Association of Fluoroquinolone Prescribing Rates With Black Box Warnings from the US Food and Drug Administration.

Importance: In 2013 and 2016, the US Food and Drug Administration (FDA) issued warnings and recommended limited use of fluoroquinolones for patients with certain acute conditions. It is not clear how prescribers have responded to these warnings. Objective: To analyze changes in prescribing of fluoroquinolones after the 2013 and 2016 FDA warnings and to examine the physician characteristics associated with these changes. Design, Setting, and Participants: This cross-sectional study used Medicare administrative claims data on Medicare fee-for-service beneficiaries and OneKey data on physicians and their organizations from January 1, 2011, to December 31, 2017. The sample was restricted to outpatient visits for sinusitis, bronchitis, and uncomplicated urinary tract infections. An interrupted time series approach was used to analyze the changes in the prescription rate after each FDA warning. Data analysis was performed between January 1, 2011, and December 31, 2017. Interventions: Two FDA black box warnings released in August 2013 and July 2016. Main Outcomes and Measures: The main outcome was an indicator for fluoroquinolone prescriptions in 3 periods: before the 2013 warning (baseline period), after the 2013 warning but before the 2016 warning (postwarning period 1), and after the 2016 warning (postwarning period 2). Results: The sample comprised 1 238 397 unique patients with a total of 2 720 071 outpatient acute care visits. Of this sample, 848 360 were women (68.5%), and the mean (SD) age was 69.7 (12.6) years. The immediate prescribing levels of fluoroquinolones in postwarning period 1 increased by 3.42 percentage points (95% CI, 3.23-3.62; P < .001) and declined by -0.77 percentage points (95% CI, -1.00 to -0.54; P < .001) in postwarning period 2. The prescribing trend increased by 0.08 percentage points per month (95% CI, 0.08-0.10; P < .001) in postwarning period 1 and 0.06 percentage points per month (95% CI, 0.04-0.08; P < .001) in postwarning period 2. In postwarning period 1, the prescribing levels for physicians who were affiliated with hospitals with a top 10th percentile case mix index vs those without such affiliation decreased by -1.13 percentage points (95% CI, -1.92 to -0.34; P = .005), whereas the levels for primary care physicians declined by -1.34 percentage points (95% CI, -1.78 to -0.88; P < .001) compared with non-primary care physicians in postwarning period 2. Physicians at teaching hospitals were the only ones who showed a decline in prescribing trend in postwarning period 1. Conclusions and Relevance: This cross-sectional study found an overall decline in prescribing of fluoroquinolones after the release of FDA warnings. Understanding the association of physician and organizational characteristics with fluoroquinolone prescribing behavior may ultimately help to identify mechanisms to improve de-adoption.

Attack on Sunscreens Continues.

The Food and Drug Administration (FDA) was required to issue and put into effect a final sunscreen monograph by November 26, 2019. On March 27, 2020, President Donald Trump signed into effect H.R. 748, the "Coronavirus Aid, Relief, and Economic Security Act" (CARES). This bill eliminated the November 2019 requirement. The CARES Act includes legislative reforms that modernize the way over-the-counter (OTC) monograph drugs are regulated in the United States. Under this Act, sunscreens will be considered generally recognized as safe and effective (GRASE), if they meet conditions newly defined by the FDA. In addition, the FDA is required to issue a proposal to revise the sun-screen requirements for GRASE not later than 18 months after enactment and will sunset by the end of the fiscal year 2022. The CARES Act also addresses the requirement for a new drug application (NDA).1-7.

Investigation of Factors Associated With Immunogenicity Labeling Updates and Characteristics of Biologics License Applications.

Immunogenicity, the potential to elicit an antidrug immune response, is a critical concern in developing biological products, but its consequences are difficult to predict with animal studies. The aims of the present study are to investigate the evolution of immunogenicity information in labeling and to identify attributes associated with immunogenicity labeling updates. Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research, US Food and Drug Administration between 2008 and 2017 were studied. A majority of BLAs described the incidence/prevalence of antidrug antibodies (ADAs) (94.9%) and neutralizing antibodies (NAbs) (68.4%) in their original labeling documents. However, less than one third of the BLAs mentioned the impact of ADAs/NAbs in the original (20.3%) and most recent (29.1%) labeling documents. BLAs with a priority review status (57.4% vs. 33.3%), orphan designation (61.5% vs. 34.2%), or a mention of ADA impact in the latest label (69.6% vs. 38.9%) had higher percentages of applications with postmarketing requirements (PMRs) directly related to immunogenicity concerns in comparison with applications without those characteristics. Among the BLAs with updated immunogenicity information, the mean time to the first update was 1,077 days, while that for BLAs with accelerated approval was shorter (709.1 ± 492.2 days vs. 1173.8 ± 661.8 days). The results suggest that there is a substantial amount of critical information lacking in the original labeling documents and an overdependence on PMRs for more evidence. Additional efforts should be made to investigate the impact of ADAs to provide timely information for improved patient care.

Comprehensive evaluation of post-approval regulatory actions during the drug lifecycle - a focus on benefits and risks.

Background: Prior studies investigated regulatory actions that reflected a negative impact on drug risks. We aimed to evaluate occurrence of regulatory actions that reflected a negative or positive impact on benefits or risks, as well as relations between them.Research design and methods: We followed EMA-approved innovative drugs from approval (2009-2010) until July 2020 or withdrawal to identify regulatory actions. We assessed these for impact on benefits or risks and relations between actions. Additionally, we scrutinized drug lifecycles for time-variant characteristics that may contribute to specific patterns of regulatory actions.Results: We identified 14 letters and 361 label updates for 40 drugs. Of the label updates, 85 (24%) reflected a positive impact, mostly concerning indications, and 276 (76%) a negative impact, mostly adverse drug reactions. Many updates (54%) occurred simultaneously with other updates, also if these reflected a different impact. Furthermore, levels of patient exposure, innovativeness, needs for regulatory learning and unexpected risks may contribute to patterns of regulatory actions.Conclusions: Almost a quarter of regulatory actions reflected a positive impact on benefits and risks. Also, simultaneous learning about benefits and risks suggests an important role for drug development in risk characterization. These findings may impact regulatory analyses and decision-making.

A Legislative/Legal History of Prescription Drug Advertising and Promotion Regulation.

PURPOSE: The communication by pharmaceutical companies of promotional messages about their products has long been controversial, but deemed to be necessary by the pharmaceutical industry so that health care professionals and in some cases patients/consumers can be made aware of the latest developments through the communication vehicles they are accustomed to seeing - in the case of health care professionals, through medical advertising, direct mail, visits by company representatives, and attendance at medical meetings, and in case of patients, through the news media and television advertising. On the other hand, critics argue that such promotion, which sometimes reduces complex medical issues to advertising slogans, is inappropriate for products intended to treat and cure diseases, and that health care professionals should learn about new products from peer-reviewed medical literature.  Consequently, advertising, and promotional programs are heavily regulated by the U.S. Food and Drug Administration (FDA). However, the laws themselves raise constitutional issues of infringement on free speech.  Over the past few years, a number of lawsuits have been decided that help clarify the role of the FDA and the extent of its authority in regulating what companies or their employees say about their products. These court decisions are important because they help define how health care professionals and patients/consumers receive medical information. METHODS: This overview is intended to identify, in non-technical language, some of the more controversial and challenging issues involved in the FDA's efforts to regulate marketing communications by drug companies and how the courts view them. RESULTS: The recent lawsuits often involve complex and far-reaching legal issues.  But when examined in toto, as this paper does, they have reflected a view by the courts that truthful and non-misleading statements by drug companies about their products can be legally communicated even when the medical information is not formally approved by the FDA and included in the FDA-approved labeling.  The lawsuits thus have led to an environment in which the FDA continues to oversee with great fervor the activities of drug companies in communicating medical information but at the same time having some flexibility in keeping health care professionals and patients up to date with th latest information about medical research and new therapeutic products. CONCLUSION: How pharmaceutical products are marketed has been deemed by the U.S. Congress to be important enough to need to be subject to federal regulation.  The issues create a tension between the need for medical information to be accurate and balanced, and the guarantees of free speech.  This review provides an important perspective on how this tension is being resolved, even as dramatic advances in both medical products and technology create new challenges.

Update on ICH E14/S7B Cardiac Safety Regulations: The Expanded Role of Preclinical Assays and the "Double-Negative" Scenario.

For nearly 2 decades, regulators have adopted a harmonized approach to drug development, which has succeeded in bringing new pharmaceuticals to market without significant cardiac liability. Ushered in by technological advancements and better understanding of cellular electrophysiology, the initial paradigm detailed in the 2005 International Conference for Harmonization E14 and S7B documents has undergone evolutionary changes designed to streamline drug development and improve regulatory decision-making and product labeling. The intent of this review is to summarize the new US Food and Drug Administration (FDA) Question and Answer update from August 2020 and key messaging from a subsequent FDA webinar describing best practices for preclinical and clinical data integration into a QT risk prediction model.

Analytical survey of tattoo inks-A chemical and legal perspective with focus on sensitizing substances.

BACKGROUND: Tattoo inks have been reported to elicit allergic contact dermatitis. OBJECTIVES: To investigate the labels and the contents of metals and pigments in tattoo inks, considering restrictions within the European Union. METHODS: Seventy-three tattoo inks currently available on the market, either bought or donated (already used), were investigated for trace metals and pigments by inductively coupled plasma mass spectrometry and by matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry. RESULTS: Ninety-three percent of the bought tattoo inks violated European, legal requirements on labeling. Fifty percent of the tattoo inks declared at least one pigment ingredient incorrectly. Sixty-one percent of the inks contained pigments of concern, especially red inks. Iron, aluminium, titanium, and copper (most in green/blue inks) were the main metals detected in the inks. The level of metal impurities exceeded current restriction limits in only a few cases. Total chromium (0.35-139 µg/g) and nickel (0.1-41 µg/g) were found in almost all samples. The levels of iron, chromium, manganese, cobalt, nickel, zinc, lead, and arsenic were found to covary significantly. CONCLUSIONS: To prevent contact allergy and toxic reactions among users it is important for tattoo ink manufacturers to follow the regulations and decrease nickel and chromium impurities.

[Drug Information Provided to Patients and Public-Present Regulatory Status and Future Prospects].

When taking a drug one must keep in mind certain risks and benefits based on the safety and efficacy information. One of the most reliable sources of information that enables patients to use drugs properly is package inserts, which are regulated under the law and therefore should include valid and accurate contents. With the recent revision of the Pharmaceutical and Medical Device Act, the information contained in the package insert, which was provided together with the drug, will now also be provided electronically and separately from the drug itself. In addition, a digital code will be displayed on the product packaging so that the latest information of the drug can be obtained from outside the package by scanning the code. The more drug information gets shared among healthcare professionals, patients and the public, the less the asymmetry in drug information among them will exist. It is necessary now more than ever to establish a framework and a system to ensure that sufficient information is provided to patients and the public to encourage their proper use of drugs. I believe that it is important for patients and the public to strive for a better understanding of drug information. It is also crucial for all relevant parties involved in drug information to work together on how best to utilize the information. In this way they would keep trying so that therapeutic effects could be maximized and the risks of side effects are minimized.

Why are certain age bands used for children in paediatric studies of medicines?

Rational prescribing of medicines requires evidence from clinical trials on efficacy, safety and the dose to be prescribed, based on clinical trials. Regulatory authorities assess these data and information is included in the approved summary of product characteristics. Regulatory guidelines on clinical investigation of medicinal products in the paediatric population generally propose that studies are done in defined age groups but advise that any classification of the paediatric population into age categories is to some extent arbitrary or that the age groups are intended only as a guide. The pharmaceutical companies tend to plan their studies using age groups the regulatory guidelines suggest, to avoid problems when applying for marketing authorisation. These age bands end up in the paediatric label, and consequently into national paediatric formularies. The age bands of the most commonly used age-subsets: neonates, infant/toddlers, children and adolescents, are more historical than based on physiology or normal development of children. Particularly problematic are the age bands for neonates and adolescents. The age of 12 years separating children from adolescents, and the upper limit of the adolescents set by the definition of paediatric age in healthcare, which varies according to the region, are particularly questionable. Modern pharmacometric methods (modelling and simulation) are being increasingly used in paediatric drug development and may allow assessment of growth and/or development as continuous covariables. Maybe time has come to reconsider the rational of the currently used age bands.

Shark Cartilage Supplement Labeling Practices and Compliance with U.S. Regulations.

The objective of this study was to analyze labeling practices and compliance with regulatory standards for shark cartilage supplements sold in the United States. The product labels of 29 commercial shark cartilage supplements were assessed for compliance with U.S. regulations. Claims, including nutrient content, prohibited disease, and nutritional support statements, were examined for compliance and substantiation. Overall, 48.3% of the samples had at least one instance of noncompliance with labeling regulations. The most common labeling violations observed were: missing a domestic address/phone number, non-compliant nutrient content claim, missing/incomplete disclaimer, missing statement of identity, prohibited disease claims, and incomplete "Supplement Facts" label. The use of prohibited disease claims and nutritional support statements without the required disclaimer is concerning from a public health standpoint because consumers may delay seeking professional treatment for a disease. The results of this study indicate a need for improved labeling compliance among shark cartilage supplements.

FDA Oncology Center of Excellence Project Renewal: Engaging the Oncology Community to Update Product Labeling for Older Oncology Drugs.

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Evaluation of Drug Labels Following the 2015 Pregnancy and Lactation Labeling Rule.

Importance: The US Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Rule (PLLR), implemented in 2015, includes information on pregnancy, lactation, and women and men with reproductive potential. Objectives: To identify the drugs that have adhered to the new PLLR format; to shed light on the continued need for implementation of pregnancy, lactation, and reproduction into clinical studies; and to evaluate how many new therapeutic products have human and animal data specific to pregnancy and lactation. Design, Setting, and Participants: This cross-sectional study of 290 new therapeutic drugs reviewed labeling data for newly FDA-approved therapeutic products from January 2010 to December 2019. Therapeutic products submitted on or after June 30, 2015, were required to be in PLLR format; those approved from June 30, 2007, to June 29, 2015, had until June 30, 2019, to be in PLLR format. Approval data and subsequent labeling revision were evaluated for pregnancy and lactation data (human and animal), pregnancy registry, black-box warnings, and inclusion of PLLR labeling format. Exposures: Date of new drug approval by FDA. Main Outcomes and Measures: Compliance with PLLR; presence of animal or human data; presence of pregnancy registries; and presence of information regarding female and male reproductive potential. Results: A total of 290 new molecular entities or therapeutic products were approved by the FDA between 2010 and 2019 in 19 categories. Black-box warnings occurred in 89 drugs (30.7%; 95% CI, 25.4%-36.3%), with 3 (3.4%; 95% CI, 0.7%-9.5%) involving pregnancy. All products submitted after June 30, 2015, were in PLLR format; however, of the 138 submitted between 2010 and that date, 45 (32.6%; 95% CI, 24.9%-41.1%) were not in PLLR format by June 30, 2019. During the 10 years of data analyzed, significantly more were in PLLR format (P for trend < .001). Most approved therapeutic products have pregnancy data derived from animal studies (260 products; 89.7%; 95% CI, 85.6%-92.9%) but only 31 (10.7%; 95% CI, 7.4%-14.8%) derived data from human studies. Only 148 therapeutic products (51.0%; 95% CI, 45.1%-56.9%) had any data associated with lactation, 143 (49.3%; 95% CI, 43.4%-55.2%) originating from animal studies and 8 (2.8%; 95% CI, 1.2%-5.4%) from human studies. Conclusions and Relevance: The results of this study show that with the implementation of PLLR in the last decade, new therapeutic products were in compliance with the new rules; however, more than one-third of labels remain out of PLLR compliance. Human data on pregnancy and lactation are available in less than 20% of new product labeling.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

PARC report: a perspective on the state of clinical pharmacogenomics testing.

In this Perspective, the authors discuss the state of pharmacogenomics testing addressing a number of advances, challenges and barriers, including legal ramifications, changes to the regulatory landscape, coverage of testing and the implications of direct-to-consumer genetic testing on the provision of care to patients. Patient attitudes toward pharmacogenomics testing and associated costs will play an increasingly important role in test acquisition and subsequent utilization in a clinical setting. Additional key steps needed include: further research trials demonstrating clinical utility and cost-effectiveness of pharmacogenetic testing, evidence review to better integrate genomic information into clinical practice guidelines in target therapeutic areas to help providers identify patients that may benefit from pharmacogenetic testing and engagement with payers to create a path to reimbursement for pharmacogenetic tests that currently have sufficient evidence of clinical utility. Increased adoption of testing by payers and improved reimbursement practices will be needed to overcome barriers, especially as the healthcare landscape continues to shift toward a system of value-based care.