Qualified placebo for trials of herbal medicine treatment in rare diseases? A cross-sectional analysis.

backgroundWhile substantial placebos have been used in herbal medicine (HM) clinical trials for rare diseases, the use and quality of reporting of HM-placebo remain unclear. We aim to describe the use of HM-placebo in clinical trials for rare diseases and determine the quality of reporting in these trials.

methodsThis is a cross-sectional study. We searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure, WanFang database, China Science and Technology Journal Database, National Institute of Informatics Support Academic Information Services, ClinicalTrials.gov and Chinese Clinical Trials Registry from their inception date to 14 February 2023 to identify registered and published trials that use placebos as a comparator in rare diseases. We collected data on placebo use reporting and the efficacy and safety of placebo. Descriptive statistics, the Chi-square test, and Binary multivariable logistic regression analysis were used to determine the placebo characteristics of the HM trial and its effect on reporting.

resultsAmong the 55 studies, we included that with a median administration time of placebo of 84 days (IQR 42-180) and a median placebo sample size of 30 (IQR 24-54). About half of the trials (27, 49.1%) did not provide their ethical approvals, and one trial had details of informed consent. None of the studies were fully reported and more than half of the items reported less than 50%. A total of 10 trials (18.2%) of placebo has active ingredients even though none of them performed pharmacological inert tests. Of the 29 studies with available data on adverse events, 5 (17.2%) trials did not show a better safety profile in the placebo group. Under the context that a relatively high-quality report is defined as a report with more than 9 items, there was a statistically significant difference between the two groups in the rate of relatively high-quality reports of the administration time (p = 0.047, OR 0.10, 95% CI 0.01 to 0.90), but the results are not representative.

conclusionThe overall situation of HM-placebo in the field of rare diseases was poor. In particular, the placebo is tied to the quality of trials, and poor placebo hinders the generation of high-quality evidence for herbal clinical trials in the field of rare diseases. We summarize the current methods of assessment involved in the use of placebos and propose various considerations for placebos in different contexts. Our study can greatly promote rare disease researchers to review the quality of their placebo and clinical trials. It is imperative to guarantee that meticulously conducted research generates clinical evidence of the highest caliber. We also expect that in the future, more rigorous relevant standards about the reporting and design of HM-placebo will be developed. High-quality clinical trials are the prerequisite for the wide clinical application of herbal medicines for rare diseases.