A systematic review of policies regulating or removing mark-ups in the pharmaceutical supply and distribution chain.

The regulation of mark-ups throughout the pharmaceutical supply and distribution chain may be a valuable approach to control prices of medicines and to achieve broader access to medicines. As part of a wider review, we aimed to systematically determine whether policies regulating mark-ups are effective in managing the prices of pharmaceutical products. We searched for studies published between January 1, 2004 and October 10, 2019, comparing policies on regulating mark-ups against other interventions or a counterfactual. Eligible study designs included randomized trials, and non-randomized or quasi-experimental studies such as interrupted time-series (ITS), repeated measures (RM), and controlled before-after studies. Studies were eligible if they included at least one of the following outcomes: price (or expenditure as a proxy for price and volume), volume, availability or affordability of pharmaceutical products. The quality of the evidence was assessed using the GRADE methodology. A total of 32,011 records were retrieved, seven of which were eligible for inclusion for this review. The limited body of evidence cautiously suggests that policies regulating mark-ups may be effective in reducing medicine prices and pharmaceutical expenditures. However, the design of mark-up regulations is a critical factor for their potential success. Additional research is required to confirm the effects of these policies on the availability, affordability or usage patterns of medicines and in low- and middle-income countries.

Evidence on the effectiveness of policies promoting price transparency - A systematic review.

Policies promoting price transparency may be an important approach to control medicine prices and achieve better access to medicines. As part of a wider review, we aimed to systematically determine whether policies promoting price transparency are effective in managing the prices of pharmaceutical products. We searched for studies published between January 1, 2004 and October 10, 2019, comparing policies promoting price transparency against other interventions or a counterfactual. Eligible study designs included randomized trials, and non-randomized or quasi-experimental studies such as interrupted time-series (ITS), repeated measures (RM), and controlled before-after studies. Studies were eligible if they included at least one of the following outcomes: price (or expenditure as a proxy for price and volume), volume, availability or affordability of pharmaceutical products. The quality of the evidence was assessed using the GRADE methodology. A total of 32011 records were retrieved, two of which were eligible for inclusion. Although based on evidence from a single study, public disclosure of medicine prices may be effective in reducing prices of medicines short-term, with benefits possibly sustained long-term. Evidence on the impact of a cost-feedback approach to prescribers was inconclusive. No evidence was found for impact on the outcomes volume, availability or affordability. The overall lack of evidence on policies promoting price transparency is a clear call for further research.

Economic Burden of Chronic Hand Eczema: A Review.

There has been no extensive synthesis of studies evaluating the cost of chronic hand eczema (CHE). This review evaluated the societal costs, healthcare resource utilisation, missed work time and job loss due to CHE. MEDLINE and 16 other databases and websites were searched in October 2020 for studies meeting prespecified inclusion criteria. Studies conducted in Europe, Australia, New Zealand or the Americas were included. Two reviewers independently assessed titles and abstracts, and full-text papers published in English between 2000 and 2020, for relevance. Data extraction was carried out by one reviewer and checked by a second reviewer. All data were based on costs between 2001 and 2013 but have been inflated to 2020 prices and converted to US dollars and Euros. A total of 30 studies (reported in 33 publications) were included in the synthesis. Mean total societal costs per year per patient ranged from $2549 (€1813) to $10,883 (€7738). Pharmacological therapy was, on average, $28.34 (€20.15) per month in Italy and $36.49 (€25.94) per month for emollients in Switzerland. Yearly treatment costs were $599.05 (€425.92) for drugs, including topical corticosteroids, topical calcineurin inhibitors, other topical treatments and oral treatments, and $178.40 for emollients, in Germany. CHE was associated with hospitalisation costs ranging from $81.86 (€58.20) per patient per month (US) to $105.04 (€74.68) per patient per month (Italy) and $639.59 (€454.75) per year (Germany). Up to 57% of patients took sick leave and up to 25% reported job loss/job change due to CHE. This review confirms the significant cost burden of CHE. Given the paucity of studies estimating the monetary costs of absenteeism, presenteeism and job loss associated with CHE, current mean societal costs are likely underestimated. Uncontrolled disease may also lead to increased costs to patients and society.

Evidence-based searching for health technology assessment: keeping up to date with SuRe Info.

BACKGROUND: Evidence syntheses of all types have their foundation in literature searches. Literature searching is developing in line with the growing use of evidence synthesis and is also informed, as a field of work, by the spirit of being evidence-based. Increasing numbers of research papers about information retrieval are being published, and keeping up to date with the latest developments in this ever more wide-ranging field is demanding. METHODS: Summarized Research in Information Retrieval for HTA (SuRe Info) is a Web site (http://www.sure-info.org) that summarizes research-based information on effective and efficient evidence identification for the different aspects of health technology assessment (HTA) and evidence synthesis. This paper describes the rationale, processes, and challenges of producing SuRe Info and insights into the pace of development in the field of evidence-based information retrieval. The paper also provides scenarios suggesting how SuRe Info can help searchers in their daily work and with specific questions. RESULTS: SuRe Info currently comprises seventeen chapters, falling into two categories: (i) chapters about general search methods relating to all types of research and (ii) chapters summarizing the methods to use when searching for specific aspects of HTA (as defined in the HTA Core Model® by the European Network for Health Technology Assessment (EUnetHTA)). CONCLUSIONS: SuRe Info is not a substitute for methods handbooks, but by providing an overview of current research evidence for major issues in information retrieval in HTA, it helps searchers in this field to keep abreast of the latest research.

Systematic reviews of ten pharmaceutical pricing policies - a research protocol.

BACKGROUND: High prices of pharmaceutical products are an increasing challenge in high- and low-income countries. Governments in many countries have implemented pricing policies to ensure affordability of medicines to patients and healthcare systems. The World Health Organization published in 2015 the Guideline on Country Pharmaceutical Pricing Policies, which was based on a series of evidence reviews in the preceding years.As part of the ongoing update of this guideline, we present a protocol for 10 systematic literature reviews on pharmaceutical pricing policies to be covered by the updated guideline. METHODS: The systematic literature reviews will be undertaken according to the principles embodied in the Cochrane Handbook and Centre for Reviews and Dissemination. The interventions studied are pharmaceutical pricing policies implemented by public institutions or a group of purchasing organizations/individuals (e.g. health services). Studies reporting price, volume, availability and/or affordability as the primary outcomes will be eligible for inclusion. Studies in any country or jurisdiction, in any language and in any setting published in 2004 or later are eligible. Eligible study designs are randomized and non-randomized trials, and observational studies including cohort studies, panel data analyses, comparative time series design (including interrupted time-series and repeated measures studies), and controlled before-after studies. A list of 21 databases of peer-reviewed and grey literature will be searched, along with supplementary searches of relevant national and international organizational and governmental websites. Risk of bias will be assessed according to the Cochrane Effective Practice and Organisation of Care (EPOC) guidelines. A summary table according to the EPOC Worksheets for preparing a Summary of Findings table (SoF) using GRADE will be provided. DISCUSSION: The results of the review will be used as part of the update of the WHO Guideline on Country Pharmaceutical Pricing Policies. The current protocol may serve as an example for performing systematic literature reviews to inform policy makers.

WHICH DATABASES SHOULD BE USED TO IDENTIFY STUDIES FOR SYSTEMATIC REVIEWS OF ECONOMIC EVALUATIONS?

OBJECTIVES: This study investigated which databases and which combinations of databases should be used to identify economic evaluations (EEs) to inform systematic reviews. It also investigated the characteristics of studies not identified in database searches and evaluated the success of MEDLINE search strategies used within typical reviews in retrieving EEs in MEDLINE. METHODS: A quasi-gold standard (QGS) set of EEs was collected from reviews of EEs. The number of QGS records found in nine databases was calculated and the most efficient combination of databases was determined. The number and characteristics of QGS records not retrieved from the databases were collected. Reproducible MEDLINE strategies from the reviews were rerun to calculate the sensitivity and precision for each strategy in finding QGS records. RESULTS: The QGS comprised 351 records. Across all databases, 337/351 (96 percent) QGS records were identified. Embase yielded the most records (314; 89 percent). Four databases were needed to retrieve all 337 references: Embase + Health Technology Assessment database + (MEDLINE or PubMed) + Scopus. Four percent (14/351) of records could not be found in any database. Twenty-nine of forty-one (71 percent) reviews reported a reproducible MEDLINE strategy. Ten of twenty-nine (34.5 percent) of the strategies missed at least one QGS record in MEDLINE. Across all twenty-nine MEDLINE searches, 25/143 records were missed (17.5 percent). Mean sensitivity was 89 percent and mean precision was 1.6 percent. CONCLUSIONS: Searching beyond key databases for published EEs may be inefficient, providing the search strategies in those key databases are adequately sensitive. Additional search approaches should be used to identify unpublished evidence (grey literature).

Challenges of identifying unpublished data from clinical trials: Getting the best out of clinical trials registers and other novel sources.

Clinical trial data are essential for assessments of the effectiveness of health care interventions. Information about ongoing or completed, but not yet formally published, trials has been more difficult to identify until the development of clinical trials registers and portals. This paper summarises research evidence on identifying sources of trial data, how and when to search those sources, and which future developments may enhance access to and retrieval of unpublished trial evidence. We conducted a literature search for relevant studies and provide a narrative review of the evidence from these studies. Clinical trial data can be found in resources including clinical trials registers, regulatory agency sources, health technology assessment websites and manufacturers' websites, and submissions for regulatory approval. The challenges of searching these resources are described. Trials registers are relatively unsophisticated in terms of their search interfaces, and searchers need to adapt to each individual register. There is overlap across registers, but little research on the degree and nature of overlap and how best to search. Despite these challenges, trials registers and other resources can be rich sources of additional unique trial data, which may not be available from journal reports. New initiatives, such as OpenTrials, aim to consolidate and link all structured data and documentation related to clinical trials. No single resource gives access to all trials, and multiple registers should be searched as sensitively as possible. Searching is challenging and should be adequately resourced. Information specialists should monitor new developments which may reduce the challenges over the coming years.

Assessing the performance of methodological search filters to improve the efficiency of evidence information retrieval: five literature reviews and a qualitative study.

BACKGROUND: Effective study identification is essential for conducting health research, developing clinical guidance and health policy and supporting health-care decision-making. Methodological search filters (combinations of search terms to capture a specific study design) can assist in searching to achieve this. OBJECTIVES: This project investigated the methods used to assess the performance of methodological search filters, the information that searchers require when choosing search filters and how that information could be better provided. METHODS: Five literature reviews were undertaken in 2010/11: search filter development and testing; comparison of search filters; decision-making in choosing search filters; diagnostic test accuracy (DTA) study methods; and decision-making in choosing diagnostic tests. We conducted interviews and a questionnaire with experienced searchers to learn what information assists in the choice of search filters and how filters are used. These investigations informed the development of various approaches to gathering and reporting search filter performance data. We acknowledge that there has been a regrettable delay between carrying out the project, including the searches, and the publication of this report, because of serious illness of the principal investigator. RESULTS: The development of filters most frequently involved using a reference standard derived from hand-searching journals. Most filters were validated internally only. Reporting of methods was generally poor. Sensitivity, precision and specificity were the most commonly reported performance measures and were presented in tables. Aspects of DTA study methods are applicable to search filters, particularly in the development of the reference standard. There is limited evidence on how clinicians choose between diagnostic tests. No published literature was found on how searchers select filters. Interviewing and questioning searchers via a questionnaire found that filters were not appropriate for all tasks but were predominantly used to reduce large numbers of retrieved records and to introduce focus. The Inter Technology Appraisal Support Collaboration (InterTASC) Information Specialists' Sub-Group (ISSG) Search Filters Resource was most frequently mentioned by both groups as the resource consulted to select a filter. Randomised controlled trial (RCT) and systematic review filters, in particular the Cochrane RCT and the McMaster Hedges filters, were most frequently mentioned. The majority indicated that they used different filters depending on the requirement for sensitivity or precision. Over half of the respondents used the filters available in databases. Interviewees used various approaches when using and adapting search filters. Respondents suggested that the main factors that would make choosing a filter easier were the availability of critical appraisals and more detailed performance information. Provenance and having the filter available in a central storage location were also important. LIMITATIONS: The questionnaire could have been shorter and could have included more multiple choice questions, and the reviews of filter performance focused on only four study designs. CONCLUSIONS: Search filter studies should use a representative reference standard and explicitly report methods and results. Performance measures should be presented systematically and clearly. Searchers find filters useful in certain circumstances but expressed a need for more user-friendly performance information to aid filter choice. We suggest approaches to use, adapt and report search filter performance. Future work could include research around search filters and performance measures for study designs not addressed here, exploration of alternative methods of displaying performance results and numerical synthesis of performance comparison results. FUNDING: The National Institute for Health Research (NIHR) Health Technology Assessment programme and Medical Research Council-NIHR Methodology Research Programme (grant number G0901496).

The costs of functional gastrointestinal disorders and related signs and symptoms in infants: a systematic literature review and cost calculation for England.

OBJECTIVES: To estimate the cost of functional gastrointestinal disorders (FGIDs) and related signs and symptoms in infants to the third party payer and to parents. STUDY DESIGN: To estimate the cost of illness (COI) of infant FGIDs, a two-stage process was applied: a systematic literature review and a COI calculation. As no pertinent papers were found in the systematic literature review, a 'de novo' analysis was performed. For the latter, the potential costs for the third party payer (the National Health Service (NHS) in England) and for parents/carers for the treatment of FGIDs in infants were calculated, by using publicly available data. In constructing the calculation, estimates and assumptions (where necessary) were chosen to provide a lower bound (minimum) of the potential overall cost. In doing so, the interpretation of the calculation is that the true COI can be no lower than that estimated. RESULTS: Our calculation estimated that the total costs of treating FGIDs in infants in England were at least £72.3 million per year in 2014/2015 of which £49.1 million was NHS expenditure on prescriptions, community care and hospital treatment. Parents incurred £23.2 million in costs through purchase of over the counter remedies. CONCLUSIONS: The total cost presented here is likely to be a significant underestimate as only lower bound estimates were used where applicable, and for example, costs of alternative therapies, inpatient treatments or diagnostic tests, and time off work by parents could not be adequately estimated and were omitted from the calculation. The number and kind of prescribed products and products sold over the counter to treat FGIDs suggest that there are gaps between treatment guidelines, which emphasise parental reassurance and nutritional advice, and their implementation.

PERFORMANCE OF OVID MEDLINE SEARCH FILTERS TO IDENTIFY HEALTH STATE UTILITY STUDIES.

OBJECTIVES: This study was designed to assess the sensitivity of three Ovid MEDLINE search filters developed to identify studies reporting health state utility values (HSUVs), to improve the performance of the best performing filter, and to validate resulting search filters. METHODS: Three quasi-gold standard sets (QGS1, QGS2, QGS3) of relevant studies were harvested from reviews of studies reporting HSUVs. The performance of three initial filters was assessed by measuring their relative recall of studies in QGS1. The best performing filter was then developed further using QGS2. This resulted in three final search filters (FSF1, FSF2, and FSF3), which were validated using QGS3. RESULTS: FSF1 (sensitivity maximizing) retrieved 132/139 records (sensitivity: 95 percent) in the QGS3 validation set. FSF1 had a number needed to read (NNR) of 842. FSF2 (balancing sensitivity and precision) retrieved 128/139 records (sensitivity: 92 percent) with a NNR of 502. FSF3 (precision maximizing) retrieved 123/139 records (sensitivity: 88 percent) with a NNR of 383. CONCLUSIONS: We have developed and validated a search filter (FSF1) to identify studies reporting HSUVs with high sensitivity (95 percent) and two other search filters (FSF2 and FSF3) with reasonably high sensitivity (92 percent and 88 percent) but greater precision, resulting in a lower NNR. These seem to be the first validated filters available for HSUVs. The availability of filters with a range of sensitivity and precision options enables researchers to choose the filter which is most appropriate to the resources available for their specific research.

Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). PATIENTS AND METHODS: Information sources were searched for blinded randomised controlled trials (RCTs), of ≥2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random-effects models were used to synthesise the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. RESULTS: In all, 56 RCTs were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments were more efficacious than placebo. Patients who received onabotulinumtoxinA (100 U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% from baseline in UIE/day. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100 U over all comparators for UIE and urgency episodes (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100 U was also associated with higher odds of achieving a 100% and ≥50% decrease in UIE/day than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. CONCLUSION: The results indicate that, after 12 weeks, onabotulinumtoxinA 100 U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network.

Quasi-experimental study designs series-paper 8: identifying quasi-experimental studies to inform systematic reviews.

OBJECTIVE: This article reviews the available evidence and guidance on methods to identify reports of quasi-experimental (QE) studies to inform systematic reviews of health care, public health, international development, education, crime and justice, and social welfare. STUDY DESIGN AND SETTING: Research, guidance, and examples of search strategies were identified by searching a range of databases, key guidance documents, selected reviews, conference proceedings, and personal communication. Current practice and research evidence were summarized. RESULTS: Four thousand nine hundred twenty-four records were retrieved by database searches, and additional documents were obtained by other searches. QE studies are challenging to identify efficiently because they have no standardized nomenclature and may be indexed in various ways. Reliable search filters are not available. There is a lack of specific resources devoted to collecting QE studies and little evidence on where best to search. CONCLUSION: Searches to identify QE studies should search a range of resources and, until indexing improves, use strategies that focus on the topic rather than the study design. Better definitions, better indexing in databases, prospective registers, and reporting guidance are required to improve the retrieval of QE studies and promote systematic reviews of what works based on the evidence from such studies.

Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis Treatments.

BACKGROUND: The antifibrotics pirfenidone and nintedanib are both approved for the treatment of idiopathic pulmonary fibrosis (IPF) by regulatory agencies and are recommended by health technology assessment bodies. Other treatments such as N-acetylcysteine are used in clinical practice but have not received regulatory approval. No head-to-head trials have been conducted to directly compare the efficacy of these therapies in IPF. OBJECTIVE: To compare the efficacy of treatments for IPF. METHODS: A systematic review was conducted up to April 2015. Phase II/III randomized controlled trials in adults with IPF were eligible. A Bayesian network meta-analysis (NMA) was used to compare pirfenidone, nintedanib, and N-acetylcysteine with respect to forced vital capacity (FVC) and mortality. RESULTS: Nine studies were included in the NMA. For change from baseline in FVC, the NMA indicated that pirfenidone and nintedanib were more effective than placebo after 1 year (pirfenidone vs. placebo: difference = 0.12 liter (L), 95% credible interval [CrI] = 0.03-0.21 L; nintedanib vs. placebo: difference = 0.11 L, 95% CrI = 0.00-0.22 L). There was no evidence that N-acetylcysteine had an effect on FVC compared with placebo (N-acetylcysteine vs. placebo: difference = 0.01 L, 95% CrI = -0.15-0.17 L). Patients treated with pirfenidone also had a lower risk of experiencing a decline in percent predicted FVC of ≥ 10% over 1 year (odds ratio [OR]: 0.58, 95% CrI = 0.40-0.88), whereas there was no conclusive evidence of a difference between nintedanib and placebo (OR: 0.65, 95% CrI = 0.42-1.02). The NMA indicated that pirfenidone reduced all-cause mortality relative to placebo over 1 year (hazard ratio [HR]: 0.52, 95% CrI = 0.28-0.92). There was no evidence of a difference in all-cause mortality between nintedanib and placebo (HR: 0.70, 95% CrI = 0.32-1.55), or N-acetylcysteine and placebo (HR: 2.00, 95% CrI=0.46-8.62). CONCLUSIONS: Our primary analysis of the available evidence indicates that over 1 year, pirfenidone and nintedanib are effective at reducing lung-function decline, and pirfenidone may reduce the odds of experiencing a decline in percent predicted FVC of ≥10% compared with placebo in the first year of treatment. The results of our analysis also suggest that pirfenidone improves survival. DISCLOSURES: Fleetwood is an employee of Quantics Consulting. McCool and Glanville are employees of York Health Economics Consortium (YHEC). Quantics and YHEC received funding from F. Hoffmann-La Roche for conducting the systematic review and network meta-analysis reported in this paper. Edwards, Gsteiger, and Daigl are employees of F. Hoffmann-La Roche. Fisher was employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. The systematic review and network meta-analysis reported in this paper were conducted by Fleetwood (Quantics Consulting) and McCool and Glanville (YHEC), funded by F. Hoffmann-La Roche. The original network analysis was funded by InterMune. Study concept and design were contributed by Edwards, Gsteiger, and Daigl, along with Fleetwood, McCool, and Glanville. Fleetwood, McCool, and Glanville collected the data, with assistance from Edwards, Gsteiger, and Daigl. Data interpretation was performed by Fleetwood and Fisher, with assistance from the other authors. The manuscript was written by Fleetwood, McCool, and Glanville, with assistance from Edwards, Daigl, and Fisher, and revised by all the authors.

SYSTEMATIC REVIEWS OF ECONOMIC EVALUATIONS: HOW EXTENSIVE ARE THEIR SEARCHES?

OBJECTIVES: Economic evaluation (EE) is an accepted element of decision making and priority setting in healthcare. As the number of published EEs grows, so does the number of systematic reviews (SRs) of EEs. Although search methodology makes an important contribution to SR quality, search methods in reviews of EEs have not been evaluated in detail. We investigated the resources used to identify studies in recent, published SRs of EEs, and assessed whether the resources reflected recommendations. METHODS: We searched MEDLINE for SRs of EEs published since January 2013 and extracted the following from eligible reviews: databases searched, health technology assessment (HTA) sources searched, supplementary search techniques used. Results were compared against the minimum search resources recommended by National Institute for Health and Care Excellence (NICE) (MEDLINE, Embase, NHS EED, EconLit) for economic evidence for single technology appraisals, and resource types suggested in the summary of current best evidence from SuRe Info (economic databases, general databases, HTA databases, HTA agency Web pages, gray literature). RESULTS: Sixty-five SRs met the inclusion criteria; data were extracted from forty-two. Five reviews (12 percent) met or exceeded the NICE recommended resources. Nine reviews (21 percent) searched at least four of the five types of resource recommended by SuRe Info. Five reviews (12 percent) searched all five. Twenty-three reviews (55 percent) did not meet the NICE recommendations or four of five of the SuRe Info recommended resource types. Search reporting was frequently unclear or incorrect. CONCLUSIONS: Searches conducted for the majority of recently published SRs of EEs do not meet two published approaches.

Interventions for drug-using offenders with co-occurring mental health problems: a systematic review and economic appraisal.

BACKGROUND: Drug-using offenders with co-occurring mental health problems are common in the criminal justice system. A combination of drug use and mental health problems makes people more likely to be arrested for criminal involvement after release compared to offenders without a mental health problem. Previous research has evaluated interventions aimed broadly at those with a drug problem but rarely with drug use and mental health problems. This systematic review considers the effectiveness of interventions for drug-using offenders with co-occurring mental health problems. METHODS: We searched 14 electronic bibliographic databases up to May 2014 and five Internet resources. The review included randomised controlled trials designed to reduce, eliminate, or prevent relapse of drug use and/or criminal activity. Data were reported on drug and crime outcomes, the identification of mental health problems, diagnoses and resource information using the Drummond checklist. The systematic review used standard methodological procedures as prescribed by the Cochrane collaboration. RESULTS: Eight trials with 2058 participants met the inclusion criteria. These evaluated: case management (RR, 1.05, 95 % CI 0.90 to 1.22, 235 participants), motivational interviewing and cognitive skills, (MD-7.42, 95 % CI-0.20.12 to 5.28, 162 participants) and interpersonal psychotherapy (RR 0.67, 95 % CI 0.3 to 1.5, 38 participants). None of these trials reported significant reductions in self-report drug misuse or crime. Four trials evaluating differing therapeutic community models showed reductions in re-incarceration (RR 0.28, 95 % CI 0.13 to 0.63, 139 participants) but not re-arrest (RR 1.65, 95 % CI 0.83 to 3.28, 370 participants) or self-report drug use (RR 0.73, 95 % CI 0.53 to 1.01, 370 participants). Mental health problems were identified across the eight trials and 17 different diagnoses were described. Two trials reported some resource information suggesting a cost-beneficial saving when comparing therapeutic communities to a prison alternative. CONCLUSIONS: Overall, the studies showed a high degree of variation, warranting a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. Specifically, tailored interventions are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.

Are Non-Pharmacological Interventions Effective in Reducing Drug Use and Criminality? A Systematic and Meta-Analytical Review with an Economic Appraisal of These Interventions.

Background: The numbers of incarcerated people suffering from drug dependence has steadily risen since the 1980s and only a small proportion of these receive appropriate treatment. A systematic review to evaluate the effectiveness and economic evidence of non-pharmacological interventions for drug using offenders was conducted. Methods: Cochrane Collaboration criteria were used to identify trials across 14 databases between 2004 and 2014. A series of meta-analyses and an economic appraisal were conducted. Results: 43 trials were identified showing to have limited effect in reducing re-arrests RR 0.97 (95% CI 0.89-1.07) and drug use RR 0.90 (95% CI 0.80-1.00) but were found to significantly reduce re-incarceration RR 0.70 (95% CI 0.57-0.85). Therapeutic community programs were found to significantly reduce the number of re-arrests RR 0.70 (95% CI 0.56-0.87). 10 papers contained economic information. One paper presented a cost-benefit analysis and two reported on the cost and cost effectiveness of the intervention. Conclusions: We suggest that therapeutic community interventions have some benefit in reducing subsequent re-arrest. We recommend that economic evaluations should form part of standard trial protocols.

Costs associated with functional gastrointestinal disorders and related signs and symptoms in infants: a systematic review protocol.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs) and FGID-related signs and symptoms have a fundamental impact on the psychosocial, physical and mental well-being of infants and their parents alike. Recent reviews and studies have indicated that FGIDs and related signs and symptoms may also have a substantial impact on the budgets of third-party payers and/or parents. The objective of this systematic review is to investigate these costs. METHODS AND ANALYSIS: The population of interest is healthy term infants (under 12 months of age) with colic, regurgitation and/or functional constipation. Outcomes of interest will include the frequency and volume of reported treatments, the cost to third-party payers and/or parents for prescribed or over the counter treatments, visits to health professionals and changes in infant formula purchases, and the loss of income through time taken off work and out of pocket costs. Relevant studies will be identified by searching databases from 2005 onwards (including MEDLINE, EMBASE, PsycINFO, NEXIS, DARE, Health Technology Assessment database, National Health Service Economic Evaluation Database and others), conferences from the previous 3 years and scanning reference lists of eligible studies. Study selection, data extraction and quality assessment will be conducted by two independent reviewers and disagreements resolved in discussion with a third reviewer. Quality assessment will involve study design-specific checklists. Relevant studies will be summarised narratively and presented in tables. An overview of treatments and costs will be provided, with any geographical or other differences highlighted. An assessment of how the totals for cost differ across countries and elements that contribute to the differences will be generated. ETHICS AND DISSEMINATION: This is a systematic review of published studies that will be submitted for publication to a peer-reviewed journal. Ethical committee approval is not required. TRIAL REGISTRATION NUMBER: CRD42016033119.

Comparative assessment of onabotulinumtoxinA and mirabegron for overactive bladder: an indirect treatment comparison.

CONTEXT: OnabotulinumtoxinA and mirabegron have recently gained marketing authorisation to treat symptoms of overactive bladder (OAB). OBJECTIVE: To evaluate the relative efficacy of mirabegron and onabotulinumtoxinA in patients with idiopathic OAB. DESIGN: Network meta-analysis. DATA SOURCES: A search of 9 electronic databases, review documents, guidelines and websites. METHODS: Randomised trials comparing any licensed dose of onabotulinumtoxinA or mirabegron with each other, anticholinergic drugs or placebo were eligible (19 randomised trials were identified). 1 reviewer extracted data from the studies and a second reviewer checked the data. Candidate trials were assessed for similarity and networks were developed for each outcome. Bayesian network meta-analysis was conducted using both fixed-effects and random-effects models. When there were differences in mean baseline values between mirabegron and onabotulinumtoxinA trials they were adjusted for using network meta-regression (NMR). RESULTS: No studies directly comparing onabotulinumtoxinA to mirabegron were identified. A network was created for each of the 7 outcomes, with 3-9 studies included in each individual network. The trials included in the networks were broadly similar. Patients in the onabotulinumtoxinA trials had more urinary incontinence and urgency episodes at baseline than patients in the mirabegron trials and these differences were adjusted for using NMR. Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency and urination. NMR supported the results of the network meta-analysis. CONCLUSIONS: In the absence of head-to-head trials comparing onabotulinumtoxinA to mirabegron, this indirect comparison indicates that onabotulinumtoxinA may be superior to mirabegron in improving symptoms of urinary incontinence, urgency and urinary frequency in patients with idiopathic OAB.

Clinical effectiveness and cost-effectiveness of parenting interventions for children with severe attachment problems: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Services have variable practices for identifying and providing interventions for 'severe attachment problems' (disorganised attachment patterns and attachment disorders). Several government reports have highlighted the need for better parenting interventions in at-risk groups. This report was commissioned to evaluate the clinical effectiveness and cost-effectiveness of parenting interventions for children with severe attachment problems (the main review). One supplementary review explored the evaluation of assessment tools and a second reviewed 10-year outcome data to better inform health economic aspects of the main review. DATA SOURCES: A total of 29 electronic databases were searched with additional mechanisms for identifying a wide pool of references using the Cochrane methodology. Examples of databases searched include PsycINFO (1806 to January week 1, 2012), MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations (1946 to December week 4, 2011) and EMBASE (1974 to week 1, 2012). Searches were carried out between 6 and 12 January 2012. REVIEW METHODS: Papers identified were screened and data were extracted by two independent reviewers, with disagreements arbitrated by a third independent reviewer. Quality assessment tools were used, including quality assessment of diagnostic accuracy studies - version 2 and the Cochrane risk of bias tool. Meta-analysis of randomised controlled trials (RCTs) of parenting interventions was undertaken. A health economics analysis was conducted. RESULTS: The initial search returned 10,167 citations. This yielded 29 RCTs in the main review of parenting interventions to improve attachment patterns, and one involving children with reactive attachment disorder. A meta-analysis of eight studies seeking to improve outcome in at-risk populations showed statistically significant improvement in disorganised attachment. The interventions saw less disorganised attachment at outcome than the control (odds ratio 0.47, 95% confidence interval 0.34 to 0.65; p < 0.00001). Much of this focused around interventions improving maternal sensitivity, with or without video feedback. In our first supplementary review, 35 papers evaluated an attachment assessment tool demonstrating validity or psychometric data. Only five reported test-retest data. Twenty-six studies reported inter-rater reliability, with 24 reporting a level of 0.7 or above. Cronbach's alphas were reported in 12 studies for the comparative tests (11 with α > 0.7) and four studies for the reference tests (four with α > 0.7). Three carried out concurrent validity comparing the Strange Situation Procedure (SSP) with another assessment tool. These had good sensitivity but poor specificity. The Disturbances of Attachment Interview had good sensitivity and specificity with the research diagnostic criteria (RDC) for attachment disorders. In our supplementary review of 10-year outcomes in cohorts using a baseline reference standard, two studies were found with disorganised attachment at baseline, with one finding raised psychopathology in adolescence. Budget impact analysis of costs was estimated because a decision model could not be justifiably populated. This, alongside other findings, informed research priorities. LIMITATIONS: There are relatively few UK-based clinical trials. A 10-year follow-up, while necessary for our health economists for long-term sequelae, yielded a limited number of papers. CONCLUSIONS: Maternal sensitivity interventions show good outcomes in at-risk populations, but require further research with complex children. The SSP and RDC for attachment disorders remain the reference standards for identification until more concurrent and predictive validity research is conducted. A birth cohort with sequential attachment measures and outcomes across different domains is recommended with further, methodologically sound randomised controlled intervention trials. The main area identified for future work was a need for good-quality RCTs in at-risk groups such as those entering foster care or adoption. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001395. FUNDING: The National Institute for Health Research Health Technology Assessment programme.