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1.
Sci Rep ; 12(1): 15497, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109566

RESUMO

Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.


Assuntos
Produção de Droga sem Interesse Comercial , Deficiência de alfa 1-Antitripsina , Aprovação de Drogas , Expectorantes/uso terapêutico , Humanos , Peptídeo Hidrolases , Doenças Raras/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration , Deficiência de alfa 1-Antitripsina/tratamento farmacológico
2.
Can J Gastroenterol Hepatol ; 2022: 3533504, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120087

RESUMO

Methods: This multicenter, double-blind, placebo-controlled, parallel-group trial included adults with chronic idiopathic constipation randomized to polyethylene glycol 3350 17 g (n = 204) or placebo (n = 100) once daily for 24 weeks. Post hoc analyses were performed using the US Food and Drug Administration endpoint (≥3 complete spontaneous bowel movements/week and an increase of ≥1 complete spontaneous bowel movement/week from baseline for ≥9/12 weeks, including 3 of the last 4 weeks) along with additional efficacy and safety outcomes. Results: The proportion of patients meeting the new endpoint was significantly higher with polyethylene glycol 3350 vs placebo (42% vs 13%; P < 0.0001). Reductions in the mean number of hard/lumpy stools/week (-2.1 vs -0.9; P = 0.0014) and the weekly mean five-point cramping rating (-0.3 vs -0.1; P = 0.0272) also significantly favored polyethylene glycol 3350. The proportion of subjects with gastrointestinal adverse events decreased markedly after the first week of treatment in the polyethylene glycol 3350 group. Conclusion: Using the current US Food and Drug Administration-recommended responder definition and other secondary outcomes, once-daily polyethylene glycol 3350 demonstrated substantial and sustained efficacy and safety over 24 weeks in patients with chronic idiopathic constipation. Trial Registration. The original trial was registered with https://clinicaltrials.gov Trial: NCT00153153.


Assuntos
Constipação Intestinal , Adulto , Doença Crônica , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Polietilenoglicóis , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
3.
JAMA Netw Open ; 5(9): e2231609, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36103178

RESUMO

Importance: The US medical device market is the world's largest, but estimates of the cost to bring a medical device to market are not available to help inform policy making and regulatory efforts to enhance device safety and innovation. Objective: To estimate the mean expected capitalized cost of developing a novel therapeutic complex medical device. Design, Setting, and Participants: In this economic evaluation, an analytical model of novel therapeutic complex medical device development using data from public and proprietary sources with coverage from 2000 through 2018 was used to estimate the cost, duration, and phase transition success probability associated with each stage of development. Data analysis was completed in September 2021. Exposures: Conduct of nonclinical and clinical studies; payment of FDA user fees for novel therapeutic complex medical devices. Main Outcomes and Measures: Mean development cost (in 2018 US dollars) incurred by developers for an FDA-approved novel therapeutic complex medical device, accounting for failures and cost of capital. Results: In this economic analysis, the mean development cost for a novel therapeutic complex medical device was $54 million (95% CI, $25 million-$200 million) excluding any postapproval studies that might be required. After accounting for the cost of failed studies and cost of capital, the mean capitalized cost of bringing a novel therapeutic complex medical device to the US market was $522 million (95% CI, $205 million-$3382 million). The key factors associated with this cost were the phase transition probabilities: 46.9% for nonclinical to feasibility study, 48.0% for feasibility to pivotal study, 75.7% pivotal study to FDA premarket approval submission, and 80.5% for FDA premarket approval submission to approval. The nonclinical development stage constituted the largest portion of overall cost at 85.0% with the FDA review stage with the highest phase transition probability accounting for only a small fraction at 0.5%. Conclusions and Relevance: In this economic evaluation study, the cost of therapeutic complex medical device development from proof of concept through postapproval stages was assessed accounting for the cost of failures and the cost of capital. Existing estimates did not account for all stages of development, capitalization, or failure costs, which this study suggests were substantial.


Assuntos
Formulação de Políticas , Humanos , Estados Unidos , United States Food and Drug Administration
4.
Front Immunol ; 13: 778635, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081514

RESUMO

Introduction: The adverse effects of neuromuscular junction dysfunctions caused by immune checkpoint inhibitor (ICI) drugs have not been thoroughly assessed in the clinics. Objective: To assess the neuromuscular junction dysfunctions in cancer patients with adverse events caused by ICI therapy by searching the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from January 2004 to December 2020 were collected to analyze the association between neuromuscular connection dysfunction and ICI use. Disproportionate analysis and Bayesian analysis were used to quantify the association between the neuromuscular junction dysfunctions and ICIs. The onset time and outcome of neuromuscular junction dysfunctions in different ICI regimens were also compared. Results: Out of 88,617 adverse event reports, 557 neuromuscular junction dysfunction reports (0.63%) were analyzed. Marketed ICI drugs, including ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab, avelumab, as well as their combinations, showed positive associations with four detection methods. Most of the adverse event reports were associated with the use of nivolumab (53.32%) and pembrolizumab (31.96%). However, nivolumab-related neuromuscular junction dysfunctions were similar with pembrolizumab (33.33% vs 33.14%, p > 0.05). The onset time of neuromuscular junction dysfunctions showed no significant difference among different ICIs (p > 0.05). Conclusions: Analysis of FAERS data identified that over 30% (32.85%) of reports of neuromuscular junction dysfunctions resulted in death. Ongoing monitoring, risk evaluations, and further comparative studies of ICIs should be considered.


Assuntos
Antineoplásicos Imunológicos , Nivolumabe , Antineoplásicos Imunológicos/efeitos adversos , Teorema de Bayes , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Junção Neuromuscular , Nivolumabe/efeitos adversos , Estados Unidos , United States Food and Drug Administration
5.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077114

RESUMO

Hidradenitis suppurativa, also known as acne inversa, is a chronic, progressive, debilitating, recurrent inflammatory skin disease characterized by the occurrence of very severe, persistent, painful nodules, abscesses, and fistulas, most commonly found in the skin folds of the axilla, groin, gluteal, and perianal areas. Treatment is rather difficult and typically requires the use of multiple modalities. Regardless of the presence of several therapeutic options, treatment often turns out to be ineffective or poorly selected concerning the clinical picture of the disease. Thus, the search for new biologics and other target treatments of hidradenitis suppurativa is ongoing. The safety and efficacy of adalimumab, still the only U.S. Food and Drug Administration approved biologic in the hidradenitis suppurativa treatment, paved the way for new drugs to be compared with it. Several more drugs with new immunological targets are currently under investigation for the treatment of acne inversa. The aim of the article was to present the current and future targets of acne inversa treatment, simultaneously providing insights into the molecular pathomechanisms of the disease.


Assuntos
Hidradenite Supurativa , Adalimumab/uso terapêutico , Hidradenite Supurativa/tratamento farmacológico , Humanos , Agentes de Imunomodulação , Estados Unidos , United States Food and Drug Administration
7.
JSLS ; 26(3)2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071989

RESUMO

Background and Objectives: This retrospective study provides preliminary qualitative assessment of the adverse events (AEs), focusing on pelvic and abdominal AEs and patient outcomes reported for three hemostatic agents used in gynecologic surgery. Methods: Utilization rates for oxidized regenerated cellulose powder (ORC), polysaccharide powder (PSP), and fibrin sealant solution (FSS) were obtained from hospitals via the Premier Healthcare databases for all surgical procedures from January 1, 2018 to September 30, 2020. All reported cases were extracted from the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for ORC and PSP and from the FDA Adverse Event Reporting System (FAERS) database for FSS. Distributions of AEs by anatomical site (MAUDE/FAERS) and surgical procedures by specialty (Premier) were evaluated for each product. Number of cases and number and types of AEs were compared to the total utilization for each product. Results: PSP was the most used product during the period analyzed (n = 126,509 uses), followed by FSS (n = 80,628 uses), and ORC (n = 41,583 uses). Distribution of surgical procedures by anatomical site varied significantly between hemostatic agents (p < 0.001). ORC was associated with more patient cases with AEs and numbers of reported AEs compared with PSP and FSS (p < 0.001). ORC was associated with higher number of infections than PSP (p < 0.001) and FSS (p < 0.001). Conclusion: These findings suggest that ORC use in abdominal and pelvic surgery may result in more postoperative complications compared with non-ORC hemostatic agents. Further prospective randomized studies are needed to compare efficacy and safety of these products.


Assuntos
Hemostáticos , Feminino , Adesivo Tecidual de Fibrina , Humanos , Pós , Estudos Retrospectivos , Estados Unidos/epidemiologia , United States Food and Drug Administration
8.
JAMA Netw Open ; 5(9): e2230973, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36083581

RESUMO

Importance: The US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking. Objective: To evaluate the accelerated approval program for nononcology drug indications over a period of 26 years. Design, Setting, and Participants: This retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022. Main Outcomes and Measures: The study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication. Results: The FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication. Conclusions and Relevance: Although the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.


Assuntos
Aprovação de Drogas , Neoplasias , Aprovação de Drogas/métodos , Humanos , Neoplasias/tratamento farmacológico , Preparações Farmacêuticas , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration
9.
Dermatol Surg ; 48(9): 943-948, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36054047

RESUMO

BACKGROUND: Multiple non-invasive modalities have become popular alternatives to surgical procedures for body contouring. OBJECTIVE: To analyze adverse events (AEs) associated with non-invasive body contouring devices reported through the Manufacturer and User Facility Device Experience (MAUDE) database. METHODS AND MATERIALS: The MAUDE database were queried for AEs associated with non-invasive body contouring devices between January 2011 and June 2021. An extensive list of keywords and brand and manufacturer names was used. RESULTS: A total of 1,325 reports with 1,590 AEs were identified among 6 modalities. More than 70% were reported in the past 5 years. Cryolipolysis made up 38.3% reports, which mostly pertained to paradoxical hyperplasia and hernias. Radiofrequency had the most reports (41.9%). Like laser devices, most of their reports described burns. Focused ultrasound was commonly associated with unintentional fat loss and surface irregularities. Focused electromagnetic field resulted in only 7 reports. CONCLUSION: The analysis of present study supports previous studies concerning common local symptoms caused by these devices, but it also reveals complications not reported in previous device studies. This study highlights the importance of proper technique and adherence to device guidelines. Practitioners should be knowledgeable of potential complications from each device to both prevent and manage them accordingly.


Assuntos
Contorno Corporal , Contorno Corporal/efeitos adversos , Bases de Dados Factuais , Humanos , Estados Unidos , United States Food and Drug Administration
10.
J Clin Pharmacol ; 62 Suppl 1: S36-S52, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106778

RESUMO

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.


Assuntos
Feto , Terapia Genética , Feminino , Humanos , Parto , Gravidez , Estados Unidos , United States Food and Drug Administration
11.
PLoS One ; 17(9): e0274115, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36094914

RESUMO

BACKGROUND: Once a drug gets FDA approved, researchers often attempt to discover new applications in different indications. The clinical impact of such post-approval activities is uncertain. We aimed to compare the clinical impact of research efforts started after approval with those started before for cancer drugs. METHODS: We used Drugs@FDA to perform a retrospective cohort study of secondary approvals for cancer drugs that were initially FDA approved between 2005 and 2017. Clinicaltrials.gov was used to identify the beginning of each research trajectory that resulted in a secondary FDA approval. Each trajectory was classified as pre- or post-approval depending on if it was initiated before or after initial drug licensure. Clinical impact was assessed by comparing secondary approvals and NCCN off-label recommendations deriving from pre- vs. post-approval trajectories, pooled effect sizes, incidence, and level of evidence. RESULTS: We identified 77 broad secondary approvals, 60 of which had at least 6 years follow-up. Of these, 9 (15%) resulted from post-approval trajectories, a proportion that is significantly lower than would be expected if the timing of research didn't impact approval (McNemar's test p = 0.001). Compared to pre-approval trajectories, approvals resulting from post-approval trajectories were for cancers with lower mean incidence (6.11 vs 14.83, p = 0.006) and were based on pivotal trials with smaller pooled effect sizes (0.69 vs 0.57, p = 0.02) that were less likely to be randomized (38.5% vs 64.1%, p = 0.145). We identified 69 NCCN off-label recommendations. The proportion stemming from post-approval trajectories was similar to that for pre-approval (56.5% vs. 43.5%). However, recommendations from post-approval trajectories were significantly more likely to involve rare diseases (76.7% vs 51.4%, p = 0.019) and nonsignificantly less likely to be based on level 1 evidence (11.6% vs 22.9%, p = 0.309). CONCLUSION: Secondary FDA approvals are less likely to result from post-approval trajectories and tend to be less impactful compared to approvals originating from research started before first FDA licensure. However, post-approval trajectories may be as likely to lead to NCCN recommendations for off-label use. Limitations of this work include our use of indirect measures of impact and limited follow-up time for trajectories. Our study protocol was pre-registered (https://osf.io/5g3jw/).


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Aprovação de Drogas , Humanos , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration
16.
Annu Rev Genomics Hum Genet ; 23: 653-673, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36044907

RESUMO

Molecular diagnostic tests enable rapid analysis of genomic and proteomic markers. These tests are subject to diverging premarket access and postmarket surveillance requirements and mechanisms in the United States and the European Union. Each of these jurisdictions has its own challenges in keeping the regulations up to date with technological developments. A specific area of attention is that of laboratory-developed tests in the United States and health institution in-house-produced tests in the European Union, for which the United States and the European Union have markedly different regulatory approaches. Both jurisdictions have specific but differing requirements for the use of test samples and test-related data under their rules regarding the protection of (personal) health data, which can cause complexity when moving samples or sample-related data from one jurisdiction to the other.


Assuntos
Patologia Molecular , Proteômica , União Europeia , Humanos , Estados Unidos , United States Food and Drug Administration
17.
Health Policy ; 126(10): 1018-1022, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35970691

RESUMO

BACKGROUND: Innovative Medicines Canada has said that companies are delaying the introduction of new drugs into Canada in anticipation of changes in how the Patented Medicine Prices Review Board determines prices for patented medicine. This study investigates whether this claim is accurate. METHODS: Delays in seeking approval for and marketing of new drugs were examined using linear regression analysis and comparing the time between approvals by Health Canada and approvals of the same drugs by the United States (US) Food and Drug Administration (FDA). Linear regression was also used to examine changes in the percent of drugs approved by the FDA and also approved by Health Canada and whether fewer drugs approved by Health Canada were being marketed. Approvals in Australia served as a control. RESULTS: There was no change in the difference in approval times between Health Canada and the FDA (p = 0.7073). Time between approval of new drugs and when they were marketed increased (p = 0.0002). Health Canada approved a smaller percent of drugs approved by the FDA (p = 0.0019) but the same trend was found in Australia. Fewer drugs approved in Canada were marketed (p = 0.0288). CONCLUSION: There is mixed evidence about whether drug companies are delaying or simply not introducing new drugs into Canada.


Assuntos
Aprovação de Drogas , Marketing , Canadá , Humanos , Preparações Farmacêuticas , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
18.
Cancer Chemother Pharmacol ; 90(4): 285-299, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36029310

RESUMO

During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents' combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure-response (E-R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011-2021 period and summarizes the main design features of clinical trials and the role of PK assessments.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration
19.
Ann Plast Surg ; 89(3): 261-266, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35993683

RESUMO

BACKGROUND: Adverse events arising in patients with breast implants during mammography reported by the Food and Drug Administration include implant rupture, pain, and impaired visualization. However, data supporting these claims were collected in 2004, and since, newer implant generations have been developed with overall rate of implantation increasing by 48%. OBJECTIVES: This article aims to determine the current incidence of implant-related adverse events arising during mammography. METHODS: We analyzed reports regarding silicone and saline breast implants published in the Food and Drug Administration Manufacturer and User Facility Device Experience database between 2008 and November 2018. Search terms included "mammogram," "mammography," "radiograph," "breast cancer screening," "breast cancer test," and "x-ray." RESULTS: Of the 20 539 implant-related adverse events available in the Manufacturer and User Facility Device Experience database, 427 were retrieved using our search strategy and 41 were related to mammography. Thirty-five of identified cases (85.4%) reported implant rupture, of which 19 (54.3%) were confirmed by a healthcare professional, 9 (25.7%) were clinically confirmed by saline implant deflation, and 7 (20.0%) were unverified reports by patients. Sixteen ruptures (45.7%) occurred with silicone implants, whereas 19 ruptures (54.3%) occurred with saline. Other adverse events included pain (29.3%), change in implant appearance (14.6%), and swelling (7.3%). CONCLUSIONS: Although implant rupture, pain, change in implant appearance, and swelling may occur, minimal implant-related adverse events arise during mammography. Given the extremely low reported risk of implant rupture, this should neither prevent patients from adhering to breast cancer screening programs nor deter patients from seeking breast implants. Patients should be aware of these reported risks and discuss screening options with their breast cancer screening team.


Assuntos
Implantes de Mama , Neoplasias da Mama , Implantes de Mama/efeitos adversos , Neoplasias da Mama/etiologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mamografia , Dor/etiologia , Falha de Prótese , Silicones , Estados Unidos , United States Food and Drug Administration
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