Drug Safety Problems Research Articles

Monitoring drug safety in Astrakhan, Russia

The problem of drug safety will never disappear as new drugs are delivered in increasing numbers. They have high biological activity and adverse drug reactions (ADR) [1]. Currently, adverse drug reactions are the fourth leading cause of death for patients.There are databases of ADRs (Vigibase, Eudravigilance), but we know that ADR manifestations may vary in different countries and regions, due to the demographic, genetic characteristics of the population and the quality of manufactured drugs [2]. In this regard, the study of the ADR at the regional level is very relevant. We aimed to optimize the work on monitoring drug safety in Astrakhan region through pharmacoepidemiological research and development of computer database for analysis of information coming to the center for drug safety monitoring (CDSM). 1. To study the rates of ADR reporting and the structure in the Astrakhan region at the regional center for drug safety monitoring.2. To analyze the outcomes of registered adverse drug reactions.3. To determine the causality of adverse drug reactions.4. To identify reports on the ineffectiveness of drugs.5. To analyze the rates and structure of ADR reporting for drugs prescribed off-label. We studied spontaneous adverse event reporting. The adverse event reports received by the regional CDSM for the period of 2010 to 2014 was analyzed. The groups of drugs were categorized according by Anatomical Therapeutic Chemical classification system. The data were analyzed using Microsoft Office Excel. The likelihood of whether an ADR was actually due to the drugs was assessed with the Naranjo algorithm. The analysis of the results showed that the establishment of the CDSM in September 2010, contributed to improvement of drug safety monitoring in health facilities of the region. Noteworthy was the increasing the number of adverse event reports in 2011 and 2012, compared with the beginning of the year 2010, when the CDSM was not yet functioning.The decrease of adverse event reporting in 2013 and 2014 was due to the fact that doctors in the region had access to better ADR drug information. Along with the increasing number of adverse event reporting we also noted the increase in the number of health facilities that monitored drug safety. The number of health facilities that reported, doubled from 2010 to 2014. We observed the increase in the number of adverse event reports submitted by pharmaceutical companies. General anti-infective drugs for systemic use (class J) were the most common cause of all registered ADRs (44%). Drugs for treatment of tuberculosis (group J04A) were the cause of adverse drug reactions in 34% of reports. ADRs associated with drugs used for treating diseases of cardiovascular system accounted for 16% of case-reports; drugs belonging to the group of Alimentary tract and metabolism (class A) and to the group of Nervous System (class A) were reported to cause ADRs in 10% of cases each. Type A adverse drug reactions, which are usually a consequence of a drug's primary pharmacological effect, were detected in 45% of cases. These reactions were often registered for drugs affecting cardiovascular system (class C), nervous system (class N), dlood and blood forming organs (class B). Type B ADRs were reported in 54% of cases. These were "idiosyncratic" reactions, which could not be predicted on the basis of the drug's main pharmacological action, were not dose-related and were severe [3]. The most frequent cause of type B adverse drug reactions was the General anti-infective medicines for systemic use (Class J). The fatality rate associated with ADRs was 0.3%. Type A adverse drug reactions resulted in death in 38% of cases. Type B ADR (anaphylactic shock) accounted for 62% of the patient's deaths. The Naranjo scale determined the causality of ADRs. The "definite" ADRs were detected in 14% of reports, "probable" - in 47%, and "possible" - in 39% of cases. The rate of reporting associated with ineffectiveness of drugs amounted to 1%. Most often the lack of therapeutic effect was reported in patients receiving drugs of class C (Cardiovascular system, 31% of all cases of inefficiency of drugs). These drugs were used in accordance with their official instructions for use. The proportion of ADR reports for drugs prescribed off-label was 1.4%. The results substantiate the need to continue drug safety monitoring in the Astrakhan region. We plan to further improve the software for ADR analysis.

Methodological framework to identify possible adverse drug reactions using population-based administrative data

Purpose: We present a framework for detecting possible adverse drug reactions (ADRs) using the Utah Medicaid administrative data. We examined four classes of ADRs associated with treatment of dementia by acetylcholinesterase inhibitors (AChEIs): known reactions (gastrointestinal, psychological disturbances), potential reactions (respiratory disturbance), novel reactions (hepatic, hematological disturbances), and death. Methods: Our cohort design linked drug utilization data to medical claims from Utah Medicaid recipients. We restricted the analysis to 50 years-old and older beneficiaries diagnosed with dementia-related diseases. We compared patients treated with AChEI to patients untreated with anti-dementia medication therapy. We attempted to remove confounding by establishing propensity-score-matched cohorts for each outcome investigated; we then evaluated the effects of drug treatment by conditional multivariable Cox-proportional-hazard regression. Acute and transient effects were evaluated by a crossover design using conditional logistic regression. Results: Propensity-matched analysis of expected reactions revealed that AChEI treatment was associated with gastrointestinal episodes (Hazard Ratio [HR]: 2.02; 95%CI: 1.28-3.2), but not psychological episodes, respiratory disturbance, or death. Among the unexpected reactions, the risk of hematological episodes was higher (HR: 2.32; 95%CI: 1.47-3.6) in patients exposed to AChEI. AChEI exposure was not associated with an increase in hepatic episodes. We also noted a trend, identified in the case-crossover design, toward increase odds of experiencing acute hematological events during AChEI exposure (Odds Ratio: 3.0; 95% CI: 0.97 - 9.3). Conclusions: We observed an expected association between AChEIs treatment and gastrointestinal disturbances and detected a signal of possible hematological ADR after treatment with AChEIs in this pilot study. Using this analytic framework may raise awareness of potential ADEs and generate hypotheses for future investigations. Early findings, or signal detection, are considered hypothesis generating since confirmatory studies must be designed to determine if the signal represents a true drug safety problem.

Methodological framework to identify possible adverse drug reactions using population-based administrative data.

We present a framework for detecting possible adverse drug reactions (ADRs) using the Utah Medicaid administrative data. We examined four classes of ADRs associated with treatment of dementia by acetylcholinesterase inhibitors (AChEIs): known reactions (gastrointestinal, psychological disturbances), potential reactions (respiratory disturbance), novel reactions (hepatic, hematological disturbances), and death. Our cohort design linked drug utilization data to medical claims from Utah Medicaid recipients. We restricted the analysis to 50 years-old and older beneficiaries diagnosed with dementia-related diseases. We compared patients treated with AChEI to patients untreated with anti-dementia medication therapy. We attempted to remove confounding by establishing propensity-score-matched cohorts for each outcome investigated; we then evaluated the effects of drug treatment by conditional multivariable Cox-proportional-hazard regression. Acute and transient effects were evaluated by a crossover design using conditional logistic regression. Propensity-matched analysis of expected reactions revealed that AChEI treatment was associated with gastrointestinal episodes (Hazard Ratio [HR]: 2.02; 95%CI: 1.28-3.2), but not psychological episodes, respiratory disturbance, or death. Among the unexpected reactions, the risk of hematological episodes was higher (HR: 2.32; 95%CI: 1.47-3.6) in patients exposed to AChEI. AChEI exposure was not associated with an increase in hepatic episodes. We also noted a trend, identified in the case-crossover design, toward increase odds of experiencing acute hematological events during AChEI exposure (Odds Ratio: 3.0; 95% CI: 0.97 - 9.3). We observed an expected association between AChEIs treatment and gastrointestinal disturbances and detected a signal of possible hematological ADR after treatment with AChEIs in this pilot study. Using this analytic framework may raise awareness of potential ADEs and generate hypotheses for future investigations. Early findings, or signal detection, are considered hypothesis generating since confirmatory studies must be designed to determine if the signal represents a true drug safety problem.

Joint medicine-information and pharmacovigilance services could improve detection and communication about drug-safety problems.

BackgroundRELIS is a Norwegian network of four regional medicine-information and pharmacovigilance centers where pharmacists and clinical pharmacologists provide feedback to health care professionals in spontaneous drug-related questions and adverse drug-reaction (ADR) reports published in a question–answer pair (QAP) database (the RELIS database) and the Norwegian ADR database, respectively.ObjectiveTo describe the potential of RELIS’s dual service to improve detection and communication of drug-safety problems.Materials and methodsWe searched the RELIS database for QAPs about ADRs with use of the Norwegian ADR database as a reference. We also searched the Norwegian ADR database for reports that used the RELIS database as a reference. Both searches were limited to the years 2003–2012. We then selected the example of pregabalin and drug abuse after the marketing of Lyrica in Norway in September 2004 to illustrate RELIS’s potential to detect new drug-safety information through a limited number of QAPs and ADR reports.ResultsA total of 5,427 (26%) of 21,071 QAPs in the RELIS database concerned ADRs. QAPs from this database were used as references in 791 (4%) of a total of 22,090 reports in the Norwegian ADR database. The Norwegian ADR database was used as a reference in 363 (7%) of 5,427 QAPs that concerned ADRs. Between September 2004 and September 2008, RELIS received eleven questions and 13 ADR reports about suspicion of Lyrica (pregabalin) and different aspects of abuse.ConclusionRELIS processes data through two databases that facilitate communication about ADRs. Our service also has the potential to detect new drug-safety problems with a limited number of questions and ADR reports.

Possible adverse drug events leading to hospital admission in a Brazilian teaching hospital

OBJECTIVES:Drug safety problems can lead to hospital admission. In Brazil, the prevalence of hospitalization due to adverse drug events is unknown. This study aims to estimate the prevalence of hospitalization due to adverse drug events and to identify the drugs, the adverse drug events, and the risk factors associated with hospital admissions.METHOD:A cross-sectional study was performed in the internal medicine ward of a teaching hospital in São Paulo State, Brazil, from August to December 2008. All patients aged ≥18 years with a length of stay ≥24 hours were interviewed about the drugs used prior to hospital admission and their symptoms/complaints/causes of hospitalization.RESULTS:In total, 248 patients were considered eligible. The prevalence of hospitalization due to potential adverse drug events in the ward was 46.4%. Overprescribed drugs and those indicated for prophylactic treatments were frequently associated with possible adverse drug events. Frequently reported symptoms were breathlessness (15.2%), fatigue (12.3%), and chest pain (9.0%). Polypharmacy was a risk factor for the occurrence of possible adverse drug events.CONCLUSION:Possible adverse drug events led to hospitalization in a high-complexity hospital, mainly in polymedicated patients. The clinical outcomes of adverse drug events are nonspecific, which delays treatment, hinders causality analysis, and contributes to the underreporting of cases.

Choosing Thresholds for Statistical Signal Detection with the Proportional Reporting Ratio

Identification of potential drug safety problems using statistical screening algorithms in routinely collected databases of adverse drug reactions (ADRs) requires decision rules based on thresholds of the chosen parameters. Choosing higher or lower thresholds changes both the sensitivity of the screening and the number of false alarms produced, and thus has an impact on the effectiveness of the detection process. The aim of this study was to evaluate the impact on the effectiveness of signal detection activities of choosing different warning thresholds for the proportional reporting ratio (PRR) and for the count of reports of any drug-event combination. Signal detection methods were tested within the EudraVigilance database of suspected ADRs. Using an established set of known ADRs, the number that could be detected and the changes in time gained for earlier investigation of the signal were calculated over a range of signal detection thresholds. These figures were set against the number of false positive signals produced by the statistical signal detection algorithms. Higher thresholds for the lower confidence bound of the PRR produced fewer false positives but this benefit was offset by important losses of sensitivity in the detection of ADRs. By contrast, increases in the threshold for the count of a specific drug-event combination produced fewer false positives with little loss of either sensitivity or time gained for investigation of adverse events. A threshold of five compared with the current European Medicines Agency threshold of three gave a reduction of 25 % in false positive signals in return for a loss of 12 % in true signals detected early. Changes in the standard threshold for the count of drug-event combinations can result in a substantial improvement in efficiency of the signal detection process. Initially this change might be applied only to products with a well-established safety profile.

Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case–control study in a new general practice database

To test the ability a new Spanish primary care research database (BIFAP) to capture the association between upper gastrointestinal bleeding (UGIB) and NSAIDs and other drugs and compare the results with previous studies. We performed a nested case-control study in persons aged 40-90 years old included in the period 2001-2005. Potential cases were selected through a computer search followed by an individual blinded review. Controls matched for age, sex and calendar year were randomly selected. The exposure window was defined as 0-30 days before the index date. Adjusted odds ratios were obtained through unconditional logistic regression models. In a study cohort of 669,115 subjects (1,576,442 person-years) we retrieved 1,193 valid incident cases. Increased risks were found with current use of NSAIDs (RR = 1.72; 95 %CI: 1.41-2.09), metamizole (1.52; 1.09-2.13), low-dose aspirin (1.74; 1.37-2.21), other antiplatelet drugs (1.73; 1.27-2.36), and oral anticoagulants (2.00; 1.44-2.77). We did not find an increased risk with current use of oral corticosteroids (1.11; 0.66-1.86), SSRIs (1.05; 0.77-1.42), or paracetamol (1.00; 0.82-1.23). Acid-suppressing drugs reduced the risk among users of NSAIDs (0.58; 0.39-0.85), particularly in users with antecedents of peptic ulcer (0.16; 0.05-0.58). We detected a decreasing time-trend in the relative risk and the population attributable proportion associated with NSAIDs over the study period. The increased risk of UGIB associated with NSAIDs was lower than previously reported, which could partly be explained by methodological differences, but a decreasing burden over time of this drug safety problem is suggested. BIFAP has shown to be a valuable tool for pharmacoepidemiological research.

Application of system-level root cause analysis for drug quality and safety problems: A case study

BackgroundAutomated surveillance indicators are used to identify problems with drug therapy. A previous study automated 39 indicators of possible drug-related emergency department visits and hospitalizations. These indicators were used to investigate the quality and safety of drug use in a large health care coalition in Florida. This study describes a method of capturing this input with an aim of applying it to a root cause analysis (RCA), which may be useful for improving system-level flaws and weaknesses in medication use. ObjectiveTo apply results of a computerized surveillance system containing selected indicators of potential drug-related emergency department and hospital admissions to an RCA for evaluation. Such evaluation might prove effective in determining criteria useful in improving the quality and safety of systemic responses to individual types of drug therapy problems. MethodsThis was a case study that brought together a study group of 6 coalition stakeholders to evaluate findings from 4 indicators. The indicators represented problems in the prescribing, adherence, and monitoring steps in the ambulatory care medication use system. The RCA included the following procedures: brainstorming of possible system failures, organizing proposed system failures into groups and corresponding system levels, voting to prioritize proposed system failures, tree diagramming to illustrate how the system failures are interconnected among system levels, and determining whether system conditions or failure sequences are common among indicator types. ResultsThe group judged 3 themes to be important contributors to drug-related problems identified by the 4 indicators, including lack of patient knowledge, patient nonadherence to medical recommendations, and lack of medication management systems. The group believed that these barriers were interconnected and the result of subsystem influences. ConclusionDrug therapy problems represented by the indicators have certain system failures, flaws, or defects in common, allowing them to occur and persist. RCA may be a useful method for evaluating population-level indicator findings to identify potential failures with the medication use system and develop interventions.

Nutzen und Risiken der modernen Pharmakotherapie des Typ-2-Diabetes

The development of new drugs for the treatment of type 2 diabetes (T2DM) and metabolic disorders is currently one of the most innovative areas of drug development. However, a considerable number of newly developed drugs have either not reached the market and were stopped late in development or have been withdrawn after initial approval soon after market authorization due to serious safety concerns. How can drug safety problems be anticipated and, even more important, how can adverse events definitely caused by a drug be differentiated from incidences of naturally occurring diseases? This review article will provide an update about the state of the art treatment of type 2 diabetes and reflect on the newest available study evidence on glitazones, incretin mimetics (GLP-1 agonists and DPP-4 inhibitors), SGLT-2 inhibitors (gliflocines) and pan-PPAR agonists (glitazars). Furthermore, new and still experimental approaches for the treatment of T2DM, such as bardoxolone, salsalate and anakinra will be briefly reviewed.

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

Adverse drug reactions (ADRs) represent an important medical issue: they result in 3–7% of all hospital admissions and are associated with a substantial increase in morbidity and mortality. Numerous methods can be used to investigate ADRs. Each has its strengths and weakness. The insufficiencies of basic (experimental) pharmacology as well as clinical trials for studying ADRs are well known. Animal physiology often differs from that of humans. Clinical trials, although necessary, do not allow definite conclusions, because they are built to evaluate efficacy more than safety. Thus, spontaneous notifications remain the cornerstone for ADRs despite their mandatory limitations (under-reporting, selective reporting, lack of denominator etc.). Intensive studies could allow quantification of a specific problem of drug safety (i.e. drug admission into hospital for ADRs). For some years, several pharmacoepidemiological methods have been used to identify and also to quantify ADRs. Among thesse methods, case–control or cohort studies are most widely used. However, their setting up requires specific organization, delay, money and also use of large databases, which are not often specifically built for evaluation of ADRs. In the present issue of the journal, clinical pharmacologists and pharmacoepidemiologists from Poitiers University Hospital (France) have used another method, working from the French PharmacoVigilance database. They used disproportionality analysis for identification of memory disorders associated with drugs [1]. The present paper discusses the benefits and strengths of this method.

Study on building index system of risk assessment of post-marketing Chinese patent medicine based on AHP-fuzzy neural network

Currently massive researches have been launched about the safety, efficiency and economy of post-marketing Chinese patent medicine (CPM) proprietary Chinese medicine, but it was lack of a comprehensive interpretation. Establishing the risk evaluation index system and risk assessment model of CPM is the key to solve drug safety problems and protect people's health. The clinical risk factors of CPM exist similarities with the Western medicine, can draw lessons from foreign experience, but also have itself multi-factor multivariate multi-level complex features. Drug safety risk assessment for the uncertainty and complexity, using analytic hierarchy process (AHP) to empower the index weights, AHP-based fuzzy neural network to build post-marketing CPM risk evaluation index system and risk assessment model and constantly improving the application of traditional Chinese medicine characteristic is accord with the road and feasible beneficial exploration.

Sex, gender, and pharmaceutical politics: From drug development to marketing

Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing. This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials. The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals. The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome. Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender.

Validation of Statistical Signal Detection Procedures in EudraVigilance Post-Authorization Data

Screening large databases of spontaneous case reports of possible adverse drug reactions (ADRs) is an established method of identifying hitherto unknown adverse effects of medicinal products; however, there is a lack of consensus concerning the value of formal statistical screening procedures in guiding such a process. This study was performed to clarify the nature of any added benefits and additional effort required when established pharmacovigilance techniques are supplemented with statistical screening. To evaluate whether statistical signal detection in spontaneous reporting data can lead to earlier detection of drug safety problems and to assess the additional regulatory work entailed. Using the EudraVigilance post-authorization module (EVPM), a screening procedure based on the proportional reporting ratio (PRR) was applied retrospectively to examine if regulatory investigations concerning ADRs in a predefined set of products could have been initiated earlier than occurred in practice. During the same time period, between September 2003 and March 2007, the number of PRR-based signals of disproportionate reporting (SDR) that arose in the same set of products was calculated and evaluated to determine the number requiring investigation. The outcome is expressed as the ratio of the number of SDRs requiring investigation compared with the number of signals pre-empted by the statistical screening approach. In those cases where the signal was discovered earlier, the delay was calculated between identification by the PRR method and by the method that originally identified the signal. In 191 chemically different products, 532 adverse reactions were added to the summary of product characteristics during the study period. Of these, 405 were designated as important medical events (IMEs) based on a comprehensive predefined list. Of the IMEs, 217 (53.6%) were identified earlier by the statistical screening technique, 79 (19.6%) were detected after the date at which they were raised by standard pharmacovigilance methods and 109 (26.9%) were not signalled during the study period. 1561 SDRs requiring further evaluation were detected during the study period, giving a ratio of 7.2 assessments for each signal pre-empted. The mean delay between the discovery of signals using the statistical methods in the EVPM and established methods in the 217 cases detected earlier was 2.45 years. A review resulted in clear explanation for why the statistical method had not pre-empted detection in all but 77 of 188 cases. The form of statistical signal detection tested in this study can provide significant early warning in a large proportion of drug safety problems; however, it cannot detect all safety issues more quickly than other pharmacovigilance processes and hence it should be used in addition to, rather than as an alternative to, established methods.

Information technology in pharmacovigilance: Benefits, challenges, and future directions from industry perspectives

Risk assessment during clinical product development needs to be conducted in a thorough and rigorous manner. However, it is impossible to identify all safety concerns during controlled clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with comorbid conditions and those being treated with concomitant medications. Therefore, postmarketing safety data collection and clinical risk assessment based on observational data are critical for evaluating and characterizing a product's risk profile and for making informed decisions on risk minimization. Information science promises to deliver effective e-clinical or e-health solutions to realize several core benefits: time savings, high quality, cost reductions, and increased efficiencies with safer and more efficacious medicines. The development and use of standard-based pharmacovigilance system with integration connection to electronic medical records, electronic health records, and clinical data management system holds promise as a tool for enabling early drug safety detections, data mining, results interpretation, assisting in safety decision making, and clinical collaborations among clinical partners or different functional groups. The availability of a publicly accessible global safety database updated on a frequent basis would further enhance detection and communication about safety issues. Due to recent high-profile drug safety problems, the pharmaceutical industry is faced with greater regulatory enforcement and increased accountability demands for the protection and welfare of patients. This changing climate requires biopharmaceutical companies to take a more proactive approach in dealing with drug safety and pharmacovigilance.

Sociology of pharmaceuticals development and regulation: a realist empirical research programme

A realist conceptualization of interests is proposed in opposition to the fashionable view that interests, objectivity and reality are merely social constructs, and that sociological analyses should be confined to discourse, actor-networks and micro-contextual practices. The objective interests of pharmaceutical companies in profit-maximization, and of patients/public health in the optimisation of drugs' benefit-risk ratios, can be empirically validated. The relationship between those interests and pharmaceutical regulation is best characterised by 'neo-liberal corporate bias' at the macro- and meso-levels. How such bias manifests itself at the micro-social level of science-based pharmaceutical testing and regulatory decision making is examined using a realist sociology of scientific knowledge, which appreciates that assessment of the validity of techno-scientific knowledge claims is essential for their sociological explanation. Commercial interests are shown to have biased science away from the interests of public health, in favour of industry. International comparisons of drug regulation demonstrate that drug injuries are not necessarily an inevitable by-product of pharmaceutical progress because some countries have fewer drug safety problems than others. Similarly, the lowering of techno-scientific standards for drug safety testing is not an inevitable cost of faster development of therapeutically valuable medicines, but a consequence of the internationalization of neo-liberal corporate bias.

Congress Responds to the IOM Drug Safety Report—In Full

THE US DRUG SAFETY SYSTEM DEVELOPED FITFULLY throughaseriesofhistoricalaccretions, typically inthe wakeofmajordrugsafetyscandals.In1962,largelyprecipitatedbythethalidomidetragedy,theKefauver-Harris amendments to the Federal Food, Drug, and Cosmetic Act required the sponsor to provide “substantial evidence” of both safety and efficacy during a premarket evaluation. The resulting multistage approval process improved the evidence base for premarket regulatory decision making about drugs, but it also created, as an unintended consequence, a postapproval environment inwhichsponsorswere largely free fromrequirements for additional evaluations. At approval, the sponsor’s scientific teamsresponsible formeetingUSFoodandDrugAdministration (FDA) requirements were generally replaced by marketing teams,andthemanufacturer’s efforts, energies, and studies were generally directed toward marketing its drugs. The formulaic preapproval evaluation process, even though usually of high quality, slowed drug approval. The 1992 Prescription Drug User Fee Act (PDUFA) provided new funds fromuser fees, limited their use to speeding preapproval evaluations, set timelines for reviews, and thus brought drugs to market more quickly. As the United States became increasingly the country of first launch for many new drugs (from 2% in 1980 to 60% in 1998), the US postmarketing safety systemaccordinglysharedalargerresponsibility for theearlydetection of safety signals. For the first 10 years following enactment of PDUFA, however, Congress prohibited the FDA from applying user fees to drug safety and provided no additional funds for monitoring marketed drugs. Not until the PDUFA reauthorization of 2002 was the FDA permitted to apply some user fees for selected safety issues. In effect, Congress largely entrusted the detection, evaluation, and timely reporting of postmarketing safety issues to the pharmaceutical industry. The withdrawal of rofecoxib and other drug safety problems have again focused attention on the limitations of the US postmarketing system. In response to an FDA request, the Institute of Medicine (IOM) undertook a thorough assessment and issued a comprehensive set of recommendations for reform. The major theme of the report was the need for an ongoing effort to acquire, integrate, and communicate information about a drug’s risks and benefits during its entire market life. This “lifecycle” approach requires the translation of premarket safety signals into high-quality postmarketing studies, sophisticated active surveillance to identify new serious safety signals, and timely assessments of the drug’s riskbenefit profile. While the FDA has already responded in part to some recommendations, others dealing with the agency’s resources and authorities required congressional action.

Real-Time Vaccine Safety Surveillance for the Early Detection of Adverse Events

Rare but serious adverse events associated with vaccines or drugs are often nearly impossible to detect in prelicensure studies and require monitoring after introduction of the agent in large populations. Sequential testing procedures are needed to detect vaccine or drug safety problems as soon as possible after introduction. To develop and evaluate a new real-time surveillance system that uses dynamic data files and sequential analysis for early detection of adverse events after the introduction of new vaccines. The Centers for Disease Control and Prevention (CDC)-sponsored Vaccine Safety Datalink Project developed a real-time surveillance system and initiated its use in an ongoing study of a new meningococcal vaccine for adolescents. Dynamic data files from 8 health plans were updated and aggregated for analysis every week. The analysis used maximized sequential probability ratio testing (maxSPRT), a new signal detection method that supports continuous or time-period analysis of data as they are collected. Using the new real-time surveillance system, ongoing analyses of meningococcal conjugate vaccine (MCV) safety are being conducted on a weekly basis. Two forms of maxSPRT were implemented: an analysis using concurrent matched controls, and an analysis based on expected counts of the outcomes of interest, which were estimated based on historical data. The analysis highlights both theoretical and operational issues, including how to (1) choose appropriate outcomes and stopping rules, (2) select control groups, and (3) accommodate variation in exposed:unexposed ratios between time periods and study sites. Real-time surveillance combining dynamic data files, aggregation of data, and sequential analysis methods offers a useful and highly adaptable approach to early detection of adverse events after the introduction of new vaccines.

Use of Triage Strategies in the WHO Signal-Detection Process

An important role for the WHO Programme for International Drug Monitoring is to identify signals of international drug safety problems as early as possible. Since 1998, Bayesian Confidence Propagation Neural Network (BCPNN) data mining has been in routine use for screening of the WHO adverse reaction database, Vigibase. The identification of drug/adverse drug reaction combinations that have disproportionately high reporting relative to the background of all reports constitutes the first, quantitative step in the Uppsala Monitoring Centre (UMC) signal-detection process. In order to improve the signal-to-noise ratio and to focus on possible signals that are less likely to be detected by individual national pharmacovigilance centres, an expert group considered a number of possible subsidiary selection algorithms to be added as a second filtering step before potential signals were sent to the UMC expert panel for clinical review. As a result of these deliberations, three selection algorithms were implemented for routine use in 2001: 'serious reaction and new drug', 'rapid reporting increase' and 'special interest terms'. The effect of applying these algorithms has been critically evaluated on the basis of the ratio of associations selected to signals found and some modifications decided. Bearing in mind that any filtering strategy is likely to exclude some potential true signals from consideration, we think that triage strategies based on a combination of pragmatic thinking and experience are effective, provided that the results are reviewed at regular intervals and the algorithms adjusted on the basis of performance.

Evaluating Drug Effects in the Post-Vioxx World

The drug approval process must determine efficacy validly, detect risks prudently, and do both in a timely and efficient way. Several high-profile medication withdrawals in recent years have refocused attention on the difficulty of the US healthcare system in meeting these goals. Rofecoxib (Vioxx, Merck) was taken off the market in September 2004 after 5 years of use by &20 million people, when its manufacturer reported that the drug doubles the risk of myocardial infarction or stroke. That experience, as well as other instances in which important side effects came to public attention long after a drug’s approval, has prompted discussion about how to repair the nation’s drug evaluation process. Some have proposed changing the degree of statistical certainty required for initial drug approval, with the hope that demanding a probability value of <0.0001 for efficacy (rather than the conventionally required 0.05) would slow down the approval process enough to increase the likelihood that adverse events would be detected. This idea is evaluated and rejected by Roth-Cline in the this issue of Circulation .1 It is true that demanding unprecedentedly stringent tests for efficacy is a poor way to fix the nation’s drug safety problem, but not necessarily for the reasons Roth-Cline advances. A better solution will have to be based on a more comprehensive understanding of how the risks of new drugs are detected, evaluated, and addressed. Article p 2253 The thalidomide tragedy of the early 1960s led to important reforms in the regulatory authority of the Food and Drug Administration (FDA), including giving it the power to require that a manufacturer demonstrate efficacy before a new drug can be marketed. We take this expectation for granted today, but it was seen as revolutionary, and bitterly opposed by many, at that time.2 The delayed “discovery” of the …

Outpatient drug safety: new steps in an old direction

Iatrogenic injury from adverse drug events (ADEs) is a common and often preventable problem in modern medical practice. Attention to this problem has focused on the inpatient hospital setting and healthcare professionals. However, most medication is prescribed and used outside of hospitals and is managed by patients or lay caregivers in homes or workplaces. To address the public health problem of outpatient drug safety, interventions to prevent adverse events must recognize the central role of the patient in medication management and environmental factors specific to the outpatient setting. Lessons and techniques from the field of injury prevention should guide the development and implementation of safety interventions. First, Haddon's phase-factor matrix can be used to help conceptualize outpatient drug safety interventions. Second, interventions to improve outpatient drug safety should be patient-centered and extend beyond patient education to include engineering innovations and enforcement strategies. Third, the sustainability of active versus passive interventions should be considered when choosing safety interventions.