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Study Letter
90 (
1
); 121-123
doi:
10.25259/IJDVL_871_2022
pmid:
37317731

Funding is associated with increased methodological and statistical reporting in onychomycosis randomised controlled/comparative clinical trials

Department of Dermatology, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States
Department of Dermatology, Rutgers New Jersey Medical School, Newark, New Jersey, United States
Department of Dermatology, Weill Cornell Medicine, New York, United States
Corresponding author: Shari R. Lipner MD, PhD, Department of Dermatology, Weill Cornell Medicine, New York, United States shl9032@med.cornell.edu
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Falotico JM, Desai AD, Lipner SR. Funding is associated with increased methodological and statistical reporting in onychomycosis randomised controlled/comparative clinical trials. Indian J Dermatol Venereol Leprol. 2024;90:121-3. doi: 10.25259/IJDVL_871_2022

Dear Editor,

Sample size calculation and primary outcome measure reporting in randomised controlled/comparative trials (RCT) are essential to evaluate and reproduce study methodology and results.1 General dermatology RCT reporting has improved over time.2 Our objectives were to characterise onychomycosis RCT reporting and to determine if funding influences trial/manuscript design and quality.

A systematic review was performed by searching PubMed, 1/9/22, for onychomycosis RCTs using the keywords “onychomycosis,” “clinical trial” and “randomised controlled trial.” Exclusion criteria were non-English language and laser/procedural-based therapies. Eligible trials were assessed for primary outcome specification, including both specific outcome measure and associated timeframe, and full sample size calculation reproducibility, including all α, β, effect size, and variance for continuous outcomes. Partial sample size calculation reproducibility was considered if at least one criterion was met. Trial and manuscript characteristics were assessed by two independent authors who were blinded to each other’s assessments (κ = 0.87; 95% confidence interval: 0.83, 0.90). Univariable analyses were performed to assess associations between funding and manuscript/trial characteristics, and multivariable logistic regression was performed to evaluate independent factors associated with funding status. Studies that received any funding were designated as funded (i.e., no cutoff values). Significance was set at P < 0.05.

Initial searches yielded 198 studies, with 102 included for analysis. Seventy-nine (77.5%) studies were conducted in/before 2012 and 23 (22.5%) were conducted after 2012. Overall, 33/102 (32.4%) studies reported both primary outcome and time, with 48/102 (47.1%) reporting outcome measures only. The most common primary outcomes were mycologic (17/65; 26.2%) and complete (16/65; 24.6%) cures. Only 56/102 (5.9%) and 67/102 (65.7%) studies had fully and partially reproducible sample size calculations, respectively. The target sample size was reported in 30/102 (29.4%) studies, with 26/30 (86.7%) achieving target size [Table 1]. Of the studies that reported a target sample size, 22/30 (73.3%) specified a primary outcome, vs. only 11/72 (15.3%) in studies without reported target sample sizes (P < 0.001). Sixty out of 102 (58.8%) studies were funded, mostly from pharmaceutical companies (51/60; 85%), followed by institutional grants (4/60; 6.7%), other (4/60; 6.7%) and organisational grants (1/60; 1.7%) (P < 0.001). Funded studies vs. non-funded studies more often reported partial sample size calculations [48/60 (80%) vs. 19/42 (45.2%) studies; P < 0.001] and primary outcomes [33/60 (55%) vs. 15/42 (35.7%) studies; P = 0.0548] were registered more frequently [15/60 (25%) vs. 1/42 (2.4%) studies; P = 0.0020], and were more likely to be multicenter [40/59 (67.8%) vs. 19/42 (45.2%) studies; P = 0.0234], and published in higher mean impact factor journals (8.2 vs. 5.9; P = 0.0315). Median sample sizes were similar in funded [148.0; interquartile range (IQR): 292.0] vs. non-funded (97.5; IQR: 74.0) studies (P = 0.0714) [Table 2]. Impact factor [odds ratio (OR): 1.15; P = 0.033] and partial reproducibility (OR: 3.61; P = 0.0151) were significantly associated with funding using multivariable logistic regression.

Table 1: Inclusion of primary outcome measure, time frame, and sample size calculation in onychomycosis randomised controlled/comparative clinical trials
Variable N %
Primary outcome specification 48/102 47.1
 All components present* 33/102 32.4
  Pre-defined primary outcome measure 48/102 47.1
  Timeframe of primary outcome measure 33/102 32.4
 Primary outcome classification 48/102 47.1
  Mycologic cure 17/65 26.2
  Complete cure 16/65 24.6
  Clinical improvement/efficacy/response 7/65 10.8
  Effective cure 3/65 4.6
  Clinical cure 3/65 4.6
  Mycologic examination 3/65 4.6
  Effective treatment 2/65 3.1
  Other 14/65 21.5
Formal sample size calculation performed
 Full reproducibility 6/102 5.9
 Partial reproducibility 67/102 65.7
 Components
  Alpha value 56/102 54.9
  Beta value 26/102 25.5
  Effect size 14/102 13.7
 Variance (for continuous outcomes) 23/30 76.7
 Target sample size reported 30/102 29.4
 Target sample size achieved 26/30 86.7

*Complete primary outcome measure specification requires both a clearly defined primary outcome measure and an associated timeframe, Requires alpha value, beta value, effect size, and standard deviations for continuous outcomes, Requires at least one measure (alpha value, beta value, effect size, or standard deviations for continuous outcomes)

Table 2: Associations between funding status and trial/manuscript characteristics
Variable Funded studies, n (%) Non-funded studies, n (%) P-value*
Trial characteristics
Funder <0.0001
 Pharmaceutical 51 (85) N/A
 Other 9 (15) N/A
Setting† 0.0234
 Multicenter 40 (67.8) 19 (45.2)
 Single center 19 (32.2) 23 (54.8)
Registered trial/published protocol 0.0020
 Yes 15 (25) 1 (2.4)
 No 45 (75) 41 (97.6)
Intervention (oral vs. topical) 0.0248
 Oral 36 (60) 34 (81.0)
 Topical 24 (40) 8 (19.1)
Blinding‡ 0.0971
 Yes 51 (85) 27 (64.3)
 No 9 (15) 15 (35.7)
Median final achieved sample size (IQR)§ 148.0 (292.0) 97.5 (74.0) 0.0714
Manuscript characteristics
Word count 0.1011
 >3000 15 (25) 5 (11.9)
 3000 45 (75) 37 (88.1)
Primary outcome measure specification 0.0548
 Yes 33 (55) 15 (35.7)
 No 27 (45) 27 (64.3)
Fully reproducible sample size calculation 0.2086
 Yes 5 (8.3) 1 (2.34)
 No 55 (91.7) 41 (97.6)
Partially reproducible sample size calculation 0.0003
 Yes 48 (80) 19 (45.2)
 No 12 (20) 23 (54.8)
Description of randomisation methods 0.0004
 Yes 29 (48.3) 6 (14.3)
 No 31 (51.7) 36 (85.7)
Journal impact factor (average, SD) 8.12 (6.0) 5.94 (3.2) 0.0315

IQR: interquartile range, N/A: not applicable, SD: standard deviation, Chisquare and Fisher’s Exact tests were used to compare categories for categorical variables and t-tests were used to compare continuous variables, *Bolded P-values are statistically significant, Setting information (multi vs. single center) was unavailable for one funded study, Single or double blinded, §Wilcoxon rank sums test used for non-parametric comparison for skewed sample size data

Our study showed that few onychomycosis RCTs had full statistical reproducibility and specified both primary efficacy measurements and times. In a previous study analyzing 205 general dermatology RCTs,2 49% reported fully reproducible calculation and 67% reported both primary outcome measure and time. Therefore, onychomycosis RCTs appear to be lacking in methodological reporting, as compared to general dermatology RCTs.

Mycologic and complete cure rates were the most common outcome measures; however, there was variability across trials, similar to previous analyses of efficacy measures in onychomycosis trials.3,4 Primary efficacy endpoints used in RCTs are required by the Food and Drug Administration for drug approvals, but might not be reflective of clinical practice.5 Therefore, although consensus in outcome measures is necessary to compare therapies, it is uncertain whether standardised measurements will translate into improved clinical outcomes.

We found that funded studies had better statistical and outcome measure reporting than non-funded studies and were also more robustly designed. Therefore, funding likely plays an important role in trial design, recruitment of participants, and hiring research coordinators and statisticians, resulting in high-quality trials that are likely to be published in high-impact journals.

Our study is limited by the inclusion of oral and topical onychomycosis studies only. We did not screen journals for Consolidated Standards of Reporting Trials (CONSORT) guideline status, and it is possible that studies published in these journals may have better reporting. Allocation concealment, which can indicate an assessment of bias in RCTs, was not collected.

Overall, our study shows that many onychomycosis RCTs lack appropriate methodological and statistical reporting, without reproducibility across trials. Funding may thus be influential in increasing RCT quality and the likelihood of publishing in journals with a wide readership, positively impacting outcomes for onychomycosis patients.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

Ms. Falotico and Mr. Desai have no conflicts of interest. Dr. Lipner has served as a consultant for Ortho Dermatologics, Hoth Therapeutics, and BelleTorus Corporation.

References

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  3. , . How do we measure efficacy of therapy in onychomycosis: Patient, physician, and regulatory perspectives. J Dermatolog Treat. 2016;27:498-504.
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  4. , , . Comparison of efficacy criteria across onychomycosis trials: Need for standardization. Int J Dermatol. 2003;42:312-5.
    [CrossRef] [PubMed] [Google Scholar]
  5. . Response to “A financial perspective on the topical treatment of onychomycosis”. J Am Acad Dermatol. 2016;75:e39.
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