Do Health Technology Assessment organisations consider manufacturers' costs in relation to drug price? A study of reimbursement reports.

INTRODUCTION: Drug reimbursement decisions are often made based on a price set by the manufacturer. In some cases, this price leads to public and scientific debates about whether its level can be justified in relation to its costs, including those related to research and development (R&D) and manufacturing. Such considerations could enter the decision process in collectively financed health care systems. This paper investigates whether manufacturers' costs in relation to drug prices, or profit margins, are explicitly mentioned and considered by health technology assessment (HTA) organisations. METHOD: An analysis of reimbursement reports for cancer drugs was performed. All relevant Dutch HTA-reports, published between 2017 and 2019, were selected and matched with HTA-reports from three other jurisdictions (England, Canada, Australia). Information was extracted. Additionally, reimbursement reports for three cases of expensive non-oncolytic orphan drugs prominent in pricing debates in the Netherlands were investigated in depth to examine consideration of profit margins. RESULTS: A total of 66 HTA-reports concerning 15 cancer drugs were included. None of these reports contained information on manufacturer's costs or profit margins. Some reports contained general considerations of the HTA organisation which related prices to manufacturers' costs: six contained a statement on the lack of price setting transparency, one mentioned recouping R&D costs as a potential argument to justify a high price. For the case studies, 21 HTA-reports were selected. One contained a cost-based price justification provided by the manufacturer. None of the other reports contained information on manufacturer's costs or profit margins. Six reports contained a discussion about lack of transparency. Reports from two jurisdictions contained invitations to justify high prices by demonstrating high costs. CONCLUSION: Despite the attention given to manufacturers' costs in relation to price in public debates and in the literature, this issue does not seem to get explicit systematic consideration in the reimbursement reports of expensive drugs.

Psychometric evaluation of the Mental Health Quality of Life (MHQoL) instrument in seven European countries.

INTRODUCTION: To make efficient use of available resources, decision-makers in healthcare may assess the costs and (health) benefits of health interventions. For interventions aimed at improving mental health capturing the full health benefits is an important challenge. The Mental Health Quality of Life (MHQoL) instrument was recently developed to meet this challenge. Evaluating the pyschometric properties of this instrument in different contexts remains important. METHODS: A psychometric evaluation of the MHQoL was performed using existing international, cross-sectional data with 7155 respondents from seven European countries (Denmark, France, Germany, Italy, Portugal, The Netherlands, Portugal and the United Kingdom). Reliability was examined by calculating Cronbach's alpha, a measure of internal consistency of the seven MHQoL dimensions, and by examining the association of the MHQoL sum scores with the MHQoL-VAS scores. Construct validity was examined by calculating Spearman's rank correlation coefficients between the MHQoL sum scores and EQ-5D index scores, EQ-VAS scores, EQ-5D anxiety/depression dimension scores, ICECAP-A index scores and PHQ-4 sum scores. RESULTS: The MHQoL was found to have good internal consistency for all seven countries. The MHQoL sum score and the MHQoL-VAS had a high correlation. Spearman's rank correlation coefficients were moderate to very high for all outcomes. CONCLUSION: Our results, based on data gathered in seven European countries, suggest that the MHQoL shows favourable psychometrical characteristics. While further validation remains important, the MHQoL may be a useful instrument in measuring mental health-related quality of life in the Western European context.

Increasing the Legitimacy of Tough Choices in Healthcare Reimbursement: Approach and Results of a Citizen Forum in The Netherlands.

BACKGROUND: Some studies in the Netherlands have gauged public views on principles for healthcare priority setting, but they fall short of comprehensively explaining the public disapproval of several recent reimbursement decisions. OBJECTIVE: To obtain insight into citizens' preferences and identify the criteria they would propose for decisions pertaining to the benefits package of basic health insurance. METHODS: Twenty-four Dutch citizens were selected for participation in a Citizen Forum, which involved 3 weekends. Deliberations took place in small groups and in plenary, guided by 2 moderators, on the basis of 8 preselected case studies, which participants later compared and prioritized under the premise that not all treatments can or need to be reimbursed. Participants received opportunities to inform themselves through written brochures and live interactions with 3 experts. RESULTS: The Citizen Forum identified 16 criteria for inclusion or exclusion of treatments in the benefits package; they relate to the condition (2 criteria), treatment (11 criteria), and individual characteristics of those affected by the condition (3 criteria). In most case studies, it was a combination of criteria that determined whether or not participants favored inclusion of the treatment under consideration in the benefits package. Participants differed in their opinion about the relative importance of criteria, and they had difficulty in operationalizing and trading off criteria to provide a recommendation. CONCLUSIONS: Informed citizens are prepared to make and, to a certain extent, capable of making reasoned choices about the reimbursement of health services. They realize that choices are both necessary and possible. Broad public support and understanding for making tough choices regarding the benefits package of basic health insurance is not automatic: it requires an investment.

Improvement in the ability to have sex in patients with Peyronie's disease treated with Collagenase Clostridium histolyticum.

Objective: To describe the results of intralesional Collagenase Clostridium histolyticum (CCH) treatment in patients with Peyronie's disease (PD) in real-world setting. PD is characterized by curvature of the erect penis caused by fibrotic tissue in the tunica albuginea. Patients and methods: Patients with stable PD and curvature of 30° to 90° were prospectively enrolled. CCH injections were initially given using a scheme of four cycles of two injections within 48-72 h every 6 weeks. Later using a modified scheme of three injections every 4 weeks, combined with a vacuum erection device (VED) twice daily. All patients were requested to take pictures of the erect penis prior to and following treatment, from above and laterally. Curvature was measured by three independent researchers based on the provided pictures using a goniometer. Furthermore, patients filled in the Peyronie Disease Questionnaire-NL (PDQ-NL) and Patient Reported Outcome Measurement (PROM).The primary outcome was reduction in curvature and the ability to have penetrating sex again. Secondary outcomes include pain scores during injections, changes in PDQ-NL, PROM and complications of CCH treatment. Results: Sixty-three patients were included, mean age was 56.0 years (range 39-70) and mean reduction in curvature 20.6° (SD 10.2, range 5-49); 74.5% of the patients were able to have penetrating sex again following treatment, compared with 41.2% prior to treatment. According to the PROM questions, sexual improvement was seen in 66.7% of patients. The satisfaction rate was 6.8 (SD 1.8). All patients save two recommend treatment. Conclusions: Intralesional treatment with CCH in men with PD leads to a mean curvature improvement of 20.6°. Following treatment, 74.5% of men were able to have sexual intercourse and 54.9% of the couples were satisfied with their sex life. No major complications occurred in the patients treated with CCH. CCH is not available in Europe anymore despite good results.

Comparison of freezing tolerance, compatible solutes and polyamines in geographically diverse collections of Thellungiella sp. and Arabidopsis thaliana accessions.

BACKGROUND: Thellungiella has been proposed as an extremophile alternative to Arabidopsis to investigate environmental stress tolerance. However, Arabidopsis accessions show large natural variation in their freezing tolerance and here the tolerance ranges of collections of accessions in the two species were compared. RESULTS: Leaf freezing tolerance of 16 Thellungiella accessions was assessed with an electrolyte leakage assay before and after 14 days of cold acclimation at 4°C. Soluble sugars (glucose, fructose, sucrose, raffinose) and free polyamines (putrescine, spermidine, spermine) were quantified by HPLC, proline photometrically. The ranges in nonacclimated freezing tolerance completely overlapped between Arabidopsis and Thellungiella. After cold acclimation, some Thellungiella accessions were more freezing tolerant than any Arabidopsis accessions. Acclimated freezing tolerance was correlated with sucrose levels in both species, but raffinose accumulation was lower in Thellungiella and only correlated with freezing tolerance in Arabidopsis. The reverse was true for leaf proline contents. Polyamine levels were generally similar between the species. Only spermine content was higher in nonacclimated Thellungiella plants, but decreased during acclimation and was negatively correlated with freezing tolerance. CONCLUSION: Thellungiella is not an extremophile with regard to freezing tolerance, but some accessions significantly expand the range present in Arabidopsis. The metabolite data indicate different metabolic adaptation strategies between the species.

Towards molecular electronics with large-area molecular junctions.

Electronic transport through single molecules has been studied extensively by academic and industrial research groups. Discrete tunnel junctions, or molecular diodes, have been reported using scanning probes, break junctions, metallic crossbars and nanopores. For technological applications, molecular tunnel junctions must be reliable, stable and reproducible. The conductance per molecule, however, typically varies by many orders of magnitude. Self-assembled monolayers (SAMs) may offer a promising route to the fabrication of reliable devices, and charge transport through SAMs of alkanethiols within nanopores is well understood, with non-resonant tunnelling dominating the transport mechanism. Unfortunately, electrical shorts in SAMs are often formed upon vapour deposition of the top electrode, which limits the diameter of the nanopore diodes to about 45 nm. Here we demonstrate a method to manufacture molecular junctions with diameters up to 100 microm with high yields (> 95 per cent). The junctions show excellent stability and reproducibility, and the conductance per unit area is similar to that obtained for benchmark nanopore diodes. Our technique involves processing the molecular junctions in the holes of a lithographically patterned photoresist, and then inserting a conducting polymer interlayer between the SAM and the metal top electrode. This simple approach is potentially low-cost and could pave the way for practical molecular electronics.

Necessity under construction - societal weighing rationality in the appraisal of health care technologies.

Health care coverage decisions may employ many different considerations, which are brought together across two phases. The assessment phase examines the available scientific evidence, such as the cost-effectiveness, of the technology. The appraisal then contextualises this evidence to arrive at an (advised) coverage decision, but little is known about how this is done.In the Netherlands, the appraisal is set up to achieve a societal weighing and is the primary place where need- and solidarity-related ('necessity') argumentations are used. To elucidate how the Dutch appraisal committee 'constructs necessity', we analysed observations and recordings of two appraisal committee meetings at the National Health Care Institute, the corresponding documents (five), and interviews with committee members and policy makers (13 interviewees in 12 interviews), with attention to specific necessity argumentations.The Dutch appraisal committee constructs necessity in four phases: (1) allowing explicit criteria to steer the process; (2) allowing patient (representative) contributions to challenge the process; (3) bringing new argumentations in from outside and weaving them together; and (4) formulating recommendations to societal stakeholders. We argue that in these ways, the appraisal committee achieves societal weighing rationality, as the committee actively uses argumentations from society and embeds the decision outcome in society.

Broadening the application of health technology assessment in the Netherlands: a worthwhile destination but not an easy ride?

Currently, reimbursement decisions based on health technology assessments (HTA) in the Netherlands mostly concern outpatient pharmaceuticals. The Dutch government aspires to broaden the systematic application of full HTA towards other types of health care in order to optimise the content of the basic benefit package. This paper identifies important challenges for broadening the scope of full HTA to other types of health care. Based on a description of the Dutch reimbursement decision-making process, five important characteristics of outpatient pharmaceuticals were identified, which are all relevant to the successful application of HTA: (i) closed reimbursement system, (ii) absence of alternative policy measures, (iii) existence of marketing authorisation, (iv) identifiable and accountable counterparty, and (v) product characteristics. For a selection of other types of health care, which may be subject to HTA more frequently in the future, deviations from these characteristics of outpatient pharmaceuticals are discussed. The implications of such deviations for performing HTA and the decision-making process are highlighted. It is concluded that broadening the application of HTA will require policy makers to meet both important policy-related and methodological challenges. These challenges differ per health care domain, which may inform policy makers which expansions of the current use of HTA are most feasible.

Organic nonvolatile memory devices based on ferroelectricity.

A memory functionality is a prerequisite for many applications of electronic devices. Organic nonvolatile memory devices based on ferroelectricity are a promising approach toward the development of a low-cost memory technology. In this Review Article we discuss the latest developments in this area with a focus on three of the most important device concepts: ferroelectric capacitors, field-effect transistors, and diodes. Integration of these devices into larger memory arrays is also discussed.

Around the Tables - Contextual Factors in Healthcare Coverage Decisions Across Western Europe.

BACKGROUND: Across Western Europe, procedures and formalised criteria for taking decisions on the coverage (inclusion in the benefits basket or equivalent) of healthcare technologies vary substantially. In the decision documents, which display the justification of, the rationale for, these decisions, national healthcare institutes may employ 'contextual factors,' defined here as situation-specific considerations. Little is known about how the use of such contextual factors compares across countries. We describe and compare contextual factors as used in coverage decisions generally and 4 decision documents specifically in Belgium, England, Germany, and the Netherlands. METHODS: Four group interviews with 3 experts from the national healthcare institute of each country, document and web site analysis, and a workshop with 1 to 2 of these experts per country were followed by the examination of the documents of 4 specific decisions taken in each of the 4 countries, sampled to vary widely in type of technology and decision outcome. RESULTS: From the available decision documents, we conclude that in every country studied, contextual factors are established 'around the table,' ie, in deliberation. All documents examined feature contextual factors, with similar contextual factor patterns leading to similar decisions in different countries. The Dutch decisions employ the widest variety of factors, with the exception of the societal functioning of the patient, which is relatively common in Belgium, England, and Germany. Half of the final decisions were taken in another setting, with the consequence that no documentation was retrievable for 2 decisions. CONCLUSION: First, we conclude that in these countries, contextual factors are actively integrated in the decision document, and that this is achieved in deliberation. Conceptualising contextual factors as both situation-specific and actively-integrated affords insight into practices of contextualisation and provides an encouragement for exchange between decision-makers on more qualitative aspects of decisions. Second, the decisions that lacked a publicly accessible justification of the final decision document raised questions on the decisions' legitimacy. Further research could address patterning of contextual factors, elucidate why some factors may remain implicit, and how decisions without a publicly available decision document may enable or restrain decision-making practice.

Organic non-volatile memories from ferroelectric phase-separated blends.

New non-volatile memories are being investigated to keep up with the organic-electronics road map. Ferroelectric polarization is an attractive physical property as the mechanism for non-volatile switching, because the two polarizations can be used as two binary levels. However, in ferroelectric capacitors the read-out of the polarization charge is destructive. The functionality of the targeted memory should be based on resistive switching. In inorganic ferroelectrics conductivity and ferroelectricity cannot be tuned independently. The challenge is to develop a storage medium in which the favourable properties of ferroelectrics such as bistability and non-volatility can be combined with the beneficial properties provided by semiconductors such as conductivity and rectification. Here we present an integrated solution by blending semiconducting and ferroelectric polymers into phase-separated networks. The polarization field of the ferroelectric modulates the injection barrier at the semiconductor-metal contact. The combination of ferroelectric bistability with (semi)conductivity and rectification allows for solution-processed non-volatile memory arrays with a simple cross-bar architecture that can be read out non-destructively. The concept of an electrically tunable injection barrier as presented here is general and can be applied to other electronic devices such as light-emitting diodes with an integrated on/off switch.

Manipulating the Local Light Emission in Organic Light-Emitting Diodes by using Patterned Self-Assembled Monolayers.

Patterned organic light-emitting diodes are fabricated by using microcontact- printed self-assembled monolayers on a gold anode (see background figure). Molecules with dipole moments in opposite directions result in an increase or a decrease of the local work function (foreground picture), providing a direct handle on charge injection and enabling local modification of the light emission.

Self-assembled-monolayer formation of long alkanedithiols in molecular junctions.

The orientation of alkanedithiol molecules in self-assembled monolayers (SAMs) is of vital importance for their transport properties in molecular junctions. It is demonstrated that a too-low concentration of long alkanedithiols in ethanol leads to the formation of looped molecules, resulting in a 50-fold increase of the current through the SAM. X-ray photoelectron spectroscopy measurements show that high-concentration dithiol solutions result in a preferential standing-up phase. To obtain an almost full standing-up phase of 1,14-tetradecanedithiol (C14) a 30 mM concentration in ethanol is required, whereas a 0.3 mM concentration leads to a highly looped monolayer. The conduction through the full standing-up phase of C14 and C16 is in accordance with the exponential dependence on molecule length as obtained from shorter alkanedithiols.

The bare necessities? A realist review of necessity argumentations used in health care coverage decisions.

CONTEXT: Policy makers and insurance companies decide on coverage of care by both calculating (cost-) effectiveness and assessing the necessity of coverage. AIM: To investigate argumentations pertaining to necessity used in coverage decisions made by policy makers and insurance companies, as well as those argumentations used by patients, authors, the public and the media. METHODS: This study is designed as a realist review, adhering to the RAMESES quality standards. Embase, Medline and Web of Science were searched and 98 articles were included that detailed necessity-based argumentations. RESULTS: We identified twenty necessity-based argumentation types. Seven are only used to argue in favour of coverage, five solely for arguing against coverage, and eight are used to argue both ways. A positive decision appears to be facilitated when patients or the public set the decision on the agenda. Moreover, half the argumentation types are only used by patients, authors, the public and the media, whereas the other half is also used by policy makers and insurance companies. The latter group is more accepted and used in more different countries. CONCLUSION: The majority of necessity-based argumentation types is used for either favouring or opposing coverage, and not for both. Patients, authors, the public and the media use a broader repertoire of argumentation types than policy makers and insurance companies.

Fair Processes for Priority Setting: Putting Theory into Practice Comment on "Expanded HTA: Enhancing Fairness and Legitimacy".

Embedding health technology assessment (HTA) in a fair process has great potential to capture societal values relevant to public reimbursement decisions on health technologies. However, the development of such processes for priority setting has largely been theoretical. In this paper, we provide further practical lead ways on how these processes can be implemented. We first present the misconception about the relation between facts and values that is since long misleading the conduct of HTA and underlies the current assessment-appraisal split. We then argue that HTA should instead be explicitly organized as an ongoing evidence-informed deliberative process, that facilitates learning among stakeholders. This has important consequences for whose values to consider, how to deal with vested interests, how to consider all values in the decision-making process, and how to communicate decisions. This is in stark contrast to how HTA processes are implemented now. It is time to set the stage for HTA as learning.

Dealing with patients facing a history of sexual abuse: A cross-sectional survey among Dutch general practitioners.

BACKGROUND: Sexual abuse (SA) is a common problem. As the primary confidant, the general practitioner (GP) has a valuable role in identifying a history of abuse, specifically with regard to the commonly performed pelvic examination for cervical cancer screening. OBJECTIVES: This study focused on GPs' practice patterns, knowledge, training need and barriers concerning asking patients about SA. Furthermore, it was investigated who performs the cervical smear within the practice and if SA is taken into consideration. METHODS: The authors constructed a 31-item questionnaire, which was sent to a group of 730 Dutch GPs in September 2012. RESULTS: The response rate was 49.3%. Half of the 357 responding GPs asked their patients about SA sometimes. The majority (76.2%) stated they had some knowledge of SA. The most important barriers for not asking were 'no angle or motive for asking' (81.6%), 'presence of third parties' (73.1%), and 'not enough training' (54.1%). In most practices (84.3%), the nurse practitioner (NP) was assigned to perform the cervical smears, of which 34.8% presumably never ask about SA in advance. Additional training was in need according to 68.6%. GPs desired a clinical practice guideline regarding the counselling of SA (83.5%). CONCLUSION: This study showed SA is an under-evaluated problem in general practice, yet GPs are motivated to improve knowledge and counselling skills. NPs perform most of the cervical smears, but the majority never or rarely asked about SA in advance. Educational training and a clinical guideline regarding SA would be appreciated and hence recommended.

Cytokeratin 17 and p63 are markers of the HPV target cell, the cervical stem cell.

BACKGROUND: Basic research on HPV has focused on identifying the genetic changes that lead to cervical carcinoma. However, while focusing on the molecular biology of the cancer, understanding of its cellular biology has lagged: the target cell of the HPV infection is unknown. MATERIALS AND METHODS: In this study we identified the stem cell population of the cervical epithelium by monoclonal antibodies against p63, a homologue of the tumor suppressor gene p53 and cytokeratin 17 (CK17). RESULTS: We noted p63 expression consistently in the nuclei of reserve cells, hyperplasia of the reserve cells and the basal layer of the ectocervical epithelium, while CK17 only stained endocervical reserve cells and reserve cell hyperplasia. CONCLUSION: We conclude that both p63 and CK17 are suitable markers for cervical stem cell identification. Both markers, therefore, qualify for the identification of the HPV target cell.

Synthesis of a Conjugated Macromolecular Initiator for Nitroxide-Mediated Free Radical Polymerization.

Controlled synthesis of rod-coil block copolymers is possible with a new macroinitiator for "living" nitroxide-mediated radical polymerization (NMRP). The synthesis of the new macroinitiator which contains a rodlike, conjugated poly(p-phenylene vinylene) block is described. Electron microscopy imaging indicates microphase separation of the resulting block copolymer when cast from chloroform.

Integrating evidence on patient preferences in healthcare policy decisions: protocol of the patient-VIP study.

BACKGROUND: Despite a strong movement towards active patient involvement in healthcare policy decisions, systematic and explicit consideration of evidence of this research on patient preferences seems limited. Furthermore, little is known about the opinions of several stakeholders towards consideration of research evidence on patient preferences in healthcare policy decisions. This paper describes the protocol for an explorative study on the integration of research on patient preferences in healthcare policy decisions. The study questions: to what extent research evidence on patient preferences is considered in current procedures for healthcare policy decisions; opinions of stakeholders regarding the integration of this type of evidence in healthcare policy decisions; and what could be a decision framework for the integration of such research evidence in healthcare policy decisions. METHODS/DESIGN: The study is divided in three sub-studies, predominantly using qualitative methods. The first sub-study is a scoping review in five European countries to investigate whether and how results of research on patient preferences are considered in current procedures for coverage decisions and clinical practice guideline development. The second sub-study is a qualitative study to explore the opinions of stakeholders with regard to the possibilities for integrating evidence on patient preferences in the process of healthcare decision-making in the Netherlands. The third sub-study is the development of a decision framework for research on patient preferences. The framework will consist of: a process description regarding the place of evidence on patient preferences in the decision-making process; and a taxonomy describing different terminologies and conceptualisations of 'preferences' and an overview of existing methodologies for investigating preferences. The concept framework will be presented to and discussed with experts. DISCUSSION: This study will create awareness regarding the existence and potential value of research evidence on patient preferences for healthcare policy decision-making and provides insight in the methods for investigating patient preferences and the barriers and facilitators for integration of such research in healthcare policy decisions. Results of the study will be useful for researchers, clinical practice guideline developers, healthcare policy makers, and patient representatives.