A primer of drug safety surveillance: an industry perspective. Part II: Product labeling and product knowledge.

OBJECTIVE: To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part II of this series discusses specific issues regarding product labeling, such as developing the labeling, changing the labeling, and the legal as well as commercial ramifications of the contents of the labeling. An adverse event report scenario is further analyzed and suggestions are offered for maintaining the product labeling as an accurate reflection of the drug safety surveillance data. This article also emphasizes the necessity of product knowledge in adverse event database management. Both scientific and proprietary knowledge are required. Acquiring product knowledge is a part of the day-to-day activities of drug safety surveillance. A knowledge of the history of the product may forestall adverse publicity, as shown in the illustration. DATA SOURCES: This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. STUDY SELECTION: The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. DATA SYNTHESIS: The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered to facilitate communication of a review of adverse event data for various audiences. CONCLUSIONS: Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of the manufacturer. Attention to the basic principles is essential and, as illustrated, may be sufficient to resolve some problems.     

A primer of drug safety surveillance: an industry perspective. Part III: Managing adverse-event data.

OBJECTIVE: To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part III of this series describes management of adverse-event data. This process involves an interplay of regulations, labeling, and product knowledge. Types of databases are defined and the scope of paper files and computerized files is discussed. Database management is discussed in terms of four processes: receipt, retention, retrieval, and review of adverse-event reports. A summary of the application of the fundamentals to the incident described in the scenario shows that knowledge of the fundamentals may be sufficient to make a substantial contribution to the health of patients and the commercial well-being of manufacturers. DATA SOURCES: This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are listed in the appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. STUDY SELECTION: The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. DATA SYNTHESIS: The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered to facilitate communication of a review of adverse-event data for various audiences. CONCLUSIONS: Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of manufacturers. Attention to the basic principles is essential and, as illustrated, may be sufficient to resolve some problems.     

Adverse drug events: identification and attribution

The definition of an adverse drug event should be tailored to one's purpose in examining the incident. Although the more specific of these definitions is required for scientific evaluation of the link between drug and event, other less stringent definitions are usually adequate for clinical purposes. Knowledge about the safety profile of a drug in humans is limited at the time of marketing. The mechanisms for supplementing safety data during postmarketing include (1) the Spontaneous Reporting System maintained by the Food and Drug Administration, (2) formal projects to assemble safety data on larger or more complex populations, and (3) formal projects designed to answer specific research questions. Judgments about attribution can be no better than the data that support them. The criteria applied by the clinician to the individual adverse drug experience to determine association differ from those required to establish causation based on epidemiologic evidence. In most situations, regulatory action on drug recall should be based on epidemiologic evidence. This article will discuss the choice of a definition for an adverse drug event, examine the extent and nature of the safety data assembled on a drug at the time it is marketed, propose the best methods for collecting additional information after marketing, and designate factors to be considered in judging a drug to be causally related to an adverse event.     

Understanding the scientific issues embedded in the generic drug approval process.

OBJECTIVE: To review the major scientific issues embedded in the generic drug approval process. DATA SOURCES: Articles indexed initially under terms such as generic medications, generic drugs, bioequivalence, and bioinequivalence. These terms were used to search indexing services such as MEDLINE, International Pharmaceutical Abstracts, CINAHL (a database of nursing and allied health literature), and Science Citation Index. Additional data sources included the Code of Federal Regulations and regulatory guidances from the Food and Drug Administration (FDA) Center for Drug Evaluation and Research. STUDY SELECTION: Performed by the authors. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Despite the fact that regulations regarding bioequivalence have been in place for more than 20 years, controversies over bioequivalence continue to arise. Consensus on many of these issues is driving the development of new FDA guidances regarding bioequivalence. Still, despite the issuance of new guidance and consensus building among scientists, many clinicians and consumers remain uninformed regarding the scientific basis for establishing bioequivalence and the generic drug approval process in general. Although some have suggested that the generic drug approval process is flawed, overall, it appears that the process works. CONCLUSION: Understanding the generic drug approval process and the issues surrounding bioequivalence is of paramount importance to both clinicians and scientists.     

我国制药企业药品不良反应报告比例偏低的原因分析

目的：促进我国制药企业的药品不良反应报告和监测,完善我国药品不良反应监测体系,促进药品安全。方法：通过国内外对比,分析我国制药企业报告比例偏低的原因。结果与结论：应树立正确的认识,完善相关法律、法规,并加强药品安全责任体系建设。     

Manufacturer's drug interaction and postmarketing adverse event data: what are appropriate uses?

Governmental agencies overseeing pharmaceutical products use a risk/benefit approach to analyse data and make regulatory decisions. Comprehensive public dissemination of the safety profile of pharmaceutical products is part of an overall strategy for reducing risk associated with the use of any medical product. In the US, reports of postmarketing surveillance of approved drugs are in the public domain. Some, but not all, of the information in drug interaction studies is available to the public through the Freedom of Information Act (FOIA). However, there are concerns over the misuse of these data for commercial or other gain. The need to protect intellectual property and foster innovation in drug development, and concerns of legal liability are often cited as reasons to limit full public access to data from drug development studies. In contrast, intellectual freedom. public safety, and a mandate for transparent decision-making processes by regulatory agencies are issues that support open access to these data. Ultimately. concern for the public safety justifies open access to postmarketing surveillance data, and to a lesser degree, data regarding drug interactions in marketed products, and should outweigh the potential loss of competitive advantage by pharmaceutical companies.     

Drug-induced liver injury following positive drug rechallenge

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury.     

Adverse effects in women: implications for drug development and regulatory policies

The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.     

Clarification of terminology in drug safety.

Nomenclature surrounding drug safety needs to be clear and unambiguous, so that patients, prescribers, manufacturers, and regulators can all understand each other. In particular, it needs to make it clear how adverse events and drug therapy are related to one another, how they are best classified, and their frequency, intensity and seriousness. In this article, we therefore discuss and define terms used in the field of drug safety, particularly terms that are sometimes misunderstood or misused, including medicinal product, pharmaceutical formulation, excipient, adverse event (or experience) and adverse drug reaction (or effect). We also discuss terms used to define the seriousness, intensity, and risk of adverse reactions, and their classification.Instead of creating definitions from scratch, as is commonly done, we have taken the novel approach of critically examining definitions that have been proposed or widely used and have formulated new or modified definitions based on a logical appraisal of their merits and demerits. We hope that these definitions will lead to discussion that will allow a corpus of satisfactory definitions to be widely agreed.     

Consistent standards in medication use: the need to care for patients from research to practice.

OBJECTIVE: To propose adoption of practice standards for pharmacists based on the principles of pharmaceutical care that are parallel to internationally accepted ethical precepts governing clinical research. DATA SOURCES: Relevant literature selected by the authors. SUMMARY: Pharmaceutical care practice standards can create a continuum of high quality care for patients from research through practice and are presented as a rational solution to managing the benefits and risks of medication use. By implementing these practice standards, patients are empowered to become active participants in the treatment process, knowledge of drug effectiveness and safety is increased, and the pharmaceutical care practitioner's responsibilities are delineated. More than a quarter century ago, the research community adopted the ethical principles of respect for persons, beneficence, and justice, as outlined in the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Under these guidelines, research subjects are considered participants, knowledge of medication efficacy and safety has increased, and investigator responsibilities have been defined. However, these guidelines only apply to the life cycle of a drug before approval by the Food and Drug Administration. Once the product is released for general use, fewer standards are applied. Pharmacy has the opportunity to establish parallel standards for the clinical use of medications in patients by establishing patient care practices in consonance with pharmaceutical care practice. CONCLUSION: Pharmaceutical care practitioners need to apply new practice standards that allow them to contribute meaningfully to appropriate, effective, safe, and convenient drug therapy for all patients. Such pharmaceutical care practice standards could ensure consistent vigilance throughout the life cycle of the drug product and result in rational, appropriate, effective, safe, and convenient drug therapy for all patients.     

The role of databases in drug postmarketing surveillance

This paper describes the role of databases used for postmarketing surveillance of drugs at the United States Food and Drug Administration (FDA). First we describe the Adverse Event Reporting System (AERS), the largest database of adverse event reports in the world. Next, we explain the methods we have used for assembling these adverse event reports into a case series and analysing them, as well as techniques for employing drug use databases to construct reporting rates in the evaluation of drug safety issues. Finally, we discuss the FDA's use of the databases it accesses through its Cooperative Agreement Program to conduct high priority studies to support regulatory decision‐making. Published in 2001 by John Wiley & Sons, Ltd.     

Early detection of adverse drug events within population-based health networks: application of sequential testing methods

PURPOSE: Active surveillance of population-based health networks may improve the timeliness of detection of adverse drug events (ADEs). Active monitoring requires sequential analysis methods. Our objectives were to (1) evaluate the utility of automated healthcare claims data for near real-time drug adverse event surveillance and (2) identify key methodological issues related to the use of healthcare claims data for real-time drug safety surveillance. METHODS: We assessed the ability to detect ADEs using historical data from nine health plans involved in the HMO Research Network's Center for Education and Research on Therapeutics (CERT). Analyses were performed using a maximized sequential probability ratio test (maxSPRT). Five drug-event pairs representing known associations with an ADE and two pairs representing 'negative controls' were analyzed. RESULTS: Statistically significant (p < 0.05) signals of excess risk were found in four of the five drug-event pairs representing known associations; no signals were found for the negative controls. Signals were detected between 13 and 39 months after the start of surveillance. There was substantial variation in the number of exposed and expected events at signal detection. CONCLUSIONS: Prospective, periodic evaluation of routinely collected data can provide population-based estimates of medication-related adverse event rates to support routine, timely post-marketing surveillance for selected ADEs.     

Projecting future drug expenditures--1995.

Use of information on inflation, pharmacoeconomics, market introduction of new drug entities, practice-site-specific drug-use patterns, federal legislation, and the changing structure of health care delivery to project drug expenditures is discussed. Drug price inflation has been declining over the past several years, from 6.9% in 1991 to 2.2% for part of 1994. This can be attributed to both the growth of managed care and the industry's fear of government price controls. Pharmaceutical industry analysts project the overall price increase for pharmaceuticals in the next 12-24 months to be 2-5%. Pharmacoeconomic research is likely to become increasingly important; pharmacists will need to understand and critically evaluate this research. Drug budget projections should include a complete review of new drugs and biotechnology agents pending FDA approval, drugs pending approval for new indications, and common unlabeled uses of expensive existing agents. Various methods are available for tracking practice-site-specific drug-use patterns; those that categorize expenditures by diagnosis-related group may underestimate total expenditures associated with treating a given condition. State and federal legislation may affect drug rebates, prices, and ultimately drug expenditures. Although health care reform legislation did not pass in 1994, changes are occurring in both the pharmaceutical industry and in health care delivery, shifting the control of drug selection, utilization, and expenditures from individual prescribers to large purchasers. The accuracy of projections of drug expenditures can be improved by examining inflation, pharmacoeconomic research, the introduction of new drug entities, practice-site-specific drug-use patterns, federal legislation, and the changing structure of health care delivery.     

Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products

With a New Drug Application (NDA) innovative drug therapies are reaching the market in a specific dosage form for one or more clinically proven indications of which after expiration of the patent or the data exclusivity copies are launched using Abbreviated New Drug Applications (ANDA). Advanced therapies that emerged from launched molecules during their product life-cycle have gained considerable attention as clinical practice provides evidence for additional therapeutic values, patient centric delivery systems show improved therapeutic outcomes or emerging technologies offer efficiency gains in manufacturing or access to emerging markets. The USA and European regulatory framework has set reasonable regulations in place for these "Supergenerics" or "hybrid" applications. While these regulations are relatively recent the pharmaceutical industry is just starting to use this route for their product development and life-cycle management. From a clinical perspective the potential for advanced product development have been demonstrated. Yet, there is still a lag of common understanding between the different stakeholders regarding the development, application process and commercial incentive in developing enhanced therapeutic entities based on existing drug products for the market.     

77例抗感染药物静脉滴注引起不良反应/事件病例分析

摘要：目的 分析抗感染药物静脉滴注引起不良反应/事件的各种因素,为临床安全、合理用药提供参考。方法 对我院2010年1月～2011年12月77例抗感染静脉滴注引起药品不良反应/事件病例进行统计分析。结果 77例不良事件涉及药物55个品规,发生不良反应/事件的原因涉及单次给药剂量过大、药物浓度过高、滴注速度过快、配伍不合理、患者既往药物过敏史不详等;发生不良事件最短时间为5 min,而31～40 min有45例（58.4%）;临床表现以皮肤及其附件损害为主。结论 抗感染药物静脉滴注时应严格按照药品的说明书给药,加强药学监护,针对引起不良反应/事件的因素应采取相应的预防措施.     

Comparative risk for harms of second-generation antidepressants : a systematic review and meta-analysis

BACKGROUND: Evidence indicates that only minor differences in efficacy exist among second-generation antidepressants for the treatment of major depressive disorder (MDD). However, a comprehensive assessment of both benefits and harms is crucial to evaluate the net benefit. OBJECTIVE: To review systematically the comparative harms of second-generation antidepressants for the treatment of MDD in adults by including both experimental and observational evidence. DATA SOURCES: We searched MEDLINE((R)), EMBASE, PsychLit, The Cochrane Library and the International Pharmaceutical Abstracts from 1980 to April 2007. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database to identify unpublished research. STUDY SELECTION: Eligible study designs were trials and observational studies comparing one drug of interest with another. DATA EXTRACTION: Two persons independently reviewed abstracts and full-text articles. One investigator extracted relevant data. A senior reviewer checked data for completeness and accuracy. DATA SYNTHESIS: We included 104 experimental and observational studies. If data were sufficient, we conducted meta-analyses of randomized controlled trials on the relative risk of specific adverse events. Findings indicate that the spectrum of adverse events is similar. The frequency of specific adverse events, however, differed across drugs. Venlafaxine was associated with a significantly higher rate of nausea and vomiting than selective serotonin reuptake inhibitors. Compared with other drugs, paroxetine frequently led to more sexual adverse effects and bupropion to fewer such effects; mirtazapine and paroxetine was associated with more weight gain and sertraline with a higher rate of diarrhoea. Overall, however, these differences did not lead to different discontinuation rates. The evidence is insufficient to draw conclusions about rare but severe adverse events. CONCLUSIONS: Adverse event profiles are similar among second-generation antidepressants. However, different frequencies of specific adverse events might be clinically relevant and influence the choice of a treatment.     

Compounding botanicals: a legal perspective.

OBJECTIVE: To describe the effects of the new law, section 503A, "Pharmacy Compounding," of the Federal Food, Drug, and Cosmetic Act on the compounding of drugs, dietary supplements, and cosmetics. DATA SOURCES: The Food and Drug Administration (FDA) Modernization Act of 1997; Federal, Food, Drug, and Cosmetic Act; Code of Federal Regulations; Federal Register; Food and Drug Administration Guidances. DATA SYNTHESIS: Pharmacy compounding, which traditionally is considered part of pharmacy practice and is regulated by the states, has been confused with drug manufacturing, an activity regulated by FDA. Section 503A, "Pharmacy Compounding," was enacted as part of the Food and Drug Administration Modernization Act of 1997 to distinguish compounding from manufacturing. This law addresses the compounding of drug products, but not necessarily the compounding of botanicals, which may be considered dietary supplements, cosmetics, or drugs. CONCLUSION: Section 503A applies to the compounding of products intended for a drug use, but does not apply to compounded products that are intended for dietary supplement or cosmetic use. Compounded dietary supplements and cosmetics must instead adhere to relevant federal requirements, including those for good manufacturing practices and labeling.     

Pharmacovigilance in China: development and challenges

Background Rational drug use and drug safety are becoming increasingly important concerns in China with the increasing public access to drugs and the health-care system, and this has led to the development of pharmacovigilance in China. Aim of the review To provide a brief introduction about pharmacovigilance in China in terms of system development, utilization and challenges. Method Relevant studies on pharmacovigilance related to the study aim was undertaken through literature search to synthesize the extracted data. Results The creation and evolvement of China’s pharmacovigilance system spans across 30 years since 1989. The system consists of four progressing administrative layers: county, municipal, provincial and national levels. China has passed over 20 laws and regulations related to pharmacovigilance covering the processes of drug development, manufacture, distribution and use with the aim to guard drug safety. An online spontaneous self-reporting Adverse Drug Reaction (ADR) Monitoring System was established in 2003. ADRs are mainly reported by medical institutions, pharmaceutical manufacturers, and drug distributors. Currently there is no mandatory ADR reporting requirement for pharmaceutical manufacturers, and a proposed regulation under public comment will likely change this. China has started to build active pharmacovigilance surveillance programs in addition to the passive ADR reporting system. The China Food and Drug Administration has established the intensive Safety Monitoring Program and the National Adverse Drug Reaction Monitoring Sentinel Alliance Program based on electronic health records to further the efforts of ADR reporting, monitoring and analysis. Conclusion The practice of ADR monitoring and pharmacovigilance in China have made great progress. More efforts are needed both in system building, and creation of laws and regulations to strengthen the safe use of medicines.     

The role of electronic healthcare record databases in paediatric drug safety surveillance: a retrospective cohort study

Aim

Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0–18 years).

Methods

Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996–2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events.

Results

The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock.

Conclusion

Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance.     

The U.S. medicine chest: Understanding the U.S. pharmaceutical supply chain and the role of the pharmacist

The U.S. capacity to manufacture key essential medications has diminished. The U.S. pharmaceutical supply chain (USPSC) has diversified and now relies on international sources of active pharmaceutical ingredients and finished drug products (FDPs). Despite years of effort raising concerns about the USPSC, pharmacists and pharmacy technicians continue to spend a substantial amount of time and energy responding to, and mitigating the impact of, medication shortages, drug recalls, and the adverse outcomes related to low-quality medications. The extent of U.S. reliance on foreign sources of medications is largely unknown. Pharmacists do not have a reliable way to determine the country of origin (i.e., source), capacity, or geographic location of pharmaceutical manufacturers, limiting our ability to anticipate challenges or mitigate risks to our Nation’s drug supply. The U.S. Food and Drug Administration’s task of regulating quality and safety is challenging and will likely require additional safeguards and resources. In addition to pharmacists’ engagement, solutions will likely need to leverage a mix of policy, economic incentives, and expanded objective surveillance testing. The U.S. pharmaceutical supply chain is complex, global, and goes beyond FDPs. The 2020 American Pharmacists Association House of Delegates has rightly asserted that “The quality and safety of pharmaceutical and other medical products and the global pharmaceutical and medical product supply chain are essential to the United States national security and public health.” Pharmacy professionals on the front line engage with patients, identify medication-related issues, and engage in drug-procurement decisions. Pharmacists are essential to our nation’s overall health and must be engaged in the development and implementation of strategies to safeguard the USPSC.