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Non-inferiority trials in clinical ophthalmology: a systematic review

Eye volume 39, pages 2151–2158 (2025)Cite this article

Subjects

Abstract

Purpose

To summarize the characteristics and methodology of non-inferiority trials in ophthalmology, aiding researchers in understanding the applications and limitations of such trials in ophthalmic diseases.

Methods

PubMed, Web of Science, Embase and Scopus were searched for literature on non-inferiority randomized trials in ophthalmology published between 2000 and November 5 2023. Data on the basic characteristics were extracted and summarized. The Risk of Bias 2’s was used to assess the bias risk.

Results

A total of 294 papers were included, with 77.6% of the trials conducted in the last 10 years, and more than 2/3 (72.1%) were multicenter studies, and 79.9% were registered on platforms. The majority of trials were applied in the researches of glaucoma, cataract, age macular degeneration, macular edema, dry eye, myopia, or refractive error. Non-inferiority thresholds were reported in 88.4% of the trials. Intent-to-treat analysis was the primary outcome analysis method in only 21.8% of trials, while both intent-to-treat and per-protocol analyses were used in 29.6%. Last observation carried forward method was used to address missing values in 23.5%. However, 56.5% of the articles did not report how missing values were handled, leaving uncertainty regarding whether missing data was considered in the analysis. About 20.7% of the studies were at high risk of bias, mainly due to outcome measures and missing value treatments.

Conclusion

Non-inferiority trials are commonly used in ophthalmologic research to assess the effectiveness, safety, cost-effectiveness of treatments or surgical methods, but the quality of implementation and reporting needs to be improved.

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Fig. 1
Fig. 2
Fig. 3: Distribution of non-inferiority trials in each category (n = 294).

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Author information

Author notes

  1. These authors contributed equally: Dan-Lin Li, Jian-Hua Liu.

Authors and Affiliations

  1. School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China

    Dan-Lin Li, Jian-Hua Liu, Xing-Xuan Dong & Chen-Wei Pan

  2. Division of Science, New York University Abu Dhabi, Abu Dhabi, UAE

    Carla Lanca

  3. Comprehensive Health Research Center (CHRC), Escola Nacional de Saúde Pública, Universidade Nova de Lisboa, Lisboa, Portugal

    Carla Lanca

  4. Institute for Research in Ophthalmology, Foundation for Ophthalmology Development, Poznan, Poland

    Andrzej Grzybowski

  5. Department of Ophthalmology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, China

    Li-Jun Zhang

  6. Branch of National Clinical Research Center for Eye Diseases, Liaoning Provincial Key Laboratory of Cornea and Ocular Surface Diseases, Liaoning Provincial Optometry Technology Engineering Research Center, Dalian, China

    Li-Jun Zhang

  7. Ophthalmology and Transformational Innovation Research Center, Faculty of Medicine of Dalian University of Technology—Dalian Third People’s Hospital, Dalian, China

    Li-Jun Zhang

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Contributions

DLL and JHL conducted the search, selection, data extraction and quality assessment of relevant literature. DLL and JHL contributed to the statistical analysis and wrote the manuscript. XXD, CL, AG and LJZ revised the manuscript. CWP designed the experiment and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Li-Jun Zhang or Chen-Wei Pan.

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Competing interests

Andrzej Grzybowski is a member of the Eye editorial board. The other authors declare that they have no conflict of interest.

Ethics

This review has been prospectively registered with PROSPERO and has been given a registration number (CRD42023468112).

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Li, DL., Liu, JH., Dong, XX. et al. Non-inferiority trials in clinical ophthalmology: a systematic review. Eye 39, 2151–2158 (2025). https://doi.org/10.1038/s41433-025-03819-w

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