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.

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.

The ascent of the blessed: regulatory issues on health effects and health claims for probiotics in Europe and the rest of the world.

The outcome of the first series of health claim applications for probiotics in Europe as evaluated by the European Food Safety Authority (EFSA) has, up to 2013 almost completely yielded negative results. All recent applications also have been rejected, including the latest on prevention of mastitis in breastfeeding mothers. In other developed countries, such as Switzerland, Japan and Canada, the health effects of probiotics, for which scientific evidence has been provided, can be communicated to potential consumers. The number of clinical trials with probiotics over recent years shows a trend to level off or even decline. At the same time, clinical research into the role of (gut) microbiota in a wide variety of diseases and conditions is booming. Ultimately, this may offer new indications for gut microbiota management by probiotics, prebiotics or other food supplements.

Exclusive Drug Labeling Rights as a New Incentive for Contribution to a Communal Biomarker Resource.

Biomarkers are an important tool in modern drug development. The FDA has posited that increased use of biomarkers in clinical trials can accelerate pharmaceutical industry productivity, ushering new drugs to market. Accordingly, the FDA has created two pathways for evaluation of biomarker utility. Biomarkers incorporated into clinical trials, the traditional pathway, are effectively private to a therapeutic sponsor and to the scope of the trial. By contrast, in Biomarker Qualification ("BQ"), the second pathway, a biomarker is certified as a publicly available tool. The FDA has hoped that academic, non-profit, and industry stakeholders would work together in consortia to qualify biomarkers, cumulatively generating a common resource of broad utility. In practice, utilization of Biomarker Qualification has been paltry. Incentives for BQ that align with the interests of industry resource holders are necessary to fuel increased utilization of biomarkers in clinical trials and create the communal biomarker toolkit envisioned by the FDA. A blanket extension of exclusivity for any drug successfully paired with a companion biomarker would diminish public access to medicine by encouraging spurious biomarkers and correspondingly narrowed clinical trials. As a measured alternative, an exclusive right to include a qualified companion biomarker on an FDA drug label would balance public access externalities. This exclusivity would waylay label approval, and thus marketability, of later drugs relying on the qualified biomarker for clinical safety or efficacy. Accordingly, sponsors would find no incentive to portage an ineffective or unnecessary biomarker through clinical trials, as there would be no benefit to securing exclusive rights in a tool others saw no value in using.

Disgust but not Health Anxiety Graphic Warning Labels Reduce Motivated Attention in Smokers: A Study of P300 and Late Positive Potential Responses.

Background: Graphic health warning labels (GHWLs) on tobacco products attempt to leverage avoidance-promoting emotions, such as anxiety and disgust, to encourage cessation. Prior studies have relied on self-report or attentional metrics that may not accurately illuminate GHWLs' ability to motivate change. This report evaluates the impact of disgust- and anxiety-based GHWLs on electroencephalograph (EEG) measures of motivated attention among two groups of smokers-those that report higher versus lower cigarette dependence. We hypothesized that both anxiety and disgust GHWLs would reduce appetitive attention, as indexed by lowered P300 (P3) and late positive potential (LPP) activations. Methods: Sixty-one smokers provided demographic and smoking history before completing an oddball paradigm consisting of three counterbalanced stimuli blocks. Each block (100 trials) contained a neutral, GHWL-anxiety, or GHWL-disgust frequent image and a smoking cue as the oddball image (20%). Oddball trials for each block were averaged, P3 and LPP were identified at midline electrode positions (Fz, Cz, and Pz), and mean amplitude was analyzed. Results: Separate mixed-model ANOVAs of P3 and LPP reactivity revealed disgust-focused GHWLs reduced motivated attentional processing. Conversely, the anxiety-focused GHWL appeared to increase the salience of the smoking cue (Fz only). Less-dependent smokers showed lower P3 reactivity than those with higher dependence at Fz, but greater P3 reactivity at Cz and Pz. Conclusion: These results extend prior work in demonstrating that disgust, but not anxiety-based GHWLs, may reduce EEG-assessed motivated attention to smoking cues. Disgust may thus represent a more fruitful target for public health cessation efforts. Implications: Most GHWL evaluations have focused on fear (or anxiety) elicitation rather than disgust, an emotion that may have a unique link to smoking, having evolved specifically to facilitate the avoidance of contaminants via oral incorporation. Analyses of P300 and LPP responses to GHWLs suggest that disgust-focused images interfere with the EEG-indexed attentional processing of smoking cues and do so better than health anxiety-focused messages. However, interaction effects at different electrode sites indicated that GHWLs have complex effects in more versus less-dependent smokers and that an understanding of how smoking cues and anti-smoking imagery become associated over time is needed to identify relevant targets for public health efforts.

Updates to the US Food and Drug Administration Regulations for Mifepristone: Implications for Clinical Practice and Access to Abortion.

This article provides information on recent changes in the US Food and Drug Administration (FDA) labeling and safety regulations for mifepristone (Mifeprex). The revised label now permits midwives, advanced practice nurses, and physician assistants to order and prescribe mifepristone, eliminating the requirement for physician supervision. The updated label also extends eligibility for use from 49 to 70 days' gestation and decreases the number of required visits from 3 to 2. The recommended dose of mifepristone has been reduced, and the dosage, timing, and route of administration for misoprostol have also been changed to reflect current research. These changes have implications for clinical practice and may lead to expanded access for women in the United States.

Adulterated and Counterfeit Male Enhancement Nutraceuticals and Dietary Supplements Pose a Real Threat to the Management of Erectile Dysfunction: A Global Perspective.

Erectile dysfunction prevalence globally is noticeably high. This is accompanied by an increase in the use of nutraceuticals for male enhancement. However, the global market is invaded by counterfeit and adulterated nutraceuticals claimed to be of natural origin sold with a therapeutic claim. The objective of this article is to review male enhancement nutraceuticals worldwide with respect to claim, adulterants, and safety. The definition of such products is variable across countries. Thus, the registration procedures differ as well. This facilitates the manipulation of the process, which leads to widespread adulterated and counterfeit products without control. The tele-advertisement and Internet pharmacies aided the widespread sale of male enhancement nutraceuticals, unfortunately, the spurious ones. Finally, based on literature, most of these products were found to be adulterated with active pharmaceutical ingredients (API) and mislabeled as being natural. These products represent a major health hazard for consumers due to lack of clear regulations.

US Dietary Supplement Labeling Rules and the Possibility of Medical Cost Reduction.

US dietary supplements classified as foods are regulated under the Dietary Supplement Health and Education Act (DSHEA) and other rules. After the DSHEA established in 1994, the supplement market grew by about 4 times and reached $32 billion as of 2012. One of the major reasons for this market expansion is that consumers can recognize functions of the supplements by the structure/function (S/F) claims. S/F claims must not be false or misleading, and must be based upon reliable scientific evidence, especially clinical studies. At the same time, disclaimers must be shown on the package, which are "These statements have not been evaluated by the Food and Drug Administration (FDA). These products are not intended to diagnose, treat, cure or prevent any disease." Both the FDA and Federal Trade Commission (FTC) are responsible for label claims and advertisement of dietary supplements. S/F claims are not medical claims, but these may have impact on people's mindset to be healthier. Recent research shows utilizing dietary supplements in 4 major areas with 10 popular ingredients could hypothetically reduce medical costs by over $50 billion in the US in the period of 2013-2020. Predicted fewer health problems and reduced medical cost information will further increase awareness of supplement usage and thus may raise quality of life. These may reduce the medical cost significantly, if the products are used appropriately with sufficient consumer education.

Origins of the prohibition against off-label promotion.

The statute and regulations administered by the Food and Drug Administration ("FDA") do not explicitly prohibit the promotion of drugs and medical devices for unapproved uses, yet the government has collected billions of dollars in penalties for such "off-label" promotion. The statutory interpretations and regulatory provisions relied on by the government to take enforcement action against off-label promotion are the incidental by-products of initiatives undertaken by FDA through administrative action and litigation early in its implementation of the Federal Food, Drug, and Cosmetic Act. The actions were designed to obtain FDA authority over therapeutic claims made in advertising, even though Congress had assigned authority over advertising to the Federal Trade Commission, and to establish a prescription-only drug system, even though FDA lacked statutory authority for such a system. The principal purpose of both efforts was to prevent inappropriate self-medication. This article describes the history of those strategies, including expansion of the definition of the term "labeling" to encompass matter that was initially regarded as advertising; creation of the rule that the labeling of drugs must have adequate directions for all "intended" uses; and construction of the prescription-only drug system in a manner that allowed FDA to use the statutory requirement for labeling to have "adequate directions for use" to prohibit the off-label promotion of prescription drugs.

Botanical-drug interactions: a scientific perspective.

There is a continued predisposition of concurrent use of drugs and botanical products. A general lack of knowledge of the interaction potential together with an under-reporting of botanical use poses a challenge for the health care providers and a safety concern for patients. Botanical-drug interactions increase the patient risk, especially with regard to drugs with a narrow therapeutic index (e.g., warfarin, cyclosporine, and digoxin). Examples of case reports and clinical studies evaluating botanical-drug interactions of commonly used botanicals in the US are presented. The potential pharmacokinetic and pharmacodynamic bases of such interactions are discussed, as well as the challenges associated with the interpretation of the available data and prediction of botanical-drug interactions. Recent FDA experiences with botanical products and interactions including labeling implications as a risk management strategy are highlighted.

Current perspectives on herb-drug interactions in the European regulatory landscape.

Herb-drug interactions have turned out not to be a major issue in the European regulatory landscape. For a minority of herbal preparations, herb-drug interactions are clinically relevant, e.g., between high-dose St.John's wort extracts and a number of chemical substances. The inclusion of adequate information on such interactions into the package leaflet is important for the safe use of the products. Information on potential interactions is also part of the official HMPC monographs. However, only for some herbal preparations described in these monographs, such a potential is known. Thus, in accordance with the relevant European guidance documents, potential interactions should be assessed critically for their clinical relevance, and a balanced assessment is required when regulatory documents are established or regulatory measures are implemented.