Pivotal Role of Translation in Anti-Infective Development.

The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.

Accelerating regulation in response to COVID-19.

Regulators are finding ways to support the expedited development and distribution of novel coronavirus-related vaccines, tests and treatments. Gary Humphreys reports.

Teaching non-FDA approved nonprescription products: Educating students about potential risks and liability.

INTRODUCTION: University professors who teach self-care and nonprescription products must decide which products and ingredients to recommend to students. The Food and Drug Administration (FDA) has approved many nonprescription ingredients as both safe and effective through the evidence-based FDA Over-the-Counter (OTC) Product Review or New Drug Application (NDA) processes. However, thousands of nonprescription products sold in community pharmacies are of unproven safety and/or efficacy. These include herbs, dietary supplements, homeopathic products, and essential oils. Selling products of unproven safety and/or efficacy can have serious consequences, exposing pharmacists to legal liability due to violations of the principles of implied and/or express warranties, as found in the Uniform Commercial Code. Further, the FDA defines products lacking proven safety and efficacy as health fraud, a crime aggressively pursued by both the FDA and the Federal Trade Commission. COMMENTARY: Faculty members who limit their nonprescription ingredient recommendations to those with FDA approval can justify those recommendations by weight of evidence. If the faculty member recommends ingredients that the FDA has not approved (e.g., kava), students should be taught that those ingredients pose unknown risks and lack proven benefit, and also that their labels virtually always lack doses proven to be safe, precautions, contraindications, and drug interactions. IMPLICATIONS: Selling unproven products can lower trust in pharmacy, cause patient harm, and expose the pharmacist to legal action. These issues should be explained to students whenever unproven products are discussed or recommended.

Proposed actions for the US Food and Drug Administration to implement to minimize adverse effects associated with energy drink consumption.

Energy drink sales are expected to reach $52 billion by 2016. These products, often sold as dietary supplements, typically contain stimulants. The Dietary Supplement Protection Act claims an exemplary public health safety record. However, in 2011 the number of emergency department visits related to consumption of energy drinks exceeded 20,000. Nearly half of these visits involved adverse effects occurring from product misuse. Political, social, economic, practical, and legal factors shape the landscape surrounding this issue. In this policy analysis, we examine 3 options: capping energy drink caffeine levels, creating a public education campaign, and increasing regulatory scrutiny regarding the manufacture and labeling of energy drinks. Increased regulatory scrutiny may be in order, especially in light of wrongful death lawsuits related to caffeine toxicity resulting from energy drink consumption.

We really need to talk: adapting FDA processes to rapid change.

The rapidly evolving realm of modern commerce strains traditional regulatory paradigms. This paper traces the historical evolution of FDA crisis-response regulation and provides examples of ways in which the definitions and procedures resulting from that past continue to be challenged by new products as market entrants, some in good faith and others not, take actions that create disconnects between actual product and marketing controls and those that consumers might expect. The paper then explores some of the techniques used by other federal agencies that have faced similar challenges in environments characterized by rapid innovation, and draws from this analysis suggestions for improvement of the FDA's warning letter system.

History and overview of DSHEA.

The Dietary Supplement Health and Education Act (DSHEA), enacted in 1994, had two primary goals: to ensure continued consumer access to a wide variety of dietary supplements, and to provide consumers with more information about the intended use of dietary supplements. It accomplished these goals, and more, without changing the fundamental regulatory status of dietary supplements as a category of foods. This article explores the history and reasoning behind the major provisions of the Act and reflects on the impact of each during 15 years of experience under DSHEA.

FDA's expanding postmarket authority to monitor and publicize food and consumer health product risks: the need for procedural safeguards to reduce "transparency" policy harms in the post-9/11 regulatory environment.

This article provides a summary of the expansion of FDA's discretionary authority in the post-9/11 period, particularly with respect to FDA's authority to monitor and publicize potential health risks linked to food, dietary supplements, nonprescription drugs, and other consumer health products. In addition, this article evaluates the need for FDA to establish procedural safeguards to reduce the significant risks of unintended and undue harm to people and regulated companies that can result from adverse publicity in the more "transparent" post 9/11 FDA regulatory environment. Specifically, Part I summarizes the amendments to the FDCA enacted during the post-9/11 period that have expanded FDA's postmarket authority to monitor, evaluate, and publicize potential health risks linked to food, dietary supplements, nonprescription drugs and other consumer health products marketed in the United States, in conjunction with FDA's Sentinel Initiative, Reportable Food Registry, and other adverse event reporting requirements. Part II discusses the convergence of FDA's expanded postmarket authority to publicize product-related risks with President Obama's transparency initiative aimed at fostering "open government" through increased public access to government information. In addition, Part II considers the nature of the procedural safeguards needed in the post-9/11 FDA regulatory environment, in view of FDA's historical record and illustrative cases that help expose how adverse "transparency" surrounding FDA warning letters, recalls and safety alerts concerning products in the marketplace can have undue and unintended prejudicial and harmful effects for the people and companies that are legally responsible for such products. Finally, based on these analysis, this article concludes with some observations concerning the nature of the procedural safeguards needed to reduce the significant risks of "transparency" policy harms in the pos-9/11 regulatory environment.

How are drugs approved? Part 3. The stages of drug development.

The first article of this series on the drug development process described the historical evolution of the U.S. Food and Drug Administration (FDA), and last month's article reviewed the ethical foundations of clinical research. Before a new drug is marketed, a sequence of preclinical investigations and three phases of clinical studies are conducted. This drug development process involves the FDA, pharmaceutical companies (sponsors), clinical investigators, and institutional review boards. This article further describes this aspect of the drug development process.

Correlation of tumors with DNA adducts from methyl eugenol and tamoxifen in rats.

Data on percent tumors in male rats after administration of methyl eugenol, obtained from the National Toxicology Program, or tamoxifen were plotted on a linear scale for percent tumors against the dose on a logarithmic scale. Data on (32)P-postlabelled DNA adducts were plotted on the same graphs for each of these two compounds in order to correlate adduct formation and tumor incidence with dose. The resulting graph for methyl eugenol showed a linear response for both adduct formation and tumor incidence. The threshold dose of administered methyl eugenol for adduct formation (zero adducts) was 10(19.3) molecules of methyl eugenol/kg/day, which compared with a threshold of 10(20.1) molecules of methyl eugenol/kg/day for tumor formation; however, 30 adducts/10(8) nucleotides was the threshold for tumor formation. The dose of tamoxifen for adduct formation fit an exponential plot slightly better than a linear plot, but reached minimal values close to the threshold of 10(18.7) molecules of tamoxifen/kg/day for tumor formation. These data confirm that tumor formation coincides with adduct formation and that both have thresholds, or at least reach minimal values, above levels to which humans are exposed. Although the threshold dose for tumor formation from tamoxifen is only about 10x above the dose received by women at risk for breast cancer, this should be an adequate safety margin. The safety factor for methyl eugenol is several orders of magnitude; therefore, there should be no cause for concern for humans at current levels of exposure.

An overview of drug development in the United States and current challenges.

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.