level to marketing and clinical implementation of new infection-control devices and products. This article summarizes the perspectives of scientists, clinicians, and industry partners on the current regulatory approval process for orthopaedic anti-infective technologies as well as the proposed strategies to overcome these regulatory challenges.

Measuring Patient Preferences at the FDA Center for Devices and Radiological Health: Reflections and Projections

ObjectivesPatient preference information (PPI) is a way to incorporate the patient voice in the evaluation of medical devices. The US Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) has been working to encourage the voluntary inclusion of PPI throughout the medical device lifecycle for nearly a decade. This article reflects CDRH's efforts to encourage collection of PPI and offers perspectives on the future of PPI in the evaluation of medical devices. MethodsCDRH regulatory guidance, public meetings, and collaborations relating to PPI were explored. ResultsSince 2012 when CDRH issued guidance on how PPI can be used as scientific evidence in the benefit-risk regulatory submission, CDRH has issued 5 subsequent guidance documents expanding on the use of PPI in medical device evaluations. CDRH remains committed to advancing the science and application of PPI in the medical device ecosystem through many collaborations with professional organizations, patient advocacy groups, and academic institutions. By hosting and actively participating in multiple scientific and regulatory public meetings and conferences, CDRH fosters a continuous learning environment where the experience of using PPI in regulatory submissions can be shared. A September 2020 meeting cosponsored by FDA and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) discussed the state of PPI in regulatory applications and beyond. ConclusionThis article describes these pivotal events that have helped to increase the use of PPI in medical device evaluation as well as discusses future applications of PPI.

Endoscopic polypectomy devices.

Video 1Use of submucosal injection prior to en-bloc endoscopic mucosal resection.Video 2Use of a detachable loop ligating device prior to hot snare resection of a pedunculated polyp.

An LC-MS/MS Method for the Determination of Antibiotic Residues in Distillers Grains: Collaborative Study.

Antibiotics are used in ethanol production to discourage the growth of bacteria that would lower the yield of the product. Any antibiotic residues remaining in distillers grain (DG) co-product could lead to antimicrobial resistance, which is a public health concern. The U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) previously developed an LC-MS/MS analytical method to detect residues of erythromycin A, penicillin G, virginiamycin M1, and virginiamycin S1 in DG to enable regulatory decision making. The objective of this study was to ensure the method's robustness by carrying out a multi-laboratory validation of the method. Test portions were extracted with a mixture of acetonitrile and buffer. The extract was cleaned by solid phase extraction. The concentrated eluant was reconstituted and analyzed by LC-MS/MS. Eight laboratories participated in the study. Average accuracies for the combined three matrixes for all four compounds at all fortification levels ranged from 83->109% with repeatability relative standard deviation (RSDr; within laboratory) ≤17% and reproducibility relative standard deviation (RSDR; between laboratory) ≤21%. The Horwitz ration (HorRat) values ranged 0.4-1.0 indicating that method reproducibility is acceptable. An interlaboratory study was successfully conducted to evaluate an LC-MS/MS method for the determination of the drugs of interest in DG. The results demonstrate that the method is fit for purpose to determine the drugs in DG and could serve as a regulatory method capable of being used for compliance actions for DG containing these antibiotic contaminants. The method was posted to the FDA/Foods Program Compendium of Analytical Laboratory Methods.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Opioid exposure associated with poppy consumption reported to poison control centers and the U.S. Food and Drug Administration

Objective To assess characteristics of exposures to contaminated poppy and identify trends in exposure and poppy-related deaths. Methods Cross-sectional analysis of adverse events associated with exposure to poppy products (primarily poppy seeds) from the American Association of Poison Control Centers’ National Poison Data System (NPDS), 2000–2018, supplemented with analysis of overdoses and deaths related to poppy from the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS) (2004–2018), and the FDA Adverse Event Reporting System (FAERS) (1968–2018). Results There were 591 NPDS exposure cases involving poppy between 2000 and 2018 including 392 in persons aged 13+. Rates of intentional exposures in NPDS increased among the age 13+ group over the study period. Most intentional exposures occurred in males in their teens and twenties. NPDS included 18 overdoses and three deaths likely attributable to poppy, most involving poppy seed tea. CAERS and FAERS included five additional deaths likely attributable to opioids in poppy. Conclusions Including previously reported cases, there are now at least 19 U.S. deaths associated with poppy seeds in the literature. We recommend that practitioners working in opioid treatment and recovery be alert to use of poppy to treat pain and symptoms of withdrawal.

Leveraging the Value of CDISC SEND Data Sets for Cross-Study Analysis: Incidence of Microscopic Findings in Control Animals.

Implementation of the Clinical Data Interchange Standards Consortium (CDISC)'s Standard for Exchange of Nonclinical Data (SEND) by the United States Food and Drug Administration Center for Drug Evaluation and Research (US FDA CDER) has created large quantities of SEND data sets and a tremendous opportunity to apply large-scale data analytic approaches. To fully realize this opportunity, differences in SEND implementation that impair the ability to conduct cross-study analysis must be addressed. In this manuscript, a prototypical question regarding historical control data (see Table of Contents graphic) was used to identify areas for SEND harmonization and to develop algorithmic strategies for nonclinical cross-study analysis within a variety of databases. FDA CDER's repository of >1800 sponsor-submitted studies in SEND format was queried using the statistical programming language R to gain insight into how the CDISC SEND Implementation Guides are being applied across the industry. For each component needed to answer the question (defined as "query block"), the frequency of data population was determined and ranged from 6 to 99%. For fields populated <90% and/or that did not have Controlled Terminology, data extraction methods such as data transformation and script development were evaluated. Data extraction was successful for fields such as phase of study, negative controls, and histopathology using scripts. Calculations to assess accuracy of data extraction indicated a high confidence in most query block searches. Some fields such as vehicle name, animal supplier name, and test facility name are not amenable to accurate data extraction through script development alone and require additional harmonization to confidently extract data. Harmonization proposals are discussed in this manuscript. Implementation of these proposals will allow stakeholders to capitalize on the opportunity presented by SEND data sets to increase the efficiency and productivity of nonclinical drug development, allowing the most promising drug candidates to proceed through development.

Methods Development and Modeling Research: Contributions to Advancing TRS and Informing Regulations

The US Food and Drug Administration's (FDA) Center for Tobacco Products (CTP) funds a wide range of research studies. Methods development and modeling research (MDMR) are 2 areas of interest, as they can help advance tobacco regulatory science (TRS) by fostering data synthesis and exploration of complex relationships. Our analyses of the CTP portfolio found that 13% of publications focused on MDMR, and the most commonly addressed CTP priority research domains were knowledge, attitudes, and behaviors, and toxicity and carcinogenicity. MDMR publications were cited by 1,186 publications, 5 FDA proposed rules and guidance documents, and 3 dockets. MDMR publications are characterized as foundational research and help build the evidence base that informs policy. While MDMR represents a small portion of the CTP research portfolio, they have made important contributions to advancing TRS and informing regulatory actions.

Antimicrobial use data collection in animal agriculture.

Antimicrobial drug use can contribute to the emergence of antimicrobial drug-resistant organisms; therefore, judicious use of this important category of drugs is critical in both human and animal medicine to slow the development and spread of resistance. The US Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) is committed to advancing efforts to implement good antimicrobial stewardship practices in veterinary settings as part of our mission to protect human and animal health. In order to understand the drivers of resistance in veterinary settings and assess the impact of interventions designed to slow the development and spread of resistance, it is vital to have access to scientifically sound data on antimicrobial use and resistance. In 2016, FDA awarded funds in the form of cooperative agreements to support pilot projects for the collection of farm-level antimicrobial use data in animal agriculture. These funded data collection efforts are intended to provide needed information on antimicrobial use practices in various animal production settings and to inform the development of long-term strategies for collecting and reporting such data in a sustainable and nationally representative manner. Data were collected from records of participating dairy and feedlot cattle operations, swine companies, and broiler and turkey companies. Information from the first 2years of the pilot projects is presented in this special issue, along with discussions related to challenges of collecting and reporting antimicrobial use data.

New Drugs Regulatory Program Modernization: Vision, Strategic Objectives, and Impact.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration’s Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

Lipid laden macrophages and electronic cigarettes in healthy adults.

BackgroundAn outbreak of E-cigarette or Vaping Product Use-Associated Lung Injury (EVALI) with significant morbidity and mortality was reported in 2019. While most patients with EVALI report vaping tetrahydrocannabinol (THC) oils contaminated with vitamin E acetate, a subset report only vaping with nicotine-containing electronic cigarettes (e-cigs). Whether or not e-cigs cause EVALI, the outbreak highlights the need for identifying long term health effects of e-cigs. EVALI pathology includes alveolar damage, pneumonitis and/or organizing pneumonia, often with lipid-laden macrophages (LLM). We assessed LLM in the lungs of healthy smokers, e-cig users, and never-smokers as a potential marker of e-cig toxicity and EVALI.MethodsA cross-sectional study using bronchoscopy was conducted in healthy smokers, e-cig users, and never-smokers (n = 64). LLM, inflammatory cell counts, and cytokines were determined in bronchial alveolar fluids (BAL). E-cig users included both never-smokers and former light smokers.FindingsHigh LLM was found in the lungs of almost all smokers and half of the e-cig users, but not those of never-smokers. LLM were not related to THC exposure or smoking history. LLM were significantly associated with inflammatory cytokines IL-4 and IL-10 in e-cig users, but not smoking-related cytokines.InterpretationThis is the first report of lung LLM comparing apparently healthy smokers, e-cig users, and never-smokers. LLM are not a specific marker for EVALI given the frequent positivity in smokers; whether LLMs are a marker of lung inflammation in some e-cig users requires further study.FundingThe National Cancer Institute, the National Heart, Lung, and Blood Institute, the Food and Drug Administration Center for Tobacco Products, the National Center For Advancing Translational Sciences, and Pelotonia Intramural Research Funds

Cover Story: Matters of Perspective: Appreciating Diversity and Promoting Inclusion in Health Technology Professions.

Cover Story: Matters of Perspective: Appreciating Diversity and Promoting Inclusion in Health Technology Professions.

Do topically aplied skin creams containing retinyl palmitate affect the photocarcinogenecity of simulated solar light?

Retinyl palmitate (all-trans-retinyl palmitate; RP) was nominated in 2001 by the U.S. Food and Drug Administration's Center for Food Safety and Applied Nutrition (CFSAN) to the National Toxicology Program (NTP) as a high priority compound for phototoxicity and photocarcinogenicity studies at the National Center for Toxicological Research (NCTR). Studies with SKH-1 hairless mice are required to test whether topical application of RP enhances the phototoxicity and photocarcinogenicity of simulated solar light and UV light. Mechanistic studies are needed to provide insight into the disposition of RP in vitro and on the skin of mice, and to test thoroughly whether genotoxic damage by UV-induced radicals may participate in any toxicity of topically applied RP in the presence of UV light.

BL30SEC Method for Detection of Beta-Lactams in Raw Commingled Cow Milk: AOAC Performance Tested MethodSM 061902.

Testing milk for antibiotics before acceptance into dairies is required by the U.S. Pasteurized Milk Ordinance. Technological advances in tests have reduced screening times and improved detection accuracy. This work describes the validation of the Charm Rapid One Step Assay Beta-Lactam 30 Second Test according to the U.S. Food and Drug Administration Center for Veterinary Medicine protocol for raw commingled milk. Milk is added to the lateral flow test strip in an incubator/reader to deliver a 30 second result. Independent laboratory validation followed sensitivity, interference, and incurred residue protocols. Sensitivity, in parts per billion (ppb = µg/kg), using a probit curve determined 90% percent detection with 95% confidence, which met National Conference of Interstate Milk Shipments (NCIMS) specifications. Six U.S. approved beta-lactam drugs were detected below, but within 50% of, target/tolerance levels for penicillin G 2.9 ppb, ampicillin 5.9 ppb, amoxicillin 5.8 ppb, cephapirin 13 ppb, cloxacillin 8.1 ppb, and ceftiofur metabolites 73 ppb. No interferences were observed from 33 animal drugs at 100 ppb, somatic cells at 1.2 million/mL, or bacterial levels of >300000 CFU/mL. Incurred residue detection levels were similar to levels determined with the spiked parent compound. The data support NCIMS that the BL30SEC method met U.S. criteria for testing milk for beta-lactams.

Data Integrity in Global Clinical Trials: Discussions From Joint US Food and Drug Administration and UK Medicines and Healthcare Products Regulatory Agency Good Clinical Practice Workshop.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials. Regulatory agencies conduct GCP inspections to verify the integrity of data generated in clinical trials and to assure the protection of human research subjects, in addition to ensuring that clinical trials are conducted according to the applicable regulations. The first joint GCP workshop of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA-UK) was held in October 2018 and provided the agencies' perspectives on the importance of data quality management practices on data integrity. Regulatory perspectives on data blinding to minimize introduction of bias, and the role of audit trails in assessing data integrity in global clinical trials were discussed. This paper summarizes considerations of both agencies on these topics, along with case examples.

THE EFFECT OF ANESTHETIC TIME AND CONCENTRATION ON BLOOD GASES, ACID-BASE STATUS, AND ELECTROLYTES IN KOI (CYPRINUS CARPIO) ANESTHETIZED WITH BUFFERED TRICAINE METHANESULFONATE (MS-222).

Anesthesia is commonly employed in aquatic medicine to facilitate physical exams, diagnostics, and surgical interventions. Tricaine methanesulfonate (MS-222) is the most commonly used anesthetic for fish and is currently the only anesthetic approved by the US Food and Drug Administration Center for Veterinary Medicine for food-producing fish. Despite the frequency of anesthetic procedures in fish, anesthetic monitoring remains rudimentary in many facilities. This study evaluated the impact on blood gases, acid-base balance, and electrolytes in koi (Cyprinus carpio) anesthetized at concentrations of 100 mg/L and 150 mg/L MS-222. Blood samples from 25 fish per treatment were collected at 5 and 20 min of anesthetic immersion. Forty-nine of 50 fish recovered uneventfully from anesthesia; one fish did not recover and was euthanatized. Results showed significant increases in partial pressure of carbon dioxide (pCO2) (P = 0.006) and hyperglycemia (P = <0.0001) with increasing anesthetic concentration and time under anesthesia and a significant decrease in partial pressure of oxygen (pO2) with increased anesthetic time (P = 0.021). There were several electrolyte changes observed with both increasing anesthetic time and concentration. All electrolytes except potassium remained within published reference ranges for koi, while potassium showed a significant decrease in concentration associated with anesthetic time and concentration. The results of this study indicate that MS-222 at 100 mg/L and 150 mg/L represent safe anesthetic concentrations for koi undergoing minimally invasive diagnostics; however, koi anesthetized with MS-222 at a concentration of 150 mg/L experienced more significant changes in blood gases, acid-base balance, and electrolyte concentrations.

FCC Announces Its Existing RF Exposure Limits Apply to 5G [Health Matters

Citing support from the U.S. Food and Drug Administration's Center for Devices and Radiological Health, the U.S. Federal Communications Commission (FCC) announced in December 2019 that it reaffirms the RF radiation exposure li mits it first adopted in 1996 fa The action was undertaken in the face of appeals from some to tighten, and others to loosen, the existing limits. In the process, the FCC also resolved and terminated a 2013 Notice of Inquiry that sought public input on whether it should modify its existing RF exposure rules considering recent scientific opinions and authoritative expert views, among other issues [2]. Apparently, six years since the Notice of Inquiry, the FCC deems it appropriate to maintain the existing RF exposure limits. It is interesting to observe that the FCC dedined to make changes that would stiffen the current rules or to make any changes that would effectively relax the current rules.

Echocardiography in nonclinical studies: Where are we?

Echocardiography is a powerful, noninvasive tool used both in clinical and nonclinical settings, including in drug development. When used appropriately, it can provide valuable translational information about pharmacodynamics, safety pharmacology, or toxicology, helping to define no-observed-adverse-effect levels and providing guidance for clinical monitoring and dose selection. Echocardiography is advantageous in conducting longitudinal studies and reducing the number of animals used in safety assessments. To this end, there has been no clear enunciation of what constitutes appropriate use of this imaging technology in a nonclinical drug development setting. In this review, we describe the use of echocardiography in nonclinical studies in regulatory submissions to the US Food and Drug Administration Center for Drug Evaluation and Research. In addition, we discuss three main areas: the operator, image acquisition, and image analysis, where variability may affect the reliability of information generated in an echocardiography study. As a path forward, our recommendation is for a multi-disciplinary expert working group to establish guidelines for education and credentialing of nonclinical echocardiographers as well as quality assurance standards for nonclinical echocardiography labs.

Trends in FDA drug approvals over last 2 decades: An observational study.

Introduction:The discovery of novel drugs is critical for pharmaceutical research and development as well as for patient treatment. Repurposing existing drugs that may have anticipated effects as potential candidate is one way to meet this important goal. Systematic investigation and comprehensive analysis of approved drugs could provide valuable insights into trends in the discovery and may contribute to further discovery of newer drugs systematically. Food and drug administration (FDA's) Center for Drug Evaluation and Research (CDER) every year summarizes novel drugs, some of which are truly innovative and help in advancing clinical care. This study was conducted to find a trend in drug approvals by FDA in the last 2 decades. Awareness of these new drugs amongst the primary care physicians is also crucial as they have been prescribing these agents in the past.Methodology:In this cross-sectional study, we collected, surveyed, and analyzed drugs approved by U.S. Food and Drug Administration (USFDA) from the year 2000 till 2017 identified from ClinicalTrials.gov and online database of FDA. Drugs approved every year were assessed for total number, class of drug, indication, and category of approval. Type of accelerated regulatory pathways and reasons for speedy approvals every year were also studied. Microsoft Office Excel 2007 was used for tabulation and analysis.Results:Total 209 were approved from 2000 to 2008. Out of these 9.09% were indicated for cardiovascular disorders and 12.91% for neurological disorders. Antibiotics (5.26%) and antivirals (5.74%) were least contributed, whereas anticancer drugs (11.96%) and biologics (7.17%) approval remained constant. Whereas, out of three hundred and two drugs approved during 2009--2017, 5.29% were for cardiovascular disorders, 9.93% for neurological disorders. Antibiotics (5.29%) and antivirals (5.96%) were least in number, whereas anticancer drugs (17.54%) and biologics (15.56%) approval took a steep rise in these years. Also, a wide variation in the number and category of approval was observed over a period of years. The use of fast track, accelerated approval, and priority review programs have also been steadily increasing since 2000.Conclusion:There has been a steady rate of introduction of new drugs by CDER over the last two decades. Expedited approval of anticancer and biologics is seen as recent trend in drug development. Relatively, slow progress in approval of drugs for neurological disorders (depression, psychosis, multiple sclerosis, etc.) and lifestyle diseases like obesity, atherosclerosis, diabetes, etc., were seen. These findings reflect more emphasis being laid down in research for anticancer drugs and biologics.

Chromium propionate in broilers: human food and broiler safety

Chromium propionate (Cr Prop) is approved by the U.S. Food and Drug Administration Center for Veterinary Medicine for supplementation to broiler diets up to 0.20 mg Cr/kg diet. A 49-D study was conducted to: 1) determine the safety of Cr Prop when supplemented at 2 and 10 times (×) the approved feeding level over the normal life span of broilers, and 2) determine the effects of supplementing Cr Prop on Cr concentrations of tissues consumed by humans. On day zero, 216 Ross 708 broilers were stratified by weight within sex and randomly assigned to treatments. Dietary treatments were 0 (control), 0.40, and 2.0 mg supplemental Cr/kg diet from Cr Prop. There were 6 replicate cages each of male and female broilers per treatment. At the end of the study blood was collected for determination of plasma biochemical measurements and tissue samples were collected for Cr analysis. Supplementing 0.40 mg Cr/kg diet (2×) did not adversely affect broiler performance, mortality, plasma biochemical measurements or Cr concentrations in breast muscle, skin with adhering fat, or liver. Chromium propionate supplemented at 2.0 mg Cr/kg (10×) did not affect Cr concentrations in breast muscle or skin with adhering fat, but increased (P < 0.05) liver Cr concentrations. Supplementing Cr Prop at 10× the approved feeding level decreased feed intake and gain in male but not female broilers from days 21 to 49. Results of this study support the safety of Cr Prop in broiler diets, and indicate that Cr Prop supplementation to broiler diets at 2 or 10× the approved feeding level does not present a human health concern.