BackgroundThere is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus.MethodsRecords were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded.ResultsTwo hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used.ConclusionsOur findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments.PROSPERO registrationThe systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users.

BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.