Reporting assessment of multicenter clinical trial protocols: A cross‐sectional study

Randomized controlled trials (RCTs) are the top evidence for effectiveness research of a new intervention or treatment. Multicenter design is commonly used in RCTs to increase the sample size and improve the external validity, particularly in Phase II or III studies.1 With the globalization of drug development, increasing emphasis is being placed on multicenter randomized controlled trials (MRCTs).2 However, MRCTs reach their full potential only if they are designed, conducted, and reported appropriately. In our previous survey in 2021, we have analyzed 2844 final reports of MRCTs during 1975–2019 and found that several multicenter-related information was absent or incompletely provided in their publications. To investigate the reason for unsatisfactory reporting level ofMRCTs, we also identified that only 19% studies provided their trial protocol that can be accessed, and 11% descripted the consistency or disparity of protocols across centers.3 Given the importance of trial protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials) to provide a basic guidance for the reporting of protocol.4,5 However, it is unclear whether the reporting of published MRCT protocols are completeness according to the SPIRIT. Furthermore, no previous study has assessed whether multicenter-related aspects are fully considered in these protocols. In particular, some issues include the criteria and responsibilities of participating centers, the quality control regarding administration of intervention(s) and measurements of outcome(s) across centers, the plans of data collection, management and monitoring across centers, and the heterogeneity analysis in the statistical analysis plan (SAP) that are critical for promoting transparency of an MRCT. Therefore, this review aimed to evaluate the reporting characteristics of MRCT protocols based on the SPIRIT 2013 checklist and on a specially designed multicenter-specific checklist. In this review, we defined the protocol of anMRCT as a randomized controlled clinical trial where the data of participants will be collected from more than one center. Accordingly, MRCT protocols published in English or Chinese up to 11 November 2022 were included with no restriction to conditions, interventions, and controls. Except for the exclusionof interimanalysis, results publications, single-center studies, nonrandomized or noncontrolled studies, reviews, case reports, and nonhuman studies, we also exclude repeat records, protocols not pub-

importance of trial protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials) to provide a basic guidance for the reporting of protocol. 4,5 However, it is unclear whether the reporting of published MRCT protocols are completeness according to the SPIRIT. Furthermore, no previous study has assessed whether multicenter-related aspects are fully considered in these protocols.
In particular, some issues include the criteria and responsibilities of participating centers, the quality control regarding administration of intervention(s) and measurements of outcome(s) across centers, the plans of data collection, management and monitoring across centers, and the heterogeneity analysis in the statistical analysis plan (SAP) that are critical for promoting transparency of an MRCT. Therefore, this review aimed to evaluate the reporting characteristics of MRCT protocols based on the SPIRIT 2013 checklist and on a specially designed multicenter-specific checklist.
In this review, we defined the protocol of an MRCT as a randomized controlled clinical trial where the data of participants will be collected from more than one center. Accordingly, MRCT protocols published in English or Chinese up to 11 November 2022 were included with no restriction to conditions, interventions, and controls. Except for the exclusion of interim analysis, results publications, single-center studies, nonrandomized or noncontrolled studies, reviews, case reports, and nonhuman studies, we also exclude repeat records, protocols not pub-

Data extraction was conducted by two reviewers (ZYL and NNW)
independently using a predesigned form, which contained the following elements: types of study design (e.g., assignment, randomization, blinding, and sample size), features of participating centers (e.g., number and distribution of centers, international or national trials), types of diseases based on ICD-11, categories of intervention(s) and control(s), funding sources, and trial registration.
The reporting quality was evaluated according to (1) the SPIRIT 2013 6 and (2) a special-designed multicenter checklist, which was developed by four researchers (ZXB, CY, XZ, and TXW) based on discussion (Table 1). Scoring rules are provided in Supplementary   Tables S2 and S3. Generally, each item/question was scored in terms of two possibilities: "1" for "fully reported" or "not applicable," "0" for "insufficiently reported" or "unreported," Six reviewers (ZYL, FL, JSD, WTC, CWC, and NNW) were trained and participated the evaluations.
During the process, the quality assessment of each protocol was conducted by one author and verified by another author. Possible disagreements were resolved with the consultation of a third senior review author (XZ or ZXB).
We applied frequency and percentage to present categorical variables and median and interquartile range (IQR) to present continuous variables. For individual item of reporting quality, the compliance rate was calculated with the number of items acquired "1" based on the total number of included reports, which was further categorized as TA B L E 1 Questions for assessing the reporting of multicenter-specific items.

Q1
Whether the multicenter design was identified in the title?

Q2
Whether the multicenter design was reported in the Abstract?

Q3
Whether relevant rationale for using a multicnter design was provided in the protocol?

Q4
Whether the multicenter was specified in the trial design section?

Q5
Whether any description of participating center was provided? Such as the namelist of study centers or the selection criteria of centers, etc?

Q6
Whether any description of methods used to ensure that interventions will be administered consistent across centers was provided? Or indicated any variations across centers?

Q7
Whether any description of intervention training arrangement across centers?

Q8
Whether any description of methods to ensure consistent outcome measurements across centers was provided?

Q9
Whether any preallocation of sample size in each center was mentioned?

Q10
Whether any description of recruitment strategies across centers was provided? Such as the recruitment ways, schedule, or timeline, etc.

Q11
Whether the allocation sequence was specified as centralized or stratified by center?

Q12
Whether any description of methods for data collection across centers was provided? Such as central system used to ensure consistent among centers, or indicated any differences across centers?

Q13
Whether any statistical analysis plan for the heterogeneity assessment and adjustment for central effect was provided?

Q14
Whether any description of auditing, such as conducted for each center or centrally was provided?