Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1?year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90?mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300?mg. For clinical remission, ustekinumab 90?mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300?mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1?year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.     

Bone Mineral Density Determinations by Dual-Energy x-ray Absorptiometry in the Management of Patients with Marfan Syndrome—Some Factors Which Affect the Measurement

Reduced bone mineral density (BMD) was sporadically reported in patients with Marfan syndrome. This may or may not place the Marfan patient at increased risk for bone fracture. In comparing the BMDs of our patients with those reported in the literature, it seemed that agreement between values, and hence the degree of osteoporosis or osteopenia reported, was dependent on the instrumentation used. The objective of this study was to statistically assess this impression. Bone mineral density measurements from our previously published study of 30 adults with Marfan syndrome performed on a Lunar DPXL machine were compared with studies published between 1993–2000 measured using either Lunar or Hologic bone densitometry instruments. The differences of our measurements compared with those made on other Lunar machines were not statistically significant, but did differ significantly with published results from Hologic machines (P < 0.001). Before progress can be made in the assessment of BMD and fracture risk in Marfan patients and in the evidence-based orthopedic management of these patients, standardization of instrumental bone density determinations will be required along with considerations of height, obesity, age, and sex.     

Titration of duration discrimination in behavioral pharmacology and toxicology

This study investigated a discrete-trial, titration duration discrimination procedure in behavioral pharmacology. Pentobarbital and d-amphetamine, measured with this procedure, selectively affected discrimination more than response tendencies. Pentobarbital also tended to affect selectively discrimination of longer durations, whereas d-amphetamine did not. Further experiments showed that (1) other algorithms for modulating stimulus duration are useful in behavioral pharmacology and toxicology, (2) threshold estimates are similar with the method of constant stimuli and the method of titration, and (3) this titration procedure permits the separate examination of drug effects upon discrimination and upon response tendencies; the fixed-interval procedure does not. Baseline variability was an important correlate of drug effects in that the endpoints with more variable baselines were also more sensitive to drugs.     

How Assessment-Schedule Matching Limits Bias When Comparing Progression-Free Survival in Single-Arm Studies: An Application in Second-Line Urothelial Carcinoma Treatments

ObjectivesPopulation-adjusted comparisons of progression-free survival (PFS) from single-arm trials of cancer treatments can be derived using matching-adjusted indirect comparisons (MAICs); however, results are still susceptible to bias, particularly if the trials had different tumor assessment schedules. This study aims to assess the effects of assessment-schedule matching (ASM) on the relative effectiveness on the PFS of avelumab versus approved comparator immunotherapies or chemotherapy after population matching in the second-line (2L) setting for metastatic urothelial carcinoma.MethodsThe MAIC used patient-level data for avelumab from the JAVELIN Solid Tumor trial (NCT01772004). PFS was compared with published curves for other treatments to obtain population-adjusted hazard ratios (HRs). The MAIC was repeated after conducting ASM for differences in tumor assessment scheduled first at 6 weeks for avelumab and durvalumab and at 8 or 9 weeks for other treatments.ResultsMAIC adjustment alone altered the HR estimates up to 23%, whereas MAIC plus ASM resulted in up to 32.7% reductions from naive comparisons. Even in cases in which MAIC had little effect, ASM brought an additional change of 11.1% to 15.4%. Overall, the HR range of avelumab versus other treatments changed from 0.83 to 1.25 for naive comparisons to 0.76 to 0.99 after ASM plus MAIC, numerically favoring avelumab.ConclusionsSmall variations in assessment schedules can introduce bias in unanchored indirect treatment comparisons of interval-censored time-to-event outcomes. In this study, adjusted PFS was comparable across second-line urothelial carcinoma treatment options, numerically favoring avelumab versus immunotherapies and chemotherapy agents. Correcting this bias is especially important when HRs are applied in cost-effectiveness models to transition patients between states.     

Cultural/Ethnic Comparisons: A Research Agenda

This paper outlines some of the common problems encountered by researchers conducting ethnic or cultural comparisons. The problems are considered in relation to three linked questions that are considered with respect to a comparison of Irish-American and mainland Puerto Rican drinking behavior. With regard to the first question—whom to compare in such research— attention is drawn to the importance of selecting groups on conceptual grounds rather than on the basis of convenience or availability. The distinction between model- and meaning-driven choices is then highlighted. Problems associated with group designation, inclusion criteria, and confounding are also discussed in response to this first question. With respect to the second question—what to compare in such research—the discussion focuses on model-driven measures and generalization-driven measures and the issue of acculturation. The final question—how to insure measure comparability—is addressed with respect to measure equivalence, the problem of cross-cultural meaning and significance, and the use of backtranslation methods to insure linguistic equivalence.     

An income-weighted international average for comparative analysis of health expenditures

Data from 17 countries across 28 years are used to estimate an international health expenditure function based on real per capita GNP. Actual and expected spending levels are compared for 24 countries. Between 1960 and 1987, it has been rare for health expenditure in any country to be more than +/- 20 per cent from the projected value. The norm is for spending to rise at 1.5 times the growth rate of GDP. Two countries appear to display significant anomalies. Spending in the United Kingdom is consistently 15-25 per cent below normal for all years, and Danish expenditure has declined from 7 to 6 per cent of GDP since 1975.     

Is it possible to make cross-study comparisons of urinary continence rates in patients with overactive bladder?

ABSTRACT

Several antimuscarinic agents are available for the treatment of overactive bladder but there are few head-to-head studies to guide physicians in choosing one over another. Here we propose ways in which logical adjustments can be made to account for differences in disease severity and placebo effects when considering continence data to allow estimation of relative effectiveness across studies.     

The analysis of small-sample multivariate data with applications in clinical trials

This article discusses statistical methods for the analysis of multivariate data arising in clinical trials involving a small number of subjects randomly assigned to one of several treatment groups. Possible violations of traditional assumptions such as variance homogeneity and normality of errors are often dealt with by carrying out the statistical analysis using strategies such as transforming the data or applying nonparametric procedures. Multivariate nonparametric tests provide a realistic alternative for analyzing such data. We present a permutation procedure for analyzing data arising in randomized experiments     

ADJUSTING PAIRWISE NONPARAMETRIC EQUIVALENCE HYPOTHESIS TESTS AND CONFIDENCE INTERVALS FOR PERIOD EFFECTS IN 3×3 CROSSOVER TRIALS

In pharmacokinetic and pharmacodynamic 3×3 crossover trials, average bioequivalence and noninferiority between treatments need to be only assessed pairwise in most cases. Due to the restricted number of subjects in such trials, normal distribution assumptions cannot be checked and frequently outliers are encountered, so that a nonparametric approach is more adequate. Therefore, to assess average bioequivalence or noninferiority, a new method is proposed to derive period adjusted nonparametric confidence intervals for pairwise treatment differences.