Background When a new drug becomes available, patients and doctors require information on its benefits and harms. In 2011, Germany introduced the early benefit assessment of new drugs through the act on the reform of the market for medicinal products (AMNOG). At market entry, the pharmaceutical company responsible must submit a standardised dossier containing all available evidence of the drug's added benefit over an appropriate comparator treatment. The added benefit is mainly determined using patient relevant outcomes. The "dossier assessment" is generally performed by the Institute for Quality and Efficiency in Health Care (IQWiG) and then published online. It contains all relevant study information, including data from unpublished clinical study reports contained in the dossiers. The dossier assessment refers to the patient population for which the new drug is approved according to the summary of product characteristics. This patient population may comprise either the total populations investigated in the studies submitted to regulatory authorities in the drug approval process, or the specific subpopulations defined in the summary of product characteristics ("approved subpopulations").Objective To determine the information gain from AMNOG documents compared with non-AMNOG documents for methods and results of studies available at market entry of new drugs. AMNOG documents comprise dossier assessments done by IQWiG and publicly available modules of company dossiers; non-AMNOG documents comprise conventional, publicly available sources-that is, European public assessment reports, journal publications, and registry reports. The analysis focused on the approved patient populations. Design Retrospective analysis.Data sources All dossier assessments conducted by IQWiG between 1 January 2011 and 28 February 2013 in which the dossiers contained suitable studies allowing for a full early benefit assessment. We also considered all European public assessment reports, journal publications, and registry reports referring to these studies and included in the dossiers. Data analysisWe assessed reporting quality for each study and each available document for eight methods and 11 results items (three baseline characteristics and eight patient relevant outcomes), and dichotomised them as "completely reported" or "incompletely reported (including items not reported at all)." For each document type we calculated the proportion of items with complete reporting for methods and results, for each item and overall, and compared the findings.Results 15 out of 27 dossiers were eligible for inclusion and contained 22 studies. The 15 dossier assessments contained 28 individual assessments of 15 total study populations and 13 approved subpopulations. European public assessment reports were available for all drugs. Journal publications were available for 14 out of 15 drugs and 21 out of 22 studies. A registry report in ClinicalTrials.gov was available for all drugs and studies; however, only 11 contained results. In the analysis of...

Abstract Objective To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. Design Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. Data sources Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. Eligibility criteria for selecting studies Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. Results 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. Conclusions For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

Study Type – Therapy (systematic review) Level of Evidence 1a What's known on the subject? and What does the study add? Numerous newer (non‐standard) procedures for the treatment of benign prostatic hyperplasia (BPH) exist; however, it is unclear whether they actually have an additional patient‐relevant benefit compared to standard treatment. As no trial investigated non‐inferiority, we defined a non‐inferiority threshold on the basis of published literature. The present systematic review found no proof of an additional benefit of non‐standard treatments for BPH; an indictation of an additional benefit was only shown for holium laser resection of the prostate (HoLRP) and thulium laser resection of the prostate (TmLRP). OBJECTIVE To assess the potential additional benefit of non‐standard vs standard surgical treatments for benign prostatic hyperplasia (BPH) and to present a new methodological approach to investigate therapeutic equivalence (non‐inferiority) regarding symptom reduction. PATIENTS AND METHODS We conducted a systematic review and searched MEDLINE, Embase and the Cochrane Library (last search: 10/2009) for randomized controlled trials (RCTs) and non‐randomized controlled clinical trials (CCTs). Eligible studies were those that included patients with symptomatic BPH requiring surgical treatment and which compared non‐standard procedures (e.g. minimally invasive technologies) with standard ones (e.g. transurethral resection of the prostate, TURP). In addition, only studies analysing patient‐relevant outcomes were considered (e.g. irritative and obstructive symptoms, length of hospital stay, quality of life and adverse events). The main outcome of interest for the present analysis was superiority or non‐inferiority for symptom reduction. As no trial investigated non‐inferiority, we defined a non‐inferiority threshold (0.25 standard deviation) on the basis of published literature. If a non‐standard procedure showed non‐inferiority for symptom reduction, additional outcomes were assessed. Meta‐analyses were conducted if feasible and meaningful. RESULTS In all, 43 mainly low‐quality trials (RCTs only) compared nine non‐standard surgical treatments with standard ones. Mean follow‐up ranged from 6 to 84 months. No non‐standard procedure was superior for symptom reduction. Non‐inferiority for symptom reduction was shown in patients who had undergone holmium laser resection of the prostate (HoLRP) or thulium laser resection of the prostate (TmLRP). As procedural advantages (e.g. no occurrence of transurethral resection syndrome) and other advantages (e.g. shortened hospital stay) were found, an indication of an additional benefit of HoLRP and TmLRP was determined. CONCLUSIONS No proof of superiority for symptom reduction has been shown for non‐standard surgical treatments in patients with BPH. There is a lack of high‐quality RCTs and trials designed to investigate non‐inferiority. Future studies should define a non‐inferiority threshold (ideally, uniform) a priori, so that results of individual studies ar...

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Background:Biologics for the treatment of rheumatoid arthritis (RA) have different modes of action to target auto-inflammatory processes causing the signs and symptoms of the disease. Different biologics may thus have different effects on inflammatory markers. For instance, previous studies have shown that the interleukin-6-inhibitor tocilizumab (TOC) decreases the level of acute phase reactants (APRs) [1]. Such direct effects on inflammatory markers may lead to an overestimation of clinical response if disease activity is measured via scores including inflammatory markers, such as the Disease Activity Score 28 (DAS 28). The detected changes in disease activity may not adequately reflect the clinical improvement of signs and symptoms.Objectives:In our study, we compared biologics with each other using two different disease activity scores: the DAS 28 including APRs and the clinical disease activity index (CDAI) excluding APRs. The aim of this study was to assess whether the use of the two different scores affects comparative effectiveness studies on biologics for the treatment of RA.Methods:We compared results on the comparative effectiveness of biologics using the corresponding thresholds for low disease activity (LDA) for the DAS 28 (< 3.2) and the CDAI (≤ 10). We performed two separate network meta-analyses (NMAs) after a thorough step-by-step evaluation of the similarity, homogeneity and consistency assumptions of the patient populations and the study data.Our study formed part of a systematic review (including NMAs) that was largely based on clinical study reports and re-analyses of LDA using individual patient data provided by sponsors for studies conducted up to 2017. Thus, the analyses include hitherto unknown data on LDA analysed by means of the CDAI, especially data from older studies. An extensive comparison of DAS 28 and CDAI in different patient populations was possible.Results:For all analysed patient populations, comparisons of TOC versus other biologics yielded remarkable results: advantages for TOC were found in NMAs using the DAS 28, which were not confirmed in NMAs using the CDAI. For methotrexate (MTX)-naïve patients, using the DAS 28, TOC showed a greater benefit than abatacept (ABA), certolizumab pegol (CZP), and etanercept (ETA), which was not confirmed by the CDAI. In contrast, TOC showed less benefit than adalimumab (ADA) and ETA. For patients after MTX failure and using the DAS 28, TOC showed a greater benefit than ABA, ADA, anakinra (ANA), ETA, golimumab (GOL), and infliximab (INF). With the exception of ANA, these advantages were not confirmed by the CDAI. Similar differences between DAS 28 and CDAI were shown in patients treated with biologics in monotherapy or after failure of biologics.Conclusion:In comparative effectiveness studies of biologics, the assessment of LDA using the DAS 28 instead of the CDAI leads to a consistent overestimation of the benefit of TOC in all patient populations, regardless of pre-treatment or combined therapy with MTX. The inclusion of APRs in disease activity scores may thus introduce bias. A score excluding inflammatory markers should therefore be used to ensure valid results.References:[1]Smolen JS, Aletaha D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum 2011; 63(1): 43-52.Disclosure of Interests:Kirsten Janke: None declared, Katharina Biester: None declared, Dietmar Krause Grant/research support from: Pfizer and AbbVie (Abbott), Bernd Richter: None declared, Christoph Schürmann: None declared, Katharina Hirsch: None declared, Beate Wieseler: None declared