Considerations regarding the use of nonhuman primates in assessing safety endpoints for pharmaceuticals.

Nonhuman primates (NHP) have become a commonly used nonrodent species for general toxicity testing for pharmaceuticals reviewed by CDER. Their increased use in pharmaceutical testing appears to have been driven by both increased use in small molecule drug development programs as well as a trend for biologics making up a greater percentage of pharmaceutical development programs. While always in limited supply, the COVID-19 pandemic acutely impaired the availability of NHPs for pharmaceutical testing due to disruptions in the supply and an increased demand to support COVID-19-directed research programs. Because this disruption in the NHP supply had the potential to significantly delay the development of new medications for the treatment of diseases currently without effective treatment options, FDA issued guidance in February of 2022, under its COVID-19 Public Health Emergency authority, that was intended to help mitigate the NHP supply issue by reducing the demand for NHPs. This guidance has been withdrawn with the expiration of the public health emergency. Here we discuss what impact we expect that the withdrawal of this guidance will have on efforts to minimize NHP use.

Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies.

Previously, we provided an FDA/CDER perspective on nonclinical testing strategies and briefly discussed the opportunities and challenges of using new approach methodologies (NAMs) in drug development, especially for regulatory purposes. To facilitate the integration of NAMs into nonclinical regulatory testing, we surveyed the CDER Pharmacology/Toxicology community to identify the nonclinical challenges faced by CDER review staff, including gaps and areas of concern underserved by current nonclinical testing approaches, and to understand how development of NAMs with specific contexts of use (COUs) could potentially alleviate them. Survey outcomes were coalesced into CDER-identified needs for which NAMs with specific COUs could potentially be developed to address gaps and challenges in nonclinical safety assessments. We also discussed the current FDA procedure for validation and qualification of NAMs intended to inform regulatory decisions. This manuscript is intended to facilitate productive discussions and collaborations with regulatory, government, and academic stakeholders within the drug development community regarding the development and regulatory use of NAMs and their role in safety and efficacy assessment of pharmaceuticals.

An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals.

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.

CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 µM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 µM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 µM, whereas RDEA3170 at 100 µM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg-1 · d-1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg-1 · d-1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 µM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Similar to last year, 2021 will be remembered for the COVID-19 pandemic. Although five vaccines have been approved by the two most important drug regulatory agencies, namely the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the pandemic has still not been brought under control. However, despite the context of a global pandemic, 2021 has been an excellent year with respect to drug approvals by the FDA. In 2021, 50 drugs have been authorized, making it the fourth-best year after 2018 (59 drugs) and 1996 and 2020 (53 each). Regarding biologics, 2021 has been the third-best year to date, with 14 approvals, and it has also witnessed the authorization of 36 small molecules. Of note, nine peptides, eight monoclonal antibodies, two antibody-drug conjugates, and two oligonucleotides have been approved this year. From them, five of the molecules are pegylated and three of them highly pegylated. The presence of nitrogen aromatic heterocycles and/or fluorine atoms are once again predominant among the so-called small molecules. This report analyzes the 50 new drugs approved in 2021 from a chemical perspective, as it did for those authorized in the previous five years. On the basis of chemical structure alone, the drugs that received approval in 2021 are classified as the following: biologics (antibodies, antibody-drug conjugates, enzymes, and pegylated proteins); TIDES (peptide and oligonucleotides); combined drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

Implementation of the principles of the 3Rs of animal testing at CDER: Past, present and future.

The safety testing of pharmaceutical candidates has traditionally relied on data gathered from studies in animals, and these sources of information remain a vital component of the safety assessment for new drug and biologic products. However, there are clearly ethical implications that attend the use of animals for safety testing, and FDA fully supports the principles of the 3Rs, as it relates to animal usage; these being to replace, reduce and refine. We provide an overview of some of the events and activities (legal and programmatic) that have had, and continue to have, the greatest impact on animal use in pharmaceutical development, and highlight some ongoing efforts to further meet the challenge of achieving our mission as humanely as possible.

The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best-together with 1996-in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of these two years witnessed the authorization of 53 drugs-a number surpassed only in 2018 with 59 pharmaceutical agents. The 53 approvals in 2020 are divided between 40 new chemical entities and 13 biologic drugs (biologics). Of note, ten monoclonal antibodies, two antibody-drug conjugates, three peptides, and two oligonucleotides have been approved in 2020. Close inspection of the so-called small molecules reveals the significant presence of fluorine atoms and/or nitrogen aromatic heterocycles. This report analyzes the 53 new drugs of the 2020 harvest from a strictly chemical perspective, as it did for those authorized in the previous four years. On the basis of chemical structure alone, the drugs that received approval in 2020 are classified as the following: biologics (antibodies, antibody-drug conjugates, and proteins); TIDES (peptide and oligonucleotides); natural products; fluorine-containing molecules; nitrogen aromatic heterocycles; and other small molecules.

Anatomy of Risk Evaluation and Mitigation Strategies (REMS).

This Chapter provides an introduction and overview of the U.S. FDA REMS program and applicable regulatory aspects. Topics covered include the 2015 Draft Guidance, organization structure and functions, a discussion on pharmacovigilance and adverse event reports, and a discussion of the applicability of REMS in oncology.

Prevalence and neonatal factors associated with autism spectrum disorders in preterm infants.

OBJECTIVES: To determine the prevalence of autism spectrum disorders (ASD) across gestational age, examine the risk of ASD by gestational age controlling for other risk factors, and identify potential risk factors in the neonatal intensive care unit. STUDY DESIGN: A retrospective cohort of infants born at ≥ 24 weeks between January 1, 2000, and December 31, 2007 at 11 Kaiser Permanente Northern California hospitals (n = 195,021). ASD cases were defined by a diagnosis made at a Kaiser Permanente ASD evaluation center, by a clinical specialist, or by a pediatrician. Cox proportional hazards regression models were used to evaluate the association between gestational age and ASD as well as potential risk factors in the neonatal intensive care unit and ASD. RESULTS: The prevalence of ASD in infants <37 weeks was 1.78% compared with 1.22% in infants born ≥ 37 weeks (P < .001). Compared with term infants, infants born at 24-26 weeks had an adjusted hazard ratio (HR) for a diagnosis of ASD of 2.7 (95% CI 1.5-5.0). Infants born at 27-33 weeks (adjusted HR 1.4, 95% CI 1.1-1.8) and 34-36 weeks (adjusted HR 1.3, 95% CI 1.1-1.4) were also at increased risk. High frequency ventilation and intracranial hemorrhage were associated with ASD in infants < 34 weeks. CONCLUSIONS: ASD was ~ 3 times more prevalent in infants <27 weeks compared with term infants. Each week of shorter gestation was associated with an increased risk of ASD. High frequency ventilation and intracranial hemorrhage were associated with ASD among infants <34 weeks.

Understanding the Regulatory Pathways Used to Develop, Evaluate, Authorize, and Approve New Drugs and Vaccines in the United States.

The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.

Qualification of cardiac troponins for nonclinical use: a regulatory perspective.

The US Food and Drug Administration (FDA) Biomarker Qualification Review Team presents its perspective on the recent qualification of cardiac troponins for use in nonclinical safety assessment studies. The goal of this manuscript is to provide greater transparency into the qualification process and factors that were considered in reaching a regulatory decision. This manuscript includes an overview of the data that were submitted and a discussion of the strengths and shortcomings of these data supporting the qualification decision. The cardiac troponin submission is the first literature-based biomarker application to be reviewed by the FDA and insights gained from this experience may aid future submissions and help streamline the characterization and qualification of future biomarkers.

US-FDA Approved Drugs in 2020 and 2021: A Review.

INTRODUCTION: Throughout the years, the disruption caused by COVID-19 continues to pose an excess of challenges for the pharmaceutical industry. Throughout the entire year, questions were raised that does COVID-19 have a negative impact on new drug approvals. However, the answer to those questions was a 'big no'. METHODS: We propose a compilation and analysis of around 100 medications, including small new molecular entities (NMEs), approved by the US Food and Drug Administration for the years 2020 and 2021. Novel drug discovery is crucial for pharmaceutical research and development as well as patient care. The only possible way to achieve this crucial goal is to repurpose current medications that may have anticipated effects as possible candidates. The availability of new drugs and biological products often means new treatment options for patients and advances in health care. RESULTS: Around 40% of the drugs were approved for various types of cancers. Other major therapeutic areas that were focused on were neurological products (around 17%), infectious diseases (13-15%), and cardiovascular disorders (7-8%). Various new products were approved for rare diseases (58-60%). This study aimed to discover a pattern in FDA medicine approvals during the last two decades. CONCLUSION: This data shows that anticancer medicines and biologics are receiving increased attention in research. With a bigger number of biologically derived medications being produced, the price could rise much higher. FDA should embrace innovative techniques that will stimulate the industry to enhance research and development of novel compounds or medications that can deliver considerable improvements over existing ones. To put it briefly, FDA had to update our approach to regulation as a whole in order to effectively develop the types of technologies that are becoming available. Modernizing medical product review programmes is a part of this. These initiatives are part of the Medical Innovation Access Plan.

History, status, and politicization of the FDA.

The Center for Drug Evaluation and Research (CDER) performs an essential role in public health by ensuring, evaluating, and monitoring the safety and efficacy of drugs before they are sold in the US. Before approving new drug applications, CDER ensures that therapeutic benefits of both prescription and over-the-counter drugs (brand name and generic) provide more health benefits than the potential risks. First passed by Congress in 1992, the Prescription Drug User Fee Act (PDUFA) allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund new drug approvals. The law allowed the FDA to expedite drug approvals, but possibly lowered standards for safety and brought potential conflicts of interest within the FDA and pharmaceutical industry. To examine the conflicts of interest, we conducted a review using the Excerpta Medica database, US National Library of Medicine National Institutes of Health Database (PubMed), Scopus, and Google. Our search yielded Vioxx (rofecoxib) and Exondus-51 (eteplirsen) as examples of consequence when the FDA and pharmaceutical industry are too closely aligned. We further examine how the pharmaceutical industry may indirectly influence the FDA by lobbying to Congress or directly by hiring ex-FDA commissioners.

Insights into the FDA 2018 New Drug Approvals.

OBJECTIVE: The Center of Drug Evaluation and Research (CDER) in the food and drug administration (FDA) approves new drugs every year. This review discusses the novel drugs of the FDA in 2018, with emphasis on the breakthrough drugs, the milestones in the approved list, and drugs with the highest expected sales in 2024. METHODS: The following scientific search engines were surveyed for the clinical trials of the drugs approved by the FDA in 2018: Pubmed, Springer link, ScienceDirect, Scopus, Wiley online library, Taylor and Francis, and Google Scholar. The total forecast sales were compared based on information from the Cortellis database, EvaluatePharma, and Nature Biobusiness Briefs. RESULTS: The 2018 year was full of good news for the drug market in the USA, with 59 new drug approvals by the FDA, which is the highest number of approvals in the last twenty years. The oncology and the antimicrobial drugs represent almost 50% of the new list, which gives hope to cancer patients and subjects with infectious diseases. In the 2018 FDA list, a number of drugs are expected to exceed 1$ billion dollars of sales by 2024. CONCLUSION: The new drugs approved by the FDA in 2018 have been reviewed. This year showed the highest number of new drug approvals in the last two decades. Among the 59 drugs approved in 2018, 14 drugs are considered breakthroughs, which revive hope for many poorly managed diseases. The list also contains 19 drugs that are first in class and 43 that were given priority reviews.

Sunscreens: UV filters to protect us: Part 1: Changing regulations and choices for optimal sun protection.

Sunscreens are topical preparations containing any number of ultraviolet filters (UVFs). The first part of the review will focus on the recent Food and Drug Administration (FDA) regulations of 2019 and general use of these agents. While sunscreen products are becoming more regulated in the United States, we still lag behind other countries in our options for UVFs. Sun protection to prevent skin cancer and aging changes should be a combination of sun avoidance, protective structures, and clothing as well as use of sunscreen products. Newer and safer products are needed to help supplement and replace older agents as well as improve their cosmetic acceptability. This will be a review of ingredients, local toxicities (i.e. contact dermatitis, photocontact dermatitis), special considerations for children, and cosmesis of sunscreen preparations. Part 2 will focus on the environmental, ecological and human toxicities that have been increasingly related to UVFs.

Sunscreens: UV filters to protect us: Part 2-Increasing awareness of UV filters and their potential toxicities to us and our environment.

BACKGROUND: Sunscreens are topical preparations containing one or more compounds that filter, block, reflect, scatter, or absorb ultraviolet (UV) light. Part 2 of this review focuses on the environmental, ecological effects and human toxicities that have been attributed to UV filters. METHODS: Literature review using NIH databases (eg, PubMed and Medline), FDA and EPA databases, Google Scholar, the Federal Register, and the Code of Federal Regulations (CFR). LIMITATIONS: This was a retrospective literature review that involved many different types of studies across a variety of species. Comparison between reports is limited by variations in methodology and criteria for toxicity. CONCLUSIONS: In vivo and in vitro studies on the environmental and biological effects of UV filters show a wide array of unanticipated adverse effects on the environment and exposed organisms. Coral bleaching receives considerable attention from the lay press, but the scientific literature identifies potential toxicities of endocrine, neurologic, neoplastic and developmental pathways. These effects harm a vast array of aquatic and marine biota, while almost no data supports human toxicity at currently used quantities (with the exception of contact allergy). Much of these data are from experimental studies or field observations; more controlled environmental studies and long-term human use data are limited. Several jurisdictions have prohibited specific UV filters, but this does not adequately address the dichotomy of the benefits of photoprotection vs lack of eco-friendly, safe, and FDA-approved alternatives.

IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper.

Currently, testing for immunoglobulin E (IgE) sensitization is the cornerstone of diagnostic evaluation in suspected allergic conditions. This review provides a thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro. It discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy. Skin prick testing remains the first line approach in most instances; the added value of serum specific IgE to whole allergen extracts or components, as well as the role of basophil activation tests, is evaluated. Unproven, non-validated, diagnostic tests are also discussed. Throughout the review, the reader must bear in mind the relevance of differentiating between sensitization and allergy; the latter entails not only allergic sensitization, but also clinically relevant symptoms triggered by the culprit allergen.

How Has CDER Prepared for the Nano Revolution? A Review of Risk Assessment, Regulatory Research, and Guidance Activities.

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group's major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial. However, three risk management areas were identified for continued focus during the review of drug products containing nanomaterials: (1) the understanding of how to perform the characterization of nanomaterial properties and the analytical methods used for this characterization, (2) the adequacy of in vitro tests to evaluate drug product performance for drug products containing nanomaterials, and (3) the understanding of properties arising from nanomaterials that may result in different toxicity and biodistribution profiles for drug products containing nanomaterials. CDER continues to actively track the incorporation of nanomaterials in drug products and the methodologies used to characterize them, in order to continuously improve the readiness of our science- and risk-based review approaches. In parallel to the risk management exercise, CDER has also been supporting regulatory research in the area of nanotechnology, specifically focused on characterization, safety, and equivalence (between reference and new product) considerations. This article provides a comprehensive summary of regulatory and research efforts supported by CDER in the area of drug products containing nanomaterials and other activities supporting the development of this emerging technology.

Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles.

Oral drug absorption is a process influenced by the physicochemical and biopharmaceutical properties of the drug and its inter-relationship with the gastrointestinal tract. Drug solubility, dissolution and permeability across intestinal barrier are the key parameters controlling absorption. This review provides an overview of the factors that affect drug absorption and the classification of a drug on the basis of solubility and permeability. The biopharmaceutical classification system (BCS) was introduced in early 90׳s and is a regulatory tool used to predict bioavailability problems associated with a new entity, thereby helping in the development of a drug product. Strategies to combat solubility and permeability issues are also discussed.