Costs, challenges and opportunities of decentralised chimeric antigen receptor T-cell production: a literature review and clinical experts' interviews.

The objectives were to summarise the evidence and clinical experts' views comparing the use of decentralised produced chimeric antigen receptor (CAR) T-cell therapies versus commercially available products, regarding drug costs, time to finalised product and other reported advantages, disadvantages, challenges and facilitators. A literature review according to the PRISMA guidelines was conducted in Medline, Embase and Trip databases. Publications were included if they reported information on cost estimates, time to finalised products and other outcomes of interest of a decentralised CAR T-cell production strategy. A structured interview guide was developed and used for qualitative expert interviews. Five experts were purposively selected, and interviews were either conducted face-to-face or online, and recorded for the purpose of transcription. Transcripts were analysed and categories and codes extracted. Reporting is based on the COREQ checklist for reporting qualitative research. Costs of decentralised produced CAR T-cells appear to be lower by a factor two to 14, compared with commercial products. But there is high uncertainty about this estimate, because it is unclear whether cost components included are comparable and due to the heterogeneity of the studies. The most commonly reported advantages were proximity to patients and decreased product risks and costs, whereas the continuing dependency on centrally manufactured reagents and specific characteristics of 'fresh' CAR T-cells are reported as disadvantages. Compliance with regulatory requirements is mentioned as the biggest challenge. The availability of closed-system production devices is reported as one main facilitator, as are clear commitment, secured financing and knowledge transfer from already experienced centres. Apparent cost differences open a field for healthcare decision-makers to discuss and justify investment costs for implementation of a complementing decentralised production programme and to realise other associated benefits of such a strategy, such as flexibility, patient proximity and expanding patient access.

Abbreviated and comprehensive literature searches led to identical or very similar effect estimates: a meta-epidemiological study.

OBJECTIVES: The objective of this study was to assess the agreement of treatment effect estimates from meta-analyses based on abbreviated or comprehensive literature searches. STUDY DESIGN AND SETTING: This was a meta-epidemiological study. We abbreviated 47 comprehensive Cochrane review searches and searched MEDLINE/Embase/CENTRAL alone, in combination, with/without checking references (658 new searches). We compared one meta-analysis from each review with recalculated ones based on abbreviated searches. RESULTS: The 47 original meta-analyses included 444 trials (median 6 per review [interquartile range (IQR) 3-11]) with 360045 participants (median 1,371 per review [IQR 685-8,041]). Depending on the search approach, abbreviated searches led to identical effect estimates in 34-79% of meta-analyses, to different effect estimates with the same direction and level of statistical significance in 15-51%, and to opposite effects (or effects could not be estimated anymore) in 6-13%. The deviation of effect sizes was zero in 50% of the meta-analyses and in 75% not larger than 1.07-fold. Effect estimates of abbreviated searches were not consistently smaller or larger (median ratio of odds ratio 1 [IQR 1-1.01]) but more imprecise (1.02-1.06-fold larger standard errors). CONCLUSION: Abbreviated literature searches often led to identical or very similar effect estimates as comprehensive searches with slightly increased confidence intervals. Relevant deviations may occur.

Health Technology Assessment of Carbon-ion Beam Radiotherapy: A Systematic Review of Clinical Effectiveness and Safety for 54 Oncological Indications in 12 Tumour Regions.

BACKGROUND/AIM: Due to the unique physical dose distribution of carbon-ion radiotherapy (CIRT), CIRT can be regarded as a novel tumour irradiation technique - potentially advantageous for various tumour types. Yet it is unclear in how far, superiority or inferiority can be claimed when comparing CIRT to standard irradiation. This study aimed to assess the scientific evidence regarding the effectiveness and safety of CIRT. MATERIALS AND METHODS: A systematic literature review was performed using the European Network for Health Technology Assessment (EUnetHTA) Core Model® for rapid relative effectiveness assessment. The literature search for clinical outcome studies on CIRT was performed using four databases [Cochrane (Central), Centre for Research and Dissemination (CRD), Embase and OVID MEDLINE]. The Cochrane Risk of Bias Tool (for randomised controlled trials) and the Institute of Health Economics (IHE-18) Checklist (for observational studies) were used to assess the risk of bias of the included studies. The evidence synthesis was restricted to 54 oncological indications in 12 broad tumour regions and studies with a low or moderate risk of bias, published between 2005 and 2017. RESULTS: Twenty-seven studies were eligible for the qualitative synthesis of the evidence regarding the effectiveness and safety of CIRT: One randomised controlled trial that primarily focused on the feasibility of CIRT, three case-control studies, three before- and after- studies with a focus on quality of life, and 20 further studies of case series. Overall, insufficient scientific evidence was found for superiority or inferiority of CIRT when compared to standard irradiation for 13/54 oncologicaI indications in 7/12 tumour regions (skull base tumours, brain cancer, cancer in the ear-nose-throat region, bone and soft-tissue tumours, lung cancer, prostate cancer, gastrointestinal tumours). No scientific evidence was found for the remaining 41/54 oncological indications. CONCLUSION: CIRT is undoubtedly, theoretically, a promising cancer treatment. To date, however, it lacks randomised controlled trials assessing the long-term effectiveness and harms associated with the use of CIRT. CIRT must be considered as an experimental treatment due to the lack of high-quality clinical research.

Abbreviated literature searches were viable alternatives to comprehensive searches: a meta-epidemiological study.

OBJECTIVE: To assess the effects of abbreviated literature searches on evidence syntheses conclusions. STUDY DESIGN AND SETTING: We randomly selected 60 Cochrane reviews of clinical interventions and repeated literature searches using 14 abbreviated approaches (combinations of MEDLINE, Embase, CENTRAL with and without searches of reference lists). If abbreviated searches missed included studies, we recalculated meta-analyses. Cochrane authors determined whether the new evidence base would change conclusions. We assessed the noninferiority of abbreviated searches allowing for a maximum of 10% changed conclusions. RESULTS: We conducted 840 abbreviated literature searches. Noninferiority varied based on the definition of "changed conclusion". When the reduction of the certainty of a conclusion was of concern, all abbreviated searches were inferior. Searching Embase only rendered the greatest proportion of changed conclusions (27%, 95% confidence interval [CI]: 16%-40%); combining MEDLINE, Embase, CENTRAL with searches of references lists the lowest (8%, 95% CI 3%-18%). When falsely reaching an opposite conclusion was of concern, combining one database with another or with searches of reference lists was noninferior to comprehensive searches (2%, 95% CI: 0%-9%). CONCLUSION: If decision-makers are willing to accept less certainty and a small risk for opposite conclusions, some abbreviated searches are viable options for rapid evidence syntheses. Decisions demanding high certainty require comprehensive searches.

Cardiac contractility modulation in patients with heart failure refractory to drug treatment.

Cardiac contractility modulation in patients with heart failure refractory to drug treatment aims to strengthen myocardial activity through transmission of nonexcitatory impulses to the heart. The present study reviewed a total of 251 patients from four studies; the results, however, showed a low level of evidence. Crossover analysis showed a strong placebo effect for patients with implants that were switched on after three months. The technology is still in the development stage and further studies are needed.