The use of national reimbursement reports to support formulary decisions of the hospital's Drug and Therapeutics Committee: a comparative analysis.

Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access to patients by compiling a formulary on rational grounds. An evolving landscape of innovative molecules challenges timely formulary adaptation after national reimbursement. Aim To integrate national reimbursement reports in the hospital's appraisal, thereby promoting access for patients without delay. Method For 2019, the rationale for new molecules at Ghent University Hospital, Belgium, was compared with the public assessment report of the National Institute for Health and Disability Insurance, assessing a medicine in a specific indication following a reimbursement request by the manufacturer. Decision criteria (therapeutic value and cost) between matching medicines in both databases (national & hospital) were retrospectively compared [no (%), mean (SD)]. Results Two-hundred public reports and 30 formulary decisions were analysed (with antineoplastic & immunomodulating as most prevalent class: 41.0% resp. 36.7%). National decision often concerned hospital-only medicines (89; 44.5%) without patient co-payment (101; 50.5%). Of 13 matched medicines (same indication), time delay between national decision and formulary admission was on average 3.1 (SD 2.3) months. Comparative analysis showed that assessment in both committees was mostly based on the efficacy endpoints of Randomised Controlled Trials. Literature used in hospital appraisals was of more recent publication date: + 0.78 (SD 2.2) years. Using public reports as a horizon scan could enable quick identification of new indications. Conclusion To speed up patient access, the scientific evidence of national reimbursement reports can be used for the purpose of hospital formulary decisions.

Off-Patent Biologicals and Biosimilars Tendering in Europe-A Proposal towards More Sustainable Practices.

BACKGROUND: In Europe, off-patent biologicals and biosimilars are largely procured by means of tender procedures. The organization and design of tenders may play a key role in the evolving biosimilar market, and currently, it is not fully elucidated how tenders for off-patent biologicals and biosimilars are designed and if approaches are aligned with sustaining market competition and societal savings for healthcare systems over the long term. This study aims to (i) explore the design and implementation of tender procedures for off-patent biologicals and biosimilars in Europe, (ii) identify learnings for sustainable tender approaches from purchasers and suppliers, and (iii) formulate recommendations in support of competitive and sustainable tender practices in the off-patent biologicals market. METHODS: A mixed methods design was applied. A quantitative web-survey was conducted with hospital pharmacists and purchasers (N = 60, of which 47 completed the survey in full), and qualitative expert-interviews with purchasers and suppliers (N = 28) were carried out. RESULTS: The web survey results showed that the organization and design of tenders for off-patent biologicals and biosimilars, and the experience of hospital pharmacists and purchasers with this, considerably varies on several elements across European countries. From the qualitative interviews, signals emerged across the board that some of the current tender approaches might negatively affect market dynamics for off-patent biologicals and biosimilars. The focus on generating short-term savings and existence of originator favouring tender practices were identified as elements that may limit timely competition from and market opportunity for biosimilar suppliers. The need to optimize tender processes, considering a more long-term strategic and sustainable view, was expressed. In addition, challenges appear to exist with differentiating between products beyond price, showing the need and opportunity to guide stakeholders with the (appropriate) inclusion of award criteria beyond price. Due to the variety in tender organization in Europe, a 'one size fits all' tendering framework is not possible. However, on an overarching level, it was argued that tender procedures must aim to (i) ensure market plurality and (ii) include award criteria beyond price (warranted that criteria are objectively and transparently defined, scored and competitively rewarded). Depending on the market (maturity), additional actions may be needed. CONCLUSIONS: Findings suggest the need to adjust tender procedures for off-patent biologicals and biosimilars, considering a more long-term strategic and market sustainable view. Five main avenues for optimization were identified: (i) safeguarding a transparent, equal opportunity setting for all suppliers with an appropriate use of award criteria; (ii) fostering a timely opening of tender procedures, ensuring on-set competition; (iii) ensuring and stimulating adherence to laws on public procurement; (iv) securing an efficient process, improving plannability and ensuring timely product supply and (v) safeguarding long-term sustainable competition by stimulating market plurality.

Vancomycin dosing and therapeutic drug monitoring practices: guidelines versus real-life.

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1-Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.

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.

The impact of logarithmic dose banding of anticancer drugs on pharmacy compounding efficiency at Ghent University Hospital.

BACKGROUND: Dose banding (DB) (dose rounding with predetermined variation with prescription) enables in-advance preparation of high-turnover anticancer drugs with potential benefit for pharmacy compounding work flow. OBJECTIVES: To analyse the impact of potential situations on the efficiency of DB in the pharmacy (safe and maximum storage), calculate preparation lead times and the potential full-time equivalent (FTE) benefit. METHODS: Candidate intravenous anticancer drugs were selected for logarithmic DB according to prescribing frequency, infusion volume and stability (usage data 2015 of the tertiary Ghent University Hospital, Belgium). With a selected DB set already stored, a 2-week time study (April/November 2015) provided lead times (between prescription and transfer) for just-in-time and DB preparations. A 'maximal' storage (using all drugs with a relative incidence of ≥2% recurrent monthly prescription) and a 'safe' storage scenario (lowest monthly prescribing pattern) were used to calculate the potential future FTE change. RESULTS: Mean lead times for DB storage and just-in-time preparation were 17.1 min (95% CI 13.5 to 21.0) and 26.5 min (23.3 to 29.8). For 21 164 yearly preparations with already 5292 in DB (25%), 11 157 and 6 862 could be batch-produced in advance in a maximum storage and safe storage scenario, respectively. The existing FTE in 2015 of 5.41 could then be reduced to 4.91 and 5.27. CONCLUSION: Further development of DB could contribute to pharmacy compounding efficiency.

Policies for biosimilar uptake in Europe: An overview.

BACKGROUND: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. OBJECTIVES: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. METHODS: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. RESULTS: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. CONCLUSIONS: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market.

Experience with the Implementation of Clinical Pharmacy Services and Processes in a University Hospital in Belgium.

This article summarizes the experience with the development of clinical pharmacy services in the Ghent University Hospital in Belgium. Implementation of clinical pharmacy services in Belgian hospitals has not been evident because these activities were initially not structurally financed. The aim is to describe the strengths and weaknesses of the clinical pharmacy development process, and the milestones that enhanced the progress. Furthermore, the organisation of clinical pharmacy in the Ghent University Hospital is explained, including back- and front-office activities, seamless pharmaceutical care and medication safety improvement. Some working methods, procedures and tools are explained for different clinical pharmacy services. In particular, the clinical pharmacy projects for geriatric patients as well as the preparation of clinical pharmacy services for the accreditation process are explained. We also reflect on the organisation model and the future development of clinical pharmacy, taking into consideration facilitators and potential barriers.

Chemotherapy drug shortages in paediatric oncology: A 14-year single-centre experience in Belgium.

Shortages of chemotherapy are a growing challenge for the healthcare system. We present the burden of drug shortages of chemotherapeutics in the paediatric hemato-oncology unit of a tertiary care hospital and solutions that were used to manage them. Between January 2001 and December 2014, 54 individual shortages were detected, affecting a total number of 21 different drugs. In total, 4127 shortage days were registered with a mean duration of 196.5 SD ± 144.0 days per individual drug shortage. Methotrexate, doxorubicin and carboplatin had the longest supply disruptions. Solutions to address the problems were purchase of a generic alternative, a change of individual treatment plans, cohorting of patients and import from abroad.

[Drug shortages in the hospital: management, causes and budget impact]. / Indisponibilité des medicaments dans les hôpitaux: gestation, causes et impact sur le budget.

INTRODUCTION: Drug shortages have become an issue of growing interest for pharmacists. Both number and type of shortages have increased over the past decade and it is challenging to provide drug continuity. Aim To describe management and impact of drug shortages for the hospital pharmacy. To gain insight into the causes of shortages. METHODS: The management process for drug shortages was analysed for the hospital pharmacies of the Ghent University Hospital (GUH) and the Acute Care Hospital Sint-Lucas Ghent. Insights in possible causes were obtained by semi-structured interview with the Federation for Belgian Pharmacists (Association Pharmaceutique beIge (APB)), the Belgian association of the pharmaceutical industry (pharma.bel and the Federal Agency for Medicines and Health Products (FAMHPI. A database of 1329 drug shortages (Jan 2001-Feb 2014 of the GUH was used to define drug classes affected by shortages (mean shortage days per year, standard deviation (SDI), type of shortage [urgent/ important] %, total number (n)), formulation (parenteral:oral and duration of the shortages (median, interquartile range (IQR)). The total cost impact for the GUH pharmacy was estimated by calculating average, minimum and maximum time investment by the pharmacy team (Delphi-techniquel and by calculating the cost difference between original and alternative drug acquisition costs. Impact is presented as base case scenario (minimum as best and maximum as worst case scenario). RESULTS: The different management phases for the pharmacist are problem identification, preparation of solution and implementation. Communication and extensive administration are essential components. Causes are production related, next to distribution inequivalences, quota and European market flows. Shortages with anti-infectious, cardiovascular and hormonal system drugs have the highest and constant proportion of drug shortage days, with recently appearance of other important drug classes such as anticancer therapy [2011 and further). The average number of drug shortage days in 2011-2013 is 8020 (SD 2142 compared to period 2001-2010 with on average 4633 days (SD 1731]. Fifty-four percent of the shortages is important for the direct hospital care and 22.9% needs urgent action. The proportion parenteral versus oral in the database is 3.3:1. Median duration of a shortage is 29 [IQR 11-65]1 days. The average excess cost of an equipotent dose of the alternative drug was 4.9 (SD 31.3) Euro. Total cost impact (gross salary and drug acquisition cost] for GUH pharmacy in 2013 is 117 281.4 Euro (best case: 88 345.06 and worst case: 151,208.2 Euro. CONCLUSION: The importance of the shortages and the diversification of the drug classes involved have an impact on the hospital pharmacy management. For the GUH this represents an important workload and an increased drug acquisition cost. Causes of shortages are production related but also distributional inequivalences and quota play an important role.

Colistin and neurotoxicity: recommendations for optimal use in cystic fibrosis patients.

Case description The use of i.v. colistin reappeared recently for the treatment of multidrug-resistant Gram negative organisms in the intensive care and cystic fibrosis (CF) setting. According to the latest pharmacokinetic data, a loading dose and high antibiotic doses are given. Two cases of adverse events (paraesthesias, bad taste) were observed immediately after the start of infusion of a high dose of i.v. colistin in adult CF patients at the Ghent University Hospital. Conclusion Recommendations for optimal administration of i.v. colistin in adult CF patients are scarce. This article highlights the importance of mode of administration to avoid toxicity and relates it to recent pharmacokinetic/-dynamic literature.

Role of an electronic antimicrobial alert system in intensive care in dosing errors and pharmacist workload.

BACKGROUND: Critically ill patients are vulnerable to dosing errors. We developed an electronic Antimicrobial Dose alert based upon Creatinine clearance (ADC-alert), which gives daily antimicrobial dosing advice based upon the 24-h creatinine clearance (CLcr). OBJECTIVE: Primary objective: to verify the correctness of the ADC-alert output and its benefit for the workload of the clinical pharmacist (CP). Secondary objective to compare the ADC-alert output between patients with normal and impaired CLcr. SETTING: The 36-bed surgical and medical intensive care unit (ICU) of the Ghent University Hospital, Ghent, Belgium. METHOD: In a single centre prospective observational 44-day study, prescriptions were reviewed by CP and compared with the ADC-alert output advice. CP workload was calculated with and without the use of the ADC-alert. Impaired renal function was defined as a CLcr < 50 mL/min for at least 1 day during antimicrobial treatment in the ICU or the need for renal replacement therapy (RRT). MAIN OUTCOME MEASURES: Correct dosing recommendation by ADC-alert compared to CP review and time spent by CP with and without the ADC-alert. RESULTS: A total of 87 patients (554 daily antimicrobial prescriptions; 435 patient days) were both screened by CP and ADC-alert. Renal function impairment occurred in 39 patients (44.8 %) with 12 patients requiring RRT. The ADC-alert gave a correct dosage advice in 483 prescriptions (87.2 %). The overall sensitivity was 77.3 %; specificity was 89.9 %. Use of the ADC-alert reduces CP workload with 76.5 % (average time spent per patient: 17 vs. 4 min). Patients with a CLcr < 50 mL/min less frequently received a correct recommendation than patients with normal CLcr (P = 0.001). This was due to configuration problems in dialysis patients. CONCLUSION: We developed and evaluated an electronic alert system to generate dynamic antimicrobial dose adaptation based on the daily calculation of the 24-h CLcr of ICU patients. Its use led to substantial time savings for clinical pharmacists. However, the alert advice suffered from some developmental and other flaws. Despite resolving some of these shortcomings, bedside interpretation of the results and clinical judgement remain necessary.

Expected net benefit of clinical pharmacy in intensive care medicine: a randomized interventional comparative trial with matched before-and-after groups.

RATIONALE, AIMS AND OBJECTIVES: This study evaluated clinical pharmacy costs against drug costs. METHOD: We conducted a randomized interventional comparative trial at the surgical intensive care unit (ICU) of Ghent University Hospital, Belgium (period B: group B1 with pharmacist consultation; control group B0). We obtained before (period A) and after (period C) control groups using 1:1 propensity score matching with B1 and B0. Mean daily ICU drug costs with standard error of the mean (SEM) were compared between B1 and B0 (primary analysis) and between matched pairs (AB1, AB0, CB1 and CB0; secondary analysis). For B, we performed a 1000 bootstrapping (by resampling B1 and B0), calculated the benefit-cost ratio using pharmacy time (gross salary) as cost (euros) and drug cost savings as benefit. We performed sensitivity analysis with and without outlier drug costs (i.e. twice the standard deviation). PERSPECTIVE: Belgian health care payer. RESULTS: In period B, 135 patients were randomized: B0, n = 60; B1, n = 75. Pharmacists provided recommendations in 148/706 (21.0%) therapies with 83.1% acceptance. Mean drug cost difference between B0 (430.6 euros, SEM 406.0) and B1 (221.2 euros, SEM 58.7) (P = 0.870) became significant after excluding outlier drug costs (B0, 184.4 euros, SEM 42.5; B1, 90.5 euros, SEM 17.7; P < 0.001). Recommendations were cost-beneficial (break-even drug costs or savings) in 53.8% of patients with a benefit-cost ratio of 25:1 (confidence interval -5:1 to 94:1). In sensitivity analysis excluding outlier drug costs, B0 costs were significantly higher than both A and C, indicating high baseline expenses in B0. CONCLUSIONS: The randomized interventional comparative trial in a small ICU patient group suggested the potential cost-benefit of clinical pharmacy on daily ICU drug costs. However, after matching, this benefit was attenuated. A final conclusion demands a larger randomized trial adopting a similar design with matched controls. Future research should include clinical impact of recommendations.

Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy.

INTRODUCTION: We describe incidence and patient factors associated with augmented renal clearance (ARC) in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: A prospective observational study in a mixed cohort of surgical and medical ICU patients receiving antimicrobial therapy at the Ghent University Hospital, Belgium. Kidney function was assessed by the 24-hour creatinine clearance (Ccr); ARC defined as at least one Ccr of >130 mL/min per 1.73 m2. Multivariate logistic regression analysis: to assess variables associated with ARC occurrence. Therapeutic failure (TF): an impaired clinical response and need for alternate antimicrobial therapy. RESULTS: Of the 128 patients and 599 studied treatment days, ARC was present in 51.6% of the patients. Twelve percent permanently expressed ARC. ARC patients had a median Ccr of 144 mL/min per 1.73 m2 (IQR 98-196). Median serum creatinine concentration on the first day of ARC was 0.54 mg/dL (IQR 0.48-0.69). Patients with ARC were significantly younger (P<.001). Age and male gender were independently associated with ARC whereas the APACHE II score was not. ARC patients had more TF (18 (27.3%) vs. 8 (12.9%); P=.04). CONCLUSION: ARC was documented in approximately 52% of a mixed ICU patient population receiving antibiotic treatment with worse clinical outcome. Young age and male gender were independently associated with ARC presence.

What's in a drop? Optimizing strategies for administration of drugs in pediatrics.

Accurate administration of drugs is an essential part of pharmacotherapy in children. Small differences in the amount of drugs administered, might evoke different clinical effects. This is especially of concern in drugs with a narrow therapeutic index. Guided by a case that was observed in pediatrics, some practical recommendations for the administration of oral drops in children are described.

Epidemiology and cost analysis of pharmacist interventions at Ghent University Hospital.

BACKGROUND: Performing bedside clinical recommendations is important for the prevention of adverse drug events. From an economic perspective, the economic value of adverse drug event avoidance needs to be weighed against the labour costs of pharmacists. OBJECTIVE: To perform a cost analysis of pharmacist interventions with valproic acid, digoxin, methotrexate and penicillin. SETTING: Ghent University Hospital in Belgium (1,062-beds). METHOD: Interventions for valproic acid, digoxin, methotrexate and penicillin were selected from a clinical pharmacy database, CLINOR. The average number of registered interventions per year was 1,209 (period 2005-mid 2011). MAIN OUTCOME MEASURE: Cost difference (cost value) between that of the avoided toxicity and that of the intervention (a positive cost value is cost saving). RESULTS: Per annum, pharmacists performed interventions for valproic acid (n = 18) and digoxin (n = 21); the annual cost value of interventions for valproic acid was €18,853.7 with a standard deviation of €15,020.6; for digoxin it was €41,832.0 ± €15,348.5. With oral methotrexate, accidental toxicity occurs rarely but it can be life threatening. Two important pharmacist interventions were reported per year. The routine switching of penicillin therapy to alternative antibiotics, in patients with previous allergy, may invoke costs rather than benefits (two interventions per year). In half of cases, therapy was reinitiated without any further adverse drug event. CONCLUSION: Clinically important pharmacy interventions are not automatically cost beneficial. Interventions that prevent digoxin and valproic acid toxicity were cost effective in this setting. The routine advice to switch the antibiotic class for every reported penicillin allergy is unlikely to avoid adverse drug events and challenges the cost value of this intervention. Interventions with methotrexate are relevant because they can be lifesaving. However, due to their low incidence, effective detection of these errors is crucial for reducing harm.

Vancomycin-induced red man syndrome in pediatric oncology: still an issue?

Red man syndrome is a rare but possibly serious adverse reaction during treatment with intravenous vancomycin. It is extremely important that pediatricians, especially in oncology, recognize this reaction and treat it appropriately. Following two case-reports from a pediatric oncology setting, a series of practical recommendations to prevent or handle red man syndrome are described.

Impact of computerized physician order entry on medication prescription errors in the intensive care unit: a controlled cross-sectional trial.

INTRODUCTION: Medication errors in the intensive care unit (ICU) are frequent and lead to attributable patient morbidity and mortality, increased length of ICU stay and substantial extra costs. We investigated if the introduction of a computerized ICU system (Centricity Critical Care Clinisoft, GE Healthcare) reduced the incidence and severity of medication prescription errors (MPEs). METHODS: A prospective trial was conducted in a paper-based unit (PB-U) versus a computerized unit (C-U) in a 22-bed ICU of a tertiary university hospital. Every medication order and medication prescription error was validated by a clinical pharmacist. The registration of different classes of MPE was done according to the National Coordinating Council for Medication Error Reporting and Prevention guidelines. An independent panel evaluated the severity of MPEs. We identified three groups: minor MPEs (no potential to cause harm); intercepted MPEs (potential to cause harm but intercepted on time); and serious MPEs (non-intercepted potential adverse drug events (ADE) or ADEs, being MPEs with potential to cause, or actually causing, patient harm). RESULTS: The C-U and the PB-U each contained 80 patient-days, and a total of 2,510 medication prescriptions were evaluated. The clinical pharmacist identified 375 MPEs. The incidence of MPEs was significantly lower in the C-U compared with the PB-U (44/1286 (3.4%) versus 331/1224 (27.0%); P < 0.001). There were significantly less minor MPEs in the C-U than in the PB-U (9 versus 225; P < 0.001). Intercepted MPEs were also lower in the C-U (12 versus 46; P < 0.001), as well as the non-intercepted potential ADEs (21 versus 48; P < 0.001). There was also a reduction of ADEs (2 in the C-U versus 12 in the PB-U; P < 0.01). No fatal errors occurred. The most frequent drug classes involved were cardiovascular medication and antibiotics in both groups. Patients with renal failure experienced less dosing errors in the C-U versus the PB-U (12 versus 35 serious MPEs; P < 0.001). CONCLUSION: The ICU computerization, including the medication order entry, resulted in a significant decrease in the occurrence and severity of medication errors in the ICU.