A Methodological Approach for Measuring the Impact of HTA

There is a lack of evidence concerning the link between HTA and outcomes in terms of health improvements. This work proposes a framework for assessing the impact of HTA. This impact assessment is a necessary step in then better understanding the value for money of HTA bodies. We emphasis that this is still a work in progress. iDSI has developed a theory of change-based framework in order to evaluate the impact the iDSI has on institutional strengthening – leading to ‘better decisions’ for ‘better health’. This framework recognises that there is a complex translation process between better decisions and better health dependent on many assumptions about local factors and systems, including linkage between decisions and budgets, delivery, implementation, and data accuracy. Work has been undertaken over the last 6 months developing a methodological approach for measuring the impact of health technology assessment (HTA). Two case studies are used to illustrate the approach. At the core of impact assessment is a requirement to link causes and effects, to explain ‘how’ and ‘why’ and to identify – and thus improve or adapt – mechanisms leading to impact. Policy makers also want to know ‘to what extent’ or ‘the magnitude of impact’. The framework developed adopts an economic approach nested in theory of change as a means of both quantifying the magnitude of impact (utilising economic models) as well as explaining why and how impact happens (drawing on theory based approaches) in order to reinforce learning as to how to improve our response and optimise the use of HTA to have the greatest impact in a given context. This should also enable us to capture and explain wider impact – perhaps more intangible aspects which cannot be easily quantified. This may also possibly increase policy-makers’ ‘buy-in’

The role of the muscle metaboreflex in patients with chronic disease

Exercising muscle needs a constant supply of oxygen for the aerobic metabolism of carbohydrate and fat, and regulation of the blood supply to muscle during exercise is therefore critical. Heart rate, stroke volume and minute ventilation all increase during exercise, and sympathetic vasoconstriction diverts blood to exercising muscle. It is well recognised that receptors in skeletal muscle play a vital role in the regulation of blood flow, including receptors sensitive to products of anaerobic metabolism such as lactate and hydrogen ions: metaboreceptors. Activation of the muscle metaboreflex signals the need for an increase in blood flow, and leads to an increase in cardiac output, ventilation and sympathetic vasoconstriction to non-essential organs. Exercise intolerance is one of the most disabling symptoms in patients with a range of cardiorespiratory diseases. Abnormalities of skeletal muscle favouring anaerobic metabolism have been documented in both chronic heart failure and chronic obstructive pulmonary disease (COPD), and this is thought to be relevant to exercise limitation in these diseases. Studies looking at patients with chronic heart failure have demonstrated an increase in muscle metaboreflex activity. It is thought that abnormal skeletal muscle generates greater quantities of anaerobic metabolites, leading to increased metaboreceptor activation. This in turn causes an increased sympathetic nervous system and ventilatory response to exercise. Patients with COPD have been shown to demonstrate similar skeletal muscle abnormalities, so we hypothesised that we would also find an increase in muscle metaboreflex activity in this group. It is possible to quantify muscle metaboreflex activity by exercising a small muscle group to fatigue then isolating it from the rest of the circulation with a sphygmomanometer cuff. This traps the metabolic products of exercise in the muscle and leads to prolonged stimulation of metaboreceptors. This can be measured as a sustained increase in blood pressure and ventilation when compared with control recovery without cuff inflation. The aims of this thesis were as follows: (i) to assess if it is possible to quantify the muscle metaboreflex in a group of patients with COPD and to determine whether muscle metaboreflex activity is increased in patients with more severe disease, (ii) to determine whether supplementation with oral creatine monohydrate alters muscle metaboreflex activity, upper limb strength or endurance and respiratory muscle strength in patients with COPD, (iii) to assess the effects of diabetic autonomic neuropathy on muscle metaboreflex function, and (iv) to evaluate whether pulse transit time is of use in the measurement of muscle metaboreflex activity. In our first study, we looked at a group of patients with stable COPD and found that rhythmic forearm exercise followed by post-exercise forearm ischaemia led to a sustained increase in blood pressure and minute ventilation when compared with control recovery. These findings are in keeping with previously published observations in normal subjects and in patients with chronic heart failure. We found that there was no difference in muscle metaboreflex activity between the groups of patients with moderate or severe disease. We then performed a randomised, double-blind, placebo-controlled, crossover trial looking at the effects of loading a group of patients with stable COPD with creatine monohydrate. We demonstrated a small increase in body weight and an increase in peak inspiratory and expiratory mouth pressures, but there were no effects on muscle metaboreflex activity or forearm muscle strength, endurance or recovery. A group of patients with type I diabetes mellitus was then used to study the effects of autonomic neuropathy on muscle metaboreflex function. We found that there was no difference in metaboreflex activity between subjects with diabetic autonomic neuropathy and subjects with diabetes but no evidence of autonomic neuropathy, suggesting that the afferent and efferent limbs of the muscle metaboreflex were intact. Our final study evaluated whether pulse transit time could be used to assess muscle metaboreflex activity. Pulse transit time is defined as the time taken for a pulse wave to travel between two arterial sites, and can be easily and non-invasively measured. It is thought to reflect blood pressure and arterial tone. In a group of healthy subjects, we found that pulse transit time fell with rhythmic handgrip exercise, and post-exercise muscle ischaemia led to a sustained fall in pulse transit time when compared with control recovery. Pulse transit time therefore shows promise in the measurement of muscle metaboreflex activity, but further studies are required. Studies comparing pulse transit time with more invasive measurements such as muscle sympathetic nerve activity would be of particular interest

IDSI Reference Case work stream

This reports on the work undertaken by iDSI on each of the five objectives under the iDSI Reference Case (RC) work stream and on its future use by the Bill and Melinda Gates Foundation. The brief pilot studies’ report gives an overview of each of the pilots and extracts key issues for further RC development under iDSI going forward. The process of piloting the RC revealed that researchers found the RC challenging to fulfil every methodological and reporting standard, even those with substantial experience in economic evaluation in a low and middle income country (LMIC) context. Establishing a requirement that BMGF funded economic evaluation use of the RC ought to be accompanied by extensive efforts to build research capacity in modelling (mathematical, decision analytic) and cost-effectiveness analysis in LMICs

Economic evaluation of integrated new technologies for health and social care: suggestions for policy makers, users and evaluators

With an ageing population there is a move towards the use of assisted living technologies (ALTs) to provide social care and health care services, and to improve service processes. These technologies are at the forefront of the integration of health and social care. However, economic evaluations of ALTs, and indeed economic evaluations of any interventions providing both health benefits and benefits beyond health are complex. This paper considers the challenges faced by evaluators and presents a method of economic evaluation for use with interventions where traditional methods may not be suitable for informing funders and decision makers. We propose a method, combining economic evaluation techniques, that can accommodate health outcomes and outcomes beyond health through the use of a common numeraire. Such economic evaluations can benefit both the public and private sector, firstly by ensuring the efficient allocation of resources. And secondly, by providing information for individuals who, in the market for ALTs, face consumption decisions that are infrequent and for which there may be no other sources of information. We consider these issues in the welfarist, extra-welfarist and capabilities framework, which we link to attributes in an individual production model. This approach allows for the valuation of the health component of any such intervention and the valuation of key social care attributes and processes. Finally, we present a set of considerations for evaluators highlighting the key issues that need to be considered in this type of economic evaluation

Implementation of Bayesian methods in the pharmaceutical industry

This thesis is concerned primarily with the practical implementation of Bayesian methodology within the context of the pharmaceutical industry. The implementation includes the development, where appropriate, of analytic approximations to the posterior distributions of interest and graphical methods for mapping prior assumptions to posterior inference. Two critical areas within pharmaceutical research, critical in the sense of the controversy which they have aroused, have been investigated. First, Bayesian methods for the analysis of two-treatment crossover designs which fell in to disfavour in the late 1970's and early 1980's because of the US Food and Drug Administration's published view that the two-treatment two-period design was not the design of first choice if unequivocal evidence of a treatment effect was required were developed. Each type of design considered and for which methods are developed are illustrated with examples from clinical trials which have already been reported in the medical literature. Second, a Bayesian method is developed whose purpose is to classify test compounds into one of several toxicity classes on the basis of an LD50 estimate. The method is generalised to deal with a non-standard LD50 problem related to the prediction of results from a future LD50 experiment. Both of these applications arose out of a practical consultancy session within the context of a statistics group in the chemical/pharmaceutical industry. As part of the methods required for carrying out these analyses the zeros and weights associated with some non-standard orthogonal polynomial are developed as a result of which a new asymptotic expansion of the Behrens-Fisher density is developed. Further applications of the polynomials orthogonal to t-kernels are developed including problems associated with prediction in clinical trials. A FORTRAN program which has been implemented at a laboratory level within the pharmaceutical toxicology department at CIBA-GEIGY in Switzerland is provided SAS programs for a variety of the analyses developed for the two-treatment crossover designs are provided as are SAS programs for determining the zeros and weights of a number of different classes of orthogonal polynomials

LMC X-1: A New Spectral Analysis of the O-star in the binary and surrounding nebula

We provide new observations of the LMC X-1 O star and its extended nebula structure using spectroscopic data from VLT/UVES as well as H$\alpha$ imaging from the Wide Field Imager on the Max Planck Gesellschaft / European Southern Observatory 2.2m telescope and ATCA imaging of the 2.1 GHz radio continuum. This nebula is one of the few known to be energized by an X-ray binary. We use a new spectrum extraction technique that is superior to other methods to obtain both radial velocities and fluxes. This provides an updated spatial velocity of $\simeq 21.0~\pm~4.8$ km s$^{-1}$ for the O star. The slit encompasses both the photo-ionized and shock-ionized regions of the nebula. The imaging shows a clear arc-like structure reminiscent of a wind bow shock in between the ionization cone and shock-ionized nebula. The observed structure can be fit well by the parabolic shape of a wind bow shock. If an interpretation of a wind bow shock system is valid, we investigate the N159-O1 star cluster as a potential parent of the system, suggesting a progenitor mass of $\sim 60$ M$_{\odot}$ for the black hole. We further note that the radio emission could be non-thermal emission from the wind bow shock, or synchrotron emission associated with the jet inflated nebula. For both wind and jet-powered origins, this would represent one of the first radio detections of such a structure.Comment: 7 Figures, 4 Table

Prophylactic antibiotics for penetrating abdominal trauma

BACKGROUND : Penetrating abdominal trauma occurs when the peritoneal cavity is breached. Routine laparotomy for penetrating abdominal injuries began in the 1800s, with antibiotics first being used in World War II to combat septic complications associated with these injuries. This practice was marked with a reduction in sepsis-related mortality and morbidity. Whether prophylactic antibiotics are required in the prevention of infective complications following penetrating abdominal trauma is controversial, however, as no randomised placebo controlled trials have been published to date. There has also been debate about the timing of antibiotic prophylaxis. In 1972 Fullen noted a 7% to 11% post-surgical infection rate with pre-operative antibiotics, a 33% to 57% infection rate with intra-operative antibiotic administration and 30% to 70% infection rate with only post-operative antibiotic administration. Current guidelines state there is suJicient class I evidence to support the use of a single pre-operative broad spectrum antibiotic dose, with aerobic and anaerobic cover, and continuation (up to 24 hours) only in the event of a hollow viscus perforation found at exploratory laparotomy. OBJECTIVES : To assess the benefits and harms of prophylactic antibiotics administered for penetrating abdominal injuries for the reduction of the incidence of septic complications, such as septicaemia, intra-abdominal abscesses and wound infections. SEARCH METHODS : Searches were not restricted by date, language or publication status. We searched the following electronic databases: the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2019, issue 7 of 12), MEDLINE (OvidSP), Embase (OvidSP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) and PubMed. Searches were last conducted on 23 July 2019. SELECTION CRITERIA : All randomised controlled trials of antibiotic prophylaxis in patients with penetrating abdominal trauma versus no antibiotics or placebo. Data collection and analysis Two authors screened the literature search results independently. MAIN RESULTS : We identified no trials meeting the inclusion criteria. AUTHORS' CONCLUSIONS : There is currently no information from randomised controlled trials to support or refute the use of antibiotics for patients with penetrating abdominal trauma.http://www.cochranelibrary.com2020-12-12am2020Surger

Implementation of Bayesian methods in the pharmaceutical industry

This thesis is concerned primarily with the practical implementation of Bayesian methodology within the context of the pharmaceutical industry. The implementation includes the development, where appropriate, of analytic approximations to the posterior distributions of interest and graphical methods for mapping prior assumptions to posterior inference. Two critical areas within pharmaceutical research, critical in the sense of the controversy which they have aroused, have been investigated. First, Bayesian methods for the analysis of two-treatment crossover designs which fell in to disfavour in the late 1970's and early 1980's because of the US Food and Drug Administration's published view that the two-treatment two-period design was not the design of first choice if unequivocal evidence of a treatment effect was required were developed. Each type of design considered and for which methods are developed are illustrated with examples from clinical trials which have already been reported in the medical literature. Second, a Bayesian method is developed whose purpose is to classify test compounds into one of several toxicity classes on the basis of an LD50 estimate. The method is generalised to deal with a non-standard LD50 problem related to the prediction of results from a future LD50 experiment. Both of these applications arose out of a practical consultancy session within the context of a statistics group in the chemical/pharmaceutical industry. As part of the methods required for carrying out these analyses the zeros and weights associated with some non-standard orthogonal polynomial are developed as a result of which a new asymptotic expansion of the Behrens-Fisher density is developed. Further applications of the polynomials orthogonal to t-kernels are developed including problems associated with prediction in clinical trials. A FORTRAN program which has been implemented at a laboratory level within the pharmaceutical toxicology department at CIBA-GEIGY in Switzerland is provided SAS programs for a variety of the analyses developed for the two-treatment crossover designs are provided as are SAS programs for determining the zeros and weights of a number of different classes of orthogonal polynomials

Emulating Target Trials With Real-World Data to Inform Health Technology Assessment: Findings and Lessons From an Application to Emergency Surgery

Objectives: International health technology assessment (HTA) agencies recommend that real-world data (RWD) are used in some circumstances to add to the evidence base about the effectiveness and cost-effectiveness of health interventions. The target trial framework applies the design principles of randomized-controlled trials to RWD and can help alleviate inevitable concerns about bias and design flaws with nonrandomized studies. This article aimed to tackle the lack of guidance and exemplar applications on how this methodology can be applied to RWD to inform HTA decision making./ Methods: We use Hospital Episode Statistics data from England on emergency hospital admissions from 2010 to 2019 to evaluate the cost-effectiveness of emergency surgery for 2 acute gastrointestinal conditions. We draw on the case study to describe the main challenges in applying the target trial framework alongside RWD and provide recommendations for how these can be addressed in practice./ Results: The 4 main challenges when applying the target trial framework to RWD are (1) defining the study population, (2) defining the treatment strategies, (3) establishing time zero (baseline), and (4) adjusting for unmeasured confounding. The recommendations for how to address these challenges, mainly around the incorporation of expert judgment and use of appropriate methods for handling unmeasured confounding, are illustrated within the case study./ Conclusions: The recommendations outlined in this study could help future studies seeking to inform HTA decision processes. These recommendations can complement checklists for economic evaluations and design tools for estimating treatment effectiveness in nonrandomized studies