Cinical Need to be Addressed:
Cancer is the first or second leading cause of premature death in 134 of 183 countries, and it is estimated that global incidence of cancer will increase by 50% from 2018 to 2040. The number of cases is projected to double in countries with low Human Development Index; these countries have the least resources and infrastructure to adequately care for cancer patients. Disparities exist within countries; in the US, racial and ethnic minorities and other medically underserved populations share a disproportionate burden for many types of cancer. Most cancers can be cured if detected early and treated effectively. To reduce premature death, the World Health Organization recommends implementing early cancer detection and prevention programs at the primary care level. Yet, existing tests for early cancer detection are too complex and/or expensive to implement in primary care settings, particularly in medically underserved areas. The Center for Innovation and Translation of Point-of-Care Technologies for Equitable Cancer Care (CITEC) is working to identify high-priority clinical needs for POC cancer technologies; to accelerate development of effective, affordable POC technologies to meet these needs; to evaluate and improve the clinical and public health impact of POC technologies in diverse settings; and to train developers and users to create and disseminate more equitable POC technologies. CITEC prioritizes development of POC tests to improve screening, detection, and diagnosis of pre-cancers and early cancers that arise in epithelial surfaces.
Relevant links: https://www.nature.com/articles/s44222-023-00135-4
Representative Clinical Scenarios to be Addressed:
Cervical Cancer: In May 2018, the Director-General of the WHO announced a global call to action to eliminate cervical cancer, underscoring renewed political will to make elimination a reality (https://www.who.int/reproductivehealth/call-to-action-elimination-cervical-cancer/en/). It will be impossible to meet WHO goals with existing screening and diagnostic technologies. In high-resource settings, the standard of care includes: 1) cervical screening with cytology and/or HPV testing; 2) diagnosis of screen-positive patients with colposcopy and biopsy; and 3) treatment of precancerous lesions (cervical intraepithelial neoplasia grade 2 (CIN 2) or more severe [CIN2+]) with loop electrosurgical excision procedure (LEEP) [54]. This requires three visits, with a need for both pathology services and skilled clinicians at each step. As a result, many women are lost to follow-up and incompletely treated, especially in LMICs. The 2021 WHO guidelines include a Screen & Treat approach, where women are screened with HPV testing and, if positive, directly undergo treatment with ablation (cryotherapy or thermal ablation) or excision with a LEEP without the need for a cervical biopsy and histologic diagnosis [55]. This allows for a single-visit approach, decreasing loss to follow-up and obviating the need for gynecology and pathology services, which are often lacking in LMICs. A major limitation is that it results in overtreatment, as the majority (50-70%) of women infected with HPV do not, and will not, have high-grade cervical disease.
The preferred approach in the WHO guidelines is Screen, Triage & Treat, where treatment is based on a positive primary screening test followed by a positive second “triage” test with or without a histologically confirmed diagnosis [55]. The WHO suggests HPV genotyping, colposcopy, visual inspection with acetic acid (VIA) or cytology as possible triage tests, with the choice depending on feasibility, training, program quality assurance and local resources [55]. Unfortunately, these triage tests are not widely available in many LMICs [56] due to cost (HPV genotyping), lack of trained personnel and infrastructure (cytology, colposcopy) and limited patient access due to transportation or financial barriers. Moreover, some of these strategies (e.g., VIA) have limited reproducibility and accuracy. Point-of-care technologies are needed both to improve access to screening and to provide immediate, accurate triage.
Anal Cancer: In the US, the incidence of anal cancer is over 30 times more common in persons living with HIV than in the general population [113]. A compromised immune system makes people living with HIV (PLWH) susceptible to coinfection with HPV in the anal canal, linked to 90% of anal cancer cases [114]. The recently published ANCHOR (Anal Cancer/HSIL Outcomes Research) study showed that treatment of anal cancer precursor lesions reduces cancer risk for PLWH [115], and clinical experts recommend screening with anal cytology and/or HPV testing [116]. Screen-positive patients are asked to return for a second visit to undergo high-resolution anoscopy (HRA) [117]. Suspicious areas are biopsied and evaluated by a pathologist. HRA-guided biopsy requires a high degree of expertise; new HRA practitioners take around 200 cases to begin consistently identifying all precancerous lesions (high-grade squamous intraepithelial lesions (HSIL) or anal intraepithelial neoplasia grade 2 or more severe (AIN 2+) [118]. Patients diagnosed with AIN 2+ return for a third visit to receive treatment. While treatment of anal precancer has been shown to reduce the risk of progression to cancer significantly, the multiple visit approach has led to high patient loss-to-follow-up rates [119]. A study on the outcomes of an anal cancer-screening program from 2009 to 2019 found that only 58% of patients diagnosed with AIN 2+ returned for treatment [120]. Simplifying screening for HPV and early detection of AIN 2+ using point-of-care methods could improve anal cancer prevention. By offering an in vivo diagnosis during HRA, more selective biopsies could be performed. Additionally, the ability to delineate normal from neoplastic mucosa in real-time may facilitate “Screen & Treat” and “Screen, Triage & Treat” approaches, reducing the number of patients lost to follow-up.
Diagnostic Pathology: Histopathology plays a crucial role in early detection and treatment of cancer and precancer. Microscopic examination of cells and tissues is currently the only way to diagnose cancer, and is needed to assess disease severity, help determine and manage treatment plans, and to monitor response to therapy. Despite widespread availability of microscopes, access to diagnostic pathology is limited in many settings, including community hospitals in the rural US and in large portions of LMICs, because of the high cost of equipment (e.g., microtomes and slide stainers) and the need for trained personnel (e.g., histotechnologists and expert pathologists) [135] [48]. In one study performed in Pakistan, the average cost of five frozen margins in a patient was reported to be US$75 [136], a cost noted to be out of reach for half the world’s population. Given the shortage of expert pathologists (especially in medically underserved communities), these bottlenecks limit or delay clinical decision-making and eventually treatment, resulting in worse outcomes.
Given its critical importance, it has been recommended that Level 2 pathology labs with histopathology services should be established at all district hospitals in LMICs. Barriers to expanding access to pathology services in low-resource settings include insufficient workforce capacity, inadequate infrastructure, inadequate training programs [137], and insufficient standards and accreditation programs [48]. Affordable point-of-care tools to support quality histopathologic diagnosis are needed.
Scope of Projects:
The proposed project must focus on a specific need related to screening or early detection of epithelial pre-cancer or early cancer in a medically underserved setting and must show promise to improve health outcomes. The proposed project may consist of technology development activities including developing and/or refining technology, clinical field testing, establishing test characteristics, obtaining feedback on user steps from end users, evaluating usability, conducting market research on product concepts or prototypes with distributors, implementers, procurement agencies, policy makers or other stakeholders, evaluating test implementation, and assessing feasibility. The application should describe how additional funding and/or targeted expertise from CITEC or other consultants will enable the technology to move forward in the development pathway.
Relevant technologies that will be considered for funding include, but are not limited to, POC technologies that work with non-invasive or minimally invasive samples, POC technologies for in vitro and in vivo imaging, paper-based POC sensors, mobile-based platforms. Qualified projects should be: based on a working prototype or an existing device to be adapted; demonstrate test characteristics compatible with the ReASSURED criteria (the standards or benchmarks used to evaluate the effectiveness and reliability of diagnostic tools and strategies in informing disease control efforts, strengthening health systems, and improving patient outcomes).
Applicant Eligibility:
Applications from all sources, including domestic or foreign, public or private, and non-profit or for-profit, will be considered. Awards under this solicitation may be made only to NIH-eligible applicants. Details regarding specific requirements can be found in the NIH Grants Policy Statement Part II: Terms and Conditions of the NIH Grant Awards. Foreign parties (governments, universities, corporations, or individuals) will be screened against the various US government-restricted party lists as required by NIH guidelines.
Expected Technology Maturity:
Applicants with a working prototype or an existing assay/device (not necessarily used for the proposed application) and preliminary data to demonstrate its potential for screening or early detection of epithelial cancer in medically underserved settings will have priority.
Minimum preferred maturity levels in the four product development cycle domains: Technology: proof of concept (3) or preferably proof of feasibility (4); Regulatory: proof of concept (3) or preferably proof of feasibility (4); Marketing/Business: proof of concept (3) or preferably proof of feasibility (4); Clinical: proof of concept (3) or preferably proof of feasibility (4).
The evaluation criteria used to review applications include:
Significance:
Does the project address a critical barrier or significant problem to improve the screening, early detection or diagnosis of cancer, particularly for medically under-served communities?
Does the proposed technology have application for more than one cancer?
Scientific Basis:
Is there a sound scientific basis presented (including preliminary data) that supports the technology and the proposed research?
Responsiveness to CITEC/NIH Areas of Interest:
Is the project designed to accelerate the refinement and clinical testing of point of care technologies for early detection of cancer? Is the project designed to improve the screening, early detection or diagnosis of cancer? Will the technology under development accelerate rapid adoption into clinical practice?
Technology Performance:
Reviewers will be asked to review the Technology Performance Criteria above. Is the project at a “late stage” of development (defined as ready for clinical validation or prototype refinement)? Projects proposing prototype development or preclinical studies are not in scope. Later-stage technologies that are closer to deployment will be given priority.
Feasibility:
Does the scientific team have the transdisciplinary expertise to move the project forward (i.e., engineering, usability testing, behavioral aspects of health, clinician engagement, statistical expertise)?
Are all human subject regulatory procedures (approved IRB protocol, current human subjects training certification, project registered as a clinical trial) complete so that the project can start in a timely way?
Is it highly likely that the proposed science can be accomplished with the funding and time allotted?
Expertise:
Do one or more members of the applicant team have expertise in population/public health and implementation science?
Implementation Science:
In the application, has the applicant team considered/addressed implementation science metrics and outcomes such as acceptability, adoption, appropriateness, fidelity, penetration, and sustainability?
Equity:
Does the applicant address social determinants of health (diverse and inclusive study populations), and does it appear they strive for health equity through interventions and outcomes?
Innovation:
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Intellectual Property and Development Plan:
Secure intellectual property rights are required for funding and should be clearly outlined in the application. This includes regulatory plans for the hardware and software used in the technology. Has the team developing the technology met with the appropriate bodies to secure intellectual property and designation as an investigational device? Has the team acquired a 510k exemption? Has a path to FDA approval or clearance been identified and is it clearly articulated? Is there a patent or license that has been submitted or secured in the US or overseas?
Consumer Costs and Commercialization Strategy:
What is the commercialization strategy? Does the strategy have the potential to reach patients in medically under-served communities? Does the strategy have the potential to reduce healthcare costs for patients and/or payors?
Environment:
Do the study team and/or company have an environment that is conducive for success? Has there been outside investment in the company?
