Generic Drugs and the Struggle to Compete: The Role of Skinny Labels.

PURPOSE: The generic drug industry currently faces multiple, serious issues that threaten the US drug supply. So-called "skinny labels" are one of the few tools authorized by Congress to expedite entry into the market by generic competitors when the first patent for a brand's drug compound (only) expires. This article reviews the law on this expedited marketing pathway for generic competitors, as well as limitations on its use. METHODS: We examined the literature on patent protection of brand drugs, including the timelines for production of generic competitors. We also examined the law concerning skinny labels, including a recent decision of the US Federal Circuit Court that clearly articulates the guidelines concerning entry into the generic market, including labeling, marketing, and promotion. FINDINGS: Skinny labels that follow the regulations set forth in the Hatch-Waxman Act, including the necessary carve-out procedure for "methods of use" still protected by 1 or more active patents, do not infringe a brand drug's label. Furthermore, the skinny label does not induce or contribute to infringement merely because its label contains US Food and Drug Administration-required safety profile data-even when the data cross-reference superiority studies on still-patent protected methods of use elsewhere in the label. IMPLICATIONS: Generic drugs have become essential to the broad, general availability of clinical therapeutic agents. The Hatch-Waxman Act was intended to facilitate entry of generic competitors into the marketplace, and the skinny label is an important tool to accomplish that end. As long as the generic manufacturer follows the essential skinny-label rules, specifically including marketing the compound without promoting or advertising those methods of use still protected by ongoing patents, the law will not find induced or contributory infringement.

The Emerging Role of Cell Membrane-coated Nanomaterials in Cancer Therapy.

This review investigates the revolutionary application of cell membrane-coated nanoparticles (CMNPs) as a promising avenue for cancer therapy within the embryonic landscape of nanotechnology. Nanoparticles, pivotal in cancer treatment, are systematically examined for their diverse physicochemical structures, categorized as organic (lipid-based, protein-based, and polymer-assisted) and inorganic (carbon-based and metal) varieties. A significant focus is placed on CMNPs, which serve as an innovative drug delivery vehicle, overcoming limitations associated with conventional nanoparticle therapies. This manuscript accurately explores the advantages and challenges of various cell membranes, including those derived from cancer cells, red blood cells, platelets, stem cells, and white blood cells. Importance is placed on their roles in enhancing drug delivery precision, immune system circumvention, and targeted recognition. Detailed insights into the crafting of CMNPs are provided, elucidating membrane extraction and fusion techniques, such as sonication, extrusion, co-extrusion, and microfluidic electroporation. Maintaining membrane integrity during extraction and the benefits of coating techniques in augmenting biocompatibility and targeted drug delivery are underscored. This comprehensive resource consolidates the latest advancements in targeted drug delivery, positioning itself at the forefront of nanotechnology and biomedicine research. Encapsulating various methodologies like membrane extrusion, electrospray, and chemical conjugation, this manuscript showcases the expanding toolbox available to researchers in this dynamic field. Focusing on the unique characteristics of CMNPs, this review explores their multifaceted applications in biomedical research, particularly in tumour therapy. It provides an indepth analysis of the biocompatibility of CMNPs, their stability, immune evasion capabilities, targeted drug delivery precision, increased payload capacity, and retained biological functionality. The manuscript outlines current applications and future prospects of CMNPs in targeted chemotherapy, photothermal and photodynamic therapy, immunotherapy, gene therapy, and innovative therapeutic methods. It concludes by highlighting the advantages of CMNPs in tumour therapy and their transformative potential in reshaping the landscape of cancer treatment.

Phase I Studies: Innovations and Issues.

INTRODUCTION: Emeritus Editor-in-Chief, Richard Shader, published 2 editorials in 2014 to state that Clinical Therapeutics' would no longer consider simple innovator vs generic bioequivalence studies for publication and would require a rationale for the choice of agents when submitting drug-drug interaction studies for consideration. The intervening decade of developments in this field provides an opportunity to comment on these trends. Lewis Scheiner anchors the subsequent discussion in a "Learn and Confirm" super-structure of thinking about the goals of early development of pharmaceutical agents. Subsequent experience with newer agents that are focused on immunological targets has led to a shift from the simple No Observable Effect Level (NOEL) model to the Minimal Anticipated Biological Effect Level (MABEL) model for biologically focused effects to assess pre-clinical data in guiding the selection of a starting dose for First-in-Human studies. ELEMENTS OF PHASE I STUDIES: The primary tasks of Phase I activities are to describe the pharmacokinetics (determination of absorption, distribution, metabolism, and excretion) and essential pharmacodynamics (the dose correlation with the physiological responses, plus any untoward effects, including idiosyncratic responses) keeping in mind reporting requirements. Other Phase I activities usually conducted later in the development cycle include evaluation of drug interactions with food and other pharmaceutical agents and thorough QT studies. INNOVATIONS: Phase I studies have been evolving in response to the unrelenting pressures to improve access and efficiencies in time, cost, and effort. Changes have been occurring in the characteristics of the participating populations, the starting dose, and shifts in the enrollment schedule to a more flexible, data-driven, adaptive design. ISSUES: Additional issues have gained attention in the recent past, including Phase 0/microdosing, use of Phase I studies explicitly for treatment in the case of oncological products, involvement of Data Safety Monitoring Committees especially for first-in-class molecules, and improved means of optimizing selection of candidate agents for advancement to subsequent stages of development. Of final importance is the need for greater transparency of the presently inaccessible, early development study data maintained in commercial corporate legacy databases. Taken together, these developments and innovations by a broad range of stakeholders point to continuing opportunities for clinical investigators to explore the potential of Phase I studies to contribute to their own specialties.

Vaccination patterns and up-to-date status of children 19-35 months, 2011-2021.

INTRODUCTION: Being up-to-date with all recommended vaccines is needed to protect children from vaccine preventable diseases. Understanding vaccination patterns is needed to develop messaging and strategies to increase vaccination uptake and confidence. METHODS: Data from the 2011 to 2021 National Immunization Surveys was used to assess trends and disparities in vaccination patterns, zero vaccination status, and up-to-date status of U.S. children by 19-35 months. RESULTS: From 2011 to 2021, adherence to the recommended schedule using the stringent definition increased from 35.7 % to 52.2 % (p < 0.01), adherence to the alternate schedule decreased from 28.2 % to 15.1 % (p < 0.01), and proportion of children who were not up-to-date decreased from 49.0 % to 33.3 % (p < 0.01). However, the proportion of children who had zero vaccinations did not change from 2011 (0.9 %) to 2021 (0.9 %; p = 0.08). In 2021, children 19-23 months were less likely to follow the recommended schedule than children 24-29 months (49.2 % compared to 56.4 %, p < 0.01). Adherence to the recommended schedule among children 19-23 months decreased in 2021 compared to 2020 overall and for some subpopulations (e.g. those with non-Hispanic (NH) Black parents (33.2 % compared to 44.9 %, p < 0.01). Furthermore, it was lowest among children of NH Black parents living at or below the federal poverty level (31.2 %) compared to their respective NH White counterparts (43.6 %, p < 0.01). CONCLUSIONS: While there were overall increases in adherence to the recommended schedule from 2011 to 2021, a sustained catch-up program is needed to prevent missed vaccinations and achieve equitable vaccination coverage for all children.

Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.

The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.

The relative treatment benefit of a drug for patients during development, marketing authorization review or after approval includes an assessment of the risk of drug-induced liver injury (DILI). Reported incidences of DILI range from 0.74 to 19 per 100,000, and laboratory criteria and/or clinical outcome determine the severity of DILI. At least 10% of patients who develop jaundice caused by DILI (Hy's Law cases) develop liver failure (i.e., severe DILI). A drug's liver safety profile can be assessed using Evaluation of Drug-Induced Serious Hepatotoxicity Plots. Specific recommendations for monitoring DILI in the post-marketing setting depend on characterization of the phenotype during drug development. Risk mitigation tools include additional educational mechanisms, and risk minimization measures include Elements To Assure Safe Use (ETASU) for healthcare professionals, administration sites, and patients. The overall aim of risk management is to ensure that the benefit of a particular product exceeds the risks as far as possible for the individual patient and for the target population.

Attitudes on Equal Health Care Access versus Efficient Clinical Decisions across a Not-for-Profit Health Care System.

BACKGROUND: Professional roles within a hospital system may influence attitudes behind clinical decisions. OBJECTIVE: To determine participants' preferences about clinical decisions that either value equal health care access or efficiency. DESIGN: Deidentified survey asking participants to choose between offering a low-cost screening test to a whole population ("equal access") or a more sensitive, expensive test that could be given to only half of the population but resulting in 10% more avoided deaths ("efficient"). Data collection took place from August 18, 2021, to January 24, 2022. Study 1644 was determined to be exempt by Tufts Health Sciences Institutional Review Board (IRB). SETTING: Tufts Medicine Healthcare System. PARTICIPANTS: Approximately 15,000 hospital employees received an e-mail from the Tufts Medicine Senior Vice President of Academic Integration. MEASUREMENTS: Analysis of survey responses with chi-square and 1-sample t tests to determine the proportion who chose each option. Logistic regression models fit to examine relationships between professional role and test choice. RESULTS: A total of 1,346 participants completed the survey (∼9.0% response rate). Overall, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%). However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choice. For example, among those in nonclinical roles, women were more likely than men to choose equal health care access. In multivariable analyses, having clinical roles was significantly associated with 1.73 times the likelihood of choosing equal access (95% confidence interval = 1.33-2.25). LIMITATIONS: Generalizability concerns and survey question wording limit the study results. CONCLUSION: Clinicians were more likely than nonclinicians to choose the equal health care access option, and health care administrators were more likely to choose efficiency. These differing attitudes can affect patient care and health care quality. HIGHLIGHTS: Divergent preferences of valuing equal health care access and efficiency may be in conflict during clinical decision making.In this cross-sectional study that included 1,346 participants, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%), a nonsignificant difference. However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choiceSince clinicians were more likely than nonclinicians to choose the equal health care access option and health care administrators were more likely to choose efficiency, these differing attitudes can affect patient care and health care quality.

The US Supreme Court and Affirmative Action: The Negative Impact on the Physician Workforce.

PURPOSE: Maintaining admissions of underrepresented students to medical schools is essential to securing a diverse health care workforce. Empirical evidence indicates that minority patients may prefer practitioners of their own race. The recent US Supreme Court decision concerning affirmative action makes this goal more difficult, but medical schools can still work within the language of the law to redouble their efforts to seat a diverse class of medical students. METHODS: We examined the literature correlating the availability of minority physicians and the health outcomes of the patients they serve. We also examined the literature on race-conscious policies of medical schools intended to address the shortage of minority physicians considering the benefits achieved through a diverse field of health care workers. We also examined the law and the recent US Supreme Court opinion, including the application of equal protection principles, to suggest strategies to seat a diverse class of students within the scope of the law. FINDINGS: Institutions have maintained the status quo of disparate distributions of professions by race through structural biases that also limit access to medical schools. The new US Supreme Court decision is expected to exacerbate this disparity unless medical schools engage in admissions protocols that actively solicit the character and unique abilities that each of the applicants can offer to contribute to the medical school and the health care profession. IMPLICATIONS: The new US Supreme Court mandate is likely to create challenges for medical schools in their efforts to recruit and seat minority applicants. The mandate provides little discussion, suggesting a lack of understanding of the downstream public health consequences to patients if medical school applicants are denied the benefits of race-conscious admissions policies. Nevertheless, the language of the US Supreme Court's opinion may provide a viable path forward, at least with respect to medical schools where the need for a diverse pool of health care practitioners is particularly compelling.