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Lee NJ, McDonagh M, Chan B, et al. Drug Class Review: Topical Calcineurin Inhibitors: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2008 Oct.

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Drug Class Review: Topical Calcineurin Inhibitors: Final Report [Internet].

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Literature Search

To identify relevant citations, we searched Ovid MEDLINE® (1950 to November week 2, 2007), the Cochrane Database of Systematic Reviews® (4th quarter 2007), and the Cochrane Central Register of Controlled Trials® (4th quarter 2007) using terms for included drugs, indications, and study designs. (See Appendix A for complete search strategies). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched the United States Food and Drug Administration’s Center for Drug Evaluation and Research web site for medical and statistical reviews of individual drug products ( Finally, we requested dossiers of published and unpublished information from relevant pharmaceutical companies. All received dossiers were screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote® version 11.0).

Study Selection

All citations were reviewed for inclusion using the criteria shown in Table 2. One investigator reviewed titles and abstracts of citations while another investigator double-checked the selected references. Full-text articles were retrieved and again were assessed for inclusion by two reviewers; disagreements were resolved by consensus. Results published in abstract form (for example, as a conference proceeding) were not included because these typically do not provide sufficient detail to perform adequate quality assessment. Case reports, case series, and single-arm extension studies also were excluded.

Table 2

Table 2

Study inclusion criteria

Data Abstraction

The following data were abstracted by one reviewer and reviewed by a second: study design, setting and population characteristics (including sex, age, ethnicity, and diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results when reported.

For included systematic reviews, we abstracted the searched databases, study eligibility criteria, number of studies and patients represented, characteristics of included studies, data synthesis methods, and main efficacy and safety results.

Validity Assessment

We assessed the internal validity (quality) of trials on the basis of the predefined criteria listed in Appendix B. These criteria are based on the United States Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria.10, 11 We rated the internal validity of each trial on the basis of the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. We considered methods to meet criteria for intention-to-treat analysis if outcomes for at least 95% of participants were analyzed according to the group to which they were originally assigned. We considered total attrition of ≥20% in any of the treatment arms to be excessive.

Trials that had fatal flaws were rated poor-quality. Trials that met all criteria were rated good-quality and the remainder rated fair-quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses. The results of some fair-quality studies are likely to be valid, while others are only probably valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failing to meet combinations of items of the quality assessment checklist that work together to suggest a potential for bias.

We assessed the quality of systematic reviews using predefined criteria developed by Oxman and Guyatt (see Appendix B). These included adequacy of literature search and study selection methods, methods of assessing validity of included trials, methods used to combine studies, and validity of conclusions.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence was the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated one topical calcineurin inhibitor against another provided direct evidence of comparative effectiveness and adverse event rates. These direct comparisons were preferred over indirect comparisons. When available, these data were the primary focus. Similarly, effectiveness and long-term harms-related outcomes were preferred to efficacy and short-term tolerability outcomes.

In theory, trials that compared topical calcineurin inhibitors to other drug classes or placebo could provide evidence about comparative effectiveness. But such indirect comparisons can be difficult to interpret for a number of reasons, including heterogeneity between trial populations, interventions, and assessment of outcomes. Data from indirect comparisons were used to support direct comparisons, where they existed, and were also used as the primary comparison where no direct comparisons existed. Thus, indirect comparisons should be interpreted with caution.

Meta-analyses in this review were conducted using random effects model for outcomes for which a sufficient number of studies existed and for studies that were homogeneous enough that combining their results could be justified.12 In order to determine whether meta-analysis could be meaningfully performed, we considered the study quality and heterogeneity in design, patient population, interventions, and outcomes. An adjusted indirect comparison was performed for the outcome of resolution of disease assessed by patients by combining the results of the meta-analysis comparing tacrolimus versus vehicle with the meta-analysis comparing pimecrolimus versus vehicle. The variance of the estimate of effect was estimated as the sum of the variances of the two meta-analyses being pooled.13 Weighted mean differences between drug and control were also calculated for outcomes (change in pruritus, change in EASI score, etc). Incidence rates between drug and control were pooled for withdrawals. The Q statistic and the I2 statistic (the proportion of variation in study estimates due to heterogeneity) were also calculated to assess heterogeneity between the effects from the studies.14, 15 Analyses were conducted using “R statistical environment” and StatsDirect (CamCode, Altrincham UK) software.

We included studies with adults and children (all ages, including infants) with atopic dermatitis. Publications that pooled more than 1 trial and also provided individual trial results were included, and the data from these trials were used for our meta-analyses. We stratified data by disease severity (mild-moderate compared with moderate-severe), by treatment duration (≤12 weeks compared with >24 weeks), and by tacrolimus strength (0.03% compared with 0.1%). Our decision to stratify by tacrolimus strength was based on our indirect meta-analysis of 5 tacrolimus studies which included tacrolimus 0.03% ointment and 0.1% ointment arms.16–19 Efficacy and effectiveness outcomes that are reported in this review are Investigator Global Assessment-Atopic Dermatitis (IGA) score ≤1, Physician Global Evaluation (PGE) 90% to 100% improvement, patient assessment of pruritus, patient assessment of overall disease control, percent of patients without flares, time to first flare, percent of patients not using topical steroid rescue, and quality of life. In instances where Eczema Area and Severity Index (EASI) scores were reported similarly enough across trials for comparisons to be made, these data were reported. In this review, we defined treatment success as either achievement of IGA score ≤1 or achievement of PGE of 90% to 100% improvement in disease from baseline. And if IGA scores were reported as percent achieving a score ≤1, we combined this data with the percent of patients reporting improvements in PGE of 90 to 100%. Table 3 provides a brief description of IGA, PGE, and EASI scoring methods.

Table 3

Table 3

Description of included assessment methods

Peer Review and Public Comment

Original Drug Effectiveness Review Project reports are independently reviewed and commented upon by three to five peer reviewers. Peer reviewers are identified through a number of sources, including but not limited to members of professional societies, acknowledged experts in a particular field, authors figuring prominently in the published literature, and persons recommended by the Drug Effectiveness Review Project participating organizations. A list of peer reviewers for Drug Effectiveness Review Project reports is available on the Drug Effectiveness Review Project website (

The Drug Effectiveness Review Project process allows for a two-week public comment period prior to finalization of the report. Draft reports are posted on the Drug Effectiveness Review Project website and interested individuals or organizations can submit comments. Comments received from peer reviewers are considered and revisions made accordingly. Public comments are discussed with the Drug Effectiveness Review Project participating organizations and then a determination is made as to what revisions are appropriate.

Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10464


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