To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajo.2016.12.019 Byline: Wallace L.M. Alward Author Affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa Article History: Accepted 21 December 2016 Article Note: (footnote) Supplemental Material available at AJO.com.
Objective To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades.Design Cohort study.Setting FDA approved novel therapeutics between 1987 and 2014.Population Publicly available sources provided each drug’s year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA’s four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review.Main outcome measures Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not.Results The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction).Conclusions In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative.
Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments. Han et al. characterize global A-to-I RNA editing profiles across 17 cancer types and experimentally demonstrate the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and drug sensitivity.
Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: .)
Although new opioid legislation is a step in the right direction, substantially altering the trajectory of the opioid epidemic requires a comprehensive, integrated, and public health–oriented response coordinated throughout all branches and levels of government.
Abstract Backgroud and Aims Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-Inosine (A-to-I) RNA editing is a recently-described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR enzymes ( A denosine D e A minase that act on R NA). Emerging evidence suggests a role for RNA editing and ADARs in cancer, however the relation between RNA editing and GC development and progression remains unknown. Methods In this study, we leveraged on the next-generation sequencing (NGS) transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. Results Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation, arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His→Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. Conclusions Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous NGS analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities, through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
Acceptance and Commitment therapy (ACT) has attracted a lot of interest during the last 10–15 years with a strong increase of the number of randomized controlled trials (RCTs). The present review and meta-analysis includes 60 RCTs (4234 participants) on psychiatric disorders, somatic disorders, and stress at work. The mean effect size across all comparisons was small (0.42). Compared to the Öst (2008) meta-analysis there was no significant improvement in methodological quality and deterioration in effect size (from 0.68). When ACT was compared to various forms of cognitive or behavioral treatments a small and non-significant effect size of 0.16 was obtained. An evidence-base evaluation showed that ACT is not yet well-established for any disorder. It is probably efficacious for chronic pain and tinnitus, possibly efficacious for depression, psychotic symptoms, OCD, mixed anxiety, drug abuse, and stress at work, and experimental for the remaining disorders.
Summary Background Malaria is one of the greatest causes of mortality worldwide. Use of the most effective treatments for malaria remains inadequate for those in need, and there is concern over the emergence of resistance to these treatments. In 2010, the Global Fund launched the Affordable Medicines Facility—malaria (AMFm), a series of national-scale pilot programmes designed to increase the access and use of quality-assured artemisinin based combination therapies (QAACTs) and reduce that of artemisinin monotherapies for treatment of malaria. AMFm involves manufacturer price negotiations, subsidies on the manufacturer price of each treatment purchased, and supporting interventions such as communications campaigns. We present findings on the effect of AMFm on QAACT price, availability, and market share, 6–15 months after the delivery of subsidised ACTs in Ghana, Kenya, Madagascar, Niger, Nigeria, Uganda, and Tanzania (including Zanzibar). Methods We did nationally representative baseline and endpoint surveys of public and private sector outlets that stock antimalarial treatments. QAACTs were identified on the basis of the Global Fund's quality assurance policy. Changes in availability, price, and market share were assessed against specified success benchmarks for 1 year of AMFm implementation. Key informant interviews and document reviews recorded contextual factors and the implementation process. Findings In all pilots except Niger and Madagascar, there were large increases in QAACT availability (25·8–51·9 percentage points), and market share (15·9–40·3 percentage points), driven mainly by changes in the private for-profit sector. Large falls in median price for QAACTs per adult equivalent dose were seen in the private for-profit sector in six pilots, ranging from US$1·28 to $4·82. The market share of oral artemisinin monotherapies decreased in Nigeria and Zanzibar, the two pilots where it was more than 5% at baseline. Interpretation Subsidies combined with supporting interventions can be effective in rapidly improving availability, price, and market share of QAACTs, particularly in the private for-profit sector. Decisions about the future of AMFm should also consider the effect on use in vulnerable populations, access to malaria diagnostics, and cost-effectiveness. Funding The Global Fund to Fight AIDS, Tuberculosis and Malaria, and the Bill & Melinda Gates Foundation.
The Affordable Care Act Medicaid expansion demonstrated inconsistent effects on cancer surgery utilization rates among racial and ethnic minorities and low-income Americans. This quasi-experimental study examines whether Medicaid expansion differentially increased the utilization of surgical cancer care for low-income groups and racial minorities in states that expanded their Medicaid programs. A cohort of more than 81,000 patients 18 to 64 years of age who underwent cancer surgery were examined in Medicaid expansion versus nonexpansion states. This evaluation utilized merged data from the State Inpatient Database, American Hospital Association, and the Area Resource File for the years 2012 to 2015. Poisson interrupted time series analysis were performed to examine the impact of Medicaid expansion on the utilization of cancer surgery for the uninsured overall, low-income persons, and racial minorities, adjusting for age, sex, Elixhauser comorbidity score, population-level characteristics, and provider-level characteristics. For persons from low-income ZIP codes, Medicaid expansion was associated with an immediate 24% increase in utilization ( = .002) relative to no significant change in nonexpansion states. No significant trends, however, were observed after the Affordable Care Act expansion for racial and ethnic minorities in expansion versus nonexpansion states. Medicaid expansion was associated with greater utilization of cancer surgery by low-income Americans but provided no preferential effects for racial minorities in expansion states. Beyond the availability of coverage, these findings highlight the need for additional investigation to uncover other factors that contribute to race-ethnic disparities in surgical cancer care.
Objective To determine if drugs approved through the Food and Drug Administration’s expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.Design Retrospective cohort study.Setting FDA public records, January 1997 to April 2016.Participants 382 FDA approved drugs.Main outcome measures The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug’s time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.Results Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.Conclusions Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.