Cost Savings and Waste Reduction Through Redispensing Unused Oral Anticancer Drugs: The ROAD Study.

Importance: New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients. Redispensing unused oral anticancer drugs seems to be a promising strategy when drug quality is guaranteed. Objectives: To determine the waste reduction and net cost savings attained by redispensing oral anticancer drugs that go unused by patients compared with the standard practice of disposal. Design, Settings, and Participants: The ROAD study was a prospective single-group intervention conducted in the outpatient pharmacies of 4 hospitals in the Netherlands from February 1, 2021, to February 1, 2023, with 12-month follow-up of each patient. Patients with cancer and who had a prescription for an oral anticancer drug that could be stored at room temperature were included. Of 2426 eligible patients, 602 did not consent and 601 did not respond. Data analyses were performed from August 25, 2022, to April 19, 2023. Intervention: Participants received oral anticancer drugs for use at home in special packaging (ie, sealed packaging with time-temperature indicator), to be returned to the pharmacy should these remain unused. The pharmacy ensured quality of returned drugs based on authenticity, appearance, remaining shelf life and adequate storage temperature. Drugs fulfilling quality requirements were redispensed to other patients. Main Outcome and Measure: Total waste reduction and mean net annual cost savings per patient compared with the standard practice of disposal. Optimization of cost savings was explored by introducing variations in the quality assurance procedure and patient population. All analyses used the average exchange rate for 2021 €1 = US $1.18. Results: Of 1223 patients with cancer who consented, 1071 participated (median [IQR] age, 70 [62-75] years; 622 [58.1%] were male). In all, 171 patients (16.0%; 95% CI, 13.8%-18.3%) returned 335 unused oral anticancer drug packages. Of the returned drugs, 228 packages were redispensed, which reduced waste by 68.1% (95% CI, 67.7%-68.5%) compared with the standard practice (disposal). Redispensing unused oral anticancer drugs comprised 2.4% (95% CI, 2.2%-2.5%) of total drug costs, providing mean net annual cost savings of US $680 (95% CI, $524-$837) up to $1591 (95% CI, $1226-$2002) per participant. Conclusions and Relevance: The findings of this multicenter intervention study indicate that redispensing unused oral anticancer drugs is associated with waste reduction and cost savings, which in turn may improve the affordability and sustainability of cancer treatment. Trial Registration: World Health Organization International Clinical Trials Registry Platform Identifier: NL9208.

Effect of reimbursement restriction policy on the use of benzodiazepines in the Netherlands: an interrupted time series analysis.

OBJECTIVES: Use of benzodiazepines has health risks. Reimbursement was restricted in the Netherlands from January 2009 onwards with the goal to reduce chronic use and healthcare expenditures. The aim of this study is to assess the initial and long-term effects of this policy on benzodiazepine use. DESIGN: Interrupted time series analysis, segmented regression models, Kaplan-Meier survival analysis and Cox proportional hazards analysis. SETTING: A 10% random sample of benzodiazepine dispensings by outpatient pharmacies between January 2002 and August 2015 were obtained from the PHARMO database. This database covered a catchment area representing about 3.6 million residents in 2015. PARTICIPANTS: 2 500 800 benzodiazepine prescriptions from 128 603 patients were included. INTERVENTION: Reimbursement restriction policy from January 2009 onwards. OUTCOME MEASURES: Changes in: the volume of dispensed prescriptions and doses, the incidence, prevalence of incidental, regular and chronic use and discontinuation rates of benzodiazepines. RESULTS: The volume of dispensed prescriptions and doses decreased by 12.5% (95% CI 9.0% to 15.9%) and 15.1% (95% CI 11.4% to 17.3%) respectively in January 2009 compared with December 2008. A clear initial effect on the overall incidence (-14.7%; 95% CI -19.8% to 9.6%) and the prevalence of incidental (-17.8%; 95% CI -23.9% to 11.7%), regular (-20.0%; 95% CI -26.1% to 13.9%) and chronic (-16.0%; 95% CI -23.1% to 8.9%) use was observed. A statistically significant reduction in the monthly trend per 1000 medication users was observed for the overall incidence (-0.017; 95% CI -0.031 to 0.003) and the prevalence of incidental (-3.624; 95% CI -4.996 to 2.252) but not for regular (-0.304; 95% CI -1.204 to 0.596) and chronic (0.136; 95% CI -0.858 to 1.130) use. Patients who started treatment before policy had a slightly higher probability of discontinuation (HR=1.013; 95% CI 1.004 to 1.022). CONCLUSIONS: The reimbursement policy had a significant initial effect on the volume, incidence and prevalence of benzodiazepine use. In addition, there is a statistically significant reduction in the monthly trend of overall incidence and of the prevalence of incidental use. No statistically significant reduction in the monthly trend of chronic use, the main purpose of the reimbursement restriction, could be demonstrated.

Monitoring of Metabolic, Cardiac, and Endocrine Indicators in Youth Treated With Antipsychotics as Reported by Health Care Professionals.

BACKGROUND: It is unclear how youth treated with antipsychotics are monitored. The purpose of this study was to assess monitoring of metabolic, cardiac, and endocrine indicators in youth (<18 years old) treated with antipsychotics as reported by health care professionals in the Netherlands. METHODS: A questionnaire was designed to collect information from health care professionals regarding the monitoring of youth treated with antipsychotics. Data were collected at a national conference. FINDINGS AND RESULTS: Fifty-nine health care professionals completed the questionnaire, of which 53 (89.8%) were child and adolescent psychiatrists (approximately 20% of all child and adolescent psychiatrists in the Netherlands). More than 80% of respondents reported monitoring physical indicators-weight, height, body mass index, heart rate, and blood pressure-and over 50% reported monitoring laboratory indicators-lipid profile, blood glucose, and prolactin level. Most of the respondents reported monitoring physical indicators more than twice per year and laboratory indicators once per year. Almost all respondents (56/59, 94.9%) reported monitoring according to a clinical guideline or protocol. Only 1 respondent reported monitoring the indicators completely according to the clinical guideline. Respondents mentioned that facilitating factors for monitoring, such as access to electrocardiogram facilities, were insufficiently available. CONCLUSIONS: Although all health care professionals reported monitoring metabolic, cardiac, and endocrine indicators in youth treated with antipsychotics, great variability exists in reported monitoring practices. Factors contributing to this variability must be assessed to optimize the benefit-risk ratio for the individual patient.

Cost-effectiveness of a transitional pharmaceutical care program for patients discharged from the hospital.

BACKGROUND: To improve continuity of care at hospital admission and discharge and to decrease medication errors pharmaceutical care programs are developed. This study aims to determine the cost-effectiveness of the COACH program in comparison with usual care from a societal perspective. METHODS: A controlled clinical trial was performed at the Internal Medicine department of a general teaching hospital. All admitted patients using at least one prescription drug were included. The COACH program consisted of medication reconciliation, patient counselling at discharge, and communication to healthcare providers in primary care. The primary outcome was the proportion of patients with an unplanned rehospitalisation within three months after discharge. Also, the number of quality-adjusted life-years (QALYs) was assessed. Cost data were collected using cost diaries. Uncertainty surrounding cost differences and incremental cost-effectiveness ratios between the groups was estimated by bootstrapping. RESULTS: In the COACH program, 168 patients were included and in usual care 151 patients. There was no significant difference in the proportion of patients with unplanned rehospitalisations (mean difference 0.17%, 95% CI -8.85;8.51), and in QALYs (mean difference -0.0085, 95% CI -0.0170;0.0001). Total costs for the COACH program were non-significantly lower than usual care (-€1160, 95% CI -3168;847). Cost-effectiveness planes showed that the program was not cost-effective compared with usual care for unplanned rehospitalisations and QALYs gained. CONCLUSION: The COACH program was not cost-effective in comparison with usual care. Future studies should focus on high risk patients and include other outcomes (e.g. adverse drug events) as this may increase the chances of a cost-effective intervention. Dutch trial register NTR1519.

Instructions for clinical and biomarker monitoring in the Summary of Product Characteristics (SmPC) for psychotropic drugs: Overview and applicability in clinical practice.

The Summary of Product Characteristics (SmPC) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm. The present study evaluated which monitoring instructions are given in the SmPCs, and assessed whether instructions are informative enough to be applicable in clinical practice. Monitoring instructions were collected from complete SmPCs for psychotropic drugs (n=70). Reasons and requirements for monitoring were assessed and somatic parameters were distinguished from non-somatic parameters. Instructions were evaluated using the Systematic Information for Monitoring (SIM) score and considered applicable when a SIM score of ⩾ 3 was found. An average of 3.3 (range 0-13) instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable. Overall, an average SIM score of 2.0 (SD=1.7) was found (out of a maximum possible score of 6). In conclusion, prescribing of psychotropic drugs is accompanied by diverse instructions aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice.

Oral medicines for children in the European paediatric investigation plans.

INTRODUCTION: Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. METHODS: All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. RESULTS: A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. CONCLUSION: The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

The views of healthcare professionals, drug developers and regulators on information about older people needed for rational drug prescription.

BACKGROUND: The ICH E7 guideline intends to improve the knowledge about medicines in geriatric patients. As a legislative document, it might not reflect the needs of healthcare professionals. This study investigated what information healthcare professionals, regulatory agencies and pharmaceutical industries consider necessary for rational drug prescribing to older individuals. METHODS AND FINDINGS: A 29-item-questionnaire was composed, considering the representation in trials, pharmacokinetics, efficacy, safety, and convenience of use in older individuals, with space for additions. Forty-three European professionals with an interest in medication for older individuals were included. In order to investigate their relevance, five items were included in a second questionnaire, with 11 control items. Median scores, differences between clinical and non-clinical respondents and response consistency were analysed. Consistency was present in 10 control items. Therefore, all items of the first questionnaire and the five additional items were analysed. Thirty-seven (86%) respondents returned the first questionnaire; 31/37 (84%) the second. Information about age-related differences in adverse events, locomotor effects, drug-disease interactions, dosing instructions, and information about the proportion of included 65+ patients was considered necessary by most respondents. Clinicians considered information significantly more important than the non-clinical respondents about the inclusion of 75+, time-until-benefit in older people, anticholinergic effects, drug-disease interactions, and convenience of use. Main study limitations are the focus on information for daily practice, while the ICH E7 guideline is a legislative document focused on market approval of a new medicine. Also, a questionnaire with a Likert scale has its limitations; this was addressed by providing space for comments. CONCLUSIONS: This study reveals that items considered necessary are currently not included in the ICH E7 guideline. Also, clinicians' and non-clinicians' opinions differed significantly in 15% of the items. Therefore, all stakeholders should collaborate to improve the availability of information for the rational prescribing to older individuals.

Renal function assessment in older adults.

AIMS: The Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formulae are often used to estimate glomerular filtration rate (GFR). The objective was to determine the best method for estimating GFR in older adults. METHODS: A cross-sectional study was conducted at the geriatric wards of two hospitals in The Netherlands. Patients aged 70 years or above with an estimated (e)GFR below 60 ml min⁻¹ 1.73 m⁻² were included. The CG, CG calculated with ideal bodyweight (IBW), MDRD and CKD-EPI formulae were compared with a criterion standard, sinistrin clearance. Renal function was classified into five stages according to the National Kidney Foundation Disease Outcomes Quality Initiative chronic kidney disease classification, as follows (in ml min⁻¹ 1.73 m)⁻²: stage 1, eGFR ≥ 90; stage 2, eGFR of 60-89; stage 3, eGFR of 30-59; stage 4, eGFR of 15-29; and stage 5, eGFR < 15. RESULTS: Sixteen patients, 50% male, with a mean age of 82 years (range 71-87 years) and mean body mass index 26 kg m⁻² (range 18-36 kg m⁻²), were included. On average, all formulae slightly overestimated GFR, as follows (in ml min⁻¹ 1.73 m⁻²: CG +0.05 [95% confidence interval (CI) -28 to +28]; CG with IBW +0.03 (95% CI -20 to +20); MDRD +9 (95% CI -16 to +34); and CKD-EPI +5 (95% CI -20 to +29). They classified kidney disease correctly in 68.8% (CG), 75% (CG with IBW), 43.8% (MDRD) and 68.8% (CKD-EPI) of the participants, respectively. CONCLUSIONS: The CG, CG with IBW, MDRD and CKD-EPI formulae estimate the mean GFR of a population rather well. In individual cases, all formulae may misclassify kidney disease by one stage.

Information for adequate prescribing to older patients : an evaluation of the product information of 53 recently approved medicines.

BACKGROUND: Historically, older patients have been frequently excluded from clinical trials. This has a knock-on effect on the availability of relevant information from trials for health-care professionals prescribing medicines to older individuals in daily clinical practice. OBJECTIVE: To investigate the availability of information relevant to appropriate prescribing for older people in the summaries of product characteristics (SmPCs) of recently approved medicines. METHODS: An analysis was undertaken of the SmPCs and European public assessment reports (EPARs) of all non-generic medicines indicated for diseases that are common in older individuals and that were approved by the European Medicines Agency between January 2008 and December 2010. The EPARs were considered the second most complete, publicly available document after the pre-authorization dossier. The availability of information was evaluated for 19 items on the representation of and clinical experience in older people, as well as pharmacokinetic and drug-drug interaction studies. These items were derived from the ICH E7 guideline for studies involving geriatric populations in the SmPCs and EPARs. Information not included was classified as being essential or non-essential, based on the product characteristics. RESULTS: Fifty-three medicines were investigated. Overall, information on the ICH E7 items was available in 56 % of the SmPCs (EPARs 79 %); 41 % of the SmPCs (EPARs 24 %) did not provide information that should have been included. Twenty-seven percent of the SmPCs, but 78 % of the EPARs, provided information about the number of patients included. Moreover, 2 % of the SmPCs (EPARs 51 %) provided information about the exclusion of patients with common comorbidities, and 14 % of the SmPCs, but 81 % of the EPARs, provided information about exclusion based on age. CONCLUSIONS: SmPCs, unlike EPARs, do not sufficiently provide adequate information about older individuals. Consequently, it is not clear whether the information about efficacy and safety applies to the frail older patients often seen in daily practice. The SmPC is intended for use by health-care professionals in daily clinical practice and provides basic information for safe and effective prescribing. As the EPAR describes regulatory considerations relevant to drug approval and is too long for daily use, the information about older individuals included in the SmPCs should be improved.

Reasons for and time to discontinuation of rimonabant therapy: a modified prescription-event monitoring study.

BACKGROUND: Early treatment discontinuation will have a negative effect on a drug's benefit-risk profile if discontinuation occurs earlier in time than the positive effects of treatment. This non-persistence of therapy has been associated with an increased risk of adverse health outcomes. OBJECTIVE: The aim of this study was to explore relationships between patient characteristics and reasons for and time to discontinuation of rimonabant therapy, focusing on psychiatric events, because these were the main safety concerns for rimonabant. METHODS: A modified prescription-event monitoring (M-PEM) study was conducted for rimonabant. Descriptive statistics were used to describe the patient population. Rate ratios with 95% confidence intervals (CIs) were calculated to explore associations between patient characteristics and selected categories of reasons for stopping (RfS). Median times to discontinuation were compared using the Mann-Whitney U test. RESULTS: The cohort comprised 10,011 users of rimonabant, three of which were excluded from this analysis because of missing age or sex. A total of 7204 patients (72.0%) stopped using rimonabant (median observation time 323 days, interquartile range: 279-371 days). In addition, patients with a history of psychiatric illness were more likely to discontinue rimonabant therapy early for all reasons, but most pronounced due to psychiatric events (rate ratio 1.79; 95% CI 1.54, 2.09) than those without a history of psychiatric illness. In contrast, the rates of discontinuation due to lack of effectiveness, any clinical events and psychiatric events in patients with cardiovascular disease, type 2 diabetes mellitus, dyslipidaemia or hypertension tended to be lower (not all being significant) than those without. For patients who discontinued treatment due to lack of effectiveness, the median time to discontinuation was significantly shorter for patients with a history of psychiatric illness, compared with patients without a history of psychiatric illness (86 vs 97 days, p = 0.03). For patients discontinuing treatment due to psychiatric events, the difference in median time to discontinuation was also 11 days (64 vs 75 days, p = 0.38), although not statistically significant. For patients stopping due to any clinical event, median time to discontinuation was comparable for patients with and without a history of psychiatric illness (61 vs 63 days, p = 0.90). CONCLUSIONS: In this study, reasons for and time to discontinuation were associated with patient characteristics such as medical history. Patients discontinued treatment because of psychiatric events early after starting. In general, identification and characterization of early discontinuers, and increasing the understanding of reasons for stopping, may help healthcare professionals to develop targeted interventions to further improve treatment compliance, thereby optimizing treatment benefits and drug safety.

Effect of medication reconciliation on medication costs after hospital discharge in relation to hospital pharmacy labor costs.

BACKGROUND: Medication reconciliation aims to correct discrepancies in medication use between health care settings and to check the quality of pharmacotherapy to improve effectiveness and safety. In addition, medication reconciliation might also reduce costs. OBJECTIVE: To evaluate the effect of medication reconciliation on medication costs after hospital discharge in relation to hospital pharmacy labor costs. METHODS: A prospective observational study was performed. Patients discharged from the pulmonology department were included. A pharmacy team assessed medication errors prevented by medication reconciliation. Interventions were classified into 3 categories: correcting hospital formulary-induced medication changes (eg, reinstating less costly generic drugs used before admission), optimizing pharmacotherapy (eg, discontinuing unnecessary laxative), and eliminating discrepancies (eg, restarting omitted preadmission medication). Because eliminating discrepancies does not represent real costs to society (before hospitalization, the patient was also using the medication), these medication costs were not included in the cost calculation. Medication costs at 1 month and 6 months after hospital discharge and the associated labor costs were assessed using descriptive statistics and scenario analyses. For the 6-month extrapolation, only medication intended for chronic use was included. RESULTS: Two hundred sixty-two patients were included. Correcting hospital formulary changes saved €1.63/patient (exchange rate: EUR 1 = USD 1.3443) in medication costs at 1 month after discharge and €9.79 at 6 months. Optimizing pharmacotherapy saved €20.13/patient in medication costs at 1 month and €86.86 at 6 months. The associated labor costs for performing medication reconciliation were €41.04/patient. Medication cost savings from correcting hospital formulary-induced changes and optimizing of pharmacotherapy (€96.65/patient) outweighed the labor costs at 6 months extrapolation by €55.62/patient (sensitivity analysis €37.25-71.10). CONCLUSIONS: Preventing medication errors through medication reconciliation results in higher benefits than the costs related to the net time investment.

Serum potassium influencing interacting drugs: risk-modifying strategies also needed at discontinuation.

BACKGROUND: Although the discontinuation of a medication may have important clinical consequences, there is generally much less attention given to medication surveillance when a drug is stopped than when it is started. OBJECTIVE: To investigate the consequences on serum potassium levels of discontinuing a drug that increases the serum potassium level (PID↑) and a drug that decreases the serum potassium level (PLD↓) in patients taking both. METHODS: Patients who were hospitalized in the University Medical Centre Utrecht in 2004-2009 and were using both a PID↑ and a PLD↓ were included when one of these drugs was discontinued during hospitalization. Serum potassium levels measured before (potassium(1)) and after (potassium(2)) discontinuation were compared in patients who stopped the PLD↓ and in patients who stopped the PID↑. RESULTS: In the group of patients who stopped the PLD↓ (ie, continued the PID↑), mean serum potassium levels increased 0.19 mEq/L (range -0.9 to 1.8 mEq/L). After discontinuation of the PLD↓, serum potassium levels increased in 91 (59%) patients. Five patients (3.2%) developed hyperkalemia (potassium(2) >5.5 mEq/L). In the group of patients who stopped the PID↑ (ie, continued the PLD↓), mean serum potassium levels decreased 0.40 mEq/L (range -2.6 to 0.7 mEq/L). Serum potassium levels decreased in 61 (70%) patients after discontinuation of the PID↑. Fifteen patients (17%) developed hypokalemia (potassium(2) <3.5 mEq/L). Results were not influenced by length of stay, age, sex, renal function, and type of medication discontinued. CONCLUSIONS: The effects of serum potassium-influencing drugs need to be monitored not only after starting but also after stopping the medication. The same may hold true for the effects of other drugs. Clinical risk management should therefore focus on the risks not only when new medication is prescribed, but also when medication is stopped.

Frequency of laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium concentration increasing drugs.

PURPOSE: Although, drug-drug interactions (DDIs) between potassium-increasing drugs (PIDs) are known risk factors for developing hyperkalaemia, not much is known about their risk and management strategies during hospitalisation. This study examines the frequency of serum potassium measurements and hyperkalaemia in hospitalised patients, based on the use of one or more PIDs, and the determinants thereof. METHODS: Adult patients hospitalised in the University Medical Centre Utrecht between 2006 and 2008 were included in this cross-sectional study. The frequency of serum potassium measurements and of hyperkalaemia were compared between patients using only one PID at a time (monotherapy group) and patients using two or more PIDs concomitantly (interaction group). The determinants studied were renal failure, diabetes mellitus, use of diuretics, type of DDI, start of the PIDs within the hospital versus continued home medication and medical speciality. RESULTS: Serum potassium was measured more frequently in the interaction group than in the monotherapy group [67 vs. 56%; relative risk (RR) 1.19, 95% confidence interval (CI) 1.14-1.24] and the risk of hyperkalaemia was also increased in the interaction group (9.9 vs. 5.9%, RR 1.7, 95% CI 1.3-2.1). The combination of potassium-sparing diuretics plus a potassium supplement, start of the PID within the hospital and hospitalisation in non-internal medicine departments was associated with higher relative risk estimates for hyperkalaemia. CONCLUSIONS: Among our patient cohort, even when physicians received a direct pop-up to monitor serum potassium levels when prescribing two PIDs concomitantly, serum potassium levels were not measured in 33% of patients, and 10% of patients developed hyperkalaemia. Improved management strategies and/or clinical decision-support systems are needed to decrease the frequency of hyperkalaemia following DDIs.

[Risk of infection due to contamination of medicines]. / Infectierisico's door contaminatie van geneesmiddelen.

After minor surgery in a hospital, 7 patients suffered serious infectious complications. Microbiological analysis revealed an infection caused by contamination of the intravenous anaesthetic propofol. Several studies have shown that the administration of intravenous medication is a risky process that is prone to errors; these errors can result in harm to the patient. Within the Dutch project 'Safe medical care', the intravenous administration of medication has been chosen as one of the ten most important areas in which to patient safety can be improved. To enhance patient safety it is important to identify the separate steps that are the most prone to error, based on a good risk analysis. A systematic and coordinated approach is crucial for success in this process.

Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval.

BACKGROUND: Since November 2005, an EU Risk Management Plan (EU-RMP) has had to be submitted as part of a marketing application for all new chemical entities in the EU. In the EU-RMP, the safety profile of the medicine has to be described and pharmacovigilance activities should be proposed to study further safety concerns during use of the drug in the real-world setting. These activities include, for example, collection of spontaneously reported adverse events and post-authorization safety studies (PASS). Since the submission of an EU-RMP is a relatively new requirement, there is limited knowledge on the quality and completeness of the study protocols of PASS at the time of approval and there are no data on the influence of certain drug characteristics on the proposed pharmacovigilance activities. OBJECTIVE: To examine the types of proposed pharmacovigilance activities in a sample of EU-RMPs, describe and evaluate the methodology of PASS, identify problems and propose remedies, and compare characteristics between biologicals and small molecules. METHODS: Eighteen EU-RMPs (nine for biologicals, nine for small molecules) given a positive decision regarding the marketing application by the Committee for Medicinal Products for Human Use between November 2005 and May 2007 were included in this descriptive cohort study. The EU-RMPs were selected over time and different therapeutic areas. Classification of the safety concerns ('important identified risks', 'important potential risks', 'important missing information' within the EU-RMP was studied. For PASS, data source (registry, population-based database, sponsor-owned clinical trial database), source of study population to be included in PASS and comprehensiveness of study protocol (full protocol, limited protocol, study synopsis, short description, commitment without further information) were studied. RESULTS: Compared to small molecules, safety concerns for biologicals were less frequently classified as important identified risks (relative risk [RR] 0.6; 95% CI 0.3, 1.0) and more frequently as important missing information (RR 1.6; 95% CI 1.0, 2.7). Forty-seven PASS were proposed; 31 for biologicals and 16 for small molecules. Compared with studies proposed in population-based databases (4 for biologicals, 8 for small molecules), studies in registries (18 for biologicals, 4 for small molecules) were more frequently proposed for biologicals than for small molecules (RR 2.5; 95% CI 1.1, 5.7). About 60% of the proposed PASS will include EU inhabitants. No full study protocols were submitted; 26% involved a limited study protocol, 33% a study synopsis, 37% a short description and 4% a commitment without further information. CONCLUSION: Approximately 40% of the study proposals for PASS were classified as a short description or a commitment to perform a study without further information, precluding an adequate scientific assessment. Studying non-EU populations may give rise to difficulties with generalizability of the results to the EU due to differences in patient characteristics, differences in the indication for the medicine and different healthcare systems. This study emphasizes the need for more complete study proposals to be submitted earlier on in the evaluation period and for the inclusion of EU inhabitants in PASS. In addition, differences in the characteristics between biologicals and small molecules, e.g. in the data source proposed, support the need for individualized tailored PASS depending on the type of drug.

Laboratory tests in the clinical risk management of potential drug-drug interactions: a cross-sectional study using drug-dispensing data from 100 Dutch community pharmacies.

BACKGROUND: Patient safety and the life cycle of a drug are negatively influenced by the still increasing occurrence of potential drug-drug interactions (DDIs). Clinical risk management of potential DDIs is required in patients using drugs to influence the benefit-risk profile positively. Information about laboratory test results, in particular, may be useful in the assessment of potential DDIs for the individual patient. OBJECTIVE: The objective of this study was to examine the frequency and nature of laboratory tests required for the assessment of the clinical relevance of potential DDIs in Dutch community pharmacies. In addition, the nature and clinical relevance of these potential DDIs is analysed. METHODS: All patients from 100 Dutch community pharmacies using, according to dispensing information, two or more drugs concomitantly on a specified date (Wednesday, 4 April 2007), were included (n = 223,019). The anonymous dispensing data of the included patients were analysed against a list of DDIs requiring laboratory tests for the assessment of their clinical relevance. The number of patients at risk for these potential DDIs with severe adverse reactions was calculated. The frequency of potential DDIs requiring laboratory tests were stratified by age, sex and degree of polypharmacy. RESULTS: Of the included patients, 24.4% had one or more potential DDIs (n = 54,427). In 9.0% of the included patients, one or more laboratory tests for the assessment of clinical relevance of the potential DDI were required (n = 19,968). The frequency of DDIs requiring laboratory tests increased with increasing age and number of drugs, but was not related to sex. The most commonly required laboratory tests were for renal function (42.2%), electrolytes (20.1%) and coagulation (13.1%). The percentage of patients at risk for potential DDIs requiring laboratory tests with adverse reaction category F (serious, irrecoverable disablement or death) was 2.5%; category E (increased risk of failure of life-saving therapy) was 0.6%; and category D (inconvenience with residual symptom and failure of therapy concerning serious but non-fatal diseases) was 3.8%. CONCLUSIONS: A large number of patients in Dutch community pharmacies are at risk for potential DDIs requiring laboratory tests for the assessment of the clinical relevance of the interaction. There is a strong relationship between the frequency of DDIs requiring laboratory tests and age and the number of drugs concomitantly used. In the clinical risk management of potential DDIs, information about laboratory test results is of additional value. Future research is necessary in order to obtain more evidence on using laboratory tests in terms of which tests should be linked to pharmacy data, in which patients they should be done, how often and what actions should be taken when an abnormal value is found.