CONRAD’s preclinical laboratories have played a major role in evaluating and bringing new products and testing methodologies to late-stage development and market. Using innovative experimental techniques, the preclinical team analyzes gene and protein expression, immune cell populations, antimicrobial factors, vaginal microbiome, and HIV and herpes simplex virus infection in cervicovaginal tissues in early phase clinical trials. In addition, the preclinical lab works closely with CONRAD’s Product Development team to test candidate HIV prevention, contraceptive and reproductive health products, and develop novel methods to detect and measure product use in clinical settings.
Safety, Efficacy and Pharmacokinetics/Pharmacodynamics Assessment of Microbicide and Contraceptive Products
Since its inception, CONRAD’s network of scientists has evaluated more than 3,000 microbicide/contraceptive compounds. As a result of CONRAD’s extensive work evaluating microbicide candidates, a preclinical testing algorithm that includes in vitro, ex vivo and in vivo assays to evaluate compounds for efficacy, cervicovaginal safety and pharmacokinetics and pharmacodynamics was developed and is now a reference for the field.
CONRAD researchers are working to improve preclinical safety assessments through the development, standardization and validation of in vitro and in vivo cell-based assays of cytotoxicity and proinflammatory cytokines. With our collaborators, CONRAD has helped to develop and refine various preclinical models evaluating the safety of vaginal formulations, subdermal implants and intrauterine devices. For example, by incorporating biomarker testing to objectively assess susceptibility to HIV mucosal infection, the refined rabbit vaginal irritation model now provides more sensitive assessment of safety for topical HIV prevention products compared to the industry standard test. Additionally, panels of discriminatory biomarkers that potentially signal microbicide-induced mucosal damage have been developed using both in vitro and in vivo models. Collectively, these assays will help to refine the early safety testing of microbicide products in order to improve data used to make crucial go or no go decisions in the product development pipeline.
Using in-house capabilities, CONRAD conducts cell and tissue based antiviral efficacy studies to screen microbicide candidates and formulations. Studies are performed either in vitro using human cervicovaginal cell lines or explants isolated from genital tissues, or ex vivo using tissue biopsies taken during clinical studies. Through this viral infection assay, we are able to mimic the dynamics of early HIV and HSV infection, and to characterize the impact of microbicides, antivirals, hormones, seminal plasma and other exogenous factors on HIV infection. The goal of this work is to define the antiviral activity of candidate compounds in vitro, and to predict in vivo efficacy in order prioritize microbicide products and multipurpose prevention technologies prior to clinical trials.
Using innovative experimental techniques, the CONRAD laboratory investigates numerous pharmacodynamics outcomes in preclinical and early phase clinical testing, including gene and protein expression, immune cell populations, antimicrobial factors, vaginal microbiome and HIV infection in cervicovaginal tissues. CONRAD also partners with several collaborators to investigate the pharmacokinetics of candidate microbicides preclinically and clinically. In particular, we are interested in determining how the pharmacokinetic parameters of various products correlate with the pharmacodynamic effects observed in our laboratory.
IND-Enabling Nonclinical Activities
As an organization dedicated to developing new products from preclinical through clinical stages of development, ensuring the safety and readiness of investigational products for clinical testing is essential. Our team is uniquely experienced in developing and implementing nonclinical testing plans for drug formulations, devices and combination (drug-device) products, to enable regulatory approvals prior to initiating clinical studies. For combination products (such as intravaginal rings and subdermal implants) needing to satisfy both pharmaceutical and medical device regulation requirements, these testing plans can become very complex. Our team has a proven track record for developing successful testing strategies and navigating investigational new drugs (IND) and devices (IDE) through this enabling stage of product development.
Objective Measures of Adherence
Adherence is critical for effective HIV prevention yet has proven to be the Achilles’ heel in the clinical evaluation of efficacy of HIV prevention products. An added challenge remains the objective measure of adherence at the point of care, such that immediate feedback may enable enhanced, targeted adherence counseling. Toward this end, CONRAD has pioneered the development of novel objective measures of adherence for potentially on-site, real-time and low-cost use.
The panel of markers undergoing validation and optimization include:
- DNA and/or protein biomarkers for vaginal exposure (protocol compliance) and semen exposure (HIV risk)
- Markers/measures for product adherence via multiple approaches:
- Excipient-based measures, suitable for detecting both active and placebo product use in biological samples (e.g., vaginal swabs)
- Spectroscopy-based chemometric approaches to determining adherence in various biological sample types (e.g., vaginal swabs, blood, urine)
Our adherence method development approach begins with preclinical method development and discriminant model optimization, using controlled samples created in vitro, followed by method validation within clinical studies.