Food And Drug Administration 's Center Research Articles

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

In Case You Haven't Heard…

The U.S. Food and Drug Administration (FDA) has approved brexpiprazole (Rexulti) for agitation associated with Alzheimer's disease dementia, the agency announced last week, the medical news service MedPage Today reported. The new indication for brexpiprazole will make it the first FDA‐approved treatment for this condition. The atypical antipsychotic was previously approved for treating major depressive disorder and schizophrenia. “Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer's disease. ‘Agitation’ can include symptoms ranging from pacing or restlessness to verbal and physical aggression,” said Tiffany Farchione, M.D., director of the division of psychiatry in the FDA's Center for Drug Evaluation and Research, in a press release. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression.” Researchers found that brexpiprazole treatment achieved a statistically significant reduction in agitation over a 12‐week treatment period, based on the Cohen‐Mansfield Agitation Inventory. The most common side effects with brexpiprazole among patients with agitation associated with dementia due to Alzheimer's disease include headache, dizziness, urinary tract infection, nasopharyngitis and sleep disturbances.

Validation of an LC-MS/MS method for assessment of fenbendazole sulfone drug residue in northern bobwhite liver.

The Northern Bobwhite (Colinus virginianus) is an economically important game bird within the Rolling Plains Ecoregion. Within this region, bobwhite is experiencing extreme cyclic population fluctuations which are resulting in a net decline in total population. It is suspected that within this region two helminth parasites, an eyeworm (Oxyspirura petrowi) and a cecal worm (Aulonocephalus pennula), are contributing to this phenomenon. However, this has been difficult to study as the primary mode of investigation would be the deployment of anthelmintic treatment. Unfortunately, no registered treatments for wild bobwhite currently exist. Thus, utilizing an anthelmintictreatment for wild bobwhite would require registration of that treatment with the U.S. Food and Drug Administration (FDA). As bobwhite are game birds that are hunted, they are considered food-producing animals to the FDA, and as such require the assessment for the withdrawal of the drug residues to be assessed for human food safety. In this study, we optimized and validated a bioanalytical method for the quantification of fenbendazole sulfone in bobwhite following the U.S. FDA Center for Veterinary Medicine Guidance for Industry #208 [VICH GL 49 (R)] for assessment of fenbendazole sulfone drug residue in Northern bobwhite liver. The official method for quantifying fenbendazole sulfone in domestic chicken (Gallus gallus) was adapted for use in bobwhite. The validated method quantitation range is 2.5-30 ng/mL for fenbendazole with an average recovery of 89.9% in bobwhite liver.

A Review on Approval Process and Regulation of Medical Devices as per US FDA and CDSCO

Regulatory affairs play a significant role in the pharmaceutical industry, it is “the process of gathering, reviewing, and monitoring the existing regulatory environment and creating regulatory plans and gaining a competitive edge for securing regulatory approvals required more than just acquiring facts”. A medical device is a treatment instrument that "does not work on or in the human body in a way that is primarily intended by pharmacological, immunological, or metabolic mechanisms”. In other words, a medical device is essentially any medical product, not a medicine or biological product. By the Drugs and Cosmetics Act, Central Drugs Standard Control Organization (CDSCO) oversees approving drugs, conducting clinical trials, setting standards for drugs, monitoring the quality of drugs imported into the nation, and coordinating the efforts of state drug control organizations by offering professional advice to ensure uniformity in the application of the Drugs and Cosmetics Act. The US Food and Drug Administration (FDA), a single agency, oversees the regulation of a trillion dollars’ worth of goods, or about 25 cents of every dollar spent, including 80 percent of the food supply in the US, all medical devices, and prescription drugs, animal products, cosmetics, and even the production of tobacco products. The FDA's Center for Devices and Radiological Health regulates companies that produce, repackage, re-label, and/or import medical devices sold in the United States (CDRH). Also, CDRH is in charge of overseeing the regulation of lasers, x-ray machines, ultrasound equipment, microwave ovens, and color televisions, among other electronic gadgets that generate radiation for both medical and non-medical purposes. The IMDR, which was published in January 2017 and became effective in January 2018, was produced by the Medical Devices and Diagnostics Division of CDSCO and is a set of structured regulations for medical devices. In February 2020, the "Medical Devices (Amendment) Regulations, 2020" were established, and they became effective in April 2020. The 2020 amendment now includes a new clause called "registration of specific medical equipment."

Proceedings: PET Drugs-A Workshop on Inspections Management and Regulatory Considerations.

Recent advances in the development of new molecular imaging agents for PET have led to the approval of several new molecular entities for PET imaging by the U.S. Food and Drug Administration (FDA) within the last 10 y. However, the continued use of PET drugs for diagnostic imaging procedures is reliant on a sustainable network of PET manufacturing facilities operating in accordance with the regulations for current good manufacturing practices for PET drugs (title 21, Code of Federal Regulations, part 212). With this goal in mind, a public workshop entitled "PET Drugs: A Workshop on Inspections Management and Regulatory Considerations" was held on the FDA campus in Silver Spring, MD, on February 21, 2020. The workshop was cosponsored by the FDA's Center for Drug Evaluation and Research, the Society of Nuclear Medicine and Molecular Imaging, the Medical Imaging Technology Alliance, and the World Molecular Imaging Society, in collaboration with the Coalition of PET Drug Manufacturers. The organizing committee for the workshop consisted of representatives from academic and commercial PET manufacturers as well as FDA staff members. The coauthors on this paper are all members of the workshop-organizing committee.

Reporting Medical Device Events

The Food and Drug Administration (FDA) is responsible for protecting public health by regulating medical devices, radiation-emitting electronic devices, drugs, biologics, food, tobacco, and cosmetics. After a product reaches the market, the Agency continues to evaluate a product's safety by monitoring adverse events. FDA's Center for Devices and Radiological Health facilitates reporting of medical device events and complaints by manufacturers, importers, healthcare facilities, and the general public to help FDA identify potential safety signals and/or improve medical device performance. FDA has established 2 reporting mechanisms (1) reporting through the public MedWatch system and (2) direct user facility collaboration via the MedSun program.

Is the FDA Failing Women?

Many devices in current use were marketed before the US Food and Drug Administration (FDA) began regulating devices in 1976. Thus, manufacturers of these devices were not required to demonstrate safety and effectiveness, which presents both clinical and ethical problem for patients, especially for women, as some of the most dangerous devices-such as implanted contraceptive devices-are used only in women. This article investigates whether and to what extent devices for women receive less rigorous scrutiny than devices for men. This article also suggests how the FDA Center for Devices and Radiological Health could more effectively ensure safety and effectiveness of devices that were marketed prior to 1976.

FDA moves to ban menthol cigarettes

Last week, the Food and Drug Administration (FDA) announced it is going to ban menthol cigarettes within the year. The decision is based on the addictiveness, not of menthol, but of the nicotine. For the same reason, the FDA banned all other flavored cigarettes in 2009. “Banning menthol—the last allowable flavor—in cigarettes and banning all flavors in cigars will help save lives, particularly among those disproportionately affected by these deadly products,” said acting FDA commissioner Janet Woodcock, M.D., on April 29. “With these actions, the FDA will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low‐income populations, and LGBTQ+ individuals, all of whom are far more likely to use these tobacco products.” Studies show that menthol increases the appeal of tobacco, especially among young people and Blacks. “For far too long, certain populations, including African Americans, have been targeted, and disproportionately impacted by tobacco use,” said Mitch Zeller, J.D., director of the FDA's Center for Tobacco Products. “Despite the tremendous progress we've made in getting people to stop smoking over the past 55 years, that progress hasn't been experienced by everyone equally.” H. Westley Clark, M.D., J.D., Dean's Executive Professor at Santa Clara University, told ADAW after the announcement that farmers should be incentivized to grow non‐tobacco products, stores incentivized to sell other products, and nicotine replacement and other therapies be made available. Taxation helps as well, as does limited access to the product, he said. The FDA said it will work with partners in other federal agencies to make sure the support is there for those who are trying to quit.

Withdrawing Approval of Makena—A Proposal From the FDA Center for Drug Evaluation and Research

(Abstracted from N Engl J Med 2020;383:e131(1)–e131(4)) Makena (hydroxyprogesterone caproate injection) is currently the only drug on the market for the prevention of recurrent preterm birth (PTB). The Food and Drug Administration (FDA) granted accelerated approval for this drug in 2011.

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.

In Case You Haven't Heard…

The U.S. Food and Drug Administration (FDA) announced warning letters to 10 companies for illegally selling dietary supplements that claim to cure, treat, mitigate or prevent depression and other mental health disorders, in violation of the Federal Food, Drug, and Cosmetic Act, an FDA news release stated. The warning letters were issued to: Enlifta LLC, Lifted Naturals, Mountain Peak Nutritionals, SANA Group LLC, Wholesome Wellness, Dr. Garber's Natural Solutions, ProHealth Inc., Blossom Nature LLC, FDC Nutrition Inc. and Silver Star Brands Inc. “Dietary supplements that claim to cure, treat, mitigate or prevent depression and other mental health disorders are unapproved new drugs that could potentially harm consumers who use these products instead of seeking proven treatments from qualified health care providers,” said Steven Tave, director of the Office of Dietary Supplement Programs in the FDA's Center for Food Safety and Applied Nutrition. “This is especially concerning during the ongoing pandemic, when consumers are even more susceptible to depression and mental health issues. The agency is committed to taking action to protect the public from unlawful dietary supplements.”

Integrating the Food and Drug Administration Office of the Coordinated Outbreak Response and Evaluation Network's foodborne illness outbreak surveillance and response activities with principles of the National Incident Management System.

The Food Safety Modernization Act mandates building a national Integrated Food Safety System, which represents a seamless partnership among federal, state, local, territorial, and tribal agencies. During multistate foodborne illness outbreak investigations, local and state partners, the Centers for Disease Control and Prevention, the United States Food and Drug Administration (FDA), or the United States Department of Agriculture Food Safety Inspection Service, depending on the regulated food product, become engaged and assist in coordinating the efforts between partners involved and determine the allocation of resources. The FDA Center for Food Safety and Applied Nutrition (CFSAN) Office of the Coordinated Outbreak Response and Evaluation (CORE) Network coordinates foodborne illness outbreak surveillance, response, and post-response activities related to incidents involving multiple illnesses linked to FDA-regulated human food, dietary supplements, and cosmetic products. FDA has implemented the National Incident Management System (NIMS) Incident Command System (ICS) principles across the agency to coordinate federal response efforts, and CORE has adapted NIMS ICS principles for the emergency management of multistate foodborne illness outbreaks. CORE's implementation of ICS principles has provided several benefits to the operational cycle of foodborne illness outbreak investigations, including establishing a consistent, standardized, and transparent step-by-step approach to outbreak investigations. ICS principles have been instrumental in the development of a national platform for rapid and systematic laboratory, traceback, and epidemiologic information sharing, data analysis, and decision-making. This allows for partners across jurisdictions to reach a consensus regarding outbreak goals and objectives, deploy resources, and take regulatory and public health actions.

Abstract A34: Cancer prevention in practice at FDA

Abstract Most major categories of products reviewed at the U.S. Food and Drug Administration (FDA) undergo assessment for cancer hazard, which generally is accomplished by using qualitative findings from genotoxicity tests. In some instances, two-year rodent bioassays are used for quantitative risk assessment. In the attempt to minimize the use of animals, more recently alternative approaches have included the assessment of data from chemical characterizations, QSAR, and toxicology risk assessments. Although the focus is primarily on hazard identification, or classification of agents as genotoxic or nongenotoxic, the scope of consideration is broader, including identification of potential nongenotoxic carcinogens and consideration of negative factors for carcinogenesis, such as the absence of hormonal action, rodent neoplasia, and certain histopathologic risk factors. For many (but not all) product categories, review generally includes a risk/benefit assessment. A diversity of laws, regulations, standards, and products affects the approach to cancer risk assessment in different FDA centers. Other than tobacco, little is known about the actual human risk of many products or combinations of foods, drugs, medical devices, and other exposures, over days, years, or a lifetime, relative to cancer risk. Thus, it is difficult to find yardsticks against which to consider new products. In thinking about risks to human health and the potential for tumor development, it is useful to consider the factors generally understood to be important from animal and human studies in carcinogenesis, especially from human experience with tobacco: dose, frequency, and duration of exposure; multiple exposures to agents acting via different mechanisms; inflammatory or proliferative responses; susceptible systems (based on genetics, age, or development); and time available for tumor development. High-dose single-agent testing in animals has been validly criticized as a poor model for human cancer risk, particularly given the expense, time, and large numbers of animals required. Replacement models suitable for FDA premarket product safety review are needed, particularly representing the real world of multiple exposures and individual human susceptibilities. Citation Format: Rosalie K. Elespuru. Cancer prevention in practice at FDA [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A34.

Selected Developments in Biotechnology Law and the Biotechnology Industry

Selected Developments in Biotechnology Law and the Biotechnology Industry

Communicating Immunogenicity-Associated Risk in Current U.S. FDA Prescription Drug Labeling: A Systematic Evaluation.

Communicating the clinical impact of immunogenicity in labeling is important for safe and effective use of certain prescription products. Current U.S. Food and Drug Administration (FDA) guidance does not provide comprehensive recommendations on the communication of clinical impact of immunogenicity in labeling. To understand current labeling practice, we evaluated the immunogenicity data and clinical impact information in labeling of selected prescription products. We created a database of 71 therapeutic biologics and drug products that had an immunogenicity assessment initially approved by FDA's Center for Drug Evaluation and Research between 2014 and 2018. We analyzed the content and format of immunogenicity information (e.g., anti-drug antibody incidence and/or immunogenicity impact on pharmacokinetics (PK), safety, and/or effectiveness) in the most recent approved labeling. Immunogenicity information was in the ADVERSE REACTIONS section in 98% of the reviewed labeling. Immunogenicity impact on PK was reported in 52% of the labeling, typically within the ADVERSE REACTIONS section, but supportive PK data were often not included in the CLINICAL PHARMACOLOGY section. Additionally, the immunogenicity impact on safety and/or effectiveness was communicated in 70% of the labeling, with 23% clearly communicating the effect as clinically meaningful, and 10% providing actionable recommendations. Most of the reviewed labeling includes immunogenicity information within the ADVERSE REACTIONS section. However, there is inconsistency in providing supportive PK data and high variability in reporting immunogenicity impact on safety and effectiveness in labeling. Development of a communication framework that allows for consistent inclusion of immunogenicity impact statements in labeling could improve how immunogenicity risk is conveyed in prescription drug labeling.

A Zika Reference Panel for Molecular-Based Diagnostic Devices as a US Food and Drug Administration Response Tool to a Public Health Emergency

In 2015, Zika virus (ZIKV) appeared as an emerging pathogen, generating a global and urgent need for accurate diagnostic devices. During this public health crisis, several nucleic acid testing (NAT)-based Zika assays were submitted to the US Food and Drug Administration (FDA) for Emergency Use Authorization. The FDA's Center for Devices and Radiological Health, in collaboration with the FDA's Center for Biologics Evaluation and Research, responded to this Zika emergency by developing and producing a reference panel (RP) for Zika RNA (Zika FDA-RP) suitable for performance assessment of ZIKV NAT-based invitro diagnostic devices. Reference panels are a fundamental tool for performance assessment of molecular tests. The panel is composed of five vials: two different heat-inactivated ZIKV strains (PRVABC59 and FSS13025) in concentrated stocks and three blinded concentrations prepared from those strains. The Zika FDA-RP was shared with developers who had devices in the final stages of validation. Invitro diagnostic developers tested the Zika FDA-RP using the FDA-provided protocol. Depending on sample type, 85% (12/14) of the NAT assays had analytical sensitivities between 500 and 5000 RNA NAT-detectable units/mL (NDUs/mL). One device showed better performance (100 NDUs/mL), and another one showed lower performance (10,000 to 30,000 NDUs/mL). Vials of the Zika FDA-RP are available on request to developers who have interacted with the FDA through the review process.

A Proposed Framework for Patient-Focused Policy at the U.S. Food and Drug Administration.

Medical product sponsors are encouraged to include the patient perspective in their medical product development strategy to inform product design, augment regulatory submissions, argue for alternative clinical trial designs, or to support indications in specific patient populations. The goal is to create a patient-focused ecosystem that enables industry to integrate the patient voice throughout the medical product lifecycle. To this end, the U. S. Food and Drug Administration (FDA) has published several guidance documents to provide industry with the expectations and opportunities for conducting patient-focused activities. From an industry perspective, the Center for Devices and Radiologic Health (CDRH) and the Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER) patient-focused policies are complementary. The basic tenets promoted in all FDA patient-focused guidance could apply across therapeutic areas. However, there remain differences in these guidance documents across FDA centers, and there is no framework in place to provide industry with consistent recommendations. Without a coordinated patient-focused policy from the FDA, there is the potential for confusion and a lack of consistency among industry and regulatory decision-makers. The objective of this paper was to propose an alternative framework for patient-focused policy at the FDA, which recognizes the potential for different types of patient input to be used across therapeutic areas and medical product types. Further, these policies need to provide greater clarity on how patient input data is used, so that sponsors may navigate the opportunities to use patient input regardless of the FDA center under which their product is regulated. Creating consistent, coherent, and transparent FDA patient-focused policy will encourage sponsors to obtain patient input more often and with greater certainty of the value that these data may have to their medical product strategies.

Pharmaceutical Drugs of Uncertain Value, Lifecycle Regulation at the US Food and Drug Administration, and Institutional Incumbency.

Policy Points The US Food and Drug Administration (FDA) has in recent years allowed onto the market several drugs with limited evidence of safety and effectiveness, provided that manufacturers agree to carry out additional studies while the drugs are in clinical use.Studies suggest that these postmarketing requirements (PMRs) frequently lack transparency, are subject to delays, and fail to answer the questions of greatest clinical importance. Yet, none of the literature speaks directly to the challenges that the FDA—as a regulatory institution—encounters in enforcing PMRs.Through a series of interviews with FDA leadership, this article analyzes and situates those challenges in the midst of political threats to the FDA's public health mandate. ContextModern pharmaceutical regulation is premised on a rigorous examination of a drug's safety and effectiveness prior to its lawful sale. However, since the 1990s, the US Food and Drug Administration (FDA) has gradually shifted to a model of “lifecycle” regulation that increasingly relies on postmarketing requirements (PMRs) to encourage studies of drug safety and effectiveness following regulatory approval. This article examines the range of legal, institutional, and political challenges that FDA faces in the context of lifecycle regulation.MethodsDocument‐based legal and policy analysis was combined with a set of semistructured interviews of current and former FDA officials (n = 23) in order to explore the implications of the FDA's use of PMRs. The median interview time per official was 61 minutes, with a range of 24 to 227 minutes. All of the officials interviewed occupied positions of leadership and influence within the FDA, such as directors of an FDA center or office, key legal counsel on agency‐wide policy initiatives, and the commissioner of the FDA.FindingsInsufficient resources and coordination within the FDA, inadequate legal authorities, and the political economy of withdrawing an approved indication in the face of opposition from companies and patients all contribute to the observed shortcomings in the FDA's use and enforcement of PMRs. Further, the FDA is fully aware of these challenges, yet is seemingly resigned to and resistant to criticism of its use of PMRs.ConclusionsThis study of the FDA's shift toward lifecycle regulation reveals not simply an agency in transition, but rather an agency on guard against a set of larger political threats to its mandate. This can be characterized as a state of institutional incumbency in which the agency is engaged in an effort to reproduce key features of the regulatory system—in concert with regulated industries and others—while simultaneously sanctioning significant changes to the regulatory standards the FDA has long applied, to the detriment of public health.

Nationwide Shortage of Tuberculin Skin Test Antigens: CDC Recommendations for Patient Care and Public Health Practice

CDC is expecting a 3-10 month nationwide shortage of Aplisol, a product of Par Pharmaceuticals, and one of two purified-protein derivative (PPD) tuberculin antigens licensed by the Food and Drug Administration (FDA) for use in performing tuberculin skin tests. This time frame is the manufacturer's current estimate and is subject to change. The manufacturer notified CDC that they anticipate an interruption of supply of Aplisol 5 mL (50 multidose vials) beginning in June 2019, followed by an interruption of the supply of Aplisol 1 mL (10 multidose vials) in November 2019. The expected shortage of Aplisol 1 mL could occur before November 2019 if demand increases before then. Information on the status of this supply interruption will be updated at FDA's Center for Biologics Evaluation and Research-Regulated Products: Current Shortages website (https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/cber-regulated-products-current-shortages). This report includes CDC recommendations for mitigating a reduction in tuberculosis (TB) testing capability resulting from the anticipated Aplisol shortage (1).

First Person: Howard Koh, MD, MPH: Physician devotes his career to improving public health on many fronts.

First Person: Howard Koh, MD, MPH: Physician devotes his career to improving public health on many fronts.