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1.
Molecules ; 29(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338330

RESUMO

With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody-drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.


Assuntos
Produtos Biológicos , Aprovação de Drogas , Estados Unidos , Humanos , Flúor , Pandemias , Preparações Farmacêuticas/química , Indústria Farmacêutica , Peptídeos/uso terapêutico , Anticorpos Monoclonais , Produtos Biológicos/uso terapêutico , Produtos Biológicos/química , United States Food and Drug Administration , Oligonucleotídeos/uso terapêutico , Polietilenoglicóis
2.
Sci Rep ; 14(1): 3325, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336899

RESUMO

U.S. laws enacted since 1983 have aimed to enhance the development and marketing of new pharmaceutical products. We thoroughly characterized all new molecular entities, therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA) during the period 1980-2022 in the context of these laws and regulations. Throughout the study period, the FDA approved 1355 new pharmaceutical products. The median FDA review time decreased from 26.6 months prior to the Prescription Drug User Fee Act (1992), which authorized the FDA to collect fees from drug companies to 9.9 months after the Food and Drug Administration Safety and Innovation Act (2012), which created new designations that eliminated the requirement for evidence of added therapeutic benefit for FDA expedited drug review. The greatest increase in approvals occurred in antineoplastic and immunomodulating drugs, biologics, and orphan drugs. More than half of new drug approvals benefited from regulatory designations and pathways that did not require addressing unmet medical needs or demonstrating therapeutic benefit over available alternatives. The legislative goal of bringing more drugs to the market faster has been achieved. Further studies are needed to determine the therapeutic value to patients of new drugs approved using expedited approval pathways.


Assuntos
Produtos Biológicos , Produção de Droga sem Interesse Comercial , Estados Unidos , Humanos , United States Food and Drug Administration , Preparações Farmacêuticas , Fatores Biológicos , Aprovação de Drogas , Produtos Biológicos/uso terapêutico
4.
Health Aff (Millwood) ; 43(1): 27-35, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38190596

RESUMO

Physicians' knowledge of Food and Drug Administration (FDA) approval processes is important in informing clinical decisions and patient discussions. Among a randomly selected national sample of 509 internists, cardiologists, and oncologists, 41 percent reported moderate or better understanding of the FDA's drug approval process, and 17 percent reported moderate or better understanding of the FDA's medical device approval process. Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be very important factors required to secure regulatory approval. Also, nearly all physicians thought that the FDA should revoke approval for accelerated-approval drugs or breakthrough devices that did not show benefit in postapproval studies. Our findings suggest that physicians commonly lack familiarity with drug and medical device regulatory practices and are under the impression that the data supporting FDA drug and high-risk device approvals are more rigorous than they often are. Physicians would value more rigorous premarket evidence, as well as regulatory action for drugs and devices that do not demonstrate safety and effectiveness in the postmarket setting.


Assuntos
Oncologistas , Médicos , Estados Unidos , Humanos , United States Food and Drug Administration , Aprovação de Drogas , Projetos de Pesquisa
5.
Orphanet J Rare Dis ; 19(1): 5, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167464

RESUMO

BACKGROUND: The 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. RESULTS: A 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. CONCLUSIONS: It 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.


Assuntos
Antineoplásicos , Neoplasias , Animais , Estados Unidos , Humanos , Produção de Droga sem Interesse Comercial , Aprovação de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , United States Food and Drug Administration , Biomarcadores
9.
AAPS J ; 26(1): 12, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38177638

RESUMO

Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.


Assuntos
Medicamentos Genéricos , Estados Unidos , Equivalência Terapêutica , Preparações Farmacêuticas , Simulação por Computador , United States Food and Drug Administration
10.
Eur J Med Chem ; 265: 116124, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38183778

RESUMO

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies.


Assuntos
Aprovação de Drogas , Imunomodulação , Estados Unidos , United States Food and Drug Administration , Preparações Farmacêuticas
12.
Drug Saf ; 47(3): 271-284, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38175395

RESUMO

INTRODUCTION: In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often overlooked. The US FDA Adverse Event Reporting System (FAERS) records drug names as free text, necessitating mapping to active ingredients. Although pre-mapped databases exist, the subjectivity and lack of transparency of the mapping process lead to a loss of control over the object of study. OBJECTIVE: We implemented the DiAna dictionary, systematically mapping individual free-text instances to their corresponding active ingredients and linking them to the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification. METHODS: We retrieved all drug names reported to the FAERS (2004-December 2022). Using existing vocabularies and string editing, we automatically mapped free text to ingredients. We manually revised the mapping and linked it to the ATC classification. RESULTS: We retrieved 18,151,842 reports, with 74,143,411 drug entries. We manually checked the first 14,832 terms, up to terms occurring over 200 times (96.88% of total drug entries), to 6282 unique active ingredients. Automatic unchecked translations extend the standardization to 346,854 terms (98.94%). The DiAna dictionary showed a higher sensitivity compared with RxNorm alone, particularly for specific drugs (e.g., rimegepant, adapalene, drospirenone, umeclidinium). The most prominent drug classes in the FAERS were immunomodulating (37.40%) and neurologic drugs (29.19%). CONCLUSION: The DiAna dictionary, as a dynamic open-source tool, provides transparency and flexibility, enabling researchers to actively shape drug definitions during the mapping phase. This empowerment enhances accuracy, reproducibility, and interpretability of results.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Estados Unidos , Humanos , Reprodutibilidade dos Testes , Software , United States Food and Drug Administration
13.
J Clin Microbiol ; 62(2): e0148823, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38206042

RESUMO

In October 2023, the Food and Drug Administration (FDA) released a proposed rule that ends enforcement discretion for laboratory-developed tests (LDTs). The FDA's proposal outlines a five-stage implementation to begin regulating LDTs as they do for commercial in vitro diagnostics (IVDs), including modified FDA-approved/cleared tests. We outline here concerns from the clinical and public health microbiology laboratory perspective. It is our opinion that LDTs performed by individual Clinical Laboratory Improvement Amendments-certified diagnostic laboratories should not be regulated in the same way as commercial IVDs. This rule, if finalized, will negatively impact the diagnostic services currently offered by clinical and public health laboratories and, therefore, patients and the providers who care for them. Ending enforcement discretion will likely stifle diagnostic innovation and decrease access to diagnostic testing and health equity. Furthermore, the lack of infrastructure, including personnel and funding, at the FDA and diagnostic laboratories to support the required submissions for review is an obstacle. Like the FDA, diagnostic laboratories prioritize patient safety, accurate clinical diagnostics, and health equity. Since the scope of the LDT landscape is currently unknown, we are supportive of a registration process, along with non-burdensome adverse event reporting, to first understand the scope of clinical use of LDTs and any associated safety concerns. Any regulatory rule should be based on data that have been gathered systematically, not anecdotes or case reports. A rule must also balance the potential negative impact to patient care with realistic safety risks for infectious disease diagnostics.


Assuntos
Serviços de Laboratório Clínico , Laboratórios , Humanos , Estados Unidos , United States Food and Drug Administration
14.
JAMA Ophthalmol ; 142(2): 123-130, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38236588

RESUMO

Importance: As critical determinants of scientific rigor, reproducibility, and equity, sex and gender should be considered in clinical trial design and reporting. Objective: To evaluate the accuracy of sex and gender reporting and extent of sex- and gender-based analysis in clinical trials associated with US Food and Drug Administration (FDA) drug approvals between January 1, 1995, and December 31, 2022. Design, Setting, and Participants: In this cross-sectional study of participants enrolled in FDA ophthalmology trials, the following trial documents were reviewed by pairs of independent reviewers in decreasing order of priority: peer-reviewed publication, ClinicalTrials.gov report, and FDA medical and statistical reviews. Trial protocols and supplementary materials were also reviewed. Main Outcome and Measures: The proportion of trials that correctly applied sex and gender terminology, reported the method of assessing sex or gender, and conducted sex- or gender-based data analysis; incorrect application of sex and gender terminology was defined as interchangeable use of sex- and gender-related terms without a clear justification. Results: Between 1995 and 2022, 34 ophthalmic drugs corresponding to 85 trials (34 740 participants) received FDA approval, of which 16 drugs (47.1%) corresponding to 32 trials (18 535 participants [37.6%]) were associated with peer-reviewed publications. Sixteen trials used sex and gender terminology correctly (19.5%). No trial reported how sex and gender were collected nor enrolled participants from sexual and gender identity minority populations. Most trials reported sex- and gender-disaggregated demographic data (96.5%), but few conducted sex- or gender-based analysis for data on dropout (1.2%), primary outcomes (28.2%), secondary outcomes (2.4%), and adverse events (9.4%). Erroneous sex and gender reporting was associated with later publication year (2008.5 vs 2001.0; median difference, 7.5; 95% CI, -6.0 to 11.0; P < .001) and higher journal influence metrics, including 2022 journal impact factor (13.7 vs 5.9; median difference, 7.8; 95% CI, -1.4 to 152.4, P < .001) and 2022 journal citation indicator (4.9 vs 2.1; median difference, 2.9; 95% CI, 0-20.0, P < .001). Conclusions and Relevance: In this observational study, over three-quarters of ophthalmology trials associated with FDA drug approvals conflated sex and gender and over two-thirds lacked sex- and gender-based analyses. More rigorous integration of sex and gender appears warranted for FDA, and presumably other trials, to improve their validity, reproducibility, and equity.


Assuntos
Oftalmologia , Estados Unidos , Humanos , Masculino , Feminino , Estudos Transversais , United States Food and Drug Administration , Reprodutibilidade dos Testes , Identidade de Gênero
18.
Expert Opin Drug Saf ; 23(2): 177-186, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38221892

RESUMO

INTRODUCTION: The objective and significance of the topic is to draw attention toward regulatory aspects (and pharmacopoeias) for bioequivalence investigation, and perception for generic pharmaceuticals, especially their stereoselective bioequivalence evaluation for understanding the performance of the racemic generic products available in the market. AREAS COVERED: The areas covered include bioequivalence studies (and related USP and FDA requirements) on certain generic APIs for comparison, examples of concern related to inspection of pharmaceuticals for export/import. Literature methodology includes search through USP monographs, MDPI.com, msn.com, WHO Drug Information, certain specific web links, PubMed Central®, PubMed®, NLM's advanced biomedical information services, and several pdf published in relevant journals in the field for related authentic information. EXPERT OPINION: The USP, the USFDA, and the units alike internationally should enforce pharmaceutical companies to perform stereoselective investigations on generic APIs to show that their PK/PD parameters are (nearly) equal to the standards set by such units for allowing marketing of that API. This should be provided to professionals in the areas of patient care and every country should enforce such regulations at the time of export and import of generics.


Assuntos
Medicamentos Genéricos , Percepção , Estados Unidos , Humanos , Equivalência Terapêutica , United States Food and Drug Administration
20.
Sci Rep ; 14(1): 459, 2024 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172190

RESUMO

Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (Pobs) was calculated based on completed study characteristics and observed hazard ratio (HRobs). Studies were considered over-sampled if Pobs > expected with HRobs similar or worse than expected or if Pobs was similar to expected with HRobs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.


Assuntos
Antineoplásicos , Neoplasias da Mama , Estados Unidos , Humanos , Feminino , Aprovação de Drogas/métodos , Tamanho da Amostra , United States Food and Drug Administration , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico
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