Thea van Asselt

Implementation of outpatient schema therapy for borderline personality disorder with versus without crisis support by the therapist outside office hours: A randomized trial

OBJECTIVEnThis study aimed to evaluate the success of implementing outpatient schema focused therapy (ST) for borderline patients in regular mental healthcare and to determine the added value of therapist telephone availability outside office hours in case of crisis (TTA).nnnMETHODSnTo enhance the implementation, the following adaptations regarding the original ST protocol were applied: a reduction in the frequency and duration of the therapy; training therapists of eight regular healthcare centers in ST with a structured and piloted program supported by a set of films (DVDs) with examples of ST techniques; training and supervision given by Dutch experts. Telephone availability outside office hours was randomly allocated to 50% of the therapists of each treatment center. Patients outcome measures were assessed with a semi-structured interview and self-report measures on BPD, quality of life, general psychopathology and an ST questionnaire, before, during and after treatment.nnnRESULTSnData on 62 DSM-IV defined BPD patients were available. Intention-to-treat analyses showed that after 1.5 years of ST 42% of the patients had recovered from BPD. No added value of therapist telephone availability (TTA) was found on the BPDSI score nor on any other measure after 1.5 years of ST.nnnCONCLUSIONSnST for BPD can be successfully implemented in regular mental healthcare. Treatment results and dropout were comparable to a previous clinical trail. No additional effect of extra crisis support with TTA outside office hours ST was found.

KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis

BACKGROUNDnBowel cancer is the third most common cancer in the UK. Most bowel cancers are initially treated with surgery, but around 17% spread to the liver. When this happens, sometimes the liver tumour can be treated surgically, or chemotherapy may be used to shrink the tumour to make surgery possible. Kirsten rat sarcoma viral oncogene (KRAS) mutations make some tumours less responsive to treatment with biological therapies such as cetuximab. There are a variety of tests available to detect these mutations. These vary in the specific mutations that they detect, the amount of mutation they detect, the amount of tumour cells needed, the time to give a result, the error rate and cost.nnnOBJECTIVESnTo compare the performance and cost-effectiveness of KRAS mutation tests in differentiating adults with metastatic colorectal cancer whose metastases are confined to the liver and are unresectable and who may benefit from first-line treatment with cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone.nnnDATA SOURCESnThirteen databases, including MEDLINE and EMBASE, research registers and conference proceedings were searched to January 2013. Additional data were obtained from an online survey of laboratories participating in the UK National External Quality Assurance Scheme pilot for KRAS mutation testing.nnnMETHODSnA systematic review of the evidence was carried out using standard methods. Randomised controlled trials were assessed for quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using the QUADAS-2 tool. There were insufficient data for meta-analysis. For accuracy studies we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data were summarised as relative risks, with 95% CIs. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different tests followed by treatment with standard chemotherapy or cetuximab plus standard chemotherapy. The analysis took a no comparator approach, which implies that the cost-effectiveness of each strategy will be presented only compared with the next most cost-effective strategy. The de novo model consisted of a decision tree and Markov model.nnnRESULTSnThe online survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. The literature searches identified 7903 references, of which seven publications of five studies were included in the review. Two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy. Four RCTs provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumours. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select patients. In the linked evidence analysis the Therascreen KRAS RGQ PCR Kit (QIAGEN) was more expensive but also more effective than pyrosequencing or direct sequencing, with an incremental cost-effectiveness ratio of £17,019 per quality-adjusted life-year gained. In the assumption of equal prognostic value analysis the total costs associated with the various testing strategies were similar.nnnLIMITATIONSnThe results assume that the differences in outcomes between the trials were solely the result of the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation.nnnCONCLUSIONSnThere was no strong evidence that any one KRAS mutation test was more effective or cost-effective than any other test.nnnSTUDY REGISTRATIONnPROSPERO CRD42013003663.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment programme.

High-sensitivity troponin assays for the early rule-out or diagnosis of acute myocardial infarction in people with acute chest pain: a systematic review and cost-effectiveness analysis

BACKGROUNDnEarly diagnosis of acute myocardial infarction (AMI) can ensure quick and effective treatment but only 20% of adults with emergency admissions for chest pain have an AMI. High-sensitivity cardiac troponin (hs-cTn) assays may allow rapid rule-out of AMI and avoidance of unnecessary hospital admissions and anxiety.nnnOBJECTIVEnTo assess the clinical effectiveness and cost-effectiveness of hs-cTn assays for the early (within 4 hours of presentation) rule-out of AMI in adults with acute chest pain.nnnMETHODSnSixteen databases, including MEDLINE and EMBASE, research registers and conference proceedings, were searched to October 2013. Study quality was assessed using QUADAS-2. The bivariate model was used to estimate summary sensitivity and specificity for meta-analyses involving four or more studies, otherwise random-effects logistic regression was used. The health-economic analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different troponin (Tn) testing methods. The de novo model consisted of a decision tree and Markov model. A lifetime time horizon (60 years) was used.nnnRESULTSnEighteen studies were included in the clinical effectiveness review. The optimum strategy, based on the Roche assay, used a limit of blank (LoB) threshold in a presentation sample to rule out AMI [negative likelihood ratio (LR-) 0.10, 95% confidence interval (CI) 0.05 to 0.18]. Patients testing positive could then have a further test at 2 hours; a result above the 99th centile on either sample and a delta (Δ) of ≥u200920% has some potential for ruling in an AMI [positive likelihood ratio (LR+) 8.42, 95% CI 6.11 to 11.60], whereas a result below the 99th centile on both samples and a Δ of <u200920% can be used to rule out an AMI (LR- 0.04, 95% CI 0.02 to 0.10). The optimum strategy, based on the Abbott assay, used a limit of detection (LoD) threshold in a presentation sample to rule out AMI (LR- 0.01, 95% CI 0.00 to 0.08). Patients testing positive could then have a further test at 3 hours; a result above the 99th centile on this sample has some potential for ruling in an AMI (LR+ 10.16, 95% CI 8.38 to 12.31), whereas a result below the 99th centile can be used to rule out an AMI (LR- 0.02, 95% CI 0.01 to 0.05). In the base-case analysis, standard Tn testing was both most effective and most costly. Strategies considered cost-effective depending upon incremental cost-effectiveness ratio thresholds were Abbott 99th centile (thresholds of <u2009£6597), Beckman 99th centile (thresholds between £6597 and £30,042), Abbott optimal strategy (LoD threshold at presentation, followed by 99th centile threshold at 3 hours) (thresholds between £30,042 and £103,194) and the standard Tn test (thresholds over £103,194). The Roche 99th centile and the Roche optimal strategy [LoB threshold at presentation followed by 99th centile threshold and/or Δ20% (compared with presentation test) at 1-3 hours] were extendedly dominated in this analysis.nnnCONCLUSIONSnThere is some evidence to suggest that hs-CTn testing may provide an effective and cost-effective approach to early rule-out of AMI. Further research is needed to clarify optimal diagnostic thresholds and testing strategies.nnnSTUDY REGISTRATIONnThis study is registered as PROSPERO CRD42013005939.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment programme.

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: a systematic review and cost-effectiveness analysis

BACKGROUNDnNon-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy. Patients with NSCLC are therefore tested for EGFR-TK tumour gene mutations to inform treatment decisions. There are a variety of tests available to detect these mutations. The different tests vary in the specific mutations that they attempt to detect, the amount of tumour cells needed for the test to work, the time that it takes to give a result, the error rate of the test, and the cost of the test.nnnOBJECTIVEnTo compare the performance and cost-effectiveness of EGFR-TK mutation tests used to identify previously untreated adults with locally advanced or metastatic NSCLC, who may benefit from first-line treatment with TKIs.nnnDATA SOURCESnTwelve databases to August 2012 [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment database (HTA), Science Citation Index (SCI), Latin American and Caribbean Health Sciences Literature (LILACS), BIOSIS Previews, NIHR Health Technology Assessment programme, PROSPERO (International Prospective Register of Systematic Reviews)], research registers and conference proceedings. A web-based survey gathered data on technical performance of EGFR-TK mutation tests.nnnMETHODSnRandomised controlled trials were assessed for methodological quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using QUADAS-2. There were insufficient data for meta-analysis. For accuracy studies, we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data as relative risks, with 95% CIs. The health-economic analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different tests followed by treatment with either standard chemotherapy or a TKI. Direct sequencing was taken as the comparator. The de novo model consisted of a decision tree and a Markov model.nnnRESULTSnThe survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. Six studies provided data on the accuracy of EGFR-TK mutation testing for predicting response to treatment with TKIs. Estimates of accuracy were similar across studies. Six analyses provided data on the clinical effectiveness of TKIs compared with standard chemotherapy. There were no clear differences in the treatment effects reported by different studies, regardless of which EGFR mutation test was used to select patients. Cost-effectiveness analysis using Evidence on comparative effectiveness available and Linked evidence approaches: Therascreen(®) EGFR polymerase chain reaction (PCR) Kit (Qiagen, Venlo, the Netherlands) was both less effective and less costly than direct sequencing of all exon 19-21 mutations at an incremental cost-effectiveness ratio of £32,167 (comparative) and £32,190 (linked) per QALY lost. Assumption of equal prognostic value approach: the lowest total strategy cost was [commercial-in-confidence (CiC) information has been removed] [Sanger sequencing or Roche cobas EGFR Mutation Testing Kit(®) (Roche Molecular Systems, Inc., Branchburg, NJ, USA)] compared with (CiC information has been removed) for the most expensive strategy (fragment length analysis combined with pyrosequencing).nnnLIMITATIONSnThe cost-effectiveness analysis assumed that the differences in outcomes between the results of the trials were solely attributable to the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation.nnnCONCLUSIONnThere was no strong evidence that any one EGFR mutation test had greater accuracy than any other test. Re-testing of stored samples from previous studies, where patient outcomes are already known, could be used to provide information on the relative effectiveness of TKIs and standard chemotherapy in patients with EGFR mutation-positive and mutation-negative tumours, where mutation status is determined using tests for which adequate data are currently unavailable.nnnSTUDY REGISTRATIONnPROSPERO CRD42012002828.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment programme.

Implementation of outpatient schema therapy for borderline personality disorder: study design.

BackgroundSchema Therapy (ST) is an integrative psychotherapy based upon a cognitive schema model which aims at identifying and changing dysfunctional schemas and modes through cognitive, experiential and behavioral pathways. It is specifically developed for patients with personality disorders. Its effectiveness and efficiency have been demonstrated in a few randomized controlled trials, but ST has not been evaluated in regular mental healthcare settings. This paper describes the study protocol of a multisite randomized 2-group design, aimed at evaluating the implementation of outpatient schema therapy for patients with borderline personality disorder (BPD) in regular mental healthcare and at determining the added value of therapist telephone availability outside office hours in case of crisis.Methods/DesignPatient outcome measures will be assessed with a semi-structured interview and self-report measures on BPD, therapeutic alliance, quality of life, costs and general psychopathology at baseline, 6, 12, 18 and 36 months. Intention-to-treat analyses will be executed with survival analysis for dichotomous variables, and one-sample t-tests and ANCOVAs for continuous variables with baseline as covariate and condition as between group factor. All tests will be two-tailed with a significance level of 5%.DiscussionThe study will provide an answer to the question whether ST can be effectively implemented and whether phone support by the therapist has an additional value.Trial RegistrationThe Dutch Cochrane Center, NTR (TC = 1781).

Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga®), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8xa0%) AAP patients and 304 of 542 (56.1xa0%) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG’s critical assessment of the company’s economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. With the exception of the ERG’s preference for using the ITT population, the AC agreed with the approach taken in the ERG base case. The original company and ERG base-case incremental cost-effectiveness ratios (ICERs) were £46,722 and £57,688 per QALY gained, respectively; these changed to £28,563 and £38,061 per QALY gained, respectively, in the revised base cases applying a new PAS. Regarding the end-of-life criteria, after 24xa0months approximately 63xa0% of patients in the control group of the COU-AA-302 trial were still alive, and the median survival was 30.1xa0months (95xa0% CI 27.3–34.1). Therefore, it is unlikely that life expectancy would be less than 24xa0months. The AC stated that the most plausible ICER is likely between £28,600 and £32,800 per QALY gained, and concluded that AAP at this stage in the treatment pathway did not meet the end-of-life criterion for short life expectancy. Moreover, in March 2016, the AC produced the final guidance, stating that AAP is recommended, within its marketing authorisation, as an option for treating mCRPC.

Research Costs Investigated: A Study Into the Budgets of Dutch Publicly Funded Drug-Related Research

BackgroundThe costs of performing research are an important input in value of information (VOI) analyses but are difficult to assess.ObjectiveThe aim of this study was to investigate the costs of research, serving two purposes: (1) estimating research costs for use in VOI analyses; and (2) developing a costing tool to support reviewers of grant proposals in assessing whether the proposed budget is realistic.MethodsFor granted study proposals from the Netherlands Organization for Health Research and Development (ZonMw), type of study, potential cost drivers, proposed budget, and general characteristics were extracted. Regression analysis was conducted in an attempt to generate a ‘predicted budget’ for certain combinations of cost drivers, for implementation in the costing tool.ResultsOf 133 drug-related research grant proposals, 74 were included for complete data extraction. Because an association between cost drivers and budgets was not confirmed, we could not generate a predicted budget based on regression analysis, but only historic reference budgets given certain study characteristics. The costing tool was designed accordingly, i.e. with given selection criteria the tool returns the range of budgets in comparable studies. This range can be used in VOI analysis to estimate whether the expected net benefit of sampling will be positive to decide upon the net value of future research.ConclusionThe absence of association between study characteristics and budgets may indicate inconsistencies in the budgeting or granting process. Nonetheless, the tool generates useful information on historical budgets, and the option to formally relate VOI to budgets. To our knowledge, this is the first attempt at creating such a tool, which can be complemented with new studies being granted, enlarging the underlying database and keeping estimates up to date.

Response to Letter to the Editor Regarding “Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal”

We very much appreciate the interest Reifsnider et al. [1] have ntaken in our perspective on the single technology appraisal n(STA) of abiraterone acetate (tradename Zytiga) plus prednisolone n(AAP) acetate for the treatment of chemotherapynai n¨ve metastatic castration-resistant prostate cancer (mCRPC) nprepared for the UK National Institute for Health and Care nExcellence (NICE) [2, 3]. Here, we respond to the aspects nhighlighted by Reifsnider et al. [1] and correct factual inaccuracies nin their reasoning. The main issues are printed in italics n[1]. These points relate to (1) the statistical significance of the nCOU-AA-302 survival results and (2) the justification of the ndiscrete-event simulation (DES) approach utilised by the ncompany. Reifsnider et al. also highlight aspects that are nunrelated to these main points, and we discuss these separately.