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The Evolving Design and Methods for Trials Evaluating the Safety of Candidate Vaginal Microbicides: A Systematic Review

Jespers, Vicky MD, PhD*; Millwood, Iona Y. MD, PhD; Poynten, I. Mary MBBS, MPH, PhD; Van Damme, Lut MD, PhD§; Kaldor, John M. MD, PhD

doi: 10.1097/01.olq.0000431070.38601.03

Vaginal preexposure prophylaxis is a promising biomedical tool for HIV prevention. Although guidelines for the clinical assessment of microbicides are available, validated markers for product safety are lacking. To inform future microbicide and multipurpose vaginal product research, we reviewed the current and past safety methods used. We searched the Cochrane, EMBASE, and Ovid MEDLINE databases for clinical studies of vaginal products for the prevention of HIV that included safety evaluations. Ninety-seven clinical studies involving 21 products were identified: 63 lasted 14 days or less, 19 were longer in duration, and 15 were effectivess studies that included also safety as an outcome. Median sample size in the safety studies was 48 participants (range, 10–799). All studies reported on urogenital endpoint, 71% included colposcopy, and 67% assessed the vaginal microflora. Markers of vaginal epithelial inflammation, systemic absorption, and systemic toxicology assessments were evaluated in 29%, 26%, and 43% of studies, respectively. Excluding the effectiveness studies, these same assessments were done before 1998 in 33%, 7%, and 27% and after 2001 in 38%, 44%, and 60% of studies, respectively. Soluble inflammatory markers were introduced after 2001. Adverse event collection was reported in 73% of studies before 1998 and in 98% after 2001. In a previous review, we recommended that larger and longer safety studies were necessary to detect clinically important toxicities and to provide assurance that agents are ready for large-scale effectiveness trials. Here, we propose a stepwise clinical assessment that can be used for future guidance.

Supplemental Digital Content is available in the article. This review identifies published safety methods for vaginal HIV prevention microbicide trial design. We propose a stepwise clinical assessment for future safety assessments of vaginal anti-infectious products such as microbicides.

From the *Unit of Epidemiology and Control of HIV/STD, Institute of Tropical Medicine, Antwerp, Belgium; †Clinical Trial Service and Epidemiological Studies Units, University of Oxford, Oxford, United Kingdom; ‡Kirby Institute, University of New South Wales, Sydney, Australia; and §Bill & Melinda Gates Foundation, Seattle, WA

Conflicts of interest and source of funding: None of the following authors have an association that might pose a conflict of interest: Vicky Jespers, Iona Y. Millwood, I. Mary Poynten, Lut Van Damme, and John M. Kaldor. This work was supported by the European Commission (CHAARM 242135) and US Agency for International Development.

Correspondence: Vicky Achiel Jespers, MD, PhD, Unit of Epidemiology and Control of HIV/STD, Institute of Tropical Medicine, Antwerp, Belgium. E-mail:

Received for publication January 27, 2013, and accepted May 06, 2013.

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© Copyright 2013 American Sexually Transmitted Diseases Association