(Excerpts of) A Summary of Preclinical Topical Microbicide Vaginal Safety and Chlamydial Efficacy Evaluations in a Pigtailed Macaque Model

Patton, Dorothy L. PhD; Cosgrove Sweeney, Yvonne T. BA; Paul, Kathleen J. MPH

Background:
The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases, and it is especially important that candidate products undergo rigorous preclinical safety and efficacy testing before advancing to clinical trials.

Methods:
We have developed a standardized protocol for preclinical vaginal safety and efficacy assessment of topical microbicide candidates in a nonhuman primate model. Over 7 years of funding under an NIH contract, we evaluated a total of 28 test compounds for vaginal safety (via colposcopy, vaginal pH, and microflora) and 9 compounds for efficacy against cervical chlamydial infection. We also outline the specific criteria used to determine which products should move into efficacy trials and which should be recommended for reformulation to the manufacturer.

Results:
Overall, we noted acceptable safety profiles for 24 of 28 candidate products. Common findings included a transient decrease in vaginal pH, petechiae, and mild erythema. Four products were associated with significant adverse colposcopic findings including blisters, epithelial abrasions, and friability; all 4 products were successfully reformulated and showed acceptable safety profiles at lower concentrations. No products showed complete protection against cervical chlamydial infection.

Conclusions:
The macaque preclinical safety and efficacy model is critical to maintaining the pace of topical microbicide development, which could ultimately offer a significant opportunity for intervention in the global HIV/AIDS epidemic.

Overall safety profiles were acceptable in 24 products. Microbiologic findings common to most products included stable populations of H2O2-producing lactobacilli and Viridans streptococci and transient decreases in anaerobic Gram-negative rods.

The majority of products induced a transient decrease in vaginal pH 30 minutes after product exposure, although pH typically returned to baseline by follow-up on day 8. In studies that included cervical and vaginal biopsies, no product-induced inflammatory response was observed. Common colposcopic observations included notations of vasculature, petechiae, and mild color changes (blanched to slightly reddened tissues), all of which are considered typical findings in nonstudy animals.

In light of recent concerns regarding the safety of topical microbicides in international clinical trials, the importance of preclinical safety investigations is especially clear. Female-controlled products like microbicides offer a critical opportunity in the fight against HIV and other STIs globally, but such products must first undergo rigorous safety and efficacy testing.

Preclinical evaluations in an animal model such as ours can provide significant product comparison information obtained under standardized laboratory conditions, offering early warning of products that may have harmful effects and helping to usher promising products into clinical trials more quickly. However, it is important to bear in mind that preclinical nonhuman primate testing is necessarily limited by the small numbers of animals involved; we cannot necessarily detect rare adverse events or safety problems, which may arise when larger clinical trails are conducted.

Thus, our overall goal is not to definitively establish product safety, but rather to detect any major toxicities and recommend reformulation before the product enters clinical testing. When toxicity problems are observed, we may be able to conduct further testing to isolate the specific component of the product producing the deleterious effects, which is very useful information for the developer in terms of reformulation.

This learning process is critical to future product development. In summary, the NIH-contract mechanism provides a resource to further the development of topical microbicides aimed at the prevention and control of STIs through preclinical testing in nonhuman primates. Continuing safety evaluations and efficacy evaluations for the pathogens C. trachomatis and T. vaginalis are also supported through the recently awarded NIH/NIAID primate contract mechanism through 2014.