Modelling the Future Clinical and Economic Burden of Antimicrobial Resistance: The Feasibility and Value of Models to Inform Policy.

Due to the increasing threat to public health and the economy, governments internationally are interested in models to estimate the future clinical and economic burden of antimicrobial resistance (AMR) and to evaluate the cost-effectiveness of interventions to prevent or control resistance and to inform resource-allocation decision making. A widely cited UK report estimated that 10 million additional deaths will occur globally per annum due to AMR by 2050; however, the utility and accuracy of this prediction has been challenged. The precision of models predicting the future economic burden of AMR is dependent upon the accuracy of predicting future resistance rates. This paper reviews the feasibility and value of modelling to inform policy and resource allocation to manage and curb AMR. Here we describe methods used to estimate future resistance in published burden-of-disease models; the sources of uncertainty are highlighted, which could potentially mislead policy decision-making. While broad assumptions can be made regarding some predictable factors contributing to future resistance rates, the unexpected emergence, establishment and spread of new resistance genes introduces substantial uncertainty into estimates of future economic burden, and in models evaluating the effectiveness of interventions or policies to address AMR. Existing reporting standards for best practice in modelling should be adapted to guide the reporting of AMR economic models, to ensure model transparency and validation for interpretation by policymakers.

Value assessment of antimicrobials and the implications for development, access, and funding of effective treatments: Australian stakeholder perspective.

BACKGROUND: The frameworks used by Health Technology Assessment (HTA) agencies for value assessment of medicines aim to optimize healthcare resource allocation. However, they may not be effective at capturing the value of antimicrobial drugs. OBJECTIVES: To analyze stakeholder perceptions regarding how antimicrobials are assessed for value for reimbursement purposes and how the Australian HTA framework accommodates the unique attributes of antimicrobials in cost-effectiveness evaluation. METHODS: Eighteen individuals representing the pharmaceutical industry or policy-makers were interviewed. Interviews were transcribed verbatim, coded, and thematically analyzed. RESULTS: Key emergent themes were that reimbursement decision-making should consider the antibiotic spectrum when assessing value, risk of shortages, the impact of procurement processes on low-priced comparators, and the need for methodological transparency when antimicrobials are incorporated into the economic evaluation of other treatments. CONCLUSIONS: Participants agreed that the current HTA framework for antimicrobial value assessment is inadequate to properly inform funding decisions, as the contemporary definition of cost-effectiveness fails to explicitly incorporate the risk of future resistance. Policy-makers were uncertain about how to incorporate future resistance into economic evaluations without a systematic method to capture costs avoided due to good stewardship. Lacking financial reward for the benefits of narrower-spectrum antimicrobials, companies will likely focus on developing broad-spectrum agents with wider potential use. The perceived risks of shortages have influenced the funding of generic antimicrobials in Australia, with policy-makers suggesting a willingness to pay more for assured supply. Although antibiotics often underpin the effectiveness of other medicines, it is unclear how this is incorporated into economic models.

Estimating the utilisation of unregistered antimicrobials in Australia.

OBJECTIVE: To identify and estimate the usage of unregistered antimicrobial drugs in Australian clinical practice. METHODS: A descriptive pharmaco-epidemiological study, utilising three data sources: analysis of Special Access Scheme (SAS) applications for unregistered antimicrobials included in clinical guidelines over a five year period, analysis of antimicrobials dispensed from South Australian public hospital pharmacy departments over a two year period and analysis of National Antimicrobial Utilisation Surveillance Program (NAUSP) data for reported inpatient usage of unregistered antimicrobials in Australian hospitals over the last 5 years. RESULTS: 59 unregistered antimicrobials were identified using the mixed methods. 18,362 Special Access Scheme applications were submitted between May 2012 and April 2017 to access the 20 unregistered antimicrobials identified in the Therapeutic Guidelines® (eTG complete); 51.4% were determined by the prescriber to be for life-threatening indications. Annual applications more than doubled over the five years. 34 unregistered antimicrobials were dispensed from South Australian public hospitals between July 2015 and June 2017. On average, 1.1% of total antimicrobial usage (Defined Daily Doses) per month was accessed via the SAS, of which 87.7% were for outpatients or discharged patients. 34 unregistered antimicrobials for systemic use identified in the NAUSP database were used in Australian hospitals between 2013 and 2018. CONCLUSION: The use of unregistered antimicrobials in Australian clinical practice is not uncommon. With increasing antimicrobial resistance, there will be a continued reliance on older less-used antimicrobial agents and an increasing need for novel drugs, therefore regulatory pathways need to facilitate security of supply and assurance of medicine quality and safety.

Feasibility of de-linking reimbursement of antimicrobials from sales: the Australian perspective as a qualitative case study.

BACKGROUND: There is a disparity in the economic return achievable for antimicrobials compared with other drugs because of the need for stewardship. This has led to a decline in pharmaceutical companies' willingness to invest in the development of these drugs and a consequent global interest in funding models where reimbursement is de-linked from sales. OBJECTIVES: To explore the perspective of stakeholders regarding the feasibility of de-linked reimbursement of antimicrobials in Australia. METHODS: Semi-structured interviews were conducted with 18 participants sourced from the pharmaceutical industry and individuals representing public-sector payers or regulators. Interviews were transcribed verbatim, coded and thematically analysed using the framework method. RESULTS: Five key themes were identified in the interviews: funding silos are a barrier to de-linking reimbursement; varying levels of supporting evidence are (currently) required for funding depending upon setting; funding status or cost is used as a stewardship tool; a de-linked model may cost more; and concerns regarding governance and access to antimicrobials exist in the private sector. CONCLUSIONS: Australia's current multi-tiered funding of medicines across different levels of government was perceived as a barrier to de-linked reimbursement. Participants felt that the responsibility for antimicrobial funding and stewardship should be integrated and centralized. Implementing a nationally funded de-linked reimbursement model for new antimicrobials would require a review of funding decision-making criteria, given that most MDR infections are off-label indications and could not then be funded through the Australian Pharmaceutical Benefits Scheme. Findings from this study could be applicable to other countries with reimbursement frameworks similar to Australia.

Clinical indications treated with unregistered antimicrobials: regulatory challenges of antimicrobial resistance and access to effective treatment for patients.

Objective Increasing antimicrobial resistance and a concurrent paucity of new antimicrobials marketed increases the risk that patients will develop infections resistant to currently available drugs. This study aimed to determine the range of clinical indications for which unregistered antimicrobials are prescribed at two tertiary hospitals in South Australia to identify any trends over a 2-year period. The effects of recent regulatory changes to the Special Access Scheme (SAS) were assessed. Methods Data were extracted from application forms submitted to the Therapeutic Goods Administration to access unregistered antimicrobials via the SAS pathway at two Australian tertiary hospitals for the period July 2015-June 2017. Average weighted antimicrobial prices were retrieved from the hospital iPharmacy (DXC Technology, Macquarie Park, NSW, Australia) dispensing system. To estimate the effect of a new access pathway (Category C), the SAS classification for each application was retrospectively assessed over time with each regulatory change. Results Between July 2015 and June 2017, 477 SAS applications for 29 different antimicrobials were submitted for 353 patients at the two hospitals. The most common indications were tuberculosis (43.6%) and refractory Helicobacter pylori (10%). Regulatory changes reduced the proportion of applications requiring preapproval for access. Conclusions Although the introduction of a new pathway has decreased the administrative burden when accessing unregistered antimicrobials, this study highlights the range of clinical conditions for which there are no registered drugs available in Australia. What is known about the topic? With increasing antimicrobial resistance and a paucity of novel antimicrobials entering the market, access to older, previously less-used antimicrobials is increasingly important in clinical practice. Accessing unregistered antimicrobials is common practice in Australian hospitals, but the range of clinical indications for which they are used is unclear. What does this paper add? Increasing antimicrobial resistance and a concurrent paucity of new antimicrobials being marketed globally is increasing the risk that patients may develop infections that cannot be treated with registered products. This study describes the range of clinical conditions for which registered antimicrobials are not available or appropriate, illustrating the challenges associated with sustainable access to effective treatments. What are the implications for practitioners? Access to effective antimicrobials in a timely manner is essential for optimal patient outcomes. Reliance on unregistered products is associated with increased risks regarding timely access to safe, quality-assured, effective medicines.

Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review.

PURPOSE: We aimed to assess the clinical value of prenatal testing for cystic fibrosis (CF) and whether ethical considerations would affect endpoint selection. METHODS: To determine effectiveness, we conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and prespecified literature screening, data extraction, and synthesis processes. We conducted a scoping search on ethical considerations. RESULTS: The genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented. CONCLUSION: CF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value TOP primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.

Safety and Efficacy of Wireless pH Monitoring in Patients Suspected of Gastroesophageal Reflux Disease: A Systematic Review.

INTRODUCTION: The primary aim of this systematic review was to determine the safety, technical efficacy, and effectiveness of 48-hour wireless pH monitoring (WM) for gastroesophageal reflux disease (GERD), compared with no pH monitoring in patients who failed to tolerate a catheter. In the absence of eligible studies, the secondary aim was to determine these performance characteristics for WM relative to catheter-based pH monitoring (CBM) in patients suspected of GERD, who are able to tolerate a catheter. METHODS: A protocol was registered on the PROSPERO database (CRD42013005852) before conducting the systematic review, which included the study selection criteria, and critical appraisal methods. Several key databases were searched to identify eligible comparative studies. RESULTS: Chest pain occurred more often with WM compared with CBM; however, other adverse events were reported less frequently with WM. Technical failures, mostly due to attachment failures and early capsule detachments, were 3 times higher with WM, compared with CBM, [pooled relative risk (from meta-analysis)=3.3; 95% confidence interval, 1.63-6.81; I=0%; P=0.012; k=8). The sensitivity and specificity of WM varied widely, depending on type of analysis, monitoring time, capsule placement, reference standard, and diagnostic threshold. DISCUSSION: WM is usually better tolerated than CBM but has more technical problems. Test accuracy was highly variable between studies; therefore, conclusions could not be drawn regarding the performance of the 2 tests. To make meaningful comparisons between WM and CBM a consensus is needed on the diagnostic threshold for GERD, monitoring time, appropriate capsule positioning, and the reference standard.

Impact of the "Linked Evidence Approach" Method on Policies to Publicly Fund Diagnostic, Staging, and Screening Medical Tests.

Background: The linked evidence approach (LEA) is used in health technology assessment (HTA) to evaluate the clinical utility of new medical tests in the absence of direct trial evidence. Objective: To determine whether use of LEA affects decisions to publicly fund medical tests. Methods: Australian HTAs that evaluated medical tests before and after LEA was mandated (in 2005) were screened for eligibility. Data were extracted and the impact of LEA and other possible clinical predictors (selected a priori) on funding decisions was modelled. Regression diagnostics were performed to estimate model fit, model specification, and to inform model selection. The unit of analysis was per clinical indication for each new test, so analyses were adjusted for clustering. Results: 83 HTAs (for 173 clinical indications) were eligible from the 259 screened. When health policy was compared before and after 2005, there was an 11% reduction in overall positive funding decisions, including a 25% decrease in "interim" (coverage with evidence development) funding decisions. The odds of obtaining interim funding reduced by 98% (odds ratio = 0.02, 95% confidence interval = 0.0005, 0.17), but there was no change in the direction of funding decisions (odds ratio = 1.36, 95% confidence interval = 0.62, 3.01). Across both time periods, when LEA was used there was a very strong likelihood that the medical test would not receive interim funding (χ2 = 12.63, df = 1, P = 0.001). For positive funding decisions, the strongest predictors were whether or not the new test would replace an existing test and whether the available evidence was limited. Conclusions: The use of LEA did not predict the direction of funding decisions. Application of the method did predict that a "coverage with evidence development" decision was unlikely. This suggests that LEA may reduce decision-maker uncertainty.

Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: a systematic review and meta-analysis.

Effective off-loading is considered to be an important part of the successful clinical management of diabetic foot ulcers. The aim of this systematic review is to investigate the safety and effectiveness of different off-loading devices for the treatment of diabetic foot ulcers. The medical literature was extensively searched from January 1966 to May 2012. Systematic reviews and controlled studies that compared the use of different off-loading devices formed the evidence base. Studies were critically appraised to determine their risk of methodological bias, and data were extracted. Results were pooled using random effects meta-analysis and tested for heterogeneity. When compared with removable devices, non-removable off-loading devices were found, on average, to be more effective at promoting the healing of diabetic foot ulcers (RRp = 1.43; 95% CI 1.11, 1.84; I(2) = 66.9%; p = 0.001; k = 10). Analysis, stratified by type of removable device, did not detect a statistically significant difference between non-removable off-loading devices and removable cast walkers; however, on average non-removable off-loading devices performed better than therapeutic shoes at promoting the healing of diabetic foot ulcers (RRp = 1.68; 95% CI 1.09, 2.58; I(2) = 71.5%; p = 0.004; k = 6). The two types of non-removable off-loading devices i.e. total contact casts and instant total contact casts (removable cast walker rendered irremovable by securing with bandage or lace), were found to be equally effective (RRp = 1.06; 95% CI 0.88, 1.27; I(2) = 3.3%; p = 0.31; k = 2). In conclusion, non-removable off-loading devices regardless of type, are more likely to result in ulcer healing than removable off-loading devices, presumably because patient compliance with off-loading is facilitated.

Identifying existing health care services that do not provide value for money.

Health systems can be improved appreciably by making them more efficient and accountable, and enhancing the quality of care, without necessarily requiring additional resources. Australia, like other nations, cannot escape making difficult health care choices in the context of resource scarcity, and the challenge of delivering quality care, informed by best available evidence, to an ageing population with multiple comorbidities. An opportunity exists for a cost-saving or cost-neutral agenda of reallocation of resources within the existing health budget, through reducing the use of existing health care interventions that offer little or no benefit relative to the cost of their public subsidy. This would allow reallocation of funding towards interventions that are more cost-effective, maximising health gain. Criteria based on those developed for health technology assessment (HTA) might facilitate the systematic and transparent identification of existing, potentially ineffective practices on which to prioritise candidates for assessment as to their cost-effectiveness. The process could be jointly funded by all relevant stakeholders but centrally administered, with HTA groups resourced to undertake identification and assessment and to liaise with clinicians, consumers and funding stakeholders.

Evidence-based practice in rural and remote clinical practice: where is the evidence?

OBJECTIVE: To critically review the evidence regarding barriers to implementing research findings in rural and remote settings, and the ways those barriers have been addressed. DESIGN: A systematic review that included searching several electronic databases, Internet sites and reference lists of relevant articles, assessment of methodological quality of the studies, and data extraction and analysis where possible. Eligibility for the review was not limited by study design. SETTINGS/PARTICIPANTS: Studies that reported on: (1) barriers to the implementation of evidence by health professionals in rural and remote areas, or (2) interventions for implementing evidence-based practice or an element of evidence-based practice in rural and remote areas. RESULTS: There were no experimental data available on the implementation of research findings in rural and remote clinical settings. The small amounts of empirical research undertaken (surveys) showed that some of the problems experienced by general practitioners were exacerbated by rural and remote location, particularly with relation to isolation, lack of time and locum cover, and poor information technology infrastructure. CONCLUSION: There is a paucity of empirical literature on implementing evidence-based practice in rural and remote settings. This is in contrast to the large amount of literature available on implementing evidence in other clinical settings. A clear finding from the literature was that getting evidence into practice needs to be context-specific and yet very little research has been conducted into the rural and remote context. Research is needed into how evidence can be implemented in contextually specific ways in rural and remote areas.