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BackgroundScaffold-free cell-dense implants, termed “cell sheets”, are routinely fabricated using temperature-responsive commercial cell culture surfaces. In vivo regenerative capacity of human juvenile cartilage-derived chondrocyte (JCC) sheets is reported in both human clinical studies and nude rat defect models. How human cell source variables affect sheet tissue regeneration remains unelucidated.PurposeTo evaluate the variation of detailed histological neo-cartilage outcomes in an established rat defect model treated with human JCC sheets fabricated from various donors and different JCC passages.Study DesignDescriptive laboratory study.MethodsJCCs were isolated from 8 amputated human polydactylous digits. Passage 2 (P2) JCC sheets from all donors and P9 JCC sheets from one donor were transplanted into nude rat chondral defects for 4 weeks. Defect-only group served as control. Histological samples were stained for safranin-O, collagen 1 (COL1), and collagen 2 (COL2). Modified O’Driscoll scores, %COL1 and %COL2 areas, and COL2/1 ratios were applied for histological semi-quantitative evaluations. (1) All samples were scored and correlation coefficients for each score calculated. (2) Donors treated with P2 JCC sheets were divided into “more effective” and “less effective” groups based on these scores. Then, differences between each group in each category of modified O’Driscoll scoring were evaluated. (3) Scores of P2 and P9 samples from the same JCC donor were compared.Results(1) Mean modified O’Driscoll score, IHC %COL1 and COL2 areas, and COL2/1 ratio was 20.7±3.8, 37.9±27.5, 63.1±30.1, and 3.9±4.0, respectively. Modified O’Driscoll scores were negatively correlated with %COL1 area, and positively correlated with %COL2 area and COL2/1 ratio. (2) Four of 8 donors exhibited significantly higher modified O’Driscoll scores and %COL2 areas compared to the defect-only control group. JCC donors were divided into two groups by average score values: groups 3, 4, 6, and 7 (group ‘more effective’) and groups 1, 2, 5, and 8 (group less effective’). Significant differences between the two groups were observed in Modified O’Driscoll categories of “Nature of predominant”, “Reconstruction of subchondral bone”, and “Safranin-O staining”. (3) Modified O’Driscoll scores and COL2/1 ratio for JCC P2 were significantly higher than that from P9.ConclusionThe combined histological evaluation method employed is useful for detailedin vivoefficacy assessments of cartilage defect regeneration models. The analysis demonstrated that regenerative effects with JCC sheets varied both by JCC donor and passage number. Variations in histological evaluations among JCC donors were correlated to the quality of regenerated cartilage hyaline structure and subchondral bone remodeling observed in the nude rat defect model.Clinical RelevanceThis study provides a useful screening and prediction algorithm for cartilage regenerative success from human cell-derived implants in a rodent defect model.What is known about the subjectHuman juvenile cartilage-derived chondrocyte (JCC) sheets have shown safety and cartilage regenerative capacity in both nude rat chondral defects and a recent limited allogenic human clinical research study. Allogenic cell source variability is known to affect cell-based cartilage regeneration outcomes. Few predictive correlates exist to predict cell source regenerative success. Both Passage 2 (P2) and Passage 9 (P9) JCC-derived chondrogenic pellets exhibit strong characteristic safranin-O staining, but cultured P9 cultured pellet size is smaller than that of P2 pellets.What this study adds to existing knowledgeCartilage regenerative effects vary highly with banked cell source. Current cartilage regenerative strategies in preclinical models do not predict human performance and are clinically unreliable; few off-the-shelf, scalable “living” options are available. Cartilage regeneration using banked human JCC sheets represents a scalable, allogenic, scaffold-free approach now successfully tested both in nude rat and human chondral defects. This study shows that histological evaluation of sheets from several JCC donor demonstrated variable regenerated cartilage hyaline structure and subchondral bone remodeling in a nude rat across donor and passage. Tools to better predict cell-based cartilage regenerative reliability by screening banked allogenic human cell sources in a rat model are described.

Vaccines are essential to ensuring a nation’s health, wellbeing and prosperity. After the coronavirus pandemic commenced, the Australian Government introduced social restrictions to constrain virus transmission, seeing significant economic impacts. Reflecting the extraordinary circumstances, subsequent vaccination rollout forwent usual health technology assessment (HTA) processes, facilitating restrictions removal and leading to societal and economic recovery. However, in ‘usual’ circumstances, HTA may not consider such broader effects of vaccines, making it challenging for them to achieve timely funding. We used detailed modelling to compare economic impacts under continued lockdowns against population-wide vaccination rollout between January 2020 and June 2023 and examined global HTA vaccine evaluation methodologies and efforts to develop broader valuation approaches. Australian gross domestic product reduces by approximately AUD 395 billion with lockdowns. With vaccination rollout, this effect is approximately AUD 214bn, a positive incremental impact of AUD 181bn. Vaccination contributes to large estimated positive effects for tourism (AUD 28bn) and education (AUD 26bn) exports, employment (142,000 jobs) and government finances (AUD 259bn). Conversely, global HTA methods generally only consider direct patient health outcomes and healthcare system-related costs, with broader effects usually not impacting funding decisions. Our results suggest that recent efforts to propose broader HTA valuation frameworks warrant further policy consideration.

Magnetic Resonance Imaging (MRI) is increasingly a fundamental component of the diagnostic pathway across a range of conditions. Historically, the presence of a cardiac implantable electronic device (CIED) has been a contraindication for MRI, however, development ofMR Conditionaldevices that can be scanned under strict protocols has facilitated the provision of MRI for patients. Additionally, there is growing safety data to support MR scanning in patients with CIEDs that do not have MR safety labelling or withMR ConditionalCIEDs where certain conditions are not met, where the clinical justification is robust. This means that almost all patients with cardiac devices should now have the same access to MRI scanning in the National Health Service as the general population. Provision of MRI to patients with CIED, however, remains limited in the UK, with only half of units accepting scan requests even for patients withMR ConditionalCIEDs. Service delivery requires specialist equipment and robust protocols to ensure patient safety and facilitate workflows, meanwhile demanding collaboration between healthcare professionals across many disciplines. This document provides consensus recommendations from across the relevant stakeholder professional bodies and patient groups to encourage provision of safe MRI for patients with CIEDs.

Objectives Deliberative processes for health technology assessment (HTA) are intended to facilitate participatory decision making, using discussion and open dialogue between stakeholders. Increasing attention is being given to deliberative processes, but guidance is lacking for those who wish to design or use them. Health Technology Assessment International (HTAi) and ISPOR—The Professional Society for Health Economics and Outcomes Research initiated a joint Task Force to address this gap. Methods The joint Task Force consisted of fifteen members with different backgrounds, perspectives, and expertise relevant to the field. It developed guidance and a checklist for deliberative processes for HTA. The guidance builds upon the few, existing initiatives in the field, as well as input from the HTA community following an established consultation plan. In addition, the guidance was subject to two rounds of peer review. Results A deliberative process for HTA consists of procedures, activities, and events that support the informed and critical examination of an issue and the weighing of arguments and evidence to guide a subsequent decision. Guidance and an accompanying checklist are provided for (i) developing the governance and structure of an HTA program and (ii) informing how the various stages of an HTA process might be managed using deliberation. Conclusions The guidance and the checklist contain a series of questions, grouped by six phases of a model deliberative process. They are offered as practical tools for those wishing to establish or improve deliberative processes for HTA that are fit for local contexts. The tools can also be used for independent scrutiny of deliberative processes.

Glioblastomas are known to be highly therapy resistant tumors. The description of tumor microtubes (TMs) as long cellular protrusions that connect glioblastoma cells to a network resistant against all standard therapies advanced the basic biological understanding of the disease and offers a new therapeutic target. An antisense oligonucleotide (ASO) against the production of a protein involved in formation and function of TMs was developed and tested in a xenograft mouse model of human glioblastoma cells. After the implantation of fluorescent tumor cells under a chronic cranial window and the establishment of the tumor, the ASO treatment was started with a continuous micropump application directly into the central nervous system (CNS) and treatment effects were observed in a two-photon microscope. Furthermore, co-treatment with irradiation was tested and tumor size as well as protein expression evaluated in and ex vivo. This led to the conclusion that the setup of combined continuous pump application and two photon microscopy is technically feasible and tolerable. It offers the possibility of applying compounds directly into the CNS under live and longitudinal readouts. The fluorescently tagged ASO was traced in the brain parenchyma over weeks proving a high stability of the compound. In combination with radiotherapy, animals treated with the active ASO against the protein of formation and function of TMs showed a smaller tumor size than animals treated with radiotherapy and the non-targeting ASO. The targeted protein was expressed less in the treated animals then the animals receiving the control ASO and the extend of protein expression correlated with tumor size. Hence, after successful therapies with ASOs in other neurologic diseases and the need for better therapeutic options for glioblastoma patients, the development of an ASO against a protein involved in the TM formation and function offers a new therapeutic option with high translational potential.

2562 Background: Anti-PD-L1 antibodies are well-established as potent immune effectors in solid tumors expressing PD-L1 and demonstrate binding to these tumor cells within the TME. By contrast, due to the ubiquitous expression of CD47 on normal cells and tissues, anti-CD47 therapeutic agents with an active antibody Fc can lead to serious dose-limiting toxicities and profound biodistribution problems. To overcome these issues, we have generated LB101, a next-generation conditionally activated PD-L1xCD47 bispecific mAb with two anti-CD47 domains blocked by two further anti-PD-L1 domains, linked by two proprietary IgG-derived hinges, which inhibit CD47 interactions in the periphery, but are degraded in the PD-L1+ TME, thereby activating CD47 blockade to induce antibody-dependent cellular phagocytosis (ADCP). Methods: An IgG1-based, conditionally activated bispecific molecule was examined in binding, phagocytosis, PD-L1 blocking and flow cytometry assays. Efficacy analyses were performed in an hPD-L1+ syngeneic model in hPD-L1+/hPD1+ C57BL/6 mice, and preliminary safety and exposure analyses were completed in monkey. Results: In its intact locked form, LB101 exhibited anti-PD-L1 assay potency similar to atezolizumab. CD47 binding was only observed for LB101 after unlocking by hinge linker cleavage, leading to strongly enhanced ADCP by human CD14+ cells. In monkey, plasma stability of the locked construct was established with a PK profile mimicking that of a typical PD-L1 mAb. In the MC38 mouse model, systemically administered LB101 monotherapy delivered at equimolar dose to atezolizumab, led to no anemia, weight-loss, or overt toxicity. Monotherapy LB101 exhibited greatly improved efficacy and durability of response (14/16 tumors eradicated) over isotype control IgG (0/16) and atezolizumab (1/16). The CD47 naked parent IgG1 mAb was not tolerated in mouse, with 100% lethality above 2mg/kg. In rechallenge experiments, all naïve mice established tumors rapidly while none of the mice from groups with prior LB101-induced regressions exhibited tumor growth. Conclusions: Single agent LB101 immunotherapy delivered systemically in a difficult to treat syngeneic mouse model resulted in PD-L1 directed, local tumor-specific CD47 effector engagement leading to significant tumor regressions as compared to atezolizumab without overt toxicity. Future developments will focus on developing LB101 as a single agent therapeutic and exploring the potential of LockBody technology in improving the therapeutic index of other anti-cancer biological effectors through conditional activation within the TME.

The CO2 emissions from offshore production of oil and gas are typically less than 5% of the total life cycle emissions of the fossil hydrocarbons, but national reduction targets, CO2 taxes and fees and total value chain decarbonisation are compelling reasons to eliminate them. Reduction is possible through many measures, ranging from well-known like improving energy efficiency to new solutions under development like ammonia fuel cells and compact CO2 capture. The most suitable solution for an installation depends on factors such as platform type, field lifetime, energy demand and CO2 emission profiles, distance of the field from the fuel source, local availability of low carbon energy, whether it is existing or new facility implementation, the degree of CO2 reduction on the facility and the scale of the measure. The measures presented and discussed in this article are efficiency improvement, adding bottoming cycles to open cycles; electrification (from shore, offshore power plants with CCS or offshore wind), hydrogen and ammonia, bio- and synthetic fuels, and onboard CCS. Some measures have no further value when the installations reach end of life, whereas others can facilitate or stimulate further low carbon value chain development. There are still technology gaps that need closing and the abatement cost must be reduced for many of these solutions to come to fruition.

Background There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term ‘surrogate endpoint’ implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. Scope Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). Findings Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. Conclusions Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

Aim: Several recently developed frameworks aim to assess the value of cancer treatments, but the most appropriate metrics remain uncertain. Methods: We use data from the Patient Access to Cancer care Excellence Continuous Innovation Indicators to examine the relationship between hazard ratios (HRs) from clinical trials and dynamic therapeutic value accumulating over time. Results: Our analysis shows that HRs from initial clinical trials poorly predict the eventual therapeutic value of cancer treatments. Conclusion: Relying strongly on HRs from registration trials to predict the long-term success of treatments leaves a lot of the variance unexplained. The Continuous Innovation Indicators offer a complementing, dynamic method to track the therapeutic value of cancer treatments and continuously update value assessments as additional evidence accumulates.

Study Objective To assess the safety and effectiveness of the Minerva Endometrial Ablation System for the treatment of heavy menstrual bleeding in premenopausal women. Design Multicenter, randomized, controlled, international study (Canadian Task Force classification I). Setting Thirteen academic and private medical centers. Patients Premenopausal women (n = 153) suffering from heavy menstrual bleeding (PALM-COEIN: E, O). Intervention Patients were treated using the Minerva Endometrial Ablation System or rollerball ablation. Measurements and Main Results At 1-year post-treatment, study success (alkaline hematin ≤80 mL) was observed in 93.1% of Minerva subjects and 80.4% of rollerball subjects with amenorrhea reported by 71.6% and 49% of subjects, respectively. The mean procedure times were 3.1 minutes for Minerva and 17.2 minutes for rollerball. There were no intraoperative adverse events and/or complications reported. Conclusion The results of this multicenter randomized controlled trial demonstrate that at the 12-month follow-up, the Minerva procedure produces statistically significantly higher rates of success, amenorrhea, and patient satisfaction as well as a shorter procedure time when compared with the historic criterion standard of rollerball ablation. Safety results were excellent and similar for both procedures.

Experts in regulatory and HTA agencies are urging the pharmaceutical industry to make more effort to include patients’ perspectives in the medicine development process to further improve the quality and relevance of evidence of effectiveness and value. Indeed, much of the product development activity within companies is geared around meeting goals for regulatory approvals and market access. Therefore, the pharmaceutical industry has an interest in responding to changes in how these agencies consider evidence and make decisions. Many companies make considerable effort to involve patients during the development process as an essential part of improving the overall efficiency of that process. The pharmaceutical industry is benefiting from insights that improve the efficiency of medicine development, while ensuring patient organisations are able to become involved in regulatory and HTA processes. International and national guidelines provide governance to the process and ensure this involvement will occur transparently, without influence and without any overt promotion of specific products (European Federation of Pharmaceutical Industry Associations 2011; Perfetto et al. 2015). This chapter will review the evolution and value of patient involvement in medicine development and assessment processes, discuss legal constraints on communication between the pharmaceutical industry and patients and the importance of patient education and training.

Objectives: Health technology assessment (HTA) yields information that can be ideally used to address deficiencies in health systems and to create a wider understanding of the impact of different policy considerations around technology reimbursement and use. The structure of HTA programs varies across different jurisdictions according to decision-maker needs. Moreover, conducting HTA requires specialized skills. Effective decision making should include multiple criteria (medical, economic, technical, ethical, social, legal, and cultural) and requires multi-disciplinary teams of experts working together to produce these assessments. A workshop explored the multi-disciplinary skills and competencies required to build an effective and efficient HTA team, with a focus on low- and middle-income settings.Methods: This proceeding summarizes main points from a workshop on capacity building, drawing on presentations and group discussions among attendees including different points of view.Results and Conclusions: The workshop and thus this study would have benefited from a larger variety of stakeholders. Therefore, the conclusions arising from the workshop are not the opinion of a representative sample of HTA professionals. Nonetheless, organizations and speakers were carefully selected to provide a valuable approach to this theme. Thus, these proceedings highlight some of the gaps and needs in the education and training programs offered worldwide and calls for further investigation.

Objectives: The aim of this study was to estimate the relationship between the financial impact of a new drug and the recommendation for reimbursement by the Australian Pharmaceutical Benefits Advisory Committee (PBAC).Methods: Data in the PBAC summary database were abstracted for decisions made between July 2005 and November 2009. Financial impact—the upper bound of the values presented in the PBAC summary database—was categorized as ≤A$0, >A$0 up to A$10 million, A$10 million up to A$30 million, and >A$30 million per year. Descriptive, logistic, survival, and recursive partitioning decision analyses were used to estimate the relationship between the financial impact of a new drug indication and the recommendation for reimbursement. Multivariable analyses controlled for other clinical and economic variables, including cost per quality-adjusted life-year gained.Results: Financial impact was a significant predictor of the recommendation for reimbursement. In the logistic analysis, the odds ratios of reimbursement for drug submissions with financial impacts ≥A$10 million to ≥A$30 million or >A$0 to Conclusions: In Australia, financial impact on the drug budget is an important determinant of whether a new drug is recommended for reimbursement when cost-effectiveness estimates and other clinical and economic variables are controlled.

The recovery of hydrogen from gas mixtures with hydrocarbons may provide a commercial niche for carbon molecular sieve membranes. A potential application is the recovery of hydrogen transmitted with natural gas in a mixed network in a hydrogen economy scenario. Performance data measured on the bench-scale were applied to a techno-economic evaluation of hydrogen recovery and the results were compared to a commercial polyimide membrane's performance. The carbon membranes produced higher purity hydrogen, consumed less energy in separation and achieved competitive specific separation costs under certain conditions. Recovery of 90% of the hydrogen from a feed stream containing 5 mol% hydrogen was feasible in a single stage.

Published data for an operating power plant, the ELCOGAS 315 MWe Puertollano plant, has been used as a basis for the simulation of an integrated gasification combined cycle process with CO 2 capture. This incorporated a fixed site carrier polyvinylamine membrane to separate the CO 2 from a CO-shifted syngas stream. It appears that the modified process, using a sour shift catalyst prior to sulphur removal, could achieve greater than 85% CO 2 recovery at 95 vol% purity. The efficiency penalty for such a process would be approximately 10% points, including CO 2 compression. A modified plant with CO 2 capture and compression was calculated to cost €2320/kW, producing electricity at a cost of 7.6 € cents/kWh and a CO 2 avoidance cost of about €40/tonne CO 2 .

Carbon molecular sieve membranes derived from cellulose–hemicellulose have been evaluated for hydrogen separation from light hydrocarbons. Copper(II) nitrate was added to the precursor in the range of 0–6 wt%, resulting in increased hydrogen/methane permselectivity at the expense of permeability. Carbonization temperature was varied from 400 to 700 °C, with the best performance for membranes produced between 550 and 650 °C. Mixed gas tests with H2, CO2, C1–C4 and N2 showed that these membranes tolerate light hydrocarbons and separated hydrogen with a permeability of about 480 Barrer and hydrogen/methane permselectivity >1000. Hydrogen/carbon dioxide permselectivity was found to be approximately 23 at 25 °C. Transport was activated and an increase of 65 °C doubled the mixed gas hydrogen permeability. Performance was strongly influenced by exposure to air.

Polydimethylsiloxane, surface‐modified glass, unmodified glass, and hollow‐fiber were evaluated as membrane materials for chlorine beneficiation. The purification of industrial grade chlorine and the recovery of chlorine from a tail gas in a chlor‐alkali process were considered. Polydimethylsiloxane (at low temperature) appeared to be a suitable material for both cases. The cost of separation was €0.04/kg Cl2 recovered for Case 1 and €0.07/kg Cl2 for Case 2. The selectivity of the surface‐modified glass is lower and complex, expensive configurations were required. Glass hollow fibers achieved the purity specifications but low permeabilities necessitate large modules.

Three different types of membranes were experimentally evaluated for CO 2 recovery from blast furnace effluents: semi-commercial adsorption selective carbon membranes, in-house tailored carbon molecular sieving membranes, and fixed site carrier (FSC) membranes with amine groups in the polymer backbone for active transport of CO 2 . In the single gas experiments the FSC membranes showed superior selectivity for CO 2 over the other relevant gases (CO, N 2 and H 2 ) and high CO 2 permeance (productivity). In addition, it is easy to process and handle, relatively inexpensive to produce and the water in the feed gas is an advantage rather than a problem, since the membrane must be humidified during operation. Based on these experiments a simulation study of a full scale process was performed. The technology showed notable low energy cost, even when converted to the thermal equivalent. Total costs for the CO 2 recovery unit (CO 2 prepared for pipeline transport) were estimated to be in the range 15.0–17.5 €/tonnes CO 2 .

At a health system level, the importance of patient and public input into healthcare decision making is well recognised. Patient and public involvement not only provides a mechanism to legitimise decisions, but also contributes to improved translation of these decisions into practice, ultimately leading to better patient outcomes. Recent reviews in the health technology assessment space have identified the need for, and increased use of, patient input through systematic methodologies. Yet, what does this mean in practical terms? This paper outlines both short- and longer-term options for strengthening patient input into health technology assessment deliberations. This is particularly important given the planned reforms in this area and the commitment to public consultation as part of the reform process.

Background: Soybeans contain estrogenic isoflavones that may influence plasma concentrations of transforming growth factor � 1 (TGF-� 1) and plasma lipid and hemostatic risk factors for coronary heart disease. Objective: We compared the effects of moderate intakes of soy protein containing intact phytoestrogens (high-isoflavone diet) and soy protein from which most of the phytoestrogens had been extracted (low-isoflavone diet) on active TGF-� 1 concentrations and plasma lipid and hemostatic risk factors for coronary heart disease. Design: A randomized crossover trial was conducted in 22 young, healthy, normolipidemic subjects (5 men and 17 women) who consumed diets providing 56 or 2 mg isoflavones/d for 17 d each with a 25-d washout period between treatments. Fasting blood samples were obtained on days 13 and 14 of each treatment to measure plasma isoflavone, lipid, fibrinogen, and active TGF-� 1 concentrations and factor VII coagulant and plasminogen activator inhibitor type 1 activities. Results: Plasma isoflavone concentrations were 100‐999 times greater after the high-isoflavone diet than after the low-isoflavone diet (P < 0.05). Plasma HDL-cholesterol and apolipoprotein A-I concentrations were 4% (95% CI: 1%, 8%) and 6% (95% CI: 3%, 10%) higher, respectively, after the high-isoflavone diet than after the low-isoflavone diet (P < 0.01 for both). Conclusion: Compared with soy protein from which most of the phytoestrogens have been extracted, soy protein with intact phytoestrogens increases HDL-cholesterol and apolipoprotein A-I concentrations but does not influence LDL-cholesterol, TGF-� 1, or fibrinogen concentrations; factor VII coagulant activity; or plasminogen activator inhibitor type 1 activity in normolipidemic, healthy subjects. Am J Clin Nutr 2002;76:373‐7.

This article presents an analytic tool populated with data from published studies to illustrate the likely impacts of a switch from typical to atypical antipsychotic drugs over a 3-year period on individual, family, and societal outcomes for a U.S. schizophrenia population. Data taken from clinical trials and observational data studies are used. Changes in annual health care costs, schizophrenia symptom days, extrapyramidal symptom (EPS) days, suicide rates, and employment days are estimated. For each 1,000 people treated with typical drugs, the base case scenario gives estimates of annual medical care costs of dollar 28.9 million with 80,253 moderate/severe schizophrenia symptom days and 92,006 EPS days. In the base case scenario, after switching to atypical drugs, schizophrenia symptom days are estimated to decrease up to 33 percent, EPS days up to 50 percent, and total medical care costs up to 19 percent over the 3-year period. Suicide rates fall and employment rates increase. The direction of the impacts remain the same for a wide range of input parameter values used in sensitivity analyses. Thus, switching to atypical drugs will likely reduce total medical care costs and decrease other disease burdens for people with schizophrenia, their families, and society.

When the late Freddie Mercury penned these words (1), perhaps he had in mind bringing innovative medicines and devices to patients more quickly.

We performed a meta-analysis to compare insulin lispro and human regular insulin across a range of outcomes common in modern diabetes management to establish a basis for subsequent economic evaluation. We included all identifiable head-to-head randomized controlled trials, pooling dichotomous and continuous outcomes using appropriate statistical methods. Measures associated with various aspects of glycemic control (preprandial and postprandial glycemic control, glucose excursion, and glycated hemoglobin) and with hypoglycemia were evaluated. Results showed significant differences in favor of insulin lispro in the outcomes associated with postprandial glycemic control without an increase in hypoglycemia. Outcomes associated with fasting glycemic control and overall long-term glycemic control were not significantly different between insulin lispro and human regular insulin. Alternative approaches to the meta-analysis were explored but did not alter the conclusions. Thus our meta-analysis supports the existence of significant differences between insulin lispro and human regular insulin in terms of important postprandial outcome measures in diabetes. In addition, there is a practical differences in injection timing relative to meals: human regular insulin should be administered 30 to 45 minutes before eating, whereas insulin lispro can be administered 15 minutes or less before eating. These differences should be the subject of an economic evaluation to assist in determining the place of insulin lispro in diabetes management.

Patient and public participation in health technology assessment (HTA) of medicines has been cited as an important component of the decision-making structure; however, how to actually achieve meaningful involvement is less understood. Our objectives were to conduct a pilot study to form the basis of future research and to gain insight into how to practically and meaningfully advance patient and public input in HTAs for medicines. Semi-structured interviews (n=13) with informants in Australia (n=7), Canada (n=3), and the UK (n=3) were conducted across agencies and experts (n = 9), as well as patient and advocacy groups (n = 4). Results: This pilot study identified through structured interviews three areas for further consideration. Advancement area 1 indicates that industry could help bring the patient perspective into the HTA process through incorporating patient experiences early in the drug development process and by including qualitative research on patient experiences in HTA dossiers. Advancement area 2 involves recognizing and supporting the role of patient advocacy groups, and making use of their access to the genuine patient perspective and experience of living with the condition in question. Finally, advancement area 3 is the continuous development of HTA systems and processes to better facilitate involvement, increasing transparency and feedback, exploring new options for reaching patients, and focusing on creating an active and informed health consumer. The HTA process is becoming increasingly transparent to patients and the public; however, more effort is required to fully engage patients in the decision-making processes for medicine HTAs. This pilot study identified three key areas for further advancement in this field, and recognized a need for further research in the areas of measuring the impact of patient engagement on decision making in medicine HTAs, as well as the best methods to better prepare patient advocacy groups through HTA education and training. These research recommendations will form the basis of a future study with a larger, more comprehensive sample.

Background Bisphenol A is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol A (uBPA) and increased incidence of reported cardiovascular diagnoses. Methodology/Principal Findings To estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in The Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n = 86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD = 5.96 ng/ml OR = 1.43, CI 1.03 to 1.98, p = 0.033), and near significant for intermediate disease (OR = 1.69, CI 0.98 to 2.94, p = 0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined. Conclusions/Significance BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established.

Comparative effectiveness research (CER) represents the next stage in an evolution of research and knowledge development in regard to medical interventions. In this article we describe the challenges currently facing the innovative pharmaceuticals industry and briefly summarize the history of drug development, as context for the current movement to comparative effectiveness. CER should be considered alongside the wider field of health technology assessment (HTA), and we review the status of both CER and HTA internationally and their role in health policy. Limitations as to what can be achieved with HTA and limitations to the availability of evidence of comparative effectiveness at the time of market authorization provide ongoing challenges to all stakeholders. However, embracing CER is regarded as an essential step for the innovative pharmaceutical industry, as companies strive to more clearly demonstrate the effectiveness of their pipeline products with evidence that is compelling to payers and HTA agencies. Examples are given of how these evolving requirements from regulatory and HTA agencies are impacting on drug development efforts and how one company is responding. Finally, there are signs of increasing understanding and alignment across the various partners in drug development, registration and evaluation, and further suggestions are provided for consideration as the field matures and expands.

Objectives: The aim of this study was to describe the current issues surrounding Coverage with Evidence Development (CED). CED is characterized by restricted coverage for a new technology in parallel with targeted research when the stated goal of the research or data collection is to provide definitive evidence for the clinical or cost-effectiveness impact of the new technology.Methods: Presented here is information summarized and interpreted from presentations and discussions at the 2008 Health Technology Assessment International (HTAi) meeting and additional information from the medical literature. This study describes the differences between CED and other conditional coverage agreements, provides a brief history of CED, describes real-world examples of CED, describes the areas of consensus between the stakeholders, discusses the areas for future negotiation between stakeholders, and proposes criteria to assist stakeholders in determining when CED could be appropriate.Results: Payers could interpret the evidence obtained from a CED program either positively or negatively, and a range of possible changes to the reimbursement status of the new technology may result. Striking an appropriate balance between the demands for prompt access to new technology and acknowledging that some degree of uncertainty will always exist is a critical challenge to the uptake of this innovative form of conditional coverage.Conclusions: When used selectively for innovative procedures, pharmaceuticals, or devices in the appropriate disease areas, CED may provide patients access to promising medicines or technologies while data to minimize uncertainty are collected.

NsrR is a nitric oxide-sensitive regulator of transcription. In Escherichia coli, NsrR is a repressor of the hmp gene encoding the flavohemoglobin that detoxifies nitric oxide. Three other transcription units (ytfE, ygbA, and hcp-hcr) are known to be subject to regulation by NsrR. This chapter describes experimental and statistical protocols used to identify NsrR-binding sites in the E. coli chromosome using chromatin immunoprecipitation and microarray analysis. The methods are applicable, with suitable modifications, to any regulatory protein and any organism.

e17783 Background: Measuring progress in cancer treatment research is complicated by the reality that various stakeholders judge achievements differently, because they have diverse priorities and v...

Objective: To examine the relationship between academic psychiatry and the pharmaceutical industry, focusing on a partnership between academics in Melbourne and Eli Lilly and Company (Lilly Melbourne Academic Psychiatry). Conclusions: Relationships between the pharmaceutical industry and the medical profession (including psychiatry) are under scrutiny as never before. Despite the complex nature of the relationship, the present paper argues that partnerships with external corporations such as pharmaceutical companies are of increasing importance for academic departments of psychiatry and research institutes, in environments in which core funding for tertiary institutes is being reduced. The partnership between Melbourne psychiatric academics and Eli Lilly and Company shows that benefits accrue to both parties, and suggests that there is a worthwhile place for other industry-academic collaborations of a similar nature in Australia.

Improved drug therapy for schizophrenia may represent the best strategy for reducing the costs of schizophrenia and the recurrent chronic course of the disease. Olanzapine and risperidone are atypical antipsychotic agents developed to meet this need. We report a multicenter, double-blind, parallel, 30-week study designed to compare the efficacy, safety, and associated resource use for olanzapine and risperidone in Australia and New Zealand. The study sample consisted of 65 patients who met DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder. Olanzapine-treated patients showed a significantly greater reduction in Positive and Negative Syndrome Scale (PANSS) total, Brief Psychiatric Rating Scale (BPRS) total, and PANSS General Psychopathology scores at endpoint compared to the risperidone-treated patients. Response rates through 30 weeks showed a significantly greater proportion of olanzapine-treated patients had achieved a 20% or greater improvement in their PANSS total score compared to risperidone-treated patients. Olanzapine and risperidone were equivalent in their improvement of PANSS positive and negative scores and Clinical Global Impression-Severity of Illness scale (CGI-S) at endpoint. Using generic and disease-specific measures of quality of life, olanzapine-treated patients showed significant within-group improvement in most measures, and significant differences were observed in favor of olanzapine over risperidone in Quality of Life Scale (QLS) Intrapsychic Foundation and Medical Outcomes Study Short Form 36-item instrument (SF-36) Role Functioning Limitations-Emotional subscale scores. Despite the relatively small sample size, our study suggests that olanzapine has a superior risk:benefit profile compared to risperidone.

This willingness-to-pay (WTP) analysis is the first study of its kind undertaken in Australia to support an application for listing of a new drug on the Australian national formulary. The technique offers the advantage of being able to summarise diverse outcomes of therapy in a single unit of measure. Willingness to pay is used to value benefits in cost—benefit analysis (CBA), and CBA represents an absolute decision rule. An open—ended question with a bid—up approach was used to minimise bias and elicit the maximum amount patients would be willing to pay for insulin lispro. The WTP study incorporated scenarios describing the outcomes from insulin lispro and neutral (regular) insulin, the results from a formal metaanalysis and a description of the injection characteristics of the therapies. A sample of 83 patients with type I or II diabetes mellitus were surveyed using an open questionnaire to determine their maximum willingness to pay for the therapy they preferred. Overall, 92% of patients preferred insulin lispro (referred to as insulin A) and 8% preferred neutral insulin (referred to as insulin B). The incremental benefit per patient was calculated as 452.16 Australian dollars ($A) per year. Insulin lispro was listed on the Australian national formulary at a 36% premium over neutral insulin, so the additional cost per patient would be $A70.32 per year. Therefore, costs were exceeded by the benefits and insulin lispro was deemed to offer a net benefit. A multivariate analysis indicated that those patients who were middle—aged had the strongest preference for insulin lispro.