Do You Want to Stay Single? Considerations on Single-Arm Trials in Drug Development and the Postregulatory Space.

Single-arm trials (SATs), while not preferred, remain in use throughout the drug development cycle. They may be accepted by regulators in particular contexts (e.g., in oncology or rare diseases) when the potential effects of new treatments are very large and placebo treatment is unethical. However, in the postregulatory space, SATs are common, and perhaps even more poorly suited to address the questions of interest. In this manuscript, we review regulatory and HTA positions on SATs; challenges posed by SATs to address research questions beyond regulators, evolving statistical methods to provide context for SATs, case studies where SATs could and could not address questions of interest, and communication strategies to influence decision making and optimize study design to address evidence needs.

Posttraumatic Perfusion Analysis of Quadriceps, Patellar, and Achilles Tendon Regeneration With Dynamic Contrast-Enhanced Ultrasound and Dynamic Contrast-Enhanced Magnetic Resonance Imaging: Preliminary Results.

OBJECTIVES: The healing process of tendons after surgical treatment of tendon ruptures mainly depends on the perfusion of the tendon and its surrounding tissue. Dynamic contrast-enhanced ultrasound (DCE-US) and dynamic contrast-enhanced MRI (DCE-MRI) can provide additional information about the local microperfusion. In this pilot study, the feasibility of these techniques to assess the vascularization during tendon regeneration was evaluated. METHODS: Between 2013 and 2015, 23 patients with surgical treatment of traumatic rupture of quadriceps, patellar, and Achilles tendons were involved. All patients received clinical follow-up examinations at 6, 12, and at least 52 weeks postoperatively. Dynamic contrast-enhanced US and DCE-MRI examinations were performed 6 and 12 weeks postoperatively. Dynamic contrast-enhanced US perfusion was quantified by the parameters peak enhancement, wash-in area under the curve, rise time, and initial area under the curve. Correlations between these parameters were examined via the Spearman rank correlation. The clinical and functional outcomes were assessed via the Lysholm Knee Score and Knee and Osteoarthritis Outcome Score at 12 and 52 weeks postoperatively. RESULTS: Fourteen patients with quadriceps (n = 8), patellar (n = 4) and Achilles (n = 2) tendon ruptures with complete follow-up were available. The microperfusion could be successful assessed. We could detect a strong correlation of DCE-US (peak enhancement) parameters with DCE-MRI (initial area under the curve) parameters after 6 and 12 weeks. CONCLUSIONS: In this pilot study, DCE-US was able to visualize the microperfusion of healing tendons with a strong correlation with DCE-MRI. Our initial results are in favor of DCE-US as a potential quantitative imaging tool for evaluating the vascularization in tendon regeneration as a complementary method.

Combination of several matching adjusted indirect comparisons (MAICs) with an application in psoriasis.

In health technology assessment (HTA), beside network meta-analysis (NMA), indirect comparisons (IC) have become an important tool used to provide evidence between two treatments when no head-to-head data are available. Researchers may use the adjusted indirect comparison based on the Bucher method (AIC) or the matching-adjusted indirect comparison (MAIC). While the Bucher method may provide biased results when included trials differ in baseline characteristics that influence the treatment outcome (treatment effect modifier), this issue may be addressed by applying the MAIC method if individual patient data (IPD) for at least one part of the AIC is available. Here, IPD is reweighted to match baseline characteristics and/or treatment effect modifiers of published data. However, the MAIC method does not provide a solution for situations when several common comparators are available. In these situations, assuming that the indirect comparison via the different common comparators is homogeneous, we propose merging these results by using meta-analysis methodology to provide a single, potentially more precise, treatment effect estimate. This paper introduces the method to combine several MAIC networks using classic meta-analysis techniques, it discusses the advantages and limitations of this approach, as well as demonstrates a practical application to combine several (M)AIC networks using data from Phase III psoriasis randomized control trials (RCT).

Survival and success of implants in a private periodontal practice: a 10 year retrospective study.

BACKGROUND: To assess long-term results of implants (XiVE/Frialit-2 Synchro) in a private periodontal practice according to survival and success rates (biological and technical complications) and to detect possible influencing factors, retrospectively. METHODS: Implant placement of at least one implant took place 10 years ±6 months before clinical and radiographic re-examination. Incidence of implant loss as main and incidence of mucositis/ peri-implantitis as secondary outcome were detected. Also, patient-related and implant-related influencing factors were determined by regression analyses. RESULTS: 100 patients (59.0% female) with 242 implants were included into analysis. Survival rate was 94.0% (XiVE: 97.7%; Frialit-2-Synchro: 66.7%). Mucositis was found in 77.6% of all patients, moderate/severe peri-implantitis in 16.3%. In logistic regression analyses statistically significant influencing factors for implant loss was implant type (p < 0.001), for mucositis a wider implant diameter (p = 0.0438) and a high modified Plaque Index (p = 0.0253), for peri-implantits number of implants per patient (p = 0.0075) and a wider implant diameter (p = 0.0079). Technical complications were found in 47 implants (19.4%). CONCLUSIONS: XiVE implants showed a high survival rate over a 10-year follow-up, on the other hand Frialit-2 Synchro implants had worse survival rates. Success rates regarding biological complications are in line with other implant systems.

Alternative Weighting Approaches for Anchored Matching-Adjusted Indirect Comparisons via a Common Comparator.

BACKGROUND: Adjusted indirect comparisons (anchored via a common comparator) are an integral part of health technology assessment. These methods are challenged when differences between studies exist, including inclusion/exclusion criteria, outcome definitions, patient characteristics, as well as ensuring the choice of a common comparator. OBJECTIVES: Matching-adjusted indirect comparison (MAIC) can address these challenges, but the appropriate application of MAICs is uncertain. Examples include whether to match between individual-level data and aggregate-level data studies separately for treatment arms or to combine the arms, which matching algorithm should be used, and whether to include the control treatment outcome and/or covariates present in individual-level data. RESULTS: Results from seven matching approaches applied to a continuous outcome in six simulated scenarios demonstrated that when no effect modifiers were present, the matching methods were equivalent to the unmatched Bucher approach. When effect modifiers were present, matching methods (regardless of approach) outperformed the Bucher method. Matching on arms separately produced more precise estimates compared with matching on total moments, and for certain scenarios, matching including the control treatment outcome did not produce the expected effect size. The entropy balancing approach was used to determine whether there were any notable advantages over the method proposed by Signorovitch et al. When unmeasured effect modifiers were present, no approach was able to estimate the true treatment effect. CONCLUSIONS: Compared with the Bucher approach (no matching), the MAICs examined demonstrated more accurate estimates, but further research is required to understand these methods across an array of situations.

Effects of staining and polishing on different types of enamel surface sealants.

OBJECTIVE: To assess surface discoloration of four enamel sealants based on different chemical compositions after exposure to artificial aging and staining solutions. Furthermore, their cleanability after polishing will be evaluated. MATERIALS AND METHODS: Selected sealants were a composite resin-based sealant with fillers (Pro Seal), a composite resin-based sealant without fillers (Light BondSealant), a resin-modified glass ionomer-based sealant (ClinproXT Varnish) and a silicon-based sealant (Protecto). Natural teeth served as medium. Immersion solutions were water, juice, tea, and turmeric. In a standardized setting, all samples were measured seven times with a spectroradiometer (Photoresearch PR670) at baseline, after thermocycling; 7 days; 2 and 4 weeks of immersion; and after finally polishing. RESULTS: Thermocycling had no significant effect on color stability. After exposure to staining solutions, all sealed surfaces showed significant color changes. Color change predominately occurred for all sealants in the first week of staining (P ≤ .01). Best resistance to staining decreased as follows: Protecto > Light Bond Sealant > ProSeal > Clinpro XT Varnish. Surface cleaning by polishing significantly reduced the color change. CONCLUSION: Sealed enamel surfaces are prone to discoloration, which is most prominent in filled composite and glass-ionomer-based sealants. Staining can be reduced by polishing; however, in this in vitro setting the original color could not be restored. CLINICAL SIGNIFICANCE: Enamel sealants might exert adverse effects in terms of discoloration. This should be taken into consideration by clinicians and patients, particularly when sealants are applied in esthetically critical areas.

Fiber-reinforced composite fixed dental prostheses: A 4-year prospective clinical trial evaluating survival, quality, and effects on surrounding periodontal tissues.

STATEMENT OF PROBLEM: Although fiber-reinforced composite fixed dental prostheses (FRC FDPs) are a reliable treatment option for the restoration of single missing teeth, comparatively few prospective clinical trials (PCT) exist. PURPOSE: The purpose of this PCT was to evaluate the survival, quality outcome, and effect of FRC FDPs on periodontal health over 4 years. MATERIAL AND METHODS: Twenty-six consecutive patients (16 men, 10 women) receiving FRC FDPs with preimpregnated unidirectional fiber reinforcement were included in the trial. Eighteen FRC FDPs were placed in the maxilla and 8 in the mandible. Data from baseline, 12-, 36-, and 48-months of follow-up were recorded, and the prostheses were classified as "success," "survival," or "failure." Periodontal parameters (probing depth, clinical attachment level, plaque index, and bleeding index were assessed, and the quality was rated according to modified United States Public Health Service (USPHS)/Ryge or World Dental Federation (FDI) criteria. RESULTS: Functional survival at 4 years was 73.5% (95% confidence interval [CI], 52.9-87.3) with 17 FRC FDPs still functioning. Twelve of these were classified as "success" and 5 as "survival." Overall survival was 53.0% (95% CI, 30.4-74.4). Six FRC FPDs failed completely. Periodontal parameters did not change over the observation period. Regression analysis showed that probing depth and clinical attachment level did not influence the survival of FRC FDPs. According to USPHS/Ryge/FDI criteria only "wear" and "surface luster" increased significantly over 4 years. CONCLUSIONS: The survival rate of FRC FPDs confirms existing data. Negative effects on periodontal health were not seen over the period of observation. Aging effects such as wear were recorded and indicated that FRC FPDs are at risk of disintegration, as they are composed of a fiber framework and veneering composite resin.

Yield of active screening for tuberculosis among asylum seekers in Germany: a systematic review and meta-analysis.

All asylum seekers in Germany undergo upon-entry screening for tuberculosis TB, but comprehensive evidence on the yield is lacking. We compared the national estimates with the international literature in a systematic review and meta-analysis of studies reporting the yield of TB, defined as the fraction of active TB cases detected among asylum seekers screened in Germany upon entry. We searched 11 national and international databases for empirical studies and the internet for grey literature published in English or German without restrictions on publication time. Among 1,253 screened articles, we identified six articles reporting the yield of active TB based on German data, ranging from 0.72 (95% confidence interval (CI): 0.45-1.10) to 6.41 (95% CI: 4.19-9.37) per 1,000 asylum seekers. The pooled estimate across all studies was 3.47 (95% CI: 1.78-5.73; I2 = 94.9%; p < 0.0001) per 1,000 asylum seekers. This estimate was in line with international evidence (I2 = 0%; p for heterogeneity 0.55). The meta-analysis of available international estimates resulted in a pooled yield of 3.04 (95% CI: 2.24-3.96) per 1,000. This study provides an estimate across several German federal states for the yield of TB screening in asylum seekers. Further research is needed to develop more targeted screening programmes.

In vitro evaluation of different dental materials used for the treatment of extensive cervical root defects using human periodontal cells.

INTRODUCTION: Repair materials for extensive cervical root defects may come in direct contact with periodontal tissues. This in vitro study compared the effects of four calcium silicate cements (CSC), one resin-modified glass ionomer cement, and one glass carbomer cement on primary human gingival fibroblasts (HGF), alveolar osteoblasts (HAO), and a human osteoblast cell line (hFOB 1.19). METHODS: HGF, HAO, and hFOB were seeded on discoid test specimens. Relative numbers of viable cells were quantitatively assessed after 1 and 24 h for cytotoxicity/adhesion assays and after 4, 24, 48, and 72 h for proliferation assays. Data were statistically analyzed using non-parametric tests (α = 0.05). RESULTS: Relative to the control (100 %), CSC allowed for mean numbers of 71-81 % viable HGF and 80-82 % viable HAO. Then, 64 % of HGF and 56 % of HAO were assessed on GC Fuji II LC. Mean numbers of viable cells were 59-64 % HGF and 67-68 % HAO for GCP Glass Fill specimens. Cells exposed to CSC over 24 h remained viable and even increased in number. Both cell types adhered almost equally well to CSC and GC Fuji II LC. GCP Glass Fill continued to decrease cell viability and adhesion. CSC-based materials and GC Fuji II LC allowed for HGF and hFOB proliferation; however, none of the tested materials specifically stimulated cell proliferation. CONCLUSIONS: CSC characterized by low cytotoxicity. GC Fuji II LC shows moderate cytotoxic effects. ProRoot MTA, Harvard MTA, Biodentine, EndoSequence putty, and GC Fuji II LC allow HGF and HAO to adhere and HGF and hFOB to proliferate. GCP Glass Fill decreases cell viability, adhesion, and proliferation. CLINICAL RELEVANCE: CSC remain the paramount biologic choice for the repair of extensive cervical root defects. GC Fuji II LC might be considered in addition to CSC when the defect comprises supracrestal areas and the restoration requires superior aesthetic and mechanical characteristics.

Long-term stability of splinted anterior mandibular teeth during supportive periodontal therapy.

OBJECTIVE: The aim of the study was to retrospectively assess the survival rate and stability of periodontally compromised and mobile anterior mandibular teeth after splinting in patients under supportive periodontal therapy (SPT). MATERIALS AND METHODS: Thirty-nine patients with splinted anterior mandibular teeth and SPT (≥1 visit/year) for 3-15 years were re-examined. Periodontal status, patient and tooth-related factors were assessed retrospectively before (baseline) and 3 years after splinting (n = 39 patients, 162 splinted teeth). For patients with splints inserted for more than 3 years, retrospective data after 5 (n = 30), 7 (n = 24), 10 (n = 16), 12 (n = 8) and 15 years (n = 4) was included, if available. At baseline, splinted teeth included at least one tooth with increased mobility combined with clinical attachment loss (CAL) ≥ 5 mm and ≥50% relative bone loss (RBL). Baseline RBL of splinted teeth was assessed for all patients. Change in RBL was assessed after 10 years, if available. RESULTS: No splinted tooth was lost within the first 3 years after splinting. One splinted tooth was lost 7 years after baseline and one 12 years after baseline. After 3 years mean(SD) periodontal probing depth of splinted teeth decreased from 3.39(1.41) mm to 2.12(0.37) mm and mean(SD) CAL from 5.61(1.66) mm to 5.09(1.67) mm and remained stable over the observation period. No change in RBL was observed over a 10-year period (p = .213). The survival rate of the splints until fracture or debonding was 74.4% after 3 years. CONCLUSIONS: Periodontally compromised splinted teeth show a high survival-rate and periodontal stability during SPT.

Endodontic status and retention of molars in periodontally treated patients: results after 10 or more years of supportive periodontal therapy.

OBJECTIVES: To assess the influence of endodontic status on retention of molars in patients under supportive periodontal treatment (SPT). MATERIAL & METHODS: A total of 136 subjects with 1015 molars at baseline were examined retrospectively, including 188 endodontically treated molars in 90 patients. Multilevel Cox regression analysis identified factors contributing to loss of molars. RESULTS: Root canal treatments contributed significantly to loss of molars during on average 13.2 years of SPT (Hazard ratio: 2.98, 95% CI: 1.74-5.1, p < 0.001). Endodontic treatment was more frequently present in first molars (p < 0.001) and in the maxilla (p = 0.01). In endodontically treated molars, degree III furcation involvement could be detected more often compared to molars without root canal treatment (p < 0.001). Among the root canal-treated molars, several patient and tooth-related factors showed an impact on tooth retention, but only molars with a periapical index of 4 and 5 (labelled "diseased") were significantly more often lost. CONCLUSION: The retention of molars in periodontally compromised patients after periodontal treatment is influenced by periodontal as well as endodontal factors. On a long-term basis, it is feasible to retain these teeth via active periodontal treatment and SPT for more than 10 years.

Loss of molars in periodontally treated patients: results 10 years and more after active periodontal therapy.

AIM: To identify risk factors for loss of molars during supportive periodontal therapy (SPT). MATERIALS AND METHODS: A total of 136 subjects with 1015 molars at baseline were examined retrospectively. The association of risk factors with loss of molars was assessed using a multilevel Cox regression analysis. Furcation involvement (FI) was assessed clinically at start of periodontal therapy and assigned according to Hamp et al. (1975). RESULTS: Fifty molars were extracted during active periodontal therapy (APT) and 154 molars over the average SPT period of 13.2 ± 2.8 years. FI degree III (HR 4.68, p < 0.001), baseline bone loss (BL) > 60% (HR 3.74, p = 0.009), residual mean probing pocket depth (PPD, HR 1.43, p = 0.027), and endodontic treatment (HR 2.98, p < 0.001) were identified as relevant tooth-related factors for loss of molars during SPT. However, mean survival time for molars with FI III or BL > 60% were 11.8 and 14.4 years, respectively. Among the patient data, age (HR 1.57, p = 0.01), female gender (HR 1.99, p = 0.035), smoking (HR 1.97, p = 0.034), and diabetes mellitus (HR 5.25, p = 0.021) were significant predictors for loss of molars. CONCLUSION: Overall, periodontal therapy results in a good prognosis of molars. Degree III FI, progressive BL, endodontic treatment, residual PPD, age, female gender, smoking, and diabetes mellitus strongly influence the prognosis for molars after APT.

Efficiency of powered systems for interproximal enamel reduction (IER) and enamel roughness before and after polishing-an in vitro study.

OBJECTIVE: This aims to evaluate the efficiency of three different powered interproximal enamel reduction (IER) systems and to assess enamel roughness before and after polishing using different polishing times. MATERIAL AND METHODS: Four metal strips of the G5 ProLign Set (swissdentacare, SDC, Grancia, Switzerland), four segmental discs of the ASR-Set 4594 and two sonic tips of the SonicLine Set (both Gebr. Basseler GmbH & Co. KG, Komet, Lemgo, Germany) were evaluated. Human extracted incisors served as the medium. Enamel reduction was determined in five intervals of 15 s each. Polishing was performed for 15 and 30 s using the manufacturers' recommended polishing systems. Enamel roughness (Ra) was quantitatively assessed by confocal laser scanning microscopy (CLSM). RESULTS: Significant differences in terms of enamel reduction were found among the working ends of all tested systems. The time needed to remove 0.1, 0.2 and 0.3 mm of enamel was determined. Surface analysis showed significantly higher mean Ra values for nine out of ten working ends before polishing. This was still the case for five working ends after 15 s and for two after 30 s of polishing. CONCLUSION: The graining and the system used have a significant influence on enamel reduction. The time needed for polishing depends on the last working end used; a polishing time of 30 s is not always appropriate. CLINICAL RELEVANCE: Knowledge about the cutting efficiency of powered IER working ends might help the clinician to estimate better the amount of enamel reduction during the stripping process.

[Systematic review and evidence mapping of empirical studies on health status and medical care among refugees and asylum seekers in Germany (1990-2014)]. / Systematische Übersicht und "Mapping" empirischer Studien des Gesundheitszustands und der medizinischen Versorgung von Flüchtlingen und Asylsuchenden in Deutschland (1990-2014).

BACKGROUND: Owing to a lack of routine statistics on the health status and medical care of asylum seekers, empirical studies play a major role in the mapping of these aspects. OBJECTIVES: The aim of this review is to provide a comprehensive overview of the research landscape in this area, synthesizing knowledge from empirical studies and identifying evidence gaps. METHODS: A three-tiered search strategy included searching for empirical studies in national/international databases and on the internet, screening reference lists, and contacting experts. Studies meeting predefined inclusion criteria were thematically organized and described in a narrative synthesis. RESULTS: The searches generated 1,190 hits; 52 articles met the inclusion criteria. Of these, 41 were quantitative studies (78.9 %), 10 qualitative (19.2 %), and 1 was a review (1.9 %). A total of 30 primary articles (58.9 %) analyzed mental health aspects, followed by infectious diseases (n = 12, 23.5 %). Qualitative studies, mainly ethnographies and case studies, explored mental health and social determinants of health, providing evidence for the impact of living conditions on health and medical care. Few studies analyzed chronic diseases (n = 3) or childhood illnesses (n = 6). No studies analyzed the health needs or medical care of asylum-seeking women during pregnancy and child birth. In 62.7 % of the primary studies, a single sampling point was used to recruit asylum seekers. Nationwide external validity was given in two quantitative studies. CONCLUSION: The priority research areas identified are chronic diseases and childhood and maternal health. The divergency and heterogeneity of the studies hamper a comprehensive and comparable acquisition of knowledgeand emphasize the  need for collaborative research to close the existing evidence gaps.

Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p = 0.006) as well as progression-free survival (p = 0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities.

Hand suture versus stapler for closure of loop ileostomy--a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The aims of this study are to compare the 30-day rate of bowel obstruction for stapled vs. handsewn closure of loop ileostomy, and to further assess efficacy and safety for each technique by secondary endpoints such as operative time, rates of anastomotic leakage, and other post-operative complications within 30 days. METHODS: A systematic literature search (MEDLINE, The Cochrane Library, EMBASE and ISI Web of Science) was performed to identify randomized controlled trials (RCTs) comparing stapled and handsewn closure of loop ileostomy after low anterior resection. Random effects meta-analyses were calculated and presented as risk ratio (RR) and mean difference (MD) with corresponding 95 % confidence intervals. RESULTS: Forty publications were retrieved and 4 RCTs (649 patients) were included. There was methodological and clinical heterogeneity of included trials, but statistical heterogeneity was low for most endpoints. Stapler use significantly reduced the rate of bowel obstruction compared to hand-sewn closure (RR 0.53 [0.32, 0.88]; P = 0.01). The operation time was significantly lower for stapling compared to hand suture (MD -15.5 min [-18.4, 12.6]; P < 0.001). All other secondary outcomes did not show significant differences. CONCLUSIONS: This meta-analysis shows superiority of stapled closure of loop ileostomy compared to handsewn closure in terms of bowel obstruction rate and mean operation time. Other relevant complications such as anastomotic leakage are equivalent. Even so, both techniques are options with opposing advantages and disadvantages.

Methods used for indirect comparisons of systemic treatments for psoriasis. A systematic review.

Background: Indirect comparisons (including network meta-analyses [NMAs]) allow us to compare benefits and risks of multiple interventions for the same clinical condition when head-to-head comparisons are not feasible. Objective: To provide guidance to the clinical community on better understanding indirect comparison methods to help them to interpret their results by applying two quality standards to published indirect comparisons of systemic biologics for moderate to severe psoriasis. Methods: A systematic literature review (SLR) of published indirect comparisons of biologics for the treatment of moderate to severe psoriasis in adults was conducted. Data extraction was performed using a predefined subset of NICE TSD7 (National Institute for Health and Care Excellence Technical Support Document 7) checklist questions and methods used to perform each analysis were descriptively compared. Methodological quality of the SLR underlying each indirect comparison was assessed using AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews version 2). Results: Twenty-two NMAs and four adjusted indirect comparisons (AICs) were identified. Although there were some similarities, for example, application of Bayesian random-effects models, several important methodological aspects varied considerably across NMAs identified, for example, classes of drugs, number of treatments and studies included, reporting and handling of different doses, and reporting of both checks for and investigations of inconsistency. Methodological comparisons across AICs were limited by the small number. The quality of most underlying SLRs described, assessed as overall level of confidence in the results, was 'critically low'. Conclusions: Understanding that there are different methodologies employed to answer differing research questions is key to helping clinicians to interpret the indirect evidence currently available in psoriasis.

Validating the Assumptions of Population Adjustment: Application of Multilevel Network Meta-regression to a Network of Treatments for Plaque Psoriasis.

BACKGROUND: Network meta-analysis (NMA) and indirect comparisons combine aggregate data (AgD) from multiple studies on treatments of interest but may give biased estimates if study populations differ. Population adjustment methods such as multilevel network meta-regression (ML-NMR) aim to reduce bias by adjusting for differences in study populations using individual patient data (IPD) from 1 or more studies under the conditional constancy assumption. A shared effect modifier assumption may also be necessary for identifiability. This article aims to demonstrate how the assumptions made by ML-NMR can be assessed in practice to obtain reliable treatment effect estimates in a target population. METHODS: We apply ML-NMR to a network of evidence on treatments for plaque psoriasis with a mix of IPD and AgD trials reporting ordered categorical outcomes. Relative treatment effects are estimated for each trial population and for 3 external target populations represented by a registry and 2 cohort studies. We examine residual heterogeneity and inconsistency and relax the shared effect modifier assumption for each covariate in turn. RESULTS: Estimated population-average treatment effects were similar across study populations, as differences in the distributions of effect modifiers were small. Better fit was achieved with ML-NMR than with NMA, and uncertainty was reduced by explaining within- and between-study variation. We found little evidence that the conditional constancy or shared effect modifier assumptions were invalid. CONCLUSIONS: ML-NMR extends the NMA framework and addresses issues with previous population adjustment approaches. It coherently synthesizes evidence from IPD and AgD studies in networks of any size while avoiding aggregation bias and noncollapsibility bias, allows for key assumptions to be assessed or relaxed, and can produce estimates relevant to a target population for decision-making. HIGHLIGHTS: Multilevel network meta-regression (ML-NMR) extends the network meta-analysis framework to synthesize evidence from networks of studies providing individual patient data or aggregate data while adjusting for differences in effect modifiers between studies (population adjustment). We apply ML-NMR to a network of treatments for plaque psoriasis with ordered categorical outcomes.We demonstrate for the first time how ML-NMR allows key assumptions to be assessed. We check for violations of conditional constancy of relative effects (such as unobserved effect modifiers) through residual heterogeneity and inconsistency and the shared effect modifier assumption by relaxing this for each covariate in turn.Crucially for decision making, population-adjusted treatment effects can be produced in any relevant target population. We produce population-average estimates for 3 external target populations, represented by the PsoBest registry and the PROSPECT and Chiricozzi 2019 cohort studies.

Impact of clinical and demographic characteristics on patient preferences for psoriasis treatment features: Results from a discrete-choice experiment in a multicountry study.

OBJECTIVES: This study aimed to elicit preferences for psoriasis treatment features and to test for preference heterogeneity across groups of respondents. MATERIALS AND METHODS: A discrete-choice experiment was employed to elicit preferences of patients with plaque psoriasis in multiple countries. The survey instrument included a series of choice questions between three hypothetical treatments, each characterized by varying levels of six attributes (namely, lesion reduction, risk of impairing side effects, time to reach results, mode and frequency of administration, itching reduction, and side effects). Random parameters logit was used to model the data. Results were compared across a total of 18 subgroup sets. RESULTS: The data analysis from 1,123 respondents showed that, on average, respondents receive more utility gain from higher levels of lesion reduction and lower risks of impairing side effects than changes in other attributes included in the study. Systematic differences were detected for 13 sets; the most pronounced differences were observed based on disease severity, nail psoriasis, biologic experience, and quality-of-life scores. CONCLUSION: These many sources of preference heterogeneity identified by our analysis suggest that to improve patient satisfaction and, probably, adherence and persistence, clinicians should discuss options with patients when prescribing their treatment.

Indirect comparisons of ixekizumab versus three interleukin-23 p19 inhibitors in patients with moderate-to-severe plaque psoriasis - efficacy findings up to week 12.

BACKGROUND: It is challenging to select the most appropriate biologic treatment for patients with moderate-to-severe plaque psoriasis. OBJECTIVE: To compare speed of onset and level of skin improvement between the interleukin (IL)-17A antagonist ixekizumab and the IL-23 p19 inhibitors guselkumab, tildrakizumab, and risankizumab in patients with moderate-to-severe plaque psoriasis. METHODS: Using data from controlled clinical trials, both adjusted indirect comparisons (AICs) and matching adjusted indirect comparisons (MAICs) were performed to determine the risk difference (RD) between ixekizumab and each IL-23 p19 inhibitor for the proportion of patients with ≥75%/90%/100% improvement compared with baseline in Psoriasis Area and Severity Index (PASI 75/90/100) up to week 12. Placebo, etanercept, or ustekinumab were used as the comparator bridge. RESULTS: In all (M)AICs, RDs generally significantly favored ixekizumab over guselkumab (placebo bridge), tildrakizumab (placebo or etanercept bridge), and risankizumab (placebo or ustekinumab bridge) from the earliest assessment time (≥ week 2) to week 12 when considering PASI 75/90/100 responses. CONCLUSION: Ixekizumab provides a faster onset of effect and earlier clinical benefits than guselkumab, tildrakizumab, or risankizumab in patients with moderate-to-severe psoriasis, as reflected by higher levels of skin improvement than with these IL-23 p19 inhibitors up to week 12.