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.

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.

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.

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.

Drug-Drug Interactions: How to Manage the Risk-A Stakeholder Approach.

Drug-drug interactions (DDIs) are well-recognized, chronic, multidimensional issues that have defied efforts to make substantial reductions in the burden of effects on patients and the health care system. This Commentary offers a stakeholder approach to characterizing the problem and identifying potential ways to address the risks posed by DDIs. Stakeholders may comprise 2 groups: a triad consisting of the patient, the prescriber, and the pharmacist and a pentad of institutional stakeholders consisting of institutions of education and training for prescribers and pharmacists, drug development sector companies, regulatory agencies, payer institutions, and publishing companies of journals on healthcare topics. Suggested strategic opportunities to mitigate the risk of harm from DDIs include the following: (1) identify critical leadership to set the agenda, manage the process, and mark progress; (2) enhance self-advocacy skills, particularly for patients; (3) create more opportunities for patients to learn, understand, and participate in the process; (4) establish and enhance partnerships between and among stakeholders; (5) seek broader use of regulatory machinery; (6) institutionalize principles of conservative prescribing and deprescribing in medical education and professional training; (7) establish, highlight, and promote DDI in HEDIS quality metrics, key performance indicators, and balanced scorecards; (8) encourage publishers to engage the issue more deeply by developing dedicated specialty journals for physicians, pharmacists, and cross-professional audiences and encourage journal editors to dedicate sections in pharmacy and clinical journals; and (9) involve the political process to include markers for DDI mitigation and to set performance goals in US Food and Drug Administration-directed legislation.

The Alendronate Conundrum: Balancing the Competing Influences for Truly Informed Consent About Drug Safety in an Era of Rapid Change.

This commentary highlights critical decision points regarding the responsibilities of the key stakeholders-pharmaceutical companies, the US Food and Drug Administration, clinicians, and patients-regarding the communication of the risk of a medication. It addresses responsibility for remaining current about emerging drug reactions that often cannot be appreciated during the initial approval period of new drugs and biologics. Further complicating the issue are the medical systems that limit a clinician's time and bandwidth to keep abreast of emerging adverse reactions and to engage in an informed consent process with a lay patient who often has a limited understanding of medical terms and quantitative methods that can provide context for understanding rare complications and adverse drug reactions. Nevertheless, the risk of not finding an amenable way forward for all stakeholders is a descent into the unending crippling malpractice settlements that will only inexorably raise the costs of health care and encourage the exodus of clinicians from the profession.

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.

COVID-19 booster vaccination coverage among adults, children and adolescents and reasons for non-receipt, United States.

We assessed COVID-19 booster vaccination coverage and reasons for non-receipt using a large, nationally representative survey (June - August, 2022). Booster vaccination coverage was 71.7% among adults, 36.8% among children, and 51.6% among adolescents. Reasons for non-receipt included the belief that it was not necessary and lack of time for vaccination. All eligible individuals should receive the updated booster vaccines as soon as possible to protect against new variants of COVID-19.

Trends in vaccination schedules and up-to-date status of children 19-35 months, United States, 2015-2020.

OBJECTIVES: To estimate trends in, and factors associated with, vaccination patterns and up-to-date immunization status of U.S. children by 19 to 35 months of age. METHODS: Data from the 2015 to 2020 National Immunization Surveys were used to assess trends in vaccination patterns, up-to-date status, and zero vaccination status of U.S. children by 19-35 months. Vaccination patterns were categorized as: 1) recommended, 2) alternate, or 3) unknown or unclassifiable. Multivariable analyses were conducted to examine factors associated with each vaccination pattern and up-to-date status for all recommended vaccines. RESULTS: From 2015 to 2020, the proportion of U.S. children completing the recommended schedule increased from 62.5% to 69.4%, alternative schedule decreased from 21.6% to 16.2%, and unknown or unclassifiable schedules decreased from 15.9% to 14.3%. In addition, being not up-to-date decreased from 39.7% to 35.6%. There was no change in the percentage of children receiving zero vaccinations from 2015 to 2020 (0.9% to 0.9%). Respondents with lower household income or who were uninsured were more likely to follow an alternate or unknown/unclassifiable schedule, or not be up-to-date with vaccines. CONCLUSION: Following any schedule other than the recommended schedule was associated with not being up-to-date on immunizations. Increased efforts to catch up on recommended vaccines is important for protecting children's health. Further efforts should be made to improve timely adherence to recommended vaccination schedules, particularly among populations with the largest disparities in coverage through a tailored approach to increase confidence in and access to vaccines.

Effects of the COVID-19 Pandemic on Pharmacovigilance Strategy, Systems, and Processes of Large, Medium, and Small Companies: An Industry Survey.

PURPOSE: The COVID-19 pandemic poses an unprecedented threat to global business relationships and dynamics. The pharmacovigilance function of pharmaceutical companies is particularly susceptible to changing external pressures because of its highly structured compliance activities. We conducted an industry-wide survey to provide insights on how the pharmacovigilance function responded to the challenges posed by the pandemic. We compared smaller companies and larger companies regarding impact on portfolios and operational activity metrics. METHODS: We conducted a survey through the Navitas Life Science annual benchmark of pvnetTM, a network of large enterprise (LE) companies, and pvconnectTM, a network of small and medium enterprise (SME) companies, using an online surveying tool during the first quarter of 2021. We collected information on pharmacovigilance activities, including quantitative measures of workload, costs, and key performance indicators, and qualitative data on the effects of the pandemic on product portfolios and operations. FINDINGS: Survey questions were posed to LE (pvnet) network members (n = 12) and SME (pvconnect) network members (n = 18) for the period from January 1 through December 31, 2020. The date of data collection was March 26, 2021. Descriptive median values of parameter metrics included the following: revenue ($28.4 billion for LE companies and $1.6 billion for SME companies), number of products (127 for LE companies and 19 for SME companies), and volume of individual case safety reports (391,000 for LE companies and 13,000 for SME companies). SME companies reported a greater impact on 2 survey categories, remote working and employee well-being, than did LE companies. However, LE companies reported a greater impact than did SME companies on all other survey categories: effect on strategic priorities, shift in product focus, workload changes, changes in sourcing model, effect on case reporting compliance, effect on business continuity, changes in pharmacovigilance technology strategy, impact of interactions with health authorities, effect on resource capacity, and impact on recruitment. IMPLICATIONS: Four major themes emerge from this survey: (1) shift to remote working, (2) recognition of the impact on employee well-being, (3) shift in strategic priorities, and (4) newly recognized aspects of risk mitigation. The COVID-19 pandemic has had a marked effect on every aspect of pharmaceutical companies' pharmacovigilance functions, although the effects appear to be different for LE companies than for SME companies.

Who has not been vaccinated, fully vaccinated, or boosted for COVID-19?

We assessed COVID-19 vaccination coverage (≥1 dose, full vaccination, and booster vaccination) using a large, nationally representative survey of US households (December 29, 2021-January 10, 2022). Almost 1 in 6 adults have not been vaccinated or not been fully vaccinated, and almost one-half of fully vaccinated adults have not received a booster vaccine. All eligible individuals should receive the recommended number of vaccines to prevent further transmission of COVID-19.

Review of FDA Amendments Act Section 921 Experience in Posting Data-mining Results from the FAERS Database.

PURPOSE: Title IX, § 921 of the Food and Drug Administration (FDA) Amendments Act of 2007 requires the FDA to mine data on a regular basis, using its adverse events database, the FDA Adverse Event Reporting System, to identify potential signals of serious risks/new safety information. This review of the FDA's quarterly web-posted results is the first to document the contributions of the program to maintaining the continued safe use of approved pharmaceutical drugs/biologics and the lessons that have emerged from this rich experience. METHODS: Details on proprietary prescription drugs/biologics, generic prescription drugs, and over-the-counter drugs were downloaded from the quarterly posts that begin in first quarter of 2008. Key information was tabulated, including proprietary and generic names of products or classes of products, the identified potential signals of serious risks, the labeling-decision category (updated, no action is necessary at this time, or evaluating the need for regulatory action), the labeling section (Warnings and Precautions, Adverse Reactions, Drug Safety Communications, Contraindications, or Boxed Warnings), and estimated times to updated decisions. FINDINGS: Since the beginning of the FDAAA Section 921 posting requirement, the FDA has posted 555 potential signals of serious risk or new safety information. Of these, there have been 262 posts (47%) that resulted in decisions requiring updated product labeling, 75 posts (14%) that resulted in decisions that no action was necessary, and 218 posts (39%) indicating that the FDA was evaluating the need for regulatory action. Of the 262 posts that required updating one or more sections of a product label, there was a preponderance of Warnings and Precautions, with 172 (66%); followed by Adverse Reactions, with 114 (44%); Drug Safety Communications, 44 (18%); Contraindications, 27 (10%); and Boxed Warnings, 19 (7%). The median times to update decisions were 12 months for Warnings & Precautions, Adverse Reactions, and Boxed Warnings, and 11 months for Contraindications. IMPLICATIONS: Important themes from the present analysis include the following: (1) nearly 80% of posts resulted in updated product labeling; (2) 20% of decisions concerned classes of proprietary and generic drug/biologic products; (3) product-use errors, such as name confusion, continue to be important; (4) the safe use of pharmaceuticals in children is gaining attention but still has a long way to go; and (5) drug-drug interactions are of continuing concern. The FDA Amendments Act § 921 program will continue to have an important place in the future of pharmacovigilance practices.

Dynamic Dossier in the Cloud: A Sociotechnical Architecture for a Real-Time and Metrics-Based Data Tracking System with Gene and Cell Therapies as a Case Study.

BACKGROUND: Data sharing among stakeholders in the development, access, and use of drug therapies is critical but the current system and process are inefficient. METHODS: We take a Systems Engineering approach with a realistic use case to propose a scalable design for multi-stakeholder data sharing. RESULTS: We make three major contributions to the drug development and healthcare communities: first, a methodology for developing a multi-stakeholder data sharing system, with its focus on high-level requirements that influence the design of the system architecture and technology choice; second, the development of a realistic use case for long-term patient and therapy data tracking and sharing in the use of potentially curative and durable gene and cell therapies. Further, a bridge for the 'awareness gap' was found between the payer (Payer is organization which takes care of financial and operational aspects (which include insurance plans, provider network) of providing health care to US citizens. Or refer to health care insurers.) and the regulator communities by illustrating the common data tracking needs, which highlights the need for coordinated data activities; and third, a proposed system architecture for scalable, multi-stakeholder data sharing. Next steps are briefly discussed. CONCLUSION: We present a system design for multiple stakeholders such as the payer, the regulator, the developer (drug manufacturer), and the healthcare provider to share data for their decision-making. The stakeholder community would benefit from collaboratively moving the system development proposal forward for efficient and cost-effective data sharing.

COVID-19: Regulatory Landscape of Medicinal and Medical Device Products for Human Use.

Against the backdrop of the COVID pandemic, the scientific and medical communities are working with all deliberate speed with state-of-the-art technologies to develop diagnostic and therapeutic products that can identify, treat, and prevent infection with SARS-CoV-2. These activities may only be legally conducted with the necessary statutes and regulations in place to facilitate the timely development, manufacturing, evaluation, and distribution of products that meet quality standards. The present regulatory landscape for medicinal and medical products for human use has been shaped by nearly 12 decades of statutory history that followed in reaction to disasters and tragedies. Five distinct, closely woven threads of statutory history have led to the regulatory infrastructure we have in place: (1) standardized processes for routine development of medicinal and medical device products for human use; (2) processes for expedited development to shorten time frames and expand patient populations; (3) mechanisms of Expanded Access to make medicinal products available to patients prior to approval of the US Food and Drug Administration; (4) Emergency Use Authorization during public health emergencies; and (5) the development of pathways for bringing generic drugs and biosimilar biologics to market. These mechanisms are being brought to bear to facilitate the defeat of infection with SARS-CoV-2.

Signal Management in Pharmacovigilance: A Review of Activities and Case Studies.

PURPOSE: After nearly 12 decades of pharmaceutical catastrophes and the associated groundbreaking regulatory innovations, pharmacovigilance has come down to us in the present day as 3 interlocking core disciplines: case management, signal management, and benefit-risk management. This review provides a state-of-the-art introduction to the great variety of sources of safety information, both dependent on and independent of the Individual Case Safety Report (ICSR), and explains how this content undergoes management-system processes with globally accepted definitions, standards, and structures that make possible the ongoing safe use of a pharmaceutical product throughout its lifecycle. This occurs in the context of: (1) new products coming to market with new risks for drug-drug interactions, and (2) new global threats to safe manufacturing and distribution. METHODS: This narrative review, reflective of the author's experience, uses a large-frame system of signal management developed by the Council for International Organizations of Medical Sciences VIII Working Group and modified by the author to include governance. A key feature of the review is the regular inclusion of relevant case studies to provide a backdrop of the unexpected, with resulting tragic outcomes, to the ever-evolving regulatory landscape. FINDINGS: Regarding content, beyond the commonly appreciated sources of safety information that find their way into ICSRs are non-ICSR-based sources, including preclinical data, manufacturing data, findings from subject-matter experts who participate on data-monitoring committees, outside expert panels, advocacy groups, and independent investigator studies. Regarding process, it is important to recognize that governance is crucial in the effective conduct of signal management, in that subject-matter experts are essential to the scientific and medical aspects of decision making, and business and policy executives are essential in determining the final courses of action, as these decisions have implications for the company. IMPLICATIONS: Signal management is an integral part of pharmacovigilance practices that strive to obtain all of the information necessary for maintaining the safety profiles of a company's pharmaceutical and biological products, to support favorable benefit-risk balances, and to ensure safe use by health care providers and their patients.