Innovation in Pharmacovigilance: Use of Artificial Intelligence in Adverse Event Case Processing.

Automation of pharmaceutical safety case processing represents a significant opportunity to affect the strongest cost driver for a company's overall pharmacovigilance budget. A pilot was undertaken to test the feasibility of using artificial intelligence and robotic process automation to automate processing of adverse event reports. The pilot paradigm was used to simultaneously test proposed solutions of three commercial vendors. The result confirmed the feasibility of using artificial intelligence-based technology to support extraction from adverse event source documents and evaluation of case validity. In addition, the pilot demonstrated viability of the use of safety database data fields as a surrogate for otherwise time-consuming and costly direct annotation of source documents. Finally, the evaluation and scoring method used in the pilot was able to differentiate vendor capabilities and identify the best candidate to move into the discovery phase.

Is pharmacovigilance of biologicals cost-effective?

Pharmacovigilance is an essential part of the post-marketing surveillance of new biologicals. It not only requires a substantial investment of the marketing authorization holder but also of the clinical field to provide accurate safety information. Hence, does pharmacovigilance delivers value for money? This important question needs to be discussed in the light of regulatory requirements, value and cost.

Type I error probability spending for post-market drug and vaccine safety surveillance with binomial data.

Type I error probability spending functions are commonly used for designing sequential analysis of binomial data in clinical trials, but it is also quickly emerging for near-continuous sequential analysis of post-market drug and vaccine safety surveillance. It is well known that, for clinical trials, when the null hypothesis is not rejected, it is still important to minimize the sample size. Unlike in post-market drug and vaccine safety surveillance, that is not important. In post-market safety surveillance, specially when the surveillance involves identification of potential signals, the meaningful statistical performance measure to be minimized is the expected sample size when the null hypothesis is rejected. The present paper shows that, instead of the convex Type I error spending shape conventionally used in clinical trials, a concave shape is more indicated for post-market drug and vaccine safety surveillance. This is shown for both, continuous and group sequential analysis.

The Japanese Postmarketing Adverse Event Relief System: A Confluence of Regulatory Science, the Legal System, and Clinical Pharmacology.

The Japanese Postmarketing Relief System provides for compensation to patients with adverse reactions, based on the acknowledgment that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries' healthcare systems.

Evaluation of the adverse events following immunizations surveillance system in Harare City, Zimbabwe, 2016: a descriptive cross sectional study.

INTRODUCTION: Vaccines safety are monitored by looking for Adverse Events Following Immunizations (AEFIs). A review of the 2014 Harare City consolidated monthly return form (T5) revealed that 28 AEFIs were seen in 2014. However, only 21 were reported through the system. We therefore evaluated the Harare City AEFI surveillance system to assess its usefulness. METHODS: A descriptive cross sectional study was conducted. Twenty one of 41 clinics were randomly selected and 51 health workers were randomly recruited. Interviewer administered questionnaires were used to collect data. Epi info 7 was used to generate frequencies, means and proportions. RESULTS: Out of 51 respondents, 50 (98%) knew the purpose of AEFI system, 48 (94%) knew at least two presenting symptoms of AEFIs and 39 (77%) knew the correct date of form submission to the next level. Receiving no feedback 24 (47.1%), fear of victimisation 16 (31.4%) and work overload 11 (21.6%) were the major reasons for under reporting. Eighty six percent perceived the system to be simple and 43 (84%) were willing to continue participating. Fifty three percent (27) reported taking public health actions (such as awareness campaigns & making follow ups) basing on AEFI data collected. All 46 reviewed forms were completely filled and submitted in time. All 21 clinics had written AEFI guidelines and case definitions. Only 14 of 21 clinics had adequately stocked emergency drugs. The total cost for a single notification was estimated at US$22.30. CONCLUSION: The system was useful, simple, acceptable, timely, stable, representative but costly. The good performance of the system reported in this evaluation could be attributed to high health worker knowledge. Following this evaluation, replenishment of out of stock drugs and follow up of missing 2014 AEFI feedback from MCAZ were done. In addition, making the system electronic is recommended.

Prevention of Hospital-Acquired Adverse Drug Reactions in Older People Using Screening Tool of Older Persons' Prescriptions and Screening Tool to Alert to Right Treatment Criteria: A Cluster Randomized Controlled Trial.

OBJECTIVES: To determine whether use of the Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) criteria reduces incident hospital-acquired adverse drug reactions (ADRs), 28-day medication costs, and median length of hospital stay in older adults admitted with acute illness. DESIGN: Single-blind cluster randomized controlled trial (RCT) of unselected older adults hospitalized over a 13-month period. SETTING: Tertiary referral hospital in southern Ireland. PARTICIPANTS: Consecutively admitted individuals aged 65 and older (N = 732). INTERVENTION: Single time point presentation to attending physicians of potentially inappropriate medications according to the STOPP/START criteria. MEASUREMENTS: The primary outcome was the proportion of participants experiencing one or more ADRs during the index hospitalization. Secondary outcomes were median length of stay (LOS) and 28-day total medication cost. RESULTS: One or more ADRs occurred in 78 of the 372 control participants (21.0%; median age 78, interquartile range (IQR) 72-84) and in 42 of the 360 intervention participants (11.7%; median age 80, IQR 73-85) (absolute risk reduction = 9.3%, number needed to treat = 11). The median LOS in the hospital was 8 days (IQR 4-14 days) in both groups. At discharge, median medication cost was significantly lower in the intervention group (€73.16, IQR €38.68-121.72) than in the control group (€90.62, IQR €49.38-162.53) (Wilcoxon rank test Z statistic = -3.274, P < .001). CONCLUSION: Application of STOPP/START criteria resulted in significant reductions in ADR incidence and medication costs in acutely ill older adults but did not affect median LOS.

Impact of rosiglitazone safety alerts on oral antidiabetic sales trends: a countrywide study in Portugal.

Pharmacovigilance systems are important to monitor the safety of on-market drugs after approval. The aim of this study was to assess the impact of rosiglitazone safety alerts on trends in the sale of rosiglitazone and other oral antidiabetic drugs. An ecological study was conducted, using temporally aggregated data and linking safety alerts to countrywide sales of all oral antidiabetic drugs in Portugal from January 2002 to December 2012. Sales figures for oral antidiabetic drugs marketed in Portugal were supplied by IMS Health Portugal with a breakdown by active substance and fixed combinations. The number of defined daily doses per 1000 inhabitants per day (DIDs) of each oral antidiabetic drug sold to the estimated diabetic population using oral antidiabetic drugs in Portugal was calculated. Particular attention was paid to the case of rosiglitazone, with the results being adjusted for changes in rosiglitazone reimbursement policies. A total of four safety alerts were issued about rosiglitazone. Rosiglitazone sales registered an increase of 32.9% (0.202 DIDs; P < 0.001) after the first alert (risk of macular oedema or worsening of pre-existent macular oedema) in January 2006. After subsequent alerts about cardiovascular risks, this trend was not, however, repeated and sales fell. Following the January 2006 and January 2008 safety alerts, rosiglitazone sales described a long-term downward trend, with decreases of 3.75% (-0023 DIDs; P > 0.05) and 0.24% (-0.001 DIDs; P > 0.05), respectively. It is important to promote the dissemination and publication of drug safety alerts.

Active Surveillance versus Spontaneous Reporting for First-Line Antiretroviral Medicines in Namibia: A Cost-Utility Analysis.

INTRODUCTION: Active surveillance pharmacovigilance is a systematic approach to medicine safety assessment and health systems strengthening, but has not been widely implemented in low- and middle-income countries. This study aimed to assess the cost effectiveness of a national active surveillance pharmacovigilance system for highly active antiretroviral therapy (HAART) compared with the existing spontaneous reporting system in Namibia. METHODS: A cost-utility analysis from a governmental perspective compared active surveillance pharmacovigilance to spontaneous reporting. Data from a sentinel site active surveillance program in Namibia from August 2012 to April 2013 was projected to all HIV-infected adults initiating HAART in Namibia. Costs (pharmacovigilance program, HAART, adverse event [AE] treatment), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs, dollars/QALY) were evaluated. Analysis was completed for (i) cohort analysis: a single cohort beginning HAART in 1 year in Namibia followed over their remaining lifetime, and (ii) population analysis: patients continued to enter and leave care and treatment over 10 years. RESULTS: For the cohort analysis, totals were US$21,267,902 (2015 US dollars) and 116,224 QALYs for care and treatment under active surveillance pharmacovigilance versus US$15,257,381 and 116,122 QALYs for care and treatment under spontaneous reporting pharmacovigilance, resulting in an ICER of US$58,867/QALY for active surveillance compared with spontaneous reporting pharmacovigilance. The population analysis ICER was US$4989/QALY. Results were sensitive to quality of life associated with AEs. CONCLUSION: Active surveillance pharmacovigilance was projected to be highly cost effective to improve treatment for HIV in Namibia. Active surveillance pharmacovigilance may be valuable to improve lives of HIV patients and more efficiently allocate health resources in Namibia.

Promoting adverse drug reaction reporting: comparison of different approaches.

OBJECTIVE: To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS: We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS: All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS: We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report.

[Pharmacovigilance in Germany : It is about time]. / Pharmakovigilanz in Deutschland : Es wird langsam Zeit.

BACKGROUND: Pharmacovigilance is defined as the activities relating to the detection, assessment, and prevention of adverse drug reactions (ADRs). Although its beginnings in Germany date back more than 50 years, a stagnation in this field has been observed lately. OBJECTIVES: Different tools of pharmacovigilance will be illustrated and the reasons for its stagnation in Germany will be elucidated. CURRENT DATA: Spontaneous reporting systems are an important tool in pharmacovigilance and are based on reports of ADRs from treating physicians, other healthcare professionals, or patients. Due to several weaknesses of spontaneous reporting systems such as underreporting, media bias, confounding by comorbidity or comedication, and due to the limited quality of the reports, the development of electronic healthcare databases was publicly funded in recent years so that they can be used for pharmacovigilance research. In the US different electronic healthcare databases were merged in a project sponsored by public means resulting in more than 193 million individuals. In Germany the establishment of large longitudinal databases was never conceived as a public duty and has not been implemented so far. Further attempts to use administrative healthcare data for pharmacovigilance purposes are severely restricted by the Code of Social Law (Section 75, Book 10). This situation has led to a stagnation in pharmacovigilance research in Germany. CONCLUSIONS: Without publicly funded large longitudinal healthcare databases and an amendment of Section 75, Book 10, of the Code of Social Law, the use of healthcare data in pharmacovigilance research in Germany will remain a rarity. This could have negative effects on the medical care of the general population.

Promoting adverse drug reaction reporting: comparison of different approaches / Promoção da notificação de reações adversas a medicamentos: comparação de estratégias

ABSTRACT OBJECTIVE To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report.

RESUMO OBJETIVO Descrever diferentes abordagens de promoção da notificação de reações adversas a medicamentos entre os profissionais de saúde, determinando o seu custo-eficácia. MÉTODOS Foram analisadas e comparadas estratégias adotadas pela Unidade de Farmacovigilância do Norte (Portugal) para promoção da notificação de reações adversas a medicamentos. As estratégias foram comparadas quanto ao número e relevância das notificações de reações adversas a medicamentos obtidas e quanto aos custos envolvidos. Os custos por notificação foram calculados somando os custos iniciais e os custos de manutenção de cada estratégia. Esses custos foram então divididos pelo número de notificações obtidas em cada intervenção, para avaliar o seu custo-eficácia. RESULTADOS Todas as abordagens aumentaram o número de notificações de reações adversas a medicamentos. O maior aumento foi observado com os protocolos (321 notificações de reações adversas a medicamentos ganhas, custando 1,96 € cada), seguidos pela primeira abordagem educacional (265 notificações, 20,31 € cada) e pela colocação de hyperlinks (136 notificações, 15,59 € cada). Com relação à gravidade das reações adversas a medicamentos, os protocolos foram a estratégia mais eficiente, custando 2,29 € cada notificação, seguida da colocação de hyperlinks (30,28 € cada, sem custos de manutenção). Quanto às reações adversas a medicamentos inesperadas, o melhor resultado pertenceu aos protocolos (5,12 € cada notificação), seguido por uma primeira abordagem educativa (38,79 € cada notificação). CONCLUSÕES Os autores recomendam a implementação de protocolos em outros centros de farmacovigilância. De fato, estes parecem ser a intervenção mais eficaz, permitindo receber notificações de RAM com custos mais baixos, aplicando-se este aumento tanto ao número total de notificações de reações adversas a medicamentos, como à gravidade, imprevisibilidade e alto grau de causalidade atribuído a elas. Ainda assim, a colocação de hyperlinks apresenta a vantagem de não envolver custos de manutenção, por isso tem o segundo melhor desempenho no indicador custo por notificação de reações adversas a medicamentos.

Risk factors for recurrent wheezing in infants: a case-control study / Fatores de risco para sibilância recorrente em lactentes: estudo caso-controle

ABSTRACT OBJECTIVE To evaluate the association between recurrent wheezing and atopy, the Asthma Predictive Index, exposure to risk factors, and total serum IgE levels as potential factors to predict recurrent wheezing. METHODS A case-control study with infants aged 6-24 months treated at a specialized outpatient clinic from November 2011 to March 2013. Evaluations included sensitivity to inhalant and food antigens, positive Asthma Predictive Index, and other risk factors for recurrent wheezing (smoking during pregnancy, presence of indoor smoke, viral infections, and total serum IgE levels). RESULTS We evaluated 113 children: 65 infants with recurrent wheezing (63.0% male) with a mean age of 14.8 (SD = 5.2) months and 48 healthy infants (44.0% male) with a mean age of 15.2 (SD = 5.1) months. In the multiple analysis model, antigen sensitivity (OR = 12.45; 95%CI 1.28-19.11), positive Asthma Predictive Index (OR = 5.57; 95%CI 2.23-7.96), and exposure to environmental smoke (OR = 2.63; 95%CI 1.09-6.30) remained as risk factors for wheezing. Eosinophilia ≥ 4.0% e total IgE ≥ 100 UI/mL were more prevalent in the wheezing group, but failed to remain in the model. Smoking during pregnancy was identified in a small number of mothers, and secondhand smoke at home was higher in the control group. CONCLUSIONS Presence of atopy, positive Asthma Predictive Index and exposure to environmental smoke are associated to recurrent wheezing. Identifying these factors enables the adoption of preventive measures, especially for children susceptible to persistent wheezing and future asthma onset.

RESUMO OBJETIVO Avaliar a associação entre a sibilância recorrente e atopia, o Índice Preditivo para Asma, exposição a fatores de risco e dosagem de IgE sérica total como possíveis fatores preditores de sibilância recorrente. MÉTODOS Estudo caso-controle com crianças de seis a 24 meses de idade atendidas em ambulatório especializado entre novembro de 2011 e março de 2013. Foram avaliados a sensibilização a antígenos inaláveis e alimentares, positividade para o Índice Preditivo para Asma e outros fatores de risco para sibilância recorrente (tabagismo durante a gravidez, presença de fumaça na residência, infecções virais e dosagem de IgE total). RESULTADOS Foram avaliadas 113 crianças, sendo 65 lactentes sibilantes recorrentes (63,0% do sexo masculino) com média de idade de 14,8 (DP = 5,2) meses e 48 lactentes saudáveis (44,0% do sexo masculino) com média de idade de 15,2 (DP = 5,1) meses. No modelo de análise múltipla, a sensibilização a antígenos (OR = 12,45; IC95% 1,28-19,11), Índice Preditivo para Asma positivo (OR = 5,57; IC95% 2,23-7,96) e exposição à fumaça ambiental (OR = 2,63; IC95% 1,09-6,30) permaneceram como fatores de risco para sibilância. Eosinofilia ≥ 4,0% e IgE total ≥ 100 UI/mL foram mais prevalentes no grupo sibilante, mas não permaneceram no modelo. O tabagismo na gestação foi identificado em pequeno número de mães e o tabagismo domiciliar foi maior no grupo controle. CONCLUSÕES A presença de atopia, a positividade ao Índice Preditivo para Asma e a exposição à fumaça ambiental estão associadas à sibilância recorrente. A identificação desses fatores permite a adoção de medidas preventivas, especialmente nas crianças susceptíveis à persistência de sibilância e ao surgimento de asma no futuro.

A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.

BACKGROUND: Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. OBJECTIVE: To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. METHODS: All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. RESULTS: The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. CONCLUSIONS: This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.

Feasibility and cost of using mobile phones for capturing drug safety information in peri-urban settlement in Ghana: a prospective cohort study of patients with uncomplicated malaria.

BACKGROUND: The growing need to capture data on health and health events using faster and efficient means to enable prompt evidence-based decision-making is making the use of mobile phones for health an alternative means to capture anti-malarial drug safety data. This paper examined the feasibility and cost of using mobile phones vis-à-vis home visit to monitor adverse events (AEs) related to artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria in peri-urban Ghana. METHODS: A prospective, observational, cohort study conducted on 4270 patients prescribed ACT in 21 health facilities. The patients were actively followed by telephone or home visit to document AEs associated with anti-malarial drugs. Call duration and travel distances of each visit were recorded. Pre-paid call cards and fuel for motorbike travels were used to determine cost of conducting both follow-ups. Ms-Excel 2010 and STATA 11.2 were used for analysis. RESULTS: Of the 4270 patients recruited, 4124 (96.6 %) were successfully followed up and analyzed. Of these, 1126/4124 (27.3 %) were children under 5 years. Most 3790/4124 (91.9 %) follow-ups were done within 7 days of ACT intake. Overall, follow up by phone (2671/4124-64.8 %) was almost two times the number done by home visits (1453/4124-35.2 %). Duration of telephone calls ranged from 38 s to 53 min, costing between GH¢0.26 (0.20USD) and GH¢41.70 (27.USD). On the average, the calls lasted 3 min 51 s (SD = 3 min, 21 s) costing GH¢2.70 (0.77USD). Distance travelled for home visit ranged from 0.65 to 62 km costing GH¢0.29 (0.20USD) and GH¢279.00 (79.70USD). Thirty-two per cent (1128/4124) of patients reported AEs. In total, 1831 AE were reported, 1016/1831(55.5 %) by telephone and 815/1831 (44.5 %) by home visits. Events such as nausea, dizziness, diarrhoea, and vomiting were commonly reported. CONCLUSION: Majority of patients was successfully followed up by telephone and reported the most AEs. The cost of telephone interviewing was almost two times less than the cost of home visit. Telephone follow up should be considered for monitoring drug adverse events in low resource settings.

Pharmacovigilance in resource-limited countries.

In the past 20 years, many low- and middle-income countries have created national pharmacovigilance (PV) systems and joined the WHO's global PV network. However, very few of them have fully functional systems. Scientific evidence on the local burden of medicine-related harm and their preventability is missing. Legislation and regulatory framework as well as financial support to build sustainable PV systems are needed. Public health programs need to integrate PV to monitor new vaccines and medicines introduced through these programs. Signal analysis should focus on high-burden preventable adverse drug problems. Increased involvement of healthcare professionals from public and private sectors, pharmaceutical companies, academic institutions and the public at large is necessary to assure a safe environment for drug therapy. WHO has a major role in supporting and coordinating these developments.

A framework for assessing the economic value of pharmacovigilance in low- and middle-income countries.

Pharmacovigilance (PV) programs are an essential component of national healthcare systems. Well-functioning PV programs can improve population health by identifying and reducing medicines-related problems (MRPs). Many low- and middle-income countries lack functional PV systems, but this deficiency has not been described in terms of the potential economic value of strengthening PV systems. The assessment of economic value for PV can support rational decision making at the country level. We propose a framework for assessing the economic value of PV. We divide national PV systems into four levels: (1) no PV, (2) basic PV, (3) semi-functional PV, and (4) functional PV. These categories represent increasing levels of investment in PV capacity at the national or health facility level for all available medicines, including vaccines. The proposed framework can be used to estimate the costs of PV (including the value of investments to increase PV capacity and the costs of managing MRPs) and outcomes associated with PV (including improvements in morbidity, mortality, and quality of life as a result of the reduction in MRPs). The quantitative approach proposed for assessing costs and benefits uses a decision-analytic modeling framework that would estimate the value of the consequences of MRPs adjusted for their probability of occurrence. This allows the quantification of value using monetary outcomes (cost-benefit analysis), natural units (cost-effectiveness analysis), or mortality adjusted for quality of life or disability (cost-utility analysis). Evidence generated using this framework could assist policy makers, program managers, and donors in evaluating investments that aim to increase the capacity and efficiency of national and facility-level PV programs in low- and middle-income countries.

The cost-effectiveness of periodic safety update reports for biologicals in Europe.

We analyzed the cost-effectiveness of all Periodic Safety Update Reports (PSURs) submitted for biologicals in Europe from 1995 to 2009 by comparing two regulatory scenarios: full regulation (PSUR reporting) and limited regulation (no PSUR reporting, but all other parts of the pharmacovigilance framework remain in place). During this period, PSUR reporting resulted in the detection of 2 out of a total of 24 urgent safety issues for biologicals: (i) distant spread of botulinum toxin and (ii) edema/fluid collection associated with off-label use of dibotermin-alfa. We used Markov-chain life tables to calculate costs and health effects of PSURs. The incremental cost-effectiveness ratio (ICER) of full regulation (PSUR reporting) vs. limited regulation (no PSUR reporting) for the base-case scenario was \[euro]342,110 per quality-adjusted life year (QALY) gained. It is possible to assess the cost-effectiveness of regulatory requirements using the same methods as those used in assessing the cost-effectiveness of medical interventions.

The future of monitoring in clinical research - a holistic approach: linking risk-based monitoring with quality management principles.

Since several years risk-based monitoring is the new "magic bullet" for improvement in clinical research. Lots of authors in clinical research ranging from industry and academia to authorities are keen on demonstrating better monitoring-efficiency by reducing monitoring visits, monitoring time on site, monitoring costs and so on, always arguing with the use of risk-based monitoring principles. Mostly forgotten is the fact, that the use of risk-based monitoring is only adequate if all mandatory prerequisites at site and for the monitor and the sponsor are fulfilled.Based on the relevant chapter in ICH GCP (International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use - Good Clinical Practice) this publication takes a holistic approach by identifying and describing the requirements for future monitoring and the use of risk-based monitoring. As the authors are operational managers as well as QA (Quality Assurance) experts, both aspects are represented to come up with efficient and qualitative ways of future monitoring according to ICH GCP.