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.

Triheptanoin: First Approval.

Triheptanoin (Dojolvi™), a synthetic medium-chain triglyceride, is being developed by Ultragenyx Pharmaceutical as a pharmaceutical-grade anaplerotic compound for use in the treatment of inherited metabolic disorders. In June 2020, triheptanoin received its first regulatory approval, in the USA, for use as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). Triheptanoin has also been investigated for use as a treatment in a range of other metabolic disorders or other diseases where energy deficiency is implicated. This article summarizes the milestones in the development of triheptanoin leading to this first regulatory approval for use in the treatment of pediatric and adult patients with LC-FAOD.

Certified food dyes in over the counter medicines and supplements marketed for children and pregnant women.

Food, Drug, & Cosmetic (FD&C) dyes are synthetic color additives used in food, prescription drugs and over-the-counter medicines (OTCs). Consumption of FD&C dyes has been associated with neurobehavioral behavior in some children. The amount of dye used in commercial products is proprietary, making it difficult to assess dietary intake and determine exposure in children. To date, no studies have examined FD&C dyes in OTCs or vitamins in the United States. To address this, FD&C Red No. 40, Yellow No. 5, Yellow No. 6, Blue No. 1, and Blue No. 2 levels were measured in prenatal vitamin tablets, children's chewable and gummy vitamins, pain reliever tablets and syrups, and cough/cold/allergy tablets and syrups. Dyes were isolated using solid phase extraction (SPE) and quantified by high performance liquid chromatography (HPLC). Dye levels varied between products with highest levels in pain reliever and cough/cold/allergy syrups. Significant variability was observed within some brands. Degradation of Red No. 40, Blue No. 1, and Yellow No. 6 was observed in the vitamin gummies. Intake of FD&C Red No. 40 is two times the US FDA ADI (accepted daily intake) for some children's pain reliever syrups and almost three times the US FDA ADI for some cough/cold/allergy syrups.

Chemoprevention of Colorectal Cancer.

Although colorectal cancer (CRC) screening has reduced the incidence of and mortality from CRC, chemoprevention strategies have the potential to further reduce CRC incidence and mortality. Chemoprevention agents might be used for average-risk as well as high-risk groups, and to prevent CRC recurrence after therapy. CRC chemoprevention agents that have been studied include aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, statins, agents that target metabolic pathways, and vitamins and minerals. We review the prospect of chemoprevention of CRC, results from preclinical and human studies, challenges, and future directions.

Qualified Health Claim Language affects Purchase Intentions for Green Tea Products in the United States.

Qualified health claims (QHC) describe diet-disease relationships and summarize the quality and strength of evidence for a claim. Companies assert that QHCs increase sales and take legal action to ensure claims reflect their interests. Yet, there is no empirical evidence that QHCs influence consumers. Using green tea as a case study, this study investigated the effects of QHCs on purchase intentions among adults 55 years and older living in the US. An online survey using a between-subjects design examined QHCs about the relationship between green tea and the reduced risk of breast and/or prostate cancer or yukichi fruit juice and the reduced risk of gastrocoridalis, a fictitious relationship. QHCs written by a green tea company generated greater perceptions of evidence for the relationship, greater confidence in green tea and cancer, and increased purchase intentions for green tea than other QHCs. Factors that mitigated the claim's effects on purchase intentions are: Race/ethnicity; age; importance of health claims; supplement use; health; worry about health/becoming sick with cancer; worry that led to dietary change; green tea consumption; and familiarity with the green tea-cancer. Consumers who made health-related dietary change in the past year and consider health claims important indicated greater purchase intentions than others.

Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA.

Five years ago, an ambitious collaboration, the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA; henceforth CLARITY), was launched by three US agencies. The goal was to provide a definitive evaluation of bisphenol A (BPA) and explain disparities between traditional regulatory studies and findings from independent investigators. BPA or vehicle-treated rats from an FDA facility were used in a guideline study and animals and/or tissues were provided to academic researchers for analysis. An interim summary released in February 2018 by the FDA concluded that currently authorized uses of BPA continue to be safe. We disagree. In this Perspectives, we summarize the goals, design and problems of CLARITY. We conclude that, despite its flaws, CLARITY provides important insight and, taken together, the data provide compelling evidence that low-dose BPA exposure induces marked adverse effects. Indeed, the greatest number of effects were observed at doses 20,000 times lower than the current 'safe' dose of BPA for humans.

The Surprising Reach of FDA Regulation of Cannabis, Even After Descheduling.

As more states legalize cannabis, the push to "deschedule" it from the Controlled Substances Act is gaining momentum. At the same time, the Food and Drug Administration (FDA) recently approved the first conventional drug containing a cannabinoid derived from cannabis­cannabidiol (CBD) for two rare seizure disorders. This would all seem to bode well for proponents of full federal legalization of medical cannabis. But some traditional providers are wary of drug companies pulling medical cannabis into the regular small molecule drug development system. The FDA's focus on precise analytical characterization and on individual active and inactive ingredients may be fundamentally inconsistent with the "entourage effects" theory of medical cannabis. Traditional providers may believe that descheduling cannabis would free them to promote and distribute their products free of federal intervention, both locally and nationally. Other producers appear to assume that descheduling would facilitate a robust market in cannabis-based edibles and dietary supplements. In fact, neither of these things is true. If cannabis were descheduled, the FDA's complex and comprehensive regulatory framework governing foods, drugs, and dietary supplements would preclude much of this anticipated commerce. For example, any medical claims about cannabis would require the seller to complete the rigorous new drug approval process, the cost of which will be prohibitive for most current traditional providers. Likely also unexpected to some, there is no pathway forward for conventional foods containing cannabis constituents, with the (probably exclusive) exception of certain hemp seed ingredients, if those foods cross state lines. And it will certainly come as a shock to many that federal law already prohibits the sale of dietary supplements containing CBD--including those already on the market as well as those made from "hemp," which has recently been descheduled under the 2018 Farm Bill. This Article describes in detail the surprising reach of the FDA and then outlines three modest, but legal, pathways forward for cannabis-based products in a world where cannabis has been descheduled.

Dietary Phosphate and the Forgotten Kidney Patient: A Critical Need for FDA Regulatory Action.

Careful dietary management that reduces high phosphate intake is recommended to slow the progression of chronic kidney disease (CKD) and prevent complications of CKD and may help reduce chronic disease risks such as incident CKD associated with high phosphate intake in the healthy general population. For patients treated with maintenance dialysis, control of serum phosphorus levels is considered a marker of good care and requires a coordinated plan that limits dietary phosphate intake, uses oral phosphate binders, and provides an adequate dialysis prescription. Even with traditional thrice-weekly hemodialysis or peritoneal dialysis, use of phosphate binders, and a concerted effort to limit dietary phosphate intake, adequately controlled serum phosphorus levels are not possible in all dialysis patients. Efforts to limit phosphate intake are thwarted by the underestimated and unquantified phosphate content of processed foods and some medications due to the hidden presence of phosphate additives or excipients added during processing or drug formulation. Effectively limiting phosphate intake could potentially be achieved through simple US Food and Drug Administration regulatory actions. Mandatory labeling of phosphate content on all packaged foods and drugs would enable identification of healthy low-phosphate foods and medications and permit critically important control of total phosphate intake. Simple changes in regulatory policy and labeling are warranted and would enable better management of dietary intake of phosphate at all stages of kidney disease, as well as potentially reduced health risks in the general population.

Scientific Considerations for the Review and Approval of First Generic Mometasone Furoate Nasal Suspension Spray in the United States from the Bioequivalence Perspective.

In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product. In this case, MDRS data eliminated the need for a comparative clinical endpoint bioequivalence study. The approval of the first generic Mometasone Furoate Nasal Suspension Spray is precedent-setting and paves a new pathway to establish bioequivalence for generic nasal suspension sprays. This approval also exemplifies FDA's commitment to advance regulatory science for evaluation of generic drug products.

FDA regulatory approach to steviol glycosides.

Stevia rebaudiana (Bertoni) Bertoni, commonly known as stevia, is a plant native to South America that has been cultivated for hundreds of years. In 1995, FDA revised its import alert on stevia leaves and extracts to allow for their use as dietary ingredients in dietary supplements. In 2007, the Joint FAO/WHO Expert Committee on Food Additives established a safe level of intake and specifications for steviol glycosides that included a minimum purity of 95% of seven named steviol glycosides. In 2008, FDA responded without questions to a Generally Recognized as Safe (GRAS) notice for the use of highly purified steviol glycosides obtained from stevia leaves as a general purpose sweetener in food. Due to the existing import alert, FDA filed, evaluated, and has not objected to more than 50 GRAS notices for the use of various high-purity steviol glycosides as sweeteners in food. In this paper, we highlight FDA's practices for filing and evaluating GRAS notices for steviol glycosides. We also provide a summary of the data and information presented in GRAS notices for steviol glycosides in the GRAS Notification program. FDA has received a new wave of GRAS notices that include alternative biotechnological methods for production of steviol glycosides.

Preclinical efficacy in therapeutic area guidelines from the U.S. Food and Drug Administration and the European Medicines Agency: a cross-sectional study.

BACKGROUND AND PURPOSE: Therapeutic area guidelines (TAGs) published by the EMA and the FDA offer guidance in planning the launch of a trial in a certain indication. We assessed and compared the guidance on preclinical efficacy of all available TAGs from EMA and FDA. EXPERIMENTAL APPROACH: EMA and FDA websites and databases were searched for all TAGs. A mixed deductive and inductive approach was applied to analyse and cluster content for preclinical efficacy. KEY RESULTS: A total of 114 EMA and 120 FDA TAGs were identified, covering 126 indications. Our core finding is that 75% of EMA TAGs and 58% from the FDA TAGs do not offer any guidance on preclinical efficacy. TAGs varied widely on the extent, nature and detail of guidance. CONCLUSIONS AND IMPLICATIONS: Guidance on preclinical efficacy in a consistent, comprehensive and explicit way that still allows for justified deviations is an important but neglected aspect of transparency for drug development. This transparency would help sponsors in designing preclinical studies and in negotiating more efficiently with regulators.

The road to market implantable drug delivery systems: a review on US FDA's regulatory framework and quality control requirements.

The scope of Implantable Drug Delivery Systems (IDDSs) comprehends a variety of sterile therapeutic implements placed inside the body to exert a certain therapeutic action for extended duration. They are classified under different categories from pharmaceutical science and regulatory perspectives. The novelty and variety of IDDSs prevent the application of a uniform regulation for all IDDS products; therefore, sponsors face regulatory challenges to register and market their products. This review investigates pharmaceutical science literature and the United States Food and Drug Administration (US FDA) regulatory guidance to find how any IDDS is classified, regulated, and introduced in the market. The regulatory classification of any IDDS, as a 'drug', 'medical device' or a 'combination product', is the cornerstone in determining the regulatory pathway, which decides the quality control requirements preceding the marketing approval. IDDSs are generally recognized as combination products as they consist of two or more regulated components (drugs, medical devices or biological products) combined prior to use to function as a single entity. Although robust and defined US FDA regulatory pathways exist for each component independent of one another, the regulatory pathways for combination products are less formalized.

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.

Why Americans Need Information on Dietary Supplements.

Until a decade ago, no dietary supplement (DS) databases with open access for public use existed in the United States. They were needed by researchers, since half of American adults use dietary DSs and, without information on supplement use and composition, exposures could not be estimated. These articles on Challenges and Future Directions for Dietary Supplement Databases describe subsequent progress. They begin by describing why information on DSs is needed by the government and how it is used to ensure the health of the public. Current developments include: application of DS information to meet public health needs; research efforts on DS quality, efficacy, and safety (as conducted by the Office of Dietary Supplements and other federal agencies); enhanced regulatory activities implemented by the FDA Office of Dietary Supplement Programs, the FDA Office of Enforcement, and the Federal Trade Commission; and initiatives for broader development and dissemination of DS databases for commercial and public use. Other contributions in this journal supplement describe the challenges of working with DSs and the progress that has been made. Additional articles describe surveys of DS use among the general US population and also among special groups such as high supplement users, illustrating why there is a need in the United States for information on supplements. Likely directions for the future of DS science are summarized.