Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

Medicare Spending on Drugs With Accelerated Approval.

BACKGROUND: The U.S. Food and Drug Administration provides accelerated approval to drugs on the basis of surrogate end points deemed to be "reasonably likely" to predict clinical benefit. To receive full approval, drugs must complete a confirmatory trial. Although most accelerated approved drugs ultimately receive full approval, others remain on the market without full approval for many years, and some are withdrawn before full approval is granted. Until confirmatory trials are completed and full approval is granted, there is uncertainty surrounding each drug's clinical benefits. OBJECTIVE: To estimate fee-for-service Medicare payments on accelerated approved drugs without full approvals. DESIGN: Cross-sectional analysis. SETTING: Fee-for-service Medicare Part B and Part D drug claims in 2019. PARTICIPANTS: Beneficiaries enrolled in Medicare Part B and Part D plans. MEASUREMENTS: Medicare spending for drugs treating accelerated approved indications without full approval, beneficiary spending, and drug characteristics. RESULTS: In 2019, 45 drugs associated with 69 accelerated approved indications lacked full approval. Of those, the fee-for-service Medicare program spent $1.2 billion on 36 drugs across 55 indications. Medicare beneficiaries had $209 million in out-of-pocket spending on these drugs. Oncology drugs represented 82% of these indications and 72% of the Medicare spending. Extrapolating to Medicare Advantage, total Medicare spending on these drugs in 2019 was $1.8 billion. LIMITATIONS: The study drugs may have clinical benefit and may come to receive full approval after this analysis. The algorithm used to identify accelerated approved indications is novel. Generalizability to other years is unclear. CONCLUSION: In 2019, fee-for-service Medicare spent $1.2 billion on accelerated approved drugs without full approval. Medicare should adjust incentives to encourage sponsors to complete confirmatory trials as soon as possible. PRIMARY FUNDING SOURCE: Laura and John Arnold Foundation.

Translating Research into Health Policy: The Citizen Petition Experience with the Food and Drug Administration.

Translating research findings into policy is important. Health policy researchers often testify before Congressional subcommittees and provide background on health policy issues. A rarely used, but important, tool for facilitating translation of research into policy is via filing a Citizen Petition.

Investigating Severe Adverse Reactions: Examples of the ANTICIPATE Methodology at Work.

Severe adverse drug reactions (sADRs) are important causes of morbidity and mortality. The Southern Network on Adverse Drug Reactions (SONAR), a National Cancer Institute-funded pharmacovigilance program, has outlined a novel 9-stop methodology, termed ANTICIPATE, that has evaluated this methodology, among persons with chronic kidney disease (CKD).

Moderna, Pfizer-BioNTech, and Johnson & Johnson/Janssen Post-Covid Vaccine Hematological Adverse Events Including Cerebral Venous Sinus Thrombosis (CVST), Thrombotic Thrombocytopenia (VITT), Blood Clots, Increased Vaginal/Menstrual Bleeding and/or Miscarriage, Stillbirth Delivery, or Premature Birth.

The Centers for Disease Control (CDC) indicated in 2021 that it would monitor for possible post-COVID-19 vaccination coagulopathy adverse events (AEs).

Policing of Drug Safety Information Dissemination Under the False Claims Act.

On July 25, 2017, the second largest multi-million dollar settlement was pursued with the assistance of the Department of Justice and alleging inappropriate marketing strategies utilized by the pharmaceutical industry came to an end.

Rituximab-Associated Progressive Multifocal Leukoencephalopathy: A Twenty-Year Update.

Progressive multifocal leukoencephalopathy (PML) is a John-Cunningham virus-related central nervous system that is rarely observed in persons treated with the anti-CD20 monoclonal antibody, rituximab.

Fluoroquinolone-Associated Disability and Other Fluoroquinolone-Associated Serious Adverse Events: Unexpected Toxicities Have Emerged in Recent Years.

This study describes cases of individuals who report adverse events following consumption of the most commonly prescribed fluoroquinolone (FQ) antibiotics: ciprofloxacin, levofloxacin, or moxifloxacin. Fluoroquinolone (FQ) antibiotics are some of the most widely prescribed antibiotics in the world. Although these antibiotics have been on the market for more than 20 years, a wide range of serious FQ-associated adverse events first became apparent in 2006 and continued to be recognized for the next 15 years.

Biosimilar Epoetin in the United States: A View from the Southern Network on Adverse Reactions.

Biosimilar drugs, close copies of patented biologicals, are intended to provide access to less expensive, highly similar versions of reference (previously approved) biological agents (Kozlowski et al. in N Engl J Med 365:385-388, 2011). The biological epoetin accounts for $1.8 billion in drug spending annually worldwide (primarily for the treatment of anemia due to chronic kidney disease or anemia due to cancer chemotherapy.).

Was There Something Rotten in Denmark: Nephrogenic System Fibrosis Cases Occurring in Copenhagen.

More than half of all serious adverse drug reactions are identified seven years after FDA approval. One recent and unusual example involves a syndrome initially termed nephrogenic dermatopathic fibrosis, and then called nephrogenic systemic fibrosis (NSF).

Systemic Barriers and Potential Concerns from Reporting Serious Adverse Drug Reactions.

About 1-10% of all serious adverse drug reactions (sADRs) are reported to the Food and Drug Administration (FDA) ( Moore T, Bennett C. Underreporting of Hemorrhagic and Thrombotic Complications of Pharmaceuticals to the U.S. Food and Drug Administration: Empirical Findings for Warfarin, Clopidogrel, Ticlopidine, and Thalidomide from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38(08):905-907. https://doi.org/10.1055/s-0032-1328890 ). Prevailing opinion suggests that low reporting rates reflect time constraints.

Consequences to Patients, Clinicians, and Manufacturers When Very Serious Adverse Drug Reactions Are Identified (1997-2019): A Qualitative Analysis from the Southern Network on Adverse Reactions (SONAR).

Adverse drug/device reactions (ADRs) serious enough to lead to box warnings on drug labels or drug withdrawals occur in about one fifth of all new molecular entities.

Maximum Accuracy Machine Learning Statistical Analysis-A Novel Approach.

Logistic regression is a statistical tool of paramount significance in the field of epidemiology1 and ranks as one of the most frequently published multivariable analyses for designs involving a single binary dependent variable and one or more independent variables in the fields of public health2,3 and medical4 research.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Do radiation oncologists and urologists endorse decision aids for active surveillance of low-risk prostate cancer: Results from a national survey.

OBJECTIVE: The degree decision aids (DAs) can promote active surveillance (AS) for prostate cancer (PCa) remains poorly understood. Herein, we surveyed radiation oncologists (RO) and urologists (URO) about their attitudes towards DAs in counselling patients about AS for low-risk PCa. METHODS: We conducted a national survey of RO (n = 915) and URO (n = 940) to assess their attitudes about DAs for AS for patients with low-risk PCa. Respondents were queried about their attitudes towards DAs and proportion of PCa patients managed with AS. Multivariable logistic regression models were used to examine physician characteristics related to attitudes about DAs. RESULTS: The overall response rate was 37.3% (n = 691). Most respondents strongly agreed or agreed that DAs helped patients with low-risk PCa make informed decisions (93.9%) and also increased patient support for AS (86.6%). Having a high volume of their low-risk PCa patients on AS (>15%) was associated with endorsing the statement that use of DAs increased the likelihood of recommending AS (OR: 1.83; 95% CI: 1.00-4.61; p = .05) and being a URO versus a RO (OR: 3.37; 95% CI: 2.46-5.79; p < .001). CONCLUSIONS: Most specialists view DAs as effective tools to facilitate more informed treatment decisions and facilitate greater use of AS in appropriately selected patients.

A New Criterion for Fluoroquinolone-Associated Disability Diagnosis: Functional Gastrointestinal Disorders.

Background and Objectives: Fluoroquinolones (FQs) are a broad-spectrum class of antibiotics routinely prescribed for common bacterial infections despite recent recommendations to use them only for life-threatening cases. In addition to their antimicrobial properties, FQs act in the central nervous system as GABAA receptor inhibitors, which could potentially affect functionality of the vagus nerve at the forefront of gastrointestinal (GI) tract function. Alterations in neural control of digestion have been shown to be linked to Functional Gastrointestinal Disorders (FGIDs), which are usually diagnosed based on self-reported symptoms. The aim of this study was to assess the incidence of FGIDs following FQ use. Materials and Methods: Self-reports from the FDA Adverse Event Reporting System were analyzed together with ~300 survey responses from a social network derived sample to the Bowel Disease Questionnaire. Results: The results of this study suggested that six different FQs are associated with a wide range of GI symptoms not currently reported in the drugs' labels. The responses from the survey suggested that ~70% of FQ users scored positive for FGID, with no positive correlation between drug type, duration of administration, dosage and frequency of administration. Conclusions: This study showed that GI disorders other than nausea, vomiting and diarrhea are more common than currently reported on the drug labels, and that FGIDs are possibly a common consequence of FQ use even after single use.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 µg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

Patient- and area-level predictors of prostate cancer among South Carolina veterans: a spatial analysis.

BACKGROUND: Racial and socio-economic status (SES) disparities exist in prostate cancer (PrCA) incidence and mortality. Less is known regarding how geographical factors, including neighborhood social vulnerability and distance traveled to receive care, affect PrCA risk. The purpose of this research was to use the Veterans Administration Medical System, which provides a unique means for studying PrCA epidemiology among diverse individuals with ostensibly equal access to healthcare, to determine whether area-level characteristics influence PrCA incidence while accounting for individual-level risk factors. METHODS: From the US Veteran's Health Administration (VHA) electronic medical records (EMR) database from January 1999 to December 2015, we identified 3,736 PrCA patients and 104,017 cancer-free controls from South Carolina (SC). The VHA EMRs were linked to the US census which provided area-level factors. US census data were used to construct the Social Vulnerability Index which is a continuous composite measure of area-level vulnerability and was divided into tertiles for modeling purposes. Data were analyzed using a Bayesian multivariate conditional autoregressive model (CAR) which accounted for individual-level factors, area-level factors, spatial random effects, and autocorrelation, which were used to identify areas of higher- or lower-than-expected PrCA incidence after controlling for risk factors. RESULTS: As expected, after accounting for age (sixfold and 13-fold increases in men 40-50 years and > 50 years, respectively), race was an important risk factor, with threefold higher odds among Blacks in the fully adjusted model [ORadj 2.98 (2.77, 3.20)]. After accounting for all other factors, residing in a ZIP code tabulated areas (ZCTA) with the greatest level social vulnerability versus the lowest, least vulnerable ZCTA's, increased PrCA risk by 39% [ORadj 1.39 (1.11, 1.75)]. CONCLUSIONS: While accounting for known risk factors for PrCA, including age, race, and marital status, we found geographic areas in SC characterized by higher than average social vulnerability with higher rates of incident PrCA among veterans. Outreach for screening, education, and care coordination may be needed for veterans in these areas.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.