Comparisons of Food and Drug Administration and European Medicines Agency risk management implementation for recent pharmaceutical approvals: report of the International Society for Pharmacoeconomics and outcomes research risk benefit management working group.

OBJECTIVE: 1) To compare the Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's (EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products. METHODS: FDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs. RESULTS: We identified 95 drugs on FDA's REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%). CONCLUSIONS: Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.

Adverse drug reactions: when the risk becomes a reality for patients.

Communications about the safety of medicines are complex and generally poorly performed. Discussions may not be initiated by healthcare professionals and the lack of a 'common language' to express risk can cause confusion. In the event of a serious adverse drug reaction, prior failures in communication can cause difficulties, and patients may fail to receive adequate information about the nature of their experience. How to communicate openly with patients in order to minimize distrust and maximize future benefits from medicines requires exploration.

Challenges of drug risk communications in the Philippines.

Risk communication in the context of patient care is about conveying balanced information on benefit and risk of medical products and procedures and developments in health. It is an integral part of pharmacovigilance and healthcare communications and involves stakeholders such as regulators, industry, health professionals and patients. In the Philippines, many factors can interfere with effective risk communication and affect the safety of patients when medicinal products are used: poverty, literacy, age, social media, practice and behaviour of health professionals, industry marketing, patient expectations and product quality. These factors must be taken into consideration when formulating effective risk communications to ensure patient safety.

Protecting the people?: risk communication and the chequered history and performance of bureaucracy.

The history and characteristics of bureaucracy1 are examined with a view to understanding the impact of the bureaucratic mindset on medicines' regulation, the pharmaceutical industry and healthcare delivery with a focus on risk communication, pharmacovigilance and patient safety. Controversies and allegations relating to common, negative effects of bureaucratic regulatory and management systems are reviewed and examples of creative and effective practice provided. Strategic directions and specific actions for reform are proposed.2.

Risk Communication and the Pharmaceutical Industry: what is the reality?

Risk communication is central to the risk management strategy of a pharmaceutical company. Pharmaceutical companies primarily communicate risk through labelling tools such as the Summary of Product Characteristics (SmPC), package insert, patient information leaflet (PIL) and the carton, which are currently regulated based on templates such as those of the EU. Recent research raises concern about how effective the SmPC is alone in communicating risk. There is some evidence that carton design can influence risk comprehension. Processes to check new trade names cannot be confused with existing names is a simple measure to mitigate one form of risk. Given the central role and the vast amount of resource that is consumed, it is surprising there has not been extensive original research to see whether product information such as the SmPC is a good tool for communicating risk. Recently, EU agencies have assessed the communication value of the PIL and revised the template and guidelines. However, no evaluation of user testing has been conducted at European level since the introduction of these new requirements. As regards 'Dear Healthcare Professional Communications', there is inconsistent evidence about their ability to change patient and physician behaviour. There is a dearth of evidence about what sort of communications materials are the most effective under which circumstances. The use of templates restricts the flexibility of companies to adapt their risk messages to their targets. Effective communication requires understanding how different audiences perceive the message and what the fundamental drivers are for altering patient and prescriber behaviour to be safer. This requires careful consideration of the relationship between risk communication, perception and management. However, the focus of a company's risk communication plan is normally on the International Conference on Harmonisation (ICH) regions and their regulations. Although the same regulatory tools are used globally, we are not aware of any research into their effectiveness outside the ICH regions. What listed companies can communicate about benefits and risks is strongly influenced by the obligations of companies to the market and investors. There needs to be internal coordination for simultaneous release. Internal communications about significant issues should be restricted to those who know how to manage the risk of insider dealing from internal communications that may later be made public. Unfortunately, there is evidence that some companies do not have a cohesive strategy for communicating risk which should take into account all forms of promotional material and company-sponsored information sources on the Internet. A pharmaceutical company is not the only stakeholder responsible for communicating risks on their products. However, the relative roles and responsibilities of all relevant stakeholders are not defined and are often unclear. This means it is difficult to evaluate whether a company's actions might be duplicative or inefficient. We recommend that companies have a dedicated communications group whose role is to coordinate the company's communications strategy mapped to objectives that have been agreed with key stakeholders apart from just regulatory agencies. This same group can assess effectiveness of the communications, monitor audience reaction and adjust the communication strategy accordingly.

Risk perception and communication in sub-Saharan Africa.

In this narrative review, a brief summary of theoretical approaches to risk perception is followed by an analysis of some of the special factors influencing risk perception and risk communication in sub-Saharan Africa. Examples of recent and emergent local medicines and vaccine controversies in several countries are given along with evidence and analysis of how they were managed. These demonstrate, among other things, the extent to which ethnic, religious and cultural issues influence popular perception, and the power of rumour and anecdote in shaping public opinion and official responses to events. Where safety monitoring systems exist, they are in their infancy, with limited capacity for data collection, credible scientific review, effective public communication and robust crisis management. Although increasing democratic freedoms, including less restricted media, and evolving health systems are addressing the challenges and give hope for further progress, there are still deep and intractable issues that inhibit transparent and effective risk communication and stand in the way of African populations comprehending medicines and their risks in safer and more balanced ways. Some proposals for future change and action are offered, including the pursuit of a deeper understanding of local and national values, assumptions and beliefs that drive risk perception; tailoring public health planning and communications to specifically-targeted regions and populations; strengthening of safety surveillance and data-collection systems; giving higher priority to medicines safety issues in healthcare training and public education.

Incidence and economic burden of adverse drug reactions among elderly patients in Ontario emergency departments: a retrospective study.

BACKGROUND: The rapid rise in the availability and use of pharmaceutical agents, and particularly polypharmacy, directly increases the risk for patients to experience adverse drug reactions (ADRs). There are few studies on the overall incidence and costs of ADRs. OBJECTIVE: The aim of this study was to estimate the incidence and costs of emergency department (ED) visits related to ADRs for patients greater than 65 years of age using administrative data, and to describe risk factors for experiencing severe ADRs. METHODS: We employed a retrospective cohort design based on population-based healthcare administrative clinical databases. Identification of ADR-related ED visits from the administrative database was based on International Classification of Diseases, 10th Revision-Canadian Enhancement (ICD-10-CA) codes for each ED visit. The incidence and costs of ADR-related ED visits and subsequent hospital admissions were estimated for all adults aged 66 years and above for the period April 2003-March 2008. Costs were standardized and reported in 2008 Canadian dollars. Logistic regression was used to detect risk factors for severe ADRs. RESULTS: Approximately 0.75% of total annual ED visits among adults aged 66 years and above were found to be ADR-related, and among these patients 21.6% were hospitalized. In 2007, the cost of ADR-related visits was $333 per ED visit and $7528 per hospitalization for a total annual cost of $13.6 million in Ontario, or an estimated $35.7 million in Canada. Severe ADRs were associated with sex, age, comorbid disease burden, multiple drugs, multiple pharmacies, newly prescribed drugs, recent ED visit, recent hospitalization and long-term care (LTC) residence. CONCLUSIONS: ADRs are an important public health issue that threaten the safety of drug therapy and results in significant economic burden to the healthcare system. ED visits related to ADRs may be underestimated in retrospective studies using administrative data compared with prospective studies. Further research is needed to better understand the risk of experiencing severe ADRs among LTC residents.

Comparative evaluation of three clinical decision support systems: prospective screening for medication errors in 100 medical inpatients.

PURPOSE: Clinical decision support systems (CDSS) are promoted as powerful screening tools to improve pharmacotherapy. The aim of our study was to evaluate the potential contribution of CDSS to patient management in clinical practice. METHODS: We prospectively analyzed the pharmacotherapy of 100 medical inpatients through the parallel use of three CDSS, namely, Pharmavista, DrugReax, and TheraOpt. After expert discussion that also considered all patient-specific clinical information, we selected apparently relevant alerts, issued suitable recommendations to physicians, and recorded subsequent prescription changes. RESULTS: For 100 patients with a median of eight concomitant drugs, Pharmavista, DrugReax, and TheraOpt generated a total of 53, 362, and 328 interaction alerts, respectively. Among those we identified and forwarded 33 clinically relevant alerts to the attending physician, resulting in 19 prescription changes. Four adverse drug events were associated with interactions. The proportion of clinically relevant alerts among all alerts (positive predictive value) was 5.7, 8.0, and 7.6%, and the sensitivity to detect all 33 relevant alerts was 9.1, 87.9, and 75.8% for Pharmavista, DrugReax and TheraOpt, respectively. TheraOpt recommended 31 dose adjustments, of which we considered 11 to be relevant; three of these were followed by dose reductions. CONCLUSIONS: CDSS are valuable screening tools for medication errors, but only a small fraction of their alerts appear relevant in individual patients. In order to avoid overalerting CDSS should use patient-specific information and management-oriented classifications. Comprehensive information should be displayed on-demand, whereas a limited number of computer-triggered alerts that have management implications in the majority of affected patients should be based on locally customized and supported algorithms.

A prospective analysis of the preventability of adverse drug reactions reported in Sweden.

PURPOSE: Adverse drug reactions (ADRs) are a major patient safety issue, and a substantial proportion of ADRs are, in fact, preventable. The aim of this study was to describe the proportion and pattern of preventable ADRs in spontaneously reported suspected ADRs and to study the feasibility of using data from an ADR reporting system for this purpose. METHODS: All reports of ADRs, except those in which a vaccine was the suspected drug, submitted to the regional pharmacovigilance center of southeastern Sweden between 2008 and 2009 were analyzed. Causality between the suspected ADR and the medication was assessed using the World Health Organization (WHO) criteria, and preventability was assessed using Hallas criteria. RESULTS: During the study period, 1,290 ADRs were received and 1,255 were classified as having at least a possible causality between a reaction and a drug. Of these, 172 (14%) ADRs were considered preventable, 35 (20%) were classified as definitely preventable, and 137 (80%) as possibly preventable. Of all preventable ADRs, 96 (56%) were related to prescribing, 35 (20%) to administration, and 41 (24%) to clinical and laboratory monitoring of treatment. Warfarin, oxycodone, and ioversol were the most common drugs with preventable ADRs. CONCLUSIONS: This study found that a substantial part of reported ADRs are preventable. Most of these are related to drug prescription, suggesting that interventions aiming to reduce preventable ADRs should focus on this process. Moreover, systems for ADR reporting may be useful in the mission of reducing the unsafe use of drugs.

Anticoagulation-associated adverse drug events.

PURPOSE: Anticoagulant drugs are among the most common medications that cause adverse drug events (ADEs) in hospitalized patients. We performed a 5-year retrospective study at Brigham and Women's Hospital to determine clinical characteristics, types, root causes, and outcomes of anticoagulant-associated ADEs. METHODS: We reviewed all inpatient anticoagulant-associated ADEs, including adverse drug reactions (ADRs) and medication errors, reported at Brigham and Women's Hospital through the Safety Reporting System from May 2004 to May 2009. We also collected data about the cost associated with hospitalizations in which ADRs occurred. RESULTS: Of 463 anticoagulant-associated ADEs, 226 were medication errors (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both a medication error and ADR. Seventy percent of anticoagulant-associated ADEs were potentially preventable. Transcription errors (48%) were the most frequent root cause of anticoagulant-associated medication errors, while medication errors (40%) were a common root cause of anticoagulant-associated ADRs. Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. After an anticoagulant-associated ADR, most hospitalization expenditures were attributable to nursing costs (mean $33,189 per ADR), followed by pharmacy costs (mean $7451 per ADR). CONCLUSION: Most anticoagulant-associated ADEs among inpatients result from medication errors and are, therefore, potentially preventable. We observed an elevated 30-day mortality rate among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further quality improvement efforts to reduce anticoagulant-associated medication errors are warranted to improve patient safety and decrease health care expenditures.

Safety assessment of potentially inappropriate medications use in older people and the factors associated with hospital admission.

PURPOSE: Potentially Inappropriate Medications (PIM) use in elderly people may be responsible for the development of Adverse Drug Reaction (ADR) which, when severe, leads to hospital admissions. OBJECTIVES: to estimate the prevalence of elderly who had used PIM before being admitted to hospital admission and to identify the risk factors and the hospitalizations related to ADR arising from PIM. METHODS: A descriptive and cross-sectional study was performed in the internal medicine ward of a teaching hospital (Brazil), in 2008. With the aid of a validated form, patients aged ≥ 60 years, with length of hospital stay ≥ 24 hours, were interviewed about drugs taken prior to the hospital admission and the complaints/reasons for hospitalization. RESULTS: 19.1% (59/308) of older patients had taken PIM before hospital admission and in 4.9%; there were a causal relation between the PIM taken and the complaint reported. PIM responsible for admissions were: amiodarone, amitriptyline, cimetidine, clonidine, diazepam, digoxin, estrogen, fluoxetine, lorazepam, short-acting nifedipine and propranolol. 47.0% of the clinical manifestations of PIM-related ADR were: dizziness, fatigue, digoxin toxicity and erythema. Only polypharmacy was detected as a risk factor for the occurrence of ADR of PIM (p = 0.02). CONCLUSION: PIM use in elderly people is not a risk factor for ADR-related hospital admission. Probably, severe ADR, which lead to hospitalizations of older people, can be explained by idiosyncratic response or the predisposition of these patients to develop adverse drug events, whether or not drugs are classed as PIM.

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Signal detection of methylphenidate by comparing a spontaneous reporting database with a claims database.

Data mining is critical for signal detection in pharmacovigilance systems. In this study, we compared signals between spontaneous reporting data and health insurance claims data for a socially issued drug, methylphenidate. We implemented data-mining tools for signal detection in both databases: Reporting Odds Ratios (ROR), Proportional Reporting Ratios (PRR), Chi-squared test, and Information Component (IC), in addition to a Relative Risk (RR) tool in the claims database. The claims database generated 15, 15, 36, 1, and 1 adverse drug reactions (ADRs) by ROR, PRR, chi-square, IC, and RR, respectively. The World Health Organization (WHO) spontaneous database generated 91, 91, 137, and 96 ADRs by ROR, PRR, chi-square, and IC, respectively. We found seven potential matching associations from the claims and WHO databases, but only one of them was present in the Korean spontaneous reporting database. In Korea, spontaneous reporting is still underreported and there is a small amount of data for Koreans. Signal comparison between the claims and WHO databases can provide additional regulatory insight.

Epigenetic screening in product safety assessment: are we there yet?

There has been a growing concern that epigenetic events, that is, heritable changes in gene expression superimposed on DNA nucleotide sequences, may be involved in chemically and/or nutritionally mediated adverse health outcomes, such as reproductive toxicity and cancer. This concern has been driven by an increasing number of studies reporting toxicant-induced alterations to the epigenome in the form of changes in DNA methylation, histone/chromatin remodeling, and altered expression of non-coding RNAs. These three major mechanisms of epigenetic modifications may have coordinated, independent, or potentially antagonistic influences on gene expression. Complicating this understanding is the incomplete understanding of the normal state and dynamic variation of the epigenome, which differs widely between cells, tissues, developmental state, age, strain, and species. This review serves as a framework to outline characteristics composing an ideal epigenetic screen(s) for hazard identification in product safety assessment. In order to implement such a screen, first there needs to be a better understanding of adaptive versus adverse changes in the epigenome, which includes identification of robust and reproducible causal links between epigenetic changes and adverse apical end points, and second development of improved reporter assay tools to monitor such changes. An ideal screen would be in vitro-based, medium- to high-throughput, and assess all three branches of epigenome control (i.e. methylation, histone modifications, non-coding RNAs), although also being quantitative, objective, portable (i.e. lab to lab), and relevant to humans.

Comprehensive assessment of treatment related problems in hospitalized medicine patients in Jordan.

OBJECTIVES: The aim of this study was to identify the prevalence and characteristics of treatment related problems (TRPs) in hospitalized internal medicine patients in Jordan as well as to identify diseases and drugs associated with each specific TRP. We have also aimed at investigating physicians' acceptance of recommendations made by clinical pharmacist and to identify the outcomes of pharmacist interventions. SETTING: Internal medicine department of a general hospital in Jordan. METHODS: We have utilized a systematic, prospective, bedside, comprehensive clinical assessment approach that allowed us to effectively identify, communicate and follow up TRPs. MAIN OUTCOME MEASURES: prevalence and nature of identified TRPs, clinical significance of TRPs, associated diseases and drugs and clinical outcomes of clinical pharmacist interventions. RESULTS: 402 patients were included in the study. The average number of the identified TRPs was 9.35. Fifty-three percent of identified TRPs were classified as major and 28% were classified as moderate. Ninety-one percent of the recommendations were accepted by physicians. Efficacy related problems were the most common TRP category followed by safety related problems and indication related problems. Sixty-four percent of the TRPs were resolved or prevented through the clinical pharmacist intervention. CONCLUSIONS: We have found that prevalence of TRPs is substantially high among patients hospitalized at the internal medicine department. TRPs related to Dosage regimens, untreated conditions, patient monitoring, drug interactions, and drug choices were the most common. Most of TRPs identified by pharmacists were clinically significant. Pharmacists' interventions contributed substantially to the resolving of many of the identified TRPs. Patients suffering from higher number of medical conditions and receiving higher number of medications should be given the priority for clinical pharmacy service in hospitalized internal medicine patients.

Impact of erythropoiesis-stimulating agent prescribing at an Asian cancer center, after release of safety advisories.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) provide symptom relief and decrease blood transfusion support among patients with chemotherapy-induced anemia. However, due to increased cardiovascular events associated with off-labeled usage of ESAs, the FDA incorporated black box warnings in 2007 to include the following key points: (a) ESAs should be used only to treat anemia due to concomitant chemotherapy of a noncurative intent and (b) target hemogloblin level should not exceed 12 g/dL. Thus, this study was designed to compare the prescribing of epoetin alfa at National Cancer Centre Singapore before and after FDA black box updates. The secondary objective of this study was to evaluate the appropriateness of efficacy and toxicity monitoring of epoetin alfa. METHODS: This was a retrospective, single-centered, drug utilization review. Patients who received at least one dose of epoetin alfa were included in this study. Utilization of epoetin alfa was segregated into two time periods: January 1, 2005 to October 15, 2007 (S1, Pre-safety advisories changes) and October 16, 2007 to December 10, 2009 (S2, Post-safety advisories changes). RESULTS: A total of 171 patients were prescribed epoetin alfa at NCCS during the two time periods. However, only 139 patients were eligible for analysis, with 91 and 48 patients in S1 and S2 respectively. After safety advisory changes, there were more (18.2%) metastatic patients and fewer (19.1%) patients with cardiovascular co-morbidities who were prescribed epoetin alfa, the mean hemogloblin level when epoetin alfa was initiated was lowered by 0.46 g/dL, more (43%) dose adjustments were made for 'excessive' responders and more (40.7%) patients had fewer blood transfusions after epoetin alfa therapy (p < 0.05). However, blood pressure control, iron studies, and supplementation did not improve (p > 0.05). CONCLUSION: This study suggested that oncologists have generally adopted the new ESA safety warnings and adjusted prescribing habits.