Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.

Drug switching in the Netherlands: a cohort study of 20 active substances.

BACKGROUND: For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches. METHODS: We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient's prescribed drug with a similar drug from a different manufacturer. RESULTS: We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import. CONCLUSIONS: Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.

Quantification of Adverse Drug Reactions Related to Drug Switches in The Netherlands.

We performed a retrospective cohort study in the Dutch patient population to identify active substances with a relatively high number of adverse drug reactions (ADRs) potentially related to drug switching. For this, we analyzed drug switches and reported ADRs related to switching between June 1, 2009, and December 31, 2016, for a selection of 20 active substances. We also compared pharmacovigilance analyses based on the absolute, switch-corrected, and user-corrected numbers of ADRs. In total, 1,348 reported ADRs and over 23.8 million drug switches were obtained from the National Health Care Institute in The Netherlands and from Lareb, which is The Netherlands Pharmacovigilance Centre. There was no correlation between the number of ADRs and the number of switches, but, on average, we found 5.7 reported ADRs per 100,000 switches. The number was relatively high for rivastigmine, levothyroxine, methylphenidate, and salbutamol, with 74.9, 50.9, 47.6, and 26.1 ADRs per 100,000 switches, respectively. When comparing analyses using the absolute number and the switch-corrected number of ADRs, we demonstrate that different active substances would be identified as having a relatively high number of ADRs, and different time periods of increased numbers of ADRs would be observed. We also demonstrate similar results when using the user-corrected number of ADRs instead of the switch-corrected number of ADRs, allowing for a more feasible approach in pharmacovigilance practice. This study demonstrates that pharmacovigilance analyses of switch-related ADRs leads to different results when the number of reported ADRs is corrected for the actual number of drug switches.

Catechol glucosides act as donor/acceptor substrates of glucansucrase enzymes of Lactobacillus reuteri.

Previously, we have shown that the glucansucrase GtfA-ΔN enzyme of Lactobacillus reuteri 121, incubated with sucrose, efficiently glucosylated catechol and we structurally characterized catechol glucosides with up to five glucosyl units attached (te Poele et al. in Bioconjug Chem 27:937-946, 2016). In the present study, we observed that upon prolonged incubation of GtfA-ΔN with 50 mM catechol and 1000 mM sucrose, all catechol had become completely glucosylated and then started to reappear. Following depletion of sucrose, this glucansucrase GtfA-ΔN used both α-D-Glcp-catechol and α-D-Glcp-(1→4)-α-D-Glcp-catechol as donor substrates and transferred a glucose unit to other catechol glycoside molecules or to sugar oligomers. In the absence of sucrose, GtfA-ΔN used α-D-Glcp-catechol both as donor and acceptor substrate to synthesize catechol glucosides with 2 to 10 glucose units attached and formed gluco-oligosaccharides up to a degree of polymerization of 4. Also two other glucansucrases tested, Gtf180-ΔN from L. reuteri 180 and GtfML1-ΔN from L. reuteri ML1, used α-D-Glcp-catechol and di-glucosyl-catechol as donor/acceptor substrate to synthesize both catechol glucosides and gluco-oligosaccharides. With sucrose as donor substrate, the three glucansucrase enzymes also efficiently glucosylated the phenolic compounds pyrogallol, resorcinol, and ethyl gallate; also these mono-glucosides were used as donor/acceptor substrates.

Characterization of the starch-acting MaAmyB enzyme from Microbacterium aurum B8.A representing the novel subfamily GH13_42 with an unusual, multi-domain organization.

The bacterium Microbacterium aurum strain B8.A degrades granular starches, using the multi-domain MaAmyA α-amylase to initiate granule degradation through pore formation. This paper reports the characterization of the M. aurum B8.A MaAmyB enzyme, a second starch-acting enzyme with multiple FNIII and CBM25 domains. MaAmyB was characterized as an α-glucan 1,4-α-maltohexaosidase with the ability to subsequently hydrolyze maltohexaose to maltose through the release of glucose. MaAmyB also displays exo-activity with a double blocked PNPG7 substrate, releasing PNP. In M. aurum B8.A, MaAmyB may contribute to degradation of starch granules by rapidly hydrolyzing the helical and linear starch chains that become exposed after pore formation by MaAmyA. Bioinformatics analysis showed that MaAmyB represents a novel GH13 subfamily, designated GH13_42, currently with 165 members, all in Gram-positive soil dwelling bacteria, mostly Streptomyces. All members have an unusually large catalytic domain (AB-regions), due to three insertions compared to established α-amylases, and an aberrant C-region, which has only 30% identity to established GH13 C-regions. Most GH13_42 members have three N-terminal domains (2 CBM25 and 1 FNIII). This is unusual as starch binding domains are commonly found at the C-termini of α-amylases. The evolution of the multi-domain M. aurum B8.A MaAmyA and MaAmyB enzymes is discussed.

Carbohydrate-binding module 74 is a novel starch-binding domain associated with large and multidomain α-amylase enzymes.

Microbacterium aurum B8.A is a bacterium that originates from a potato starch-processing plant and employs a GH13 α-amylase (MaAmyA) enzyme that forms pores in potato starch granules. MaAmyA is a large and multi-modular protein that contains a novel domain at its C terminus (Domain 2). Deletion of Domain 2 from MaAmyA did not affect its ability to degrade starch granules but resulted in a strong reduction in granular pore size. Here, we separately expressed and purified this Domain 2 in Escherichia coli and determined its likely function in starch pore formation. Domain 2 independently binds amylose, amylopectin, and granular starch but does not have any detectable catalytic (hydrolytic or oxidizing) activity on α-glucan substrates. Therefore, we propose that this novel starch-binding domain is a new carbohydrate-binding module (CBM), the first representative of family CBM74 that assists MaAmyA in efficient pore formation in starch granules. Protein sequence-based BLAST searches revealed that CBM74 occurs widespread, but in bacteria only, and is often associated with large and multi-domain α-amylases containing family CBM25 or CBM26 domains. CBM74 may specifically function in binding to granular starches to enhance the capability of α-amylase enzymes to degrade resistant starches (RSs). Interestingly, the majority of family CBM74 representatives are found in α-amylases originating from human gut-associated Bifidobacteria, where they may assist in resistant starch degradation. The CBM74 domain thus may have a strong impact on the efficiency of RS digestion in the mammalian gastrointestinal tract.

Degradation of Granular Starch by the Bacterium Microbacterium aurum Strain B8.A Involves a Modular α-Amylase Enzyme System with FNIII and CBM25 Domains.

The bacterium Microbacterium aurum strain B8.A, originally isolated from a potato plant wastewater facility, is able to degrade different types of starch granules. Here we report the characterization of an unusually large, multidomain M. aurum B8.A α-amylase enzyme (MaAmyA). MaAmyA is a 1,417-amino-acid (aa) protein with a predicted molecular mass of 148 kDa. Sequence analysis of MaAmyA showed that its catalytic core is a family GH13_32 α-amylase with the typical ABC domain structure, followed by a fibronectin (FNIII) domain, two carbohydrate binding modules (CBM25), and another three FNIII domains. Recombinant expression and purification yielded an enzyme with the ability to degrade wheat and potato starch granules by introducing pores. Characterization of various truncated mutants of MaAmyA revealed a direct relationship between the presence of CBM25 domains and the ability of MaAmyA to form pores in starch granules, while the FNIII domains most likely function as stable linkers. At the C terminus, MaAmyA carries a 300-aa domain which is uniquely associated with large multidomain amylases; its function remains to be elucidated. We concluded that M. aurum B8.A employs a multidomain enzyme system to initiate degradation of starch granules via pore formation.

A 10-year analysis of the effects of media coverage of regulatory warnings on antidepressant use in The Netherlands and UK.

BACKGROUND: In 2003-2004 and 2007-2008, the regulatory banning of SSRI use in pediatrics and young adults due to concerns regarding suicidality risk coincided with negative media coverage. SSRI use trends were analyzed from 2000-2010 in the Netherlands (NL) and the UK, and whether trend changes might be associated with media coverage of regulatory warnings. METHODS: Monthly SSRIs sales were presented as DDDs/1000 inhabitants/day. SSRI-use trends were studied using time-series segmented regression analyses. Timing of trend changes was compared with two periods of media coverage of warnings. Annual Dutch SSRI prescription data were analyzed by age group. RESULTS: Trend changes in SSRI use largely corroborated with the periods of media coverage of warnings. British SSRI use declined from 3.9 to 0.7 DDDs/month (95%CI 3.3;4.5 & 0.5;0.9, respectively) before the first warning period (2003-2004). A small decrease of -0.6 DDDs/month (-1.2; -0.05) was observed in Dutch SSRI use shortly after 2003-2004. From 2007-2008, British SSRI use stabilized, whilst Dutch SSRI use diminished to -0.04 DDDs/month (-0.4;0.3). Stratified analyses showed a rapid decrease of -1.2 DDDs/month (-2.1; -1.7) in UK paroxetine use before 2003-2004, but only a minimal change in Dutch paroxetine use (-0.3 DDDs/month -0.8;0.2). Other SSRI use, especially (es)citalopram, increased during 2003-2004 in both countries. Significant reductions in Dutch paroxetine use were observed in pediatrics, adolescents, and young adults after 2003-2004. CONCLUSION: Changes in SSRI use (NL & UK) were associated with the timing of the combined effect of media coverage and regulatory warnings. Our long-term assessment illustrates that changes in SSRI use were temporal, drug-specific and more pronounced in pediatrics and young adults. The twofold increase in SSRI use over one decade indicates that regulatory warnings and media coverage may come and go, but they do not have a significant impact on the overall upward trend of SSRI use as a class in both countries.

[Cardiovascular polypill in high risk patients]. / De cardiovasculaire polypil voor hoogrisicopatiënten.

The initial theoretical concept of a polypill was a fixed-dosed combination pill containing an antiplatelet agent, a cholesterol-lowering agent and multiple blood pressure-lowering agents aimed at the prevention of atherosclerotic vascular disease in the population aged 55 years and up. The reduction in the risk of cardiovascular disease does not depend on the cholesterol level and blood pressure at the start of treatment. The pharmacological reduction in risk factors in individuals with a high risk of atherosclerotic vascular disease is often suboptimal, partly due to the complexity of the guidelines and low adherence to the therapy. A polypill may offer opportunities for improvement. Research has shown that the use of combination products leads to a greater reduction in risk factors than the use of separate substances, possibly through improved adherence to the therapy. The use of a polypill in the prevention of vascular disease in high-risk patients may lead to a more effective reduction in risk, a decrease in costs and a reduction in pharmacological expenditure.

Hybrid reuteransucrase enzymes reveal regions important for glucosidic linkage specificity and the transglucosylation/hydrolysis ratio.

The reuteransucrase enzymes of Lactobacillus reuteri strain 121 (GTFA) and L. reuteri strain ATCC 55730 (GTFO) convert sucrose into alpha-d-glucans (labelled reuterans) with mainly alpha-(1-->4) glucosidic linkages (50% and 70%, respectively), plus alpha-(1-->6) linkages. In the present study, we report a detailed analysis of various hybrid GTFA/O enzymes, resulting in the identification of specific regions in the N-termini of the catalytic domains of these proteins as the main determinants of glucosidic linkage specificity. These regions were divided into three equal parts (A1-3; O1-3), and used to construct six additional GTFA/O hybrids. All hybrid enzymes were able to synthesize alpha-glucans from sucrose, and oligosaccharides from sucrose plus maltose or isomaltose as acceptor substrates. Interestingly, not only the A2/O2 regions, with the three catalytic residues, affect glucosidic linkage specificity, but also the upstream A1/O1 regions make a strong contribution. Some GTFO derived hybrid/mutant enzymes displayed strongly increased transglucosylation/hydrolysis activity ratios. The reduced sucrose hydrolysis allowed the much improved conversion of sucrose into oligo- and polysaccharide products. Thus, the glucosidic linkage specificity and transglucosylation/hydrolysis ratios of reuteransucrase enzymes can be manipulated in a relatively simple manner. This engineering approach has yielded clear changes in oligosaccharide product profiles, as well as a range of novel reuteran products differing in alpha-(1-->4) and alpha-(1-->6) linkage ratios.

Determinants of potential drug-drug interaction associated dispensing in community pharmacies in the Netherlands.

OBJECTIVE: There are many drug-drug interactions (D-DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. METHODS: A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. MAIN OUTCOME MEASURE: The number of times the 11 undesirable interacting drug combinations were dispensed. RESULTS: Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D-DI between macrolide antibiotics and digoxin but not for the other 10 D-DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. CONCLUSION: Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D-DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations.

The effect of completeness of revascularization on event-free survival at one year in the ARTS trial.

OBJECTIVES: We sought to assess the relationship between completeness of revascularization and adverse events at one year in the ARTS (Arterial Revascularization Therapies Study) trial. BACKGROUND: There is uncertainty to what extent degree of completeness of revascularization, using up-to-date techniques, influences medium-term outcome. METHODS: After consensus between surgeon and cardiologist regarding the potential for equivalence in the completeness of revascularization, 1,205 patients with multivessel disease were randomly assigned to either bypass surgery or stent implantation. All baseline and procedural angiograms and surgical case-record forms were centrally assessed for completeness of revascularization. RESULTS: Of 1,205 patients randomized, 1,172 underwent the assigned treatment. Complete data for review were available in 1,143 patients (97.5%). Complete revascularization was achieved in 84.1% of the surgically treated patients and 70.5% of the angioplasty patients (p < 0.001). After one year, the stented angioplasty patients with incomplete revascularization showed a significantly lower event-free survival than stented patients with complete revascularization (i.e., freedom from death, myocardial infarction, cerebrovascular accident and repeat revascularization) (69.4% vs. 76.6%; p < 0.05). This difference was due to a higher incidence of subsequent bypass procedures (10.0% vs. 2.0%; p < 0.05). Conversely, at one year, bypass surgery patients with incomplete revascularization showed only a marginally lower event-free survival rate than those with complete revascularization (87.8% vs. 89.9%). CONCLUSIONS: Complete revascularization was more frequently accomplished by bypass surgery than by stent implantation. One year after bypass, there was no significant difference in event-free survival between surgically treated patients with complete revascularization and those with incomplete revascularization, but patients randomized to stenting with incomplete revascularization had a greater need for subsequent bypass surgery.