The study protocol for review was developed to determine the study designs of herbal medicine clinical trials of published papers. It was granted an exemption by the Research Ethics Committee of the Faculty of Medicine, Chiang Mai University (No. EXEMPTION-08849/2022). A systematic search was conducted in July 2021 (last update on December 31, 2022) across five electronic databases, namely PubMed, Embase, Web of Sciences, Scopus, and the Cochrane Library, using terms related to ‘herbal medicine’ and ‘clinical trials.’ The search was limited to original research articles published between 2019 and 2022, with no language restrictions.

After the initial search, the identified records were imported into EndNote X9, and duplicates were removed. Articles were screened based on title and abstract, and those deemed potentially relevant were retrieved for further assessment. Full-text articles were considered for inclusion if they reported clinical trials that used herbal medicine as an intervention and involved human participants, regardless of age, gender, or health condition. The term ‘herbal medicines’ in this study includes herbs, herbal materials, herbal preparations, and finished herbal products, all of which contain active ingredients derived from parts of plants, or other plant materials, or combinations thereof. These products could be in various forms, such as extracts, powders, or capsules, provided they retained the natural composition of the plant material. Importantly, products in which the active substances had undergone chemical modifications, additions, or synthesis, such as the inclusion of synthetic compounds or isolated constituents, were excluded from the definition of herbal medicine in this study.

Articles that did not present original clinical data were excluded, including review articles, case reports, expert opinions, conference abstracts, comments, editorials, and surveys. Additionally, studies that did not involve human participants, such as animal or in vitro studies, were not included. Furthermore, clinical trials that used combination treatments, where herbal medicine was not the primary intervention, were excluded to maintain focus on those evaluating the efficacy of herbal medicines. To ensure comprehensiveness, the reference lists of all relevant articles were screened for additional potentially eligible studies.

Two independent reviewers (C.S., P.K., and/or S.S.) conducted the screening and selection of studies to ensure a rigorous and unbiased process. Initially, the reviewers screened the titles and abstracts of all identified studies based on predefined inclusion and exclusion criteria. Any discrepancies between the reviewers were resolved through discussion, and a third reviewer (N.K. and/or M.N.) was consulted in cases where consensus could not be reached. After the initial screening, full-text articles of potentially eligible studies were retrieved and further assessed for inclusion. Any disagreements were resolved by discussion or by involving a third reviewer.

Data were extracted from the included studies with the following information: (1) study characteristics (i.e., sponsor/funder, study location, and number of human participants), (2) intervention characteristics (i.e., type of the herbal medicine intervention, comparator, route of administration, and intervention duration), (3) study design (i.e., trial phase, trial category, trial type, trial framework, randomization, blinding, number of arms, and allocation ratio), and (4) type of outcome measures (i.e., subjective (soft) outcomes (e.g., pain perception) or objective (hard) outcomes (e.g., measurable biomarkers)). Trial registration and protocol availability were also determined based on publication details. The health outcomes were classified according to the International Classification of Diseases (ICD) codes of diagnosis categories, blocks of categories, and/or chapters according to the ICD-10 WHO version 2019.

For this study, the trial phase was categorized into four phases based on the glossary of common site terms used on ClinicalTrials.gov, i.e., Phase 1, Phase 2, Phase 3, and Phase 4. In addition, clinical trials were categorized as either explanatory (designed to test the efficacy or safety of an intervention in an ideal context) or pragmatic (aimed at evaluating its effectiveness and safety in real-world practice). The clinical trial designs were classified into different trial types, i.e., (1) parallel design, where each participant is randomly assigned to receive either the intervention or control in separate groups; (2) crossover design, where each participant receives both the intervention and control but in a different order; (3) factorial design, which is suited for the study of two or more interventions in various combinations in one study setting; and (4) cluster design, where a clinical trial involves randomization by study sites or locations rather than by individual participants. Moreover, the framework of a clinical trial was also extracted, if available, based on the study’s hypothesis: superiority, non-inferiority, or equivalence.

For this study, the blinding terminology is categorized as follows: (1) “double-blind”, indicating a clinical trial in which both participants and investigators/outcome assessors were blinded; (2) “single-blind”, indicating a clinical trial in which either participants or investigators/outcome assessors were blinded; and (3) “open-label”, indicating a clinical trial in which neither participants nor investigators/outcome assessors were blinded.

Descriptive analyses were presented as either frequency with percentage (%) or mean with standard deviation, depending on data type. The statistical analyses and visualization were performed using RStudio software version 4.0.3.