Postmarketing Safety-Related Regulatory Actions for New Therapeutic Biologics Approved in the United States 2002-2014: Similarities and Differences With New Molecular Entities.
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ABSTRACT:
SUBMITTER: Bulatao I
PROVIDER: S-EPMC8159207 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAlthough prior studies of inpatient maternal mortality in the United States provide data on the overall rate and trend in inpatient maternal mortality, there are no published reports of maternal mortality data stratified by timing of its occurrence across the pregnancy continuum (antepartum, intrapartum, and postpartum).ObjectiveThe study objective was to determine whether the maternal mortality rate, trends over time, self-reported race/ethnicity, and associated factors vary based on the timing of the occurrence of death during pregnancy.MethodsWe conducted a cross-sectional analysis of the Nationwide Inpatient Sample database to identify pregnancy-related inpatient stays stratified by timing. Among women in the sample, we determined in-hospital mortality and used International Classification of Diseases, Ninth Revision, Clinical Modification codes to identify comorbidities and behavioral characteristics associated with mortality, including alcohol, drug, and tobacco use. Joinpoint regression was used to calculate rates and trends of in-hospital maternal mortality.ResultsDuring the study period, there were 7,411 inpatient maternal mortalities among an estimated 58,742,179 hospitalizations of women 15-49 years of age. In-hospital maternal mortality rate stratified by race showed that African Americans died at significantly higher rates during antepartum, intrapartum, and postpartum periods compared to hospitalizations for Whites or Hispanics during the same time period. Although the postpartum hospitalization represents only 2% of pregnancy-related hospitalizations among women aged 15-49 years, hospitalization during this time period accounted for 27.2% of all maternal deaths during pregnancy-related hospitalization.DiscussionMost in-hospital maternal mortalities occur after hospital discharge from child birth (postpartum period). Yet, the postpartum period continues to be the time period with the least maternal healthcare surveillance in the pregnancy continuum. African American women experience three times more in-hospital mortality when compared to their White counterparts.
| S-EPMC7041646 | biostudies-literature
Project description:BackgroundPostmarketing commitments are clinical studies that pharmaceutical companies agree to conduct at the time of FDA approval, but which are not required by statute or regulation. As FDA increasingly adopts a lifecycle evaluation process, greater emphasis will be placed on postmarket evidence as a component of therapeutic evaluation. Therefore, the objectives of this study were to determine how often postmarketing commitments agreed upon by pharmaceutical companies at first FDA approval lead to new clinical trials and to establish the characteristics and rates of completion and dissemination of postmarketing commitments.MethodsFor new drugs and biologics approved in 2009-2012, we used public FDA documents, ClinicalTrials.gov, and Scopus, to determine postmarketing commitments and their characteristics known at the time of FDA approval; number subject to reporting requirements, for which FDA is required to make study status information available to the public ("506B studies"), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials.ResultsAmong 110 novel drugs and biologics approved by the FDA between 2009 and 2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 33 (10.0%) were for new clinical trials; 27 of these were 506B studies subject to public reporting requirements, of which 12 (44.4%) did not have a recent (i.e., up-to-date) or closed (i.e., fulfilled or released) status provided publicly by the FDA. Although two postmarketing commitments were insufficiently described in FDA records to perform searches on ClinicalTrials.gov, nearly all (28, 90.3%) of the 31 remaining postmarketing commitments for new clinical trials were registered on ClinicalTrials.gov. Among the registered trials, 23 (23 of 28, 82.1%) were classified as completed or terminated, of which 22 (95.7%) had reported results. When considering all 29 completed or terminated clinical trials, registered or unregistered on ClinicalTrials.gov, only half (14, 48.3%) were published in peer-reviewed journals.ConclusionsWhile only 15% of postmarketing commitments agreed to by pharmaceutical companies at the time of FDA approval were for new clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, only half were published, and despite FDA public reporting requirements, recent status information was often unavailable for 506B studies.
| S-EPMC6572730 | biostudies-literature
Project description:While efficient and less onerous for the industry, the globalization of clinical drug development may lead to limited efforts to optimize drugs for regional conditions. We examined the association between clinical development pathways, approved doses, and postmarketing safety risks in Japan for 135 new molecular entities approved between 2004 and 2011. The risk of drug-related deaths seemed higher when pharmaceutical companies chose exactly the same dose as in the United States, even after conducting Japanese dose-ranging studies. We also found a positive association with drug-related deaths when the review process was expedited and when Japanese dose-ranging studies were not conducted for nonexpedited drugs. Our findings suggest that the decisions on regional dose settings and the choice of global clinical development pathways are associated in ways that may influence the postmarketing outcomes in the target populations.
| S-EPMC5504476 | biostudies-literature
Project description:OBJECTIVE:Cigarette smoking has declined in the United States. Still, identifying prevalent and modifiable barriers to quitting can help inform the next steps for tobacco control. Illicit drug use, which may be increasingly common in the United States, could be one such factor. We investigated the relationship between past-month illicit drug use and cigarette smoking status and estimated trends in the prevalence of past-month illicit drug use by cigarette smoking status from 2002 to 2014 in the United States. METHODS:The 2002-2014 National Survey on Drug Use and Health was used to obtain nationally representative data on past-month illicit drug use. RESULTS:From 2002 to 2014, past-month illicit drug use (for all drugs considered) was nearly 5 times more common among current smokers than among never smokers (adjusted odds ratio = 4.79) and nearly twice as prevalent in former smokers as in never smokers (adjusted odds ratio = 1.99). Illicit drug use increased linearly over time from 2002 to 2014 in the entire general population (ie, across and within current smokers, former smokers, and never smokers). This increasing trend in drug use was most rapid among former smokers (relative to current smokers and never smokers) and was largely, but not entirely, driven by increases in cannabis use. CONCLUSIONS:Illicit drug use is most prevalent among current cigarette smokers. Yet, the rate of increase in illicit drug use prevalence was most rapid among former smokers. Because former smokers outnumber current smokers in the general population, it may be important to monitor former smokers into the future for potential negative drug-related outcomes.
| S-EPMC6139671 | biostudies-literature
Project description:The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis.
| S-EPMC9299054 | biostudies-literature
Project description:Race, ethnicity, sex, and age are demographic factors that can influence drug exposure and/or response, and can consequently affect treatment outcome. We evaluated demographic subgroup enrollment patterns in new therapeutic products approved by the US Food and Drug Administration (FDA) for the treatment of select cancers-breast, colorectal, lung, and prostate-that have comparative differences in morbidity and/or mortality among some demographic subgroups. In submissions of products approved between 2008 and 2013, participants (n = 22,481) were white (80%), from outside the United States (74%), between 17 and 64 years old (59%), and men (56% and 53%, including and excluding sex-specific indications, respectively). In pivotal trials of products approved between2014 and 2017, participants (n = 3,612) were white (71%), between 17 and 64 years old (61%), and men (48% and 63%, including and excluding sex-specific indications, respectively). The US-relevant minority populations were under-represented. A broader representation of patient subgroups in clinical trials may contribute to better understanding of exposure and/or response variability, and consequently help personalize drug therapy.
| S-EPMC6220929 | biostudies-literature
Project description:BackgroundDespite the urgent need for new, effective antibiotics, few antibiotics of value have entered the market during the past decades. Therefore, incentives have been developed to stimulate antibiotic R&D. For these incentives to be effective, geographic availability for recently approved antibiotics needs to be better understood. In this study, we analyze geographic availability and market introduction of antibiotics approved between 1999 and 2014.Material and methodWe identified antibiotics, considered new chemical entities (NCEs) for systemic use approved globally between 1999 and 2014, from national medicine agencies' lists of approved drugs, and data from the WHO Collaborating Center for Drug Statistics. Geographic availability was mapped using sales data from IQVIA, and analyzed with regards to class, indication, safety, and origin.ResultsOf the 25 identified NCEs, only 12 had registered sales in more than 10 countries. NCEs with the widest geographic availability had registered sales in more than 70 countries within a ten-year timeframe and 30 countries within a three-year timeframe, spreading across five different geographic regions and three country income classes. Half (52%) of the NCEs had an indication for infections caused by antibiotic- resistant bacteria, little diversity was seen regarding target pathogen and indication. Antibiotics originated from and/or marketed by companies from the US or Europe had greater geographic availability compared to Japanese antibiotics, which seldom reached outside of Asia. For 20 NCEs developers chose to fully or partially sublicense marketing rights to a number of companies of different sizes.ConclusionOur findings show great variation in geographic availability of antibiotics, indicating that availability in multiple regions and country income classes is possible, but rarely seen within a few years of market authorization. Sublicensing agreements between multiple companies was common practice. Moreover, differences were seen between countries regarding benefit/risk evaluations and company behavior. These findings could be a potential source of uncertainties, and create barriers to assure that working antibiotics are developed and made available according to public health needs.
| S-EPMC6191083 | biostudies-literature
Project description:Bacteria of the genus Enterococcus are important human pathogens that are frequently resistant to a number of clinically important antibiotics. They are also used as markers of animal fecal contamination of human foods and are employed as sentinel organisms for tracking trends in resistance to antimicrobials with Gram-positive activity. As part of the National Antimicrobial Resistance Monitoring System (NARMS), we evaluated several retail meat commodities for the presence of enterococci from 2002 to 2014, and we found 92.0% to be contaminated. The majority of isolates were either Enterococcus faecalis (64.0%) or Enterococcus faecium (28.6%), and the antimicrobial resistance of each isolate was assessed by broth microdilution. The resistance prevalences for several drugs, including erythromycin and gentamicin, were significantly higher among poultry isolates, compared to retail beef or pork isolates. None of the isolates was resistant to the clinically important human drug vancomycin, only 1 isolate was resistant to linezolid, and resistance to tigecycline was below 1%. In contrast, a majority of both E. faecalis (67.5%) and E. faecium (53.7%) isolates were resistant to tetracycline. Overall, the robust NARMS testing system employed consistent sampling practices and methods throughout the testing period, with the only significant trend in resistance prevalence being decreased E. faecium resistance to penicillin. These data provide excellent baseline levels of resistance that can be used to measure future changes in resistance prevalence that may result from alterations in the use of antimicrobials in food animal production.IMPORTANCE Enterococci, including E. faecalis and E. faecium, are present in the guts of food-producing animals and are used as a measure of fecal contamination of meat. We used the large consistent sampling methods of NARMS to assess the prevalence of Enterococcus strains isolated from retail meats, and we found over 90% of meats to be contaminated with enterococci. We also assessed the resistance of the Enterococcus strains, commonly used as a measure of resistance to agents with Gram-positive activity, in foods. Resistance prevalence was over 25% for some antimicrobials and sample sources but was less than 1% for several of the most important therapeutic agents used in human medicine.
| S-EPMC5734015 | biostudies-literature
Project description: Not available
| S-EPMC4012824 | biostudies-literature
Project description:The impressive potential of biologics has been demonstrated in psoriasis, hidradenitis suppurativa, and urticaria. Numerous biologicals are entering the field for a restricted number of skin disorders. Off-label use of biologics in other recalcitrant skin diseases has increased. Mounting data point to the potential of already existing biologics acting on the IL-17/IL-23 pathway in skin disorders with epidermal hyperkeratosis (e.g., pityriasis rubra pilaris), acneiform inflammation (e.g., hidradenitis suppurativa), and loss of mucosal integrity (e.g., aphthosis). TNF-α blockers are also effective in the latter conditions but seem of particular value in granulomatous (e.g., granuloma annulare) and neutrophilic disorders (e.g., pyoderma gangrenosum). Failure of IL-17 blockade in skin diseases resulting from immune-mediated cell destruction (e.g., alopecia areata and vitiligo) illustrates its limited involvement in Th1-dependent skin immunology. Overall, disappointing results of TNF-α blockers in alopecia areata and vitiligo point to the same conclusion although promising results in toxic epidermal necrolysis suggest TNF-α exerts at least some in vivo Th1-related activities. Acting on both the Th1 and Th17 pathway, ustekinumab has a rather broad potential with interesting results in lupus and alopecia areata. The efficacy of omalizumab in bullous pemphigoid has revealed an IgE-mediated recruitment of eosinophils leading to bullae formation. Reconsidering reimbursement criteria for less common but severe diseases seems appropriate if substantial evidence is available (e.g., pityriasis rubra pilaris). For other disorders, investigator- and industry-initiated randomized clinical trials should be stimulated. They are likely to improve patient outcome and advance our understanding of challenging skin disorders.
| S-EPMC6694799 | biostudies-literature