Abstract Cervical cancer deaths have dramatically fallen in high-income countries, but cervical cancer remains one of the leading causes of cancer deaths in low- and middle-income countries (LMICs). Cervical cancer accounted for 341,800 deaths in 2020, with approximately 90% of these deaths occurring in LMICs. Treatments for precancerous lesions are highly effective for preventing cancer progression if identified and treated early. However, most LMICs and low-resource clinics that offer cervical cancer screening lack accessible treatment services, which means referral of patients to larger hospitals, leading to loss of follow up and disease progression to cancer. While loop electrosurgical excision procedure is the gold standard in the treatment of lesions, it requires highly trained clinicians and an operating environment rarely found in LMIC clinics. The World Health Organization recommends cryotherapy for cervical precancer treatment in LMICs, but the key drawback for current cryotherapy systems is their dependence on consumable cryogen gas. Access to a cryogen gas supply is unreliable, consumable gas costs are high, and heavy and bulky gas cylinders limit portability to remote clinics. Other LMIC-targeted options have been attempted, but they were poorly adopted due to high cost and discontinued manufacturer support (CryoPen) or insufficient depth of tissue necrosis for fully effective treatment (heat-based thermal ablation). Taken together, no single system exists to provide an appropriate and cost- effective solution that is suitable for widespread LMIC use. With an LMIC-appropriate treatment solution, cervical cancer mortality could be reduced by 33% (~300,000 deaths) by 2030. In this Phase II SBIR proposal, and in response to NCI’s Notice of Special Interest (NOT-CA-21-062), Ananya Health is developing the CRCL System, a portable, affordable battery-powered, closed-loop cryotherapy system for the treatment of cervical precancerous lesions in LMICs. By recirculating the cryogen fluid in a closed-loop system, the CRCL System does not require consumable cryogen gas. The rechargeable battery allows for treatment independent of electrical grid availability. Completion of all Phase I milestones established that (1) cryotherapy temperatures can be achieved in closed-loop system without consumable gases and (2) a validated list of User Needs and design inputs will drive the development of our CRCL device. In Phase II, first, we will finalize the CRCL design and verify that it meets all design inputs through in vivo animal study and non-clinical evaluations with production- equivalent test units (Aim 1). Then, we will confirm that the CRCL design meets usability and human factor requirements through simulated benchtop design validation by gynecologists and lower-level healthcare providers in the US and LMICs (Aim 2). Finally, we will test CRCL with a variety of IEC 60601-1, cleaning validation, and biocompatibility testing to confirm the design is safe and can withstand a range of environmental and use conditions (Aim 3). The completion of Phase II milestones will culminate in an FDA 510(k) submission and clearance, which will be leveraged for regulatory approval in our Kenya beachhead market.

Narrative Cervical cancer is the fourth most common cancer in women, and accounted for 341,800 deaths in 2020, where approximately 90% occurred in low- and middle-income countries (LMICs). The lack of treatment options in LMICs is a major gap in the screen-and-treat strategy highlighted by the World Health Organization’s cervical cancer elimination initiative, as existing technologies that have successfully driven down case counts in affluent countries are not suited for clinics staffed with lower- and mid-level health workers with limited resources and infrastructure. In response to the treatment gap and to National Cancer Institute’s Notice of Special Interest (NOT-CA-21-062): “Cancer Prevention, Diagnosis, and Treatment Technologies for Low-Resource Settings,” this Phase II SBIR project furthers the development of Ananya Health’s CRCL System, a highly portable, affordable, self-contained cryotherapy unit that is specifically designed with a user-centered focus to overcome infrastructure and resource constraints and enable widespread primary care treatment of cervical precancerous lesions in LMICs.