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Using Historical Data to Support Approval of Drug Products for Ophthalmia NeonatorumInnovative Approach Toward Evidence-Based Medicine

Educational Objective
To review the therapeutic clinical trials for patients with bacterial conjunctivitis to evaluate the similarity in the cause of disease and the treatment response between neonates and older children and adults.
1 Credit CME
Key Points

Question  Are ophthalmia neonatorum and bacterial conjunctivitis in older children and adults the same in terms of the cause of the disease and the response to treatment?

Findings  In this comparative effectiveness review, 3 pooled neonatal randomized clinical trials (N = 392) and 30 pooled trials of older children and adults with similar designs (N = 2018) were analyzed. Bacterial culture data showed that the ocular organisms isolated were similar between neonates and older children and adults; likewise, clinical trial cure rate data demonstrated similarity in clinical course and treatment response between neonates and older children and adults.

Meaning  Ophthalmia neonatorum and bacterial conjunctivitis in older children and adults might be sufficiently similar indications to allow extrapolation of treatment effectiveness.

Abstract

Importance  Off-label treatment was common for ophthalmia neonatorum because only erythromycin ointment had been approved by the US Food and Drug Administration (FDA) for this indication. Ophthalmia neonatorum was previously considered a different indication from bacterial conjunctivitis in older children and adults because of uncertain similarities in the cause of disease and the treatment course between the 2 populations. Prospective therapeutic clinical studies were required to demonstrate the effectiveness of treatment for ophthalmia neonatorum.

Objective  To review the therapeutic clinical trials for patients with bacterial conjunctivitis to evaluate the similarity in the cause of disease and the treatment response between neonates and older children and adults.

Design, Setting, and Participants  In this comparative effectiveness research review of pooled data from the most recent 30 bacterial conjunctivitis trials (N = 2018) submitted to the FDA to support the approval of topical ophthalmic solutions for older children and adults, 95% CIs were constructed from clinical cure rates. Cure rates in 3 neonatal randomized clinical trials (N = 392) of patients treated with ophthalmic anti-infective solutions of ciprofloxacin, gatifloxacin, and moxifloxacin were constructed and compared. The baseline ocular swab cultures were analyzed.

Main Outcomes and Measures  Cure rates of neonatal trials were compared with the 95% CIs among older children and adults. The bacterial organisms isolated from these 2 populations were compared.

Results  The 3 neonatal trials enrolled a total of 392 patients, and the 30 trials of older children and adults enrolled a total of 2018 patients. Neonatal clinical cure rates for moxifloxacin (day 4, 48%), ciprofloxacin (day 4, 49%; day 5, 61%), and gatifloxacin (day 7, 79%) were within the 95% CI for products approved to treat older children and adults with bacterial conjunctivitis. Bacterial organisms were consistent between these 2 populations.

Conclusions and Relevance  Comparison of the pooled analysis of these historical trial data suggests similarity in the cause of disease and the treatment response between neonates and older children and adults with bacterial conjunctivitis. Therefore, it was appropriate to extrapolate the effectiveness from older children and adults to neonates to support the approval of therapies for ophthalmia neonatorum. Based on this analysis, ophthalmic solutions of ciprofloxacin, gatifloxacin, and moxifloxacin are now approved for all age groups. This analysis presents an approach of using pooled data from previously underpowered individual trials to establish the similarities in the cause of disease and in treatment response between children and adults, which are the fundamental elements used to evaluate whether extrapolation of effectiveness can be used to support drug approval.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: October 24, 2020.

Published Online: December 17, 2020. doi:10.1001/jamaophthalmol.2020.5558

Corresponding Author: Wiley A. Chambers, MD, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993 (haihao.sun@fda.hhs.gov).

Author Contributions: Drs Sun and Chambers had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Sun, Chambers.

Drafting of the manuscript: Sun.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Chambers.

Administrative, technical, or material support: Sun, Chambers.

Supervision: Temeck, McCune, Chambers.

Conflict of Interest Disclosures: None reported.

Disclaimer: Views expressed in this article are those of the authors and do not necessarily reflect the official positions or policies of the US Food and Drug Administration.

References
1.
Sun HM, Temeck J, Murphy D, Chambers WA. Innovative approach of using prior trial data to support drug approval and evidence-based medicine for ophthalmia neonatorum. Poster paper presented at: 2018 Pediatric Academic Societies Annual Meeting; May 8, 2018; Toronto, Ontario, Canada.
2.
Chambers WA. Deputy Division Director review of NDA 19-992 supplement 17. US Food and Drug Administration. Published January 17, 2017. Accessed June 6, 2020. https://www.fda.gov/media/138599/download
3.
Chambers WA. Deputy Division Director review of NDA 21-598. US Food and Drug Administration. Published January 17, 2017. Accessed June 6, 2020. https://www.fda.gov/media/104593/download
4.
Chambers WA. Deputy Division Director review of NDA 21-493/S-009. US Food and Drug Administration. Published January 17, 2017. Accessed June 6, 2020. https://www.fda.gov/media/130102/download
5.
Larsen  B , Monif  GR .  Understanding the bacterial flora of the female genital tract.   Clin Infect Dis. 2001;32(4):e69-e77. doi:10.1086/318710 PubMedGoogle ScholarCrossref
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