The Population Council has proven capacity to develop contraceptive devices including GMP and GLP laboratories for materials and analytics, and regulatory, toxicology, and clinical trials expertise. ONPRC is well-suited to carry out the non-GLP preclinical studies due to the established capacity and infrastructure that includes OPERM dedicated core facilities for procedures, imaging, and processing of histologic specimens and additional ONPRC core resources. At ONPRC/OPERM, we will prioritize resources to complete preclinical animal testing needed to support the IND for PDF. The Pop Council will develop a GMP formulation of PDF and develop a program to complete all of the required toxicology studies needed for the IND in consultation with the FDA. A Project Manager will help coordinate activities between OHSU and Population Council investigators and manage timelines. In this application, we propose a series of “go” and “no-go” decisions that will guide this development program, and prioritize our resources to maximize the chance for success while mitigating risk. Since we recognize that drug and device development is inherently risky, we further propose to continue with our pre-clinical development of promising alternative approaches to NSPC identified during our previous cycle of funding (Objective 2). The successful completion of Objective 1 would provide a “go” signal to request additional future investment to support a clinical trial program for PDF. If we reach a “no-go” decision with PDF, we will consult with our advisors to shift resources toward the development of our most promising alternative approach.
Our proposed activities for Outcome 2 (see below) focus on the further development of three alternative approaches under current investigation at OPERM. While the primary goal of this activity will be to advance one or more candidates to a clinical trial program as an alternative to PDF should we reach a “no-go” decision, this research will also support the further development of method that could be safer, less expensive or more feasible than PDF and warrant further development even if we continue to move forward with PDF.
Our studies to this point have supported the use of sclerosing agents to create a tubal occlusion. Sclerosing agents work by damaging the tubal epithelium. Removing this protective ciliated layer triggers a tissue healing response. Effective agents trigger sufficient injury to favor the formation of a collagen scar over re-epithelialization and re-canalization of the tubal lumen. For instance, when we tested agents such as carbon nanotubes that failed to damage the epithelium we did not see collagen deposition or occlusion. For this reason, we hypothesize that sclerosing agents are required for tubal occlusion. Agents that inhibit epithelial cell proliferation DMPA and tissue remodeling (doxycycline) should promote this process, as they favor collagen deposition and scar formation over the repair. Therefore, we propose new studies to focus on agents or combinations of agents that either scarify the tubal epithelium or prevent cell proliferation, and/or form a scaffold for fibroblasts to deposit collagen.