Are novel drugs more risky for patients than less novel drugs?

The Food and Drug Administration has accelerated the approval of therapeutically novel drugs so that patients have faster access to innovative drug therapies. Little research, however, has examined the variation in risks among therapeutically novel and less novel drugs. Do drugs that represent greater novelty also entail greater risks for patients? This paper uses post-marketing drug safety surveillance data from the FDA to examine the adverse drug reactions (ADRs) associated with novel and less novel drugs. Negative binomial regressions are used to examine the impact of a drug's FDA novelty rating on its ADR count controlling for differences in drug utilization, the conditions being treated, disease characteristics, patient characteristics, drug review times, and year-specific effects. Results show that drugs deemed novel by the FDA are associated with a greater number of serious drug reactions, including those that result in hospitalization and death, than less novel drugs. These results suggest that novel drugs pose greater risk of serious ADRs for patients relative to less novel drugs.     

药物不良反应自觉报告制度的发展与作用

避孕药物和器具的效益与危险性和其它治疗药物或医疗器具一样,须要接受广泛的市场后监察,及时发现和淘汰对人体具有严重危害的产品。许多国家建立了全国性药物监察网络。自觉报告制度是一种费用低、效果好的市场后安全性监察实用方法。重点监察项目则在样本人群中深入调查研究药物或器具与不良反应事故的因果关系;医药刊物也是报道不良反应案例的另一个重要信息资源。从生殖健康前景看,开展药物警戒学研究,设立全国性监察体制,加强对节育技术合并症或不良反应的市场后监察,将是评价影响避孕药具使用和提高计划生育服务质量的重要措施。     

基于电子病历的ADR知识发现与应用模型研究

利用电子病历数据提高药品不良反应(ADR)的主动监测水平,为药品上市后的安全监测和个性化预警服务提供可借鉴的方法。首先提出了基于电子病历的ADR知识发现与应用模型的总体框架,然后分别对模型中涉及的基本要素和信息活动进行详细的解释和阐述;最后以痰热清注射液为例,运用DIKW层级体系探讨引起疚热清注射液疑似过敏反应的影响因素,揭示了药物不良反应“数据一信息一知识一智慧”信息链中的信息活动规律,为药品不良反应的研究与管理提供决策支持。     

Pharmacoepidemiology in pre-approval clinical trial safety monitoring

Applications of pharmacoepidemiology to the pre-approval safety monitoring of investigational drugs are examined and compared with the post-approval applications. Pre-approval epidemiologic assessments of drug safety can complement clinical assessments of rare, serious adverse events occurring in open label uncontrolled clinical trials. Applications include retrospective identification of patient risk factors for adverse drug events and incidence comparisons based on historical controls. While similar in concept to applications of pharmacoepidemiology in the analyses of uncontrolled open label post-marketing surveillance studies, answers are often needed in days rather than weeks and the emphasis is on whether human studies can continue. Advance planning of historical data sources is essential as is an effective clinical trial data management system. Implications for methodologic research and for drug development are discussed.     

Use of big data for drug development and for public and personal health and care

The use of data analytics across the entire healthcare value chain, from drug discovery and development through epidemiology to informed clinical decision for patients or policy making for public health, has seen an explosion in the recent years. The increase in quantity and variety of data available together with the improvement of storing capabilities and analytical tools offer numerous possibilities to all stakeholders (manufacturers, regulators, payers, healthcare providers, decision makers, researchers) but most importantly, it has the potential to improve general health outcomes if we learn how to exploit it in the right way. This article looks at the different sources of data and the importance of unstructured data. It goes on to summarize current and potential future uses in drug discovery, development, and monitoring as well as in public and personal healthcare; including examples of good practice and recent developments. Finally, we discuss the main practical and ethical challenges to unravel the full potential of big data in healthcare and conclude that all stakeholders need to work together towards the common goal of making sense of the available data for the common good.     

A statistical methodology for drug-drug interaction surveillance

Interaction between drug substances may yield excessive risk of adverse drug reactions (ADRs) when two drugs are taken in combination. Collections of individual case safety reports (ICSRs) related to suspected ADR incidents in clinical practice have proven to be very useful in post-marketing surveillance for pairwise drug--ADR associations, but have yet to reach their full potential for drug-drug interaction surveillance. In this paper, we implement and evaluate a shrinkage observed-to-expected ratio for exploratory analysis of suspected drug-drug interaction in ICSR data, based on comparison with an additive risk model. We argue that the limited success of previously proposed methods for drug-drug interaction detection based on ICSR data may be due to an underlying assumption that the absence of interaction is equivalent to having multiplicative risk factors. We provide empirical examples of established drug-drug interaction highlighted with our proposed approach that go undetected with logistic regression. A database wide screen for suspected drug-drug interaction in the entire WHO database is carried out to demonstrate the feasibility of the proposed approach. As always in the analysis of ICSRs, the clinical validity of hypotheses raised with the proposed method must be further reviewed and evaluated by subject matter experts.     

大数据时代的药品安全主动监测:对照选择的挑战与机遇

电子医疗数据已成为大数据时代开展药品安全主动监测的重要资源。基于此确认药品与不良事件是否存在关联，要回归传统的流行病学研究设计，选取恰当的对照进行对比。本文主要阐述不同对照选取的原理、适用情形，介绍、评价并比较各种对照选取的思路与参数，引入对照选择批量化实现的进展性成果，以期为我国利用电子医疗数据开展上市后药品安全性监测提供方法学参考。     

Post-marketing surveillance of licensed medicinal and other products

The term post-marketing surveillance is a term which should be applied to all forms of monitoring marketed drugs for all aspects of their potential to produce adverse reactions. Post-marketing surveillance to identify dangers arising from the use of medicinal products is undertaken to detect both pharmaceutical and medical hazards. Pharmaceutical hazards are sought by sampling products for evidence of contamination, mislabelling and loss of potency. Four methods currently used for the detection of medical hazards are:--(1) Quality tests, performed on batches of new products which cannot be fully evaluated by physical or chemical means (eg vaccines and blood products). (2) The "yellow card system", in which the Committee on Safety of Medicines asks doctors spontaneously to report all suspected adverse reactions to drugs. (3) Monitoring the release of a new drug, which is subject to certain restrictions that oblige doctors to feed back information to the regulatory authority. (4) Literature screening, which must be regarded as important in any comprehensive scheme of post-marketing surveillance. In addition two further methods of surveillance are described under (5) and (6):--(5) Local investigations such as intensive monitoring studies on patients receiving a particular treatment in a district general hospital or in its catchment area have been conducted in a number of centres and are cheap and successful and generate local interest and co-operation. (6) Various schemes have been proposed for national recorded release or event monitoring in which extensive studies of the clinical progress of many patients receiving the new drug are monitored.     

Patient-reported outcomes: pathways to better health,better services,and better societies

While the use of PROs in research is well established, many challenges lie ahead as their use is extended to other applications. There is consensus that health outcome evaluations that include PROs along with clinician-reported outcomes and administrative data are necessary to inform clinical and policy decisions. The initiatives presented in this paper underline evolving recognition that PROs play a unique role in adding the patient perspective alongside clinical (e.g., blood pressure) and organizational (e.g., admission rates) indicators for evaluating the effects of new products, selecting treatments, evaluating quality of care, and monitoring the health of the population. In this paper, we first explore the use of PRO measures to support drug approval and labeling claims. We critically evaluate the evidence and challenges associated with using PRO measures to improve healthcare delivery at individual and population levels. We further discuss the challenges associated with selecting from the abundance of measures available, opportunities afforded by agreeing on common metrics for constructs of interest, and the importance of establishing an evidence base that supports integrating PRO measures across the healthcare system to improve outcomes. We conclude that the integration of PROs as a key end point within individual patient care, healthcare organization and program performance evaluations, and population surveillance will be essential for evaluating whether increased healthcare expenditure is translating into better health outcomes.     

疫苗上市后安全性的准实时主动监测

疫苗上市后安全性监测是及时发现风险信号以确保疫苗安全的必要措施,包括被动监测与主动监测。其中,主动监测能够全面、持续的收集免疫接种后不良事件,及时发现并验证疫苗安全性信号,已经成为未来上市后安全性监测的主要发展趋势。随着信息时代的到来,主动监测可通过纵向链接多源电子医疗数据库开展分析,数据的快速传输与定期更新,使得接近...     

The antimicrobial resistance containment and surveillance approach--a public health tool

Antimicrobial drug resistance (AMR) is widely recognized as a global public health threat because it endangers the effectiveness of treatment of infectious diseases. In 2001 WHO issued the Global Strategy for Containment of Antimicrobial Resistance, but it has proved difficult to translate the recommendations of the Global Strategy into effective public health actions. The purpose of the Antimicrobial Resistance Containment and Surveillance (ARCS) approach is to facilitate the formulation of public health programmes and the mobilization of human and financial resources for the containment of AMR. The ARCS approach highlights the fundamental link between rational drug use and containment of AMR. Clinical management of human and animal infections should be improved through better disease control and prevention, high quality diagnostic testing, appropriate treatment regimens and consumer health education. At the same time, systems for supplying antimicrobial drugs should include appropriate regulations, lists of essential drugs, and functional mechanisms for the approval and delivery of drugs. Containment of AMR is defined in the ARCS approach as the continuous application of this package of core interventions. Surveillance of the extent and trends of antimicrobial resistance as well as the supply, selection and use of antimicrobial drugs should be established to monitor the process and outcome of containment of AMR. The ARCS approach is represented in the ARCS diagram (Fig. 2) which provides a simplified, but comprehensive illustration of the complex problem of containment and monitoring of AMR.     

Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide

A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system.     

Datenbanken als Grundlage für Monitoring-Systeme in der Arzneimittelsicherheit

Clinical trials only allow for a limited assessment of adverse drug reactions (ADRs) due to their restricted number of patients, their short duration, and their narrow inclusion criteria. To assess potential ADRs in the population actually treated after drug approval, different systems for signal generation such as spontaneous reporting systems have been established and are required by drug laws in many countries. As of today epidemiological methods for signal confirmation for rare adverse events or events with long induction periods use record linkage databases such as the United Health Care (Ingenix) in the USA or the practice databases such as the General Practice Research Database in Great Britain. However, this approach also has its limitations. This type of database will be presented in this paper. In addition, databases operated by German public health insurance will be described. The topic of linking different data sources in Germany to support pharmaco-vigilance activities will be addressed.     

Connecting pre-marketing clinical research and medical practice: opinion-based study of core issues and possible changes in drug regulation

OBJECTIVES: To identify core issues that contribute to the gap between pre-marketing clinical research and practice as seen from the perspective of medical practice, as well as possible changes and potential barriers for dosing this gap. METHODS: Interviews with 47 physicians and pharmacists who were liaised to drug regulation through their role in the pre- and post-marketing shaping of new cardiovascular drugs. Data were analyzed using methods of grounded theory and analytical evaluations. RESULTS: Six core issues were identified that referred to the standards in drug regulation, the organization of the regulatory system, and conflicting interests. Pre-marketing trials should focus more on populations and research questions relevant to medical practice. In particular, variability in drug responses between subgroups of patients and demonstration of effectiveness should become major principles in drug regulation. An interactive post-marketing process in which public interests are represented was considered necessary to further guide research and development according to the needs in daily practice. Strategies for change could be applied within the present system of drug regulation, or affect its basic principles. Regulatory authorities were primarily identified to initiate changes, but many other parties should be involved. Barriers for change were identified regarding differences in interests between parties, organizational matters, and with respect to broader healthcare policies. CONCLUSIONS: Based on the respondents' opinions, there is a need to focus regulatory standards more on the needs in medical practice. Therefore, regulatory authorities should further develop their influence in the pre- and post-marketing drug development process, together with other parties involved, in order to bridge the gap between clinical research and medical practice.     

Exploring sociodemographic and economic factors that promote adverse drug reactions reporting by patients

BackgroundAdverse drug reactions (ADRs) are recognized as a leading cause of morbidity and mortality, and an important cost factor to health systems. Patient reporting of ADRs has emerged as an important topic in recent years but reporting rates are still low in many countries.ObjectiveTo explore different countries’ sociodemographic and economic features as explanatory factors for population ADRs reporting, including the propensity of patients’ reporting to pharmacovigilance authorities.MethodsCross-sectional observational design. A data set of 42 global sociodemographic and economic factors for 44 countries were retrieved, as to analyse statistical associations between these factors and the patient reporting rate of ADRs. Multivariate logistic regression models were designed to identify the predictive covariables.ResultsHealth investment indicators, such as per capita public health expenditure, hospital bed density and under five mortality rate were the relevant factors responsible to discriminate between countries that have higher patient reporting rates.ConclusionsThis study shows that healthcare investment-related factors help explain the propensity of patients to report suspected ADRs, while pharmacovigilance features were not directly associated with higher patient participation in drug safety mechanisms. Although general, these results point a direction in further policy making to improve resources allocation concerning the promotion of patients’ participation.     

147份药品不良反应报告分析

目的为了给以后的临床用药作参考依据,该院对药品不良反应（ADR）做系统的整理和分析,以便了解这类事件发生的具体情况。方法该院对2013年8月—2014年7月一年内上报的147份ADR报告进行数据分析。结果该院ADR涉及的药品以抗病毒及抗菌药物为主;发生的器官或系统损害以皮肤及其附件损害最为突出。结论加强ADR监测工作是保证患者安全、合理用药的有效措施。     

Breaking the Bank: Three Financing Models for Addressing the Drug Innovation Cost Crisis

Background

The introduction of innovative specialty pharmaceuticals with high prices has renewed efforts by public and private healthcare payers to constrain their utilization, increase patient cost-sharing, and compel government intervention on pricing. These efforts, although rational for individual payers, have the potential to undermine the public health impact and overall economic value of these innovations for society. The emerging archetypal example is the outcry over the cost of sofosbuvir, a drug proved to cure hepatitis C infection at a cost of $84,000 per person for a course of treatment (or $1000 per tablet). This represents a radical medical breakthrough for public health, with great promise for the long-term costs associated with this disease, but with major short-term cost implications for the budgets of healthcare payers.

Objectives

To propose potential financing models to provide a workable and lasting solution that directly addresses the misalignment of incentives between healthcare payers confronted with the high upfront costs of innovative specialty drugs and the rest of the US healthcare system, and to articulate these in the context of the historic struggle over paying for innovation.

Discussion

We describe 3 innovative financing models to manage expensive specialty drugs that will significantly reduce the direct, immediate cost burden of these drugs to public and private healthcare payers. The 3 financing models include high-cost drug mortgages, high-cost drugs reinsurance, and high-cost drug patient rebates. These models have been proved successful in other areas and should be adopted into healthcare to mitigate the high-cost of specialty drugs. We discuss the distribution of this burden over time and across the healthcare system, and we match the financial burden of medical innovations to the healthcare stakeholders who capture their overall value. All 3 models work within or replicate the current healthcare marketplace mechanisms for distributing immediate high-cost events across multiple at-risk stakeholders, and/or encouraging active participation by patients as consumers.

Conclusion

The adoption of these 3 models for the financing of high-cost drugs would ameliorate decades-long economic conflict in the healthcare system over the value of, and financial responsibility for, drug innovation.     

欧洲传染病预防与控制中心监测系统分析与启示

文章介绍了欧洲传染病预防与控制中心基本情况,及其传染病监测系统发展过程、系统界定、监测方法、实验室数据融合、监测标准化与监测经验共享等。建议我国应强化各层级之间监测交流,实现信息共享;提高监测效率,增加监测产出;定期对传染病和突发公共卫生事件监测系统进行评价,以期提高我国突发公共卫生事件应急能力     

Is Australia's national medicines policy failing? The case of COX-2 inhibitors.

Australia has a National Medicines Policy with aims that include quality use of medicines, but policy stakeholders failed to protect Australia from the COX-2 (cyclo-oxygenase-2) inhibitor disaster. Drug regulators did not warn prescribers appropriately about potential cardiovascular risks. The Pharmaceutical Benefits Scheme did not limit unjustified drug expenditures on COX-2 inhibitors. Drug companies ran intense and misleading promotional campaigns on COX-2 inhibitors without adequate controls. Independent drug information was insufficient to counter the effects of the millions of dollars spent on advertising. Core elements of the National Medicines Policy--in particular the drug approval process, the post-marketing surveillance system, the control of drug promotion, and the quality of independent drug information--require major reappraisal if we want to avoid similar disasters in the future.