A stepped-wedge randomised controlled trial to assess efficacy and cost-effectiveness of a care-bundle to prevent falls in older hospitalised patients.

BACKGROUND: Patient accidental falls in a hospital environment are a serious problem for patient safety, and for the additional costs due to associated medical interventions. OBJECTIVE: The endpoints of this study were the assessment of the fall incidence in the hospital before and after the implementation of a multidisciplinary care-bundle, along with a cost-effectiveness evaluation. DESIGN: A stepped-wedge trial was conducted between April 2015 and December 2016 in Bologna University Hospital. METHODS: Incidence rates (IRs) of falls in both the control and intervention periods were calculated. A multilevel mixed-effects generalised linear model with logit link function, adjusted for age, sex, cluster cross-over timing and patients' clinical severity was used to estimate odds ratios (OR) of fall risk of patients of the intervention group respect to the controls.Intervention costs associated with the introduction of the care-bundle intervention were spread between patients per cluster-period-group of exposure. Incremental cost-effectiveness ratio was evaluated using total costs in the intervention and control groups. RESULTS: IRs of falls in control and intervention periods were respectively 3.15 and 2.58 for 1,000 bed-days. After adjustment, the subjects receiving the intervention had a statistically significant reduced risk of falling with respect to those who did not (OR = 0.71, 95% confidence interval: 0.60-0.84). According to the cost-effectiveness analysis, the incremental cost per fall prevented was €873.92 considering all costs, and €1644.45 excluding costs related falls. CONCLUSIONS: Care-bundle had a protective effect on patients, with a statistically significant reduction of the fall risk. This type of intervention appears cost-effective compared to routine practices.

Cost-effective clinical trial design: Application of a Bayesian sequential model to the ProFHER pragmatic trial.

BACKGROUND/AIMS: There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model's potential for delivering value-based research. METHODS: Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model's value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping. RESULTS: We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial's sample size. CONCLUSIONS: Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.

Which valued-based price when patients are heterogeneous?

We use a simple model to study the static and dynamic efficiency of alternative regulation regimes for the reimbursement of medical innovations when responses to a new treatment (effectiveness) are heterogeneous across the eligible population. When the rational behavior of profit-maximizing firms is taken into account, only average value-based prices can ensure both static and dynamic efficiency, but they imply higher expenditure and lower consumer surplus. Ignoring dynamic efficiency, if patients' responses are sufficiently homogeneous, marginal value-based prices may dominate from the payer's perspective. We also present a refinement of average value-based prices that could reverse this result. Overall, the cost of ensuring static and dynamic efficiency is increasing in the degree of heterogeneity. A real-world example is used to illustrate these results.

The impact of managed entry agreements on pharmaceutical prices.

Managed entry agreements (MEAs) have been used for several years, with the aim of curbing the growth of pharmaceutical expenditure and enhancing patient access to innovation. Yet, much remains to be understood about their economic implications. This paper studies the impact of MEAs on list prices, that is, prices before the deduction of any discount. Using a theoretical model, we show that, under most price setting regimes, the introduction of an MEA leads to a higher list price. This is confirmed by our empirical analysis of a sample of 156 medicines in six countries, providing a conservative estimate of the increase in price due to the MEA of 5.9%. A relevant policy implication is that payers may overestimate the financial gains that can be achieved through this  tool.

Job sick leave: Detecting opportunistic behavior.

We utilize a large administrative dataset of sickness leave in Italy (a) to investigate whether private firms are more effective than the public insurer in choosing who to monitor and (b) to study the correlation between potentially opportunistic behavior and the observable characteristics of the employee. We find that private employers are more likely to select into monitoring employees who are fit for work despite being on sick leave, if the public insurer is not supported by any data-driven tool. However, the use of a scoring mechanism, based on past records, allows the public insurer to be as effective as the employer. This result suggests that the application of machine learning to appropriate databases may improve the targeting of public monitoring to detect opportunistic behavior. Concerning the association between observable characteristics and potentially opportunistic behavior, we find that males, employees younger than 50, those on short leaves, or without a history of illness are more likely to be found fit for work.

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17ß-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24-48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin.

Is chest X-ray screening for lung cancer in smokers cost-effective? Evidence from a population-based study in Italy.

BACKGROUND: After implementation of the PREDICA annual chest X-ray (CXR) screening program in smokers in the general practice setting of Varese-Italy a significant reduction in lung cancer-specific mortality (18 %) was observed. The objective of this study covering July 1997 through December 2006 was to estimate the cost-effectiveness of this intervention. METHODS: We examined detailed information on lung cancer (LC) cases that occurred among smokers invited to be screened in the PREDICA study (Invitation-to-screening Group, n = 5815 subjects) to estimate costs and quality-adjusted life-years (QALYs) from LC diagnosis until death. The control group consisted of 156 screening-eligible smokers from the same area, uninvited and unscreened, who developed LC and were treated by usual care. We calculated the incremental net monetary benefit (INMB) by comparing LC management in screening participants (n = 1244 subjects) and in the Invitation-to-screening group versus control group. RESULTS: The average number of QALYs since LC diagnosis was 1.7, 1.49 and 1.07, respectively, in screening participants, the invitation-to-screening group, and the control group. The average total cost (screening + management) per LC case was higher in screening participants (€17,516) and the Invitation-to-screening Group (€16,167) than in the control group (€15,503). Assuming a maximum willingness to pay of €30,000/QALY, we found that the intervention was cost-effective with high probability: 79 % for screening participation (screening participants vs. control group) and 95 % for invitation-to-screening (invitation-to-screening group vs. control group). CONCLUSIONS: Based on the PREDICA study, annual CXR screening of high-risk smokers in a general practice setting has high probability of being cost-effective with a maximum willingness to pay of €30,000/QALY.

Should current criteria for detecting and repairing arteriovenous fistula stenosis be reconsidered? Interim analysis of a randomized controlled trial.

BACKGROUND: The vascular access guidelines recommend that arteriovenous fistulas (AVFs) with access dysfunction and an access blood flow (Qa) <300-500 mL/min be referred for stenosis imaging and treatment. Significant (>50%) stenosis, however, may be detected in a well-functioning AVF with a Qa > 500 mL/min, too, but whether it is worth correcting or not remains to be seen. METHODS: In October 2006, we began an open randomized controlled trial enrolling patients with an AVF with subclinical stenosis and Qa > 500 mL/min, to see how elective stenosis repair [treatment group (TX)] influenced access failure (thrombosis or impending thrombosis requiring access revision), or loss and the related cost compared with stenosis correction according to the guidelines, i.e. after the onset of access dysfunction or a Qa < 400 mL/min [control group (C)]. An interim analysis was performed in July 2012, by which time the trial had enrolled 58 patients (30 C and 28 TX). RESULTS: TX led to a relative risk of 0.47 [95% confidence interval (CI): 0.17-1.15] for access failure (P = 0.090), 0.37 [95% CI: 0.12-0.97] for thrombosis (P = 0.033) and 0.36 [95% CI: 0.09-0.99] for access loss (P = 0.041). In the setting of our study (in which all surgery was performed as in patient procedure) no significant differences in costs emerged between the two strategies. The mean incremental cost-effectiveness ratio for TX was €282 or €321 to avoid one episode of thrombosis or access loss, respectively. CONCLUSIONS: Our interim analysis showed that elective repair of subclinical stenosis in AVFs with Qa > 500 mL/min cost-effectively reduces the risk of thrombosis and access loss in comparison with the approach of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, raising the question of whether the currently recommended criteria for assessing and treating stenosis should be reconsidered.

Optimal decision rules for HTA under uncertainty: a wider, dynamic perspective.

We present a two-period framework, which combines real option and decision-theoretic approaches to health technology assessment under uncertainty. By viewing adoption, treatment and research decisions as a single economic project, we illustrate how their key dimensions affect optimal rules. We consider the results in relation to the existing literature and argue that developments in this direction could contribute substantially to efficiency gains in resource allocation.

R&D and market size: Who benefits from orphan drug legislation?

Since the early 80s, incentives have been introduced to stimulate R&D for rare diseases. We develop a theoretical model to study the impact of push and pull incentives on the intensive and extensive margin of optimal R&D investments. The model describes the mechanisms by which the type of incentives provided may favor R&D for orphan diseases with comparatively high prevalence. In our empirical analysis, we merge data on orphan drug designations by the Food and Drug Administration with Orphanet data on disease characteristics. In line with the theoretical results, we find evidence supporting the idea that the incentives adopted may have contributed substantially to widening the gap between more and less rare diseases classified as orphan. Our theoretical and empirical findings together suggest that, if providing some therapeutic option to patients with very rare diseases is a priority, a revision of the current system of incentives should be considered.

Value-Based Pricing Alternatives for Personalised Drugs: Implications of Asymmetric Information and Competition.

The market for new drugs is changing: personalised drugs will increase the heterogeneity in patients' responses and, possibly, costs. In this context, price regulation will play an increasingly important role. In this article, we argue that personalised medicine opens new scenarios in the relationship between value-based prices, regulation and industry listing strategies. Our focus is on the role of asymmetry of information and competition. We show that, if the firm has more information than the payer on the heterogeneity in patients' responses and it adopts a profit-maximising listing strategy, the outcome may be independent of the choice of the type of value-based price. In this case, the information advantage that the manufacturer has prevents the payer from using marginal value-based prices to extract part of the surplus. However, in a dynamic setting where competition by a new entrant is possible, the choice of the type of value-based price may matter. We suggest that more research should be devoted to the dynamic analysis of price regulation for personalised medicines.

An extension of the real option approach to the evaluation of health care technologies: the case of positron emission tomography.

This paper aims to incorporate option values into the economic evaluation of positron emission tomography (PET). The installation of this equipment requires a substantial capital outlay, while uncertainty, especially regarding the possibility of new applications, is relevant, because the evidence available is still insufficient. Treating the number of examinations to provide as a stochastic variable, the cost-effectiveness analysis is extended to include the value of flexibility both with respect to the timing of investment and to the size of the project. The threshold values of the stochastic variable that ensure the cost-effectiveness of a PET scan according to this approach are obtained as a function of the value of the incremental effectiveness.

Expression patterns of the glial cell line-derived neurotrophic factor, neurturin, their cognate receptors GFRalpha-1, GFRalpha-2, and a common signal transduction element c-Ret in the human skin hair follicles.

BACKGROUND: Glial cell line-derived neurotrophic factor (GDNF) and a related family member, neurturin (NTN), and their cognate receptors (GFRalpha-1 and GFRalpha-2, for GDNF and NTN, respectively) are distal members of the transforming growth factor-beta superfamily. They are involved in the control of murine hair follicle (HF) cycling. This study tests the hypothesis that GDNF and NTN, and their cognate receptors, are expressed in the human HF and their expression varies in the different stages of the HF cycle. METHODS: The expression pattern of these proteins was examined in human HF by immunofluorescence, immunoalkalinephosphatase staining methods, and reverse transcription-polymerase chain reaction (GDNF). The functional effects (GDNF and NTN) were examined in organ culture of the microdissected HFs. RESULTS: GDNF, NTN, GFRalpha-1, GFRalpha-2, and c-Ret proteins were weakly expressed in catagen and telogen HFs. In contrast, they were strongly expressed in the epithelial and mesenchymal compartments of the anagen HF. GDNF gene was transcribed, both in the human scalp skin and in the isolated anagen HFs (reverse transcription-polymerase chain reaction). In HF organ culture, GDNF (but not NTN) increased the number of the proliferating HF keratinocytes (Ki 67 + cells). GDNF partially protected HFs from transforming growth factor-beta2-induced premature catagen transition. LIMITATIONS: None. CONCLUSIONS: GDNF, NTN, GFRalpha-1, GFRalpha-2, and c-Ret proteins are differentially expressed in the different stages of HF cycle. GFRalpha-mediated signaling involves c-Ret and may play a role in human HF biology.

Reorganization of actin cytoskeleton by the phosphoinositide metabolite glycerophosphoinositol 4-phosphate.

Glycerophosphoinositol 4-phosphate (GroPIns-4P) is a biologically active, water-soluble phospholipase A metabolite derived from phosphatidylinositol 4-phosphate, whose cellular concentrations have been reported to increase in Ras-transformed cells. It is therefore important to understand its biological activities. Herein, we have examined whether GroPIns-4P can regulate the organization of the actin cytoskeleton, because this could be a Ras-related function involved in cell motility and metastatic invasion. We find that in serum-starved Swiss 3T3 cells, exogenously added GroPIns-4P rapidly and potently induces the formation of membrane ruffles, and, later, the formation of stress fibers. These actin structures can be regulated by the small GTPases Cdc42, Rac, and Rho. To analyze the mechanism of action of GroPIns-4P, we selectively inactivated each of these GTPases. GroPIns-4P requires active Rac and Rho, but not Cdc42, for ruffle and stress fiber formation, respectively. Moreover, GroPIns-4P induces a rapid translocation of the green fluorescent protein-tagged Rac into ruffles, and increases the fraction of GTP-bound Rac, in intact cells. The activation of Rac by GroPIns-4P was near maximal and long-lasting. Interestingly, this feature seems to be critical in the induction of actin ruffles by GroPIns-4P.

Late-stage pharmaceutical R&D and pricing policies under two-stage regulation.

We present a model combining the two regulatory stages relevant to the approval of a new health technology: the authorisation of its commercialisation and the insurer's decision about whether to reimburse its cost. We show that the degree of uncertainty concerning the true value of the insurer's maximum willingness to pay for a unit increase in effectiveness has a non-monotonic impact on the optimal price of the innovation, the firm's expected profit and the optimal sample size of the clinical trial. A key result is that there exists a range of values of the uncertainty parameter over which a reduction in uncertainty benefits the firm, the insurer and patients. We consider how different policy parameters may be used as incentive mechanisms, and the incentives to invest in R&D for marginal projects such as those targeting rare diseases. The model is calibrated using data on a new treatment for cystic fibrosis.

Control of human hair growth by neurotrophins: brain-derived neurotrophic factor inhibits hair shaft elongation, induces catagen, and stimulates follicular transforming growth factor beta2 expression.

Neurotrophins are important modulators of epithelial-mesenchymal interactions. Previously, we had shown that brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tyrosine kinase B (TrkB) are prominently involved in the control of murine hair follicle cycling. We now show that BDNF and TrkB are also expressed in the human hair follicle in a manner that is both hair cycle dependent and suggestive of epithelial-mesenchymal cross-talk between BDNF-secreting dermal papilla fibroblasts of anagen hair follicles and subpopulations of TrkB+ hair follicle keratinocytes. As functional evidence for an involvement of BDNF/TrkB in human hair growth control, we show in organ-cultured human anagen hair follicles that 50 ng per mL BDNF significantly inhibit hair shaft elongation, induce premature catagen development, and inhibit keratinocyte proliferation. Quantitative real-time rtPCR analysis demonstrates upregulation of the potent catagen inducer, transforming growth factor beta2 (TGFbeta2) by BDNF, whereas catagen induction by BDNF was partially reversible through co-administration of TGFbeta-neutralizing antibody. This suggests that TrkB-mediated signaling promotes the switch between anagen and catagen at least in part via upregulation of TGFbeta2. Thus, human scalp hair follicles are both a source and target of bioregulation by BDNF, which invites to target TrkB-mediated signaling for therapeutic hair growth modulation.

Two-part payments for the reimbursement of investments in health technologies.

The paper studies the impact of alternative reimbursement systems on two provider decisions: whether to adopt a technology whose provision requires a sunk investment cost and how many patients to treat with it. Using a simple economic model we show that the optimal pricing policy involves a two-part payment: a price equal to the marginal cost of the patient whose benefit of treatment equals the cost of provision, and a separate payment for the partial reimbursement of capital costs. Departures from this scheme, which are frequent in DRG tariff systems designed around the world, lead to a trade-off between the objective of making effective technologies available to patients and the need to ensure appropriateness in use.

The timing of adoption of positron emission tomography: a real options approach.

This paper presents the economic evaluation from a hospital's perspective of the investment in positron emission tomography, adopting a real options approach. The installation of this equipment requires a major capital outlay, while uncertainty on several key variables is substantial. The value of several timing strategies, including sequential investment, is determined taking into account that future decisions will be based on the information available at that time. The results show that adopting this approach may have an impact on the timing of investment, because postponing the investment may be optimal even when the Expected Net Present Value of the project is positive.