Defining the Digital Measurement of Scratching During Sleep or Nocturnal Scratching: Review of the Literature.

BACKGROUND: Digital sensing solutions represent a convenient, objective, relatively inexpensive method that could be leveraged for assessing symptoms of various health conditions. Recent progress in the capabilities of digital sensing products has targeted the measurement of scratching during sleep, traditionally referred to as nocturnal scratching, in patients with atopic dermatitis or other skin conditions. Many solutions measuring nocturnal scratch have been developed; however, a lack of efforts toward standardization of the measure's definition and contextualization of scratching during sleep hampers the ability to compare different technologies for this purpose. OBJECTIVE: We aimed to address this gap and bring forth unified measurement definitions for nocturnal scratch. METHODS: We performed a narrative literature review of definitions of scratching in patients with skin inflammation and a targeted literature review of sleep in the context of the period during which such scratching occurred. Both searches were limited to English language studies in humans. The extracted data were synthesized into themes based on study characteristics: scratch as a behavior, other characterization of the scratching movement, and measurement parameters for both scratch and sleep. We then developed ontologies for the digital measurement of sleep scratching. RESULTS: In all, 29 studies defined inflammation-related scratching between 1996 and 2021. When cross-referenced with the results of search terms describing the sleep period, only 2 of these scratch-related papers also described sleep-related variables. From these search results, we developed an evidence-based and patient-centric definition of nocturnal scratch: an action of rhythmic and repetitive skin contact movement performed during a delimited time period of intended and actual sleep that is not restricted to any specific time of the day or night. Based on the measurement properties identified in the searches, we developed ontologies of relevant concepts that can be used as a starting point to develop standardized outcome measures of scratching during sleep in patients with inflammatory skin conditions. CONCLUSIONS: This work is intended to serve as a foundation for the future development of unified and well-described digital health technologies measuring nocturnal scratching and should enable better communication and sharing of results between various stakeholders taking part in research in atopic dermatitis and other inflammatory skin conditions.

Advancing Digital Health Innovation in Oncology: Priorities for High-Value Digital Transformation in Cancer Care.

Although health care delivery is becoming increasingly digitized, driven by the pursuit of improved access, equity, efficiency, and effectiveness, progress does not appear to be equally distributed across therapeutic areas. Oncology is renowned for leading innovation in research and in care; digital pathology, digital radiology, real-world data, next-generation sequencing, patient-reported outcomes, and precision approaches driven by complex data and biomarkers are hallmarks of the field. However, remote patient monitoring, decentralized approaches to care and research, "hospital at home," and machine learning techniques have yet to be broadly deployed to improve cancer care. In response, the Digital Medicine Society and Moffitt Cancer Center convened a multistakeholder roundtable discussion to bring together leading experts in cancer care and digital innovation. This viewpoint highlights the findings from these discussions, in which experts agreed that digital innovation is lagging in oncology relative to other therapeutic areas. It reports that this lag is most likely attributed to poor articulation of the challenges in cancer care and research best suited to digital solutions, lack of incentives and support, and missing standardized infrastructure to implement digital innovations. It concludes with suggestions for actions needed to bring the promise of digitization to cancer care to improve lives.

Recent Academic Research on Clinically Relevant Digital Measures: Systematic Review.

BACKGROUND: Digital clinical measures collected via various digital sensing technologies such as smartphones, smartwatches, wearables, ingestibles, and implantables are increasingly used by individuals and clinicians to capture health outcomes or behavioral and physiological characteristics of individuals. Although academia is taking an active role in evaluating digital sensing products, academic contributions to advancing the safe, effective, ethical, and equitable use of digital clinical measures are poorly characterized. OBJECTIVE: We performed a systematic review to characterize the nature of academic research on digital clinical measures and to compare and contrast the types of sensors used and the sources of funding support for specific subareas of this research. METHODS: We conducted a PubMed search using a range of search terms to retrieve peer-reviewed articles reporting US-led academic research on digital clinical measures between January 2019 and February 2021. We screened each publication against specific inclusion and exclusion criteria. We then identified and categorized research studies based on the types of academic research, sensors used, and funding sources. Finally, we compared and contrasted the funding support for these specific subareas of research and sensor types. RESULTS: The search retrieved 4240 articles of interest. Following the screening, 295 articles remained for data extraction and categorization. The top five research subareas included operations research (research analysis; n=225, 76%), analytical validation (n=173, 59%), usability and utility (data visualization; n=123, 42%), verification (n=93, 32%), and clinical validation (n=83, 28%). The three most underrepresented areas of research into digital clinical measures were ethics (n=0, 0%), security (n=1, 0.5%), and data rights and governance (n=1, 0.5%). Movement and activity trackers were the most commonly studied sensor type, and physiological (mechanical) sensors were the least frequently studied. We found that government agencies are providing the most funding for research on digital clinical measures (n=192, 65%), followed by independent foundations (n=109, 37%) and industries (n=56, 19%), with the remaining 12% (n=36) of these studies completely unfunded. CONCLUSIONS: Specific subareas of academic research related to digital clinical measures are not keeping pace with the rapid expansion and adoption of digital sensing products. An integrated and coordinated effort is required across academia, academic partners, and academic funders to establish the field of digital clinical measures as an evidence-based field worthy of our trust.

Sensor Data Integration: A New Cross-Industry Collaboration to Articulate Value, Define Needs, and Advance a Framework for Best Practices.

Data integration, the processes by which data are aggregated, combined, and made available for use, has been key to the development and growth of many technological solutions. In health care, we are experiencing a revolution in the use of sensors to collect data on patient behaviors and experiences. Yet, the potential of this data to transform health outcomes is being held back. Deficits in standards, lexicons, data rights, permissioning, and security have been well documented, less so the cultural adoption of sensor data integration as a priority for large-scale deployment and impact on patient lives. The use and reuse of trustworthy data to make better and faster decisions across drug development and care delivery will require an understanding of all stakeholder needs and best practices to ensure these needs are met. The Digital Medicine Society is launching a new multistakeholder Sensor Data Integration Tour of Duty to address these challenges and more, providing a clear direction on how sensor data can fulfill its potential to enhance patient lives.

Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: A population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).

BACKGROUND: Many studies showing underuse of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) predated the advent of the non-vitamin K antagonist OACs. We retrospectively examined use of OACs in a large commercially insured population. METHODS: Administrative claims data from 4 research partners participating in FDA-Catalyst, a program of the Sentinel Initiative, were queried in September 2017. Patients were included if they were ≥30 years old with ≥365 days of medical/pharmacy coverage, and had ≥2 diagnosis codes for AF, a CHA2DS2-VASc score ≥2, absence of contraindications to OAC use, and no evidence of OAC use in the 365 days before the index AF diagnosis. The main outcome measures of the current analysis were rates of OAC use in the prior 12 months of cohort identification and factors associated with non-use. RESULTS: A total of 197,806 AF patients met the eligibility criteria prior to assessment of OAC treatment. Of these, 179,580 (91%) patients were ≥65 years old and 73,286 (37%) patients were ≥80 years old. Half of the patients (98,903) were randomized to the early intervention arm in the IMPACT-AFib trial and constitute the cohort for this analysis. Of these, 32,295 (33%) had no evidence of OAC use in the prior 12 months. Compared with patients with evidence of OAC use in the prior 12 months, patients without OAC use were more likely to be ≥80 years old, women, and have a history of anemia (51% vs 47%) and less likely to have diabetes (41% vs 44%), history of stroke or TIA (15% vs 19%), and history of heart failure (39% vs 48%). CONCLUSIONS: Despite a high risk of stroke, one-third of privately insured patients with AF and no obvious contraindications to an OAC were not treated with an OAC. There is an unmet need for evidence-based interventions that could lead to greater use of OACs in patients with AF at risk for stroke.

FDA-Catalyst-Using FDA's Sentinel Initiative for large-scale pragmatic randomized trials: Approach and lessons learned during the planning phase of the first trial.

BACKGROUND: The US Food and Drug Administration's Sentinel Initiative is well positioned to support pragmatic clinical trials. FDA-Catalyst combines direct contact with health plan members and/or providers with data in the Sentinel infrastructure. Here, we describe the rationale, feasibility analyses, and lessons learned from the planning phase of the first large pragmatic trial conducted using the Sentinel Initiative's delivery system capabilities-IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (the IMPACT-AFib trial). METHODS: During the planning phase, we convened representatives from five commercial health plans, FDA, study coordinating centers, and a patient representative for protocol development, institutional review board preparation, and other activities. Administrative claims data from the plans were included in a retrospective cohort analysis to assess sample size for the trial. Members ≥30 years old with ≥365 days of medical/pharmacy coverage, ≥2 diagnosis codes for atrial fibrillation, a guideline-based indication for oral anticoagulant use for stroke prevention, and no evidence of oral anticoagulant use in the 365 days prior to the index atrial fibrillation diagnosis in 2013 were included. Exclusions for the analysis included other conditions requiring anticoagulation, history of intracranial hemorrhage, and gastrointestinal bleed. We calculated rates of oral anticoagulant use, transient ischemic attack or stroke, and bleeding in the 365 days following the index atrial fibrillation diagnosis. RESULTS: A total of 44,786 members with atrial fibrillation with no evidence of recent oral anticoagulant use were identified. In total, 87% (n = 38,759) were classified as having a guideline-based indication for oral anticoagulants. Of those, 33% (n = 12,867) had a new oral anticoagulant dispensed during the following year, 15% (n = 5917) were hospitalized for stroke or transient ischemic attack, and 9% (n = 3469) for bleeding events. This information was used to develop the trial protocol including sample size, power calculations, and level of randomization. CONCLUSION: Sentinel infrastructure generated preliminary data that supported planning and implementation of a large pragmatic trial embedded in health plans. This planning identified unanticipated challenges that must be addressed in similar trials.

The Clinical Trials Transformation Initiative: Methodology supporting the mission.

The mission of the Clinical Trials Transformation Initiative, a public-private partnership co-founded by the U.S. Food and Drug Administration and Duke University, is to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. The Clinical Trials Transformation Initiative works collaboratively with key stakeholders, implements "fit-for-purpose" evidence-gathering projects, and develops actionable recommendations and tools to address the challenges faced by the clinical trials enterprise. In pursuit of its mission, The Clinical Trials Transformation Initiative follows an innovative and collaborative, five-step methodology: (1) state the problem and identify impediments to research, (2) gather evidence to identify gaps and barriers, (3) explore results by analyzing and interpreting findings, (4) finalize solutions by developing recommendations and tools, and (5) drive adoption through disseminating and implementing recommendations and tools. This article describes each step of the Clinical Trials Transformation Initiative's methodology, with a specific focus on describing the evidence-gathering activities.

The Impact of an Electronic Medication Administration Record (eMAR) and Computerized Physician Order Entry (CPOE) on Nurse Extender and Unit Clerk Staffing.

OBJECTIVE: The aim of this study is to describe the impact of the introduction of health information technology (HIT) on the utilization and payroll costs of nurse extenders and unit clerks in medicine and surgery units in a large regional health system. BACKGROUND: Long-term policy goals of HIT implementation are reported to include system-level reductions in labor costs, achieved through improved efficiency. METHODS: Using a retrospective cohort model, we analyzed how hours worked per patient day and staffing costs per patient day varied with the implementation of HIT over time at 2 different hospitals within a health system. RESULTS: Implementation of electronic medication administration records was not associated with significant changes in staffing or labor costs. Both labor hours and costs associated with nurse extenders and unit clerks were significantly reduced after the subsequent addition of computerized provider order entry. Simultaneously, units that did not implement any HIT experienced a significant increase in both labor hours and costs. CONCLUSION: Health information technology implementation in the inpatient setting is associated with significant savings in labor hours and costs in non-registered nursing roles.

Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Remote and interdisciplinary research in surgical knowledge production.

BACKGROUND: Surgical knowledge production has changed dramatically in the last 30 y, moving away from investigations by individual surgeon researchers and toward remote and interdisciplinary research. We investigated how surgeons make decisions about engaging in research and identify motivators, facilitators, and barriers to conducting research in an increasingly challenging environment. MATERIALS AND METHODS: We performed a qualitative analysis of semistructured interviews with surgeons from academic medical centers across the United States. We asked participants to describe their experiences and opinions regarding remote and interdisciplinary collaborations. RESULTS: Of 64 surgeon researchers invited, 21 (33%) agreed and participated in semistructured interviews. Each interview lasted an average (standard deviation) of 29 min (12). Surgeons were motivated by both internal and external factors, including some that might be identified as barriers. The internal desire to improve care and the need for collaboration to address increasingly complex questions requiring larger samples sizes emerged as most significant to interview participants. Social networks were identified as the dominant facilitator of multisite research, with technology playing a supporting role. Barriers to remote and interdisciplinary research ranged from individual, "micro" level barriers, through structural barriers that include institutional level challenges and competing priorities, to macrolevel system and policy-level barriers. CONCLUSIONS: Surgeons clearly recognize the importance of high-quality research aligned with current paradigms of clinical care and are using remote and interdisciplinary collaboration to improve the quality of the science they produce and align their work with the demand for increasingly high levels of evidence.

Using a Lean Six Sigma Approach to Yield Sustained Pressure Ulcer Prevention for Complex Critical Care Patients.

BACKGROUND: Under value-based purchasing, Medicare withholds reimbursements for hospital-acquired pressure ulcer occurrence and rewards hospitals that meet performance standards. With little evidence of a validated prevention process, nurse managers are challenged to find evidence-based interventions. OBJECTIVE: The aim of this study was to reduce the unit-acquired pressure ulcer (UAPU) rate on targeted intensive care and step-down units by 15% using Lean Six Sigma (LSS) methodology. METHODS: An interdisciplinary team designed a pilot program using LSS methodology to test 4 interventions: standardized documentation, equipment monitoring, patient out-of-bed-to-chair monitoring, and a rounding checklist. RESULTS: During the pilot, the UAPU rate decreased from 4.4% to 2.8%, exceeding the goal of a 15% reduction. The rate remained below the goal through the program control phase at 2.9%, demonstrating a statistically significant reduction after intervention implementation. CONCLUSIONS: The program significantly reduced UAPU rates in high-risk populations. LSS methodologies are a sustainable approach to reducing hospital-acquired conditions that should be broadly tested and implemented.

Key issues for elderly patients contemplating clinical trial participation.

This pilot study explored issues important to enrollment in clinical trials by elderly patients. We surveyed and interviewed elderly patients who had been asked to participate in trials. The information covered general attitudes toward research and specific aspects of trial recruitment. Elderly patients had favorable attitudes toward research. This favorable attitude was significantly stronger in men than in women and stronger in Whites than non-Whites but not significantly so. Altruistic motives, physician recommendations, and individual assessment of inconveniences, benefits, and risks of trial participation drove decisions. Elderly patients have positive views of research; however, this will only facilitate trial participation if patients perceive the commitment of enrolling, the potential risks, and possible side effects as reasonable.

The impact of health information technology on staffing.

Hospitals nationwide must demonstrate meaningful use by 2015 or face fines. For over 20 years, researchers have attempted to assess the impact of electronic record keeping technologies on the quality, safety, and efficiency of care, but results are inconclusive and hospital managers have little evidence on which to base staffing decisions as we hurtle toward the era of the paperless hospital.

Defining the Dimensions of Diversity to Promote Inclusion in the Digital Era of Health Care: A Lexicon.

The pandemic provided a stark reminder of the inequities faced by populations historically marginalized by the health care system and accelerated the adoption of digital health technologies to drive innovation. Digital health technologies' purported promises to reduce inefficiencies and costs, improve access and health outcomes, and empower patients add a new level of urgency to health equity. As conventional medicine shifts toward digital medicine, we have the opportunity to intentionally develop and deploy digital health technologies with an inclusion focus. The first step is ensuring that the multiple dimensions of diversity are captured. We propose a lexicon that encompasses elements critical for implementing an inclusive approach to advancing health care quality and health services research in the digital era.

Digital health technologies to strengthen patient-centred outcome assessment in clinical trials in inflammatory arthritis.

Common to all inflammatory arthritides, namely rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis, is a potential for reduced mobility that manifests through joint pain, swelling, stiffness, and ultimately joint damage. Across these conditions, consensus has been reached on the need to capture outcomes related to mobility, such as functional capacity and physical activity, as core domains in randomised controlled trials. Existing endpoints within these core domains rely wholly on self-reported questionnaires that capture patients' perceptions of their symptoms and activities. These questionnaires are subjective, inherently vulnerable to recall bias, and do not capture the granularity of fluctuations over time. Several early adopters have integrated sensor-based digital health technology (DHT)-derived endpoints to measure physical function and activity in randomised controlled trials for conditions including Parkinson's disease, Duchenne's muscular dystrophy, chronic obstructive pulmonary disease, and heart failure. Despite these applications, there have been no sensor-based DHT-derived endpoints in clinical trials recruiting patients with inflammatory arthritis. Borrowing from case studies across medicine, we outline the opportunities and challenges in developing novel sensor-based DHT-derived endpoints that capture the symptoms and disease manifestations most relevant to patients with inflammatory arthritis.

Assessing the net financial benefits of employing digital endpoints in clinical trials.

In the last few decades, developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the US clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost. For phase II trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% and 48% per indication. The net benefits were substantially higher for phase III trials, with the increase in eNPV varying from $27 million to $40 million, with ROIs that were four to six times the investment. The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.

Building the Business Case for an Inclusive Approach to Digital Health Measurement With a Web App (Market Opportunity Calculator): Instrument Development Study.

BACKGROUND: The use of digital health measurement tools has grown substantially in recent years. However, there are concerns that the promised benefits from these products will not be shared equitably. Underserved populations, such as those with lower education and income, racial and ethnic minorities, and those with disabilities, may find such tools poorly suited for their needs. Because underserved populations shoulder a disproportionate share of the US disease burden, they also represent a substantial share of digital health companies' target markets. Incorporating inclusive principles into the product development process can help ensure that the resulting tools are broadly accessible and effective. In this context, inclusivity not only maximizes societal benefit but also leads to greater commercial success. OBJECTIVE: A critical element in fostering inclusive product development is building the business case for why it is worthwhile. The Digital Health Measurement Collaborative Community (DATAcc) Market Opportunity Calculator was developed as an open-access resource to enable digital health measurement product developers to build a business case for incorporating inclusive practices into their research and development processes. METHODS: The DATAcc Market Opportunity Calculator combines data on population demographics and disease prevalence and health status from the US Census Bureau and the US Centers for Disease Control and Prevention (CDC). Together, these data are used to calculate the share of US adults with specific conditions (eg, diabetes) falling into various population segments along key "inclusion vectors" (eg, race and ethnicity). RESULTS: A free and open resource, the DATAcc Market Opportunity Calculator can be accessed from the DATAcc website. Users first select the target health condition addressed by their product, and then an inclusion vector to segment the patient population. The calculator displays each segment as a share of the overall US adult population and its share specifically among adults with the target condition, quantifying the importance of underserved patient segments to the target market. The calculator also estimates the value of improvements to product inclusivity by modeling the downstream impact on the accessible market size. For example, simplifying prompts on a hypertension-focused product to make it more accessible for adults with lower educational attainment is shown by the calculator to increase the target market by 2 million people and the total addressable market opportunity by US $200 million. CONCLUSIONS: Digital health measurement is still in its infancy. Now is the time to establish a precedent for inclusive product development to maximize societal benefit and build sustainable commercial returns. The Market Opportunity Calculator can help build the business case for "why"-showing how inclusivity can translate to financial opportunity. Once the decision has been made to pursue inclusive design, other components of the broader DATAcc toolkit for inclusive product development can support the "how."

A patient-centred conceptual model of nocturnal scratch and its impact in atopic dermatitis: A mixed-methods study supporting the development of novel digital measurements.

Background: Emerging digital measures and clinical outcome assessments (COAs) leveraging digital health technologies (DHTs) could address the need for objective, quantitative measures of symptoms of atopic dermatitis (AD), such as nocturnal scratching. Development of such measures needs to be supported by evidence reflecting meaningfulness to patients. Objectives: To assess nocturnal scratching as a concept of interest associated with meaningful aspects of health of patients with AD (adults and children); and to explore patient-centred considerations for novel COAs measuring nocturnal scratch using DHTs. Methods: Phase 1 evaluated disease impacts on everyday life and the lived experience with nocturnal scratching through qualitative interviews of AD patients and caregivers. Phase 2 deployed a quantitative survey to a sample of AD patients as well as caregivers. Results: Four cohorts with various AD severity levels participated in Phase 1: (1) adults with AD (n = 15), (2) their caregivers/spouses/partners (n = 6), (3) children with AD (n = 14), and (4) their adult caregivers (n = 14). Findings were used to develop a conceptual model for nocturnal scratching as a potential concept of interest. The Phase 2 survey was completed by 1349 of 27640 invited adults with AD and caregivers of children with AD. The most burdensome aspects of AD reported were itchy skin and scratching. Overall, ∼65% of participants reported nocturnal scratching ≥1 day/week, resulting in ∼1-1.4 h of sleep lost per night. In all, 85%-91% of respondents considered it at least somewhat valuable that a treatment reduces night-time scratching. About 50% reported willingness to use technology to this end and ∼25% were unsure. Conclusion: Our results represented by the conceptual model confirm that nocturnal scratch is a concept of interest related to meaningful aspects of health for patients with AD and therefore is worth being captured as a distinct outcome for clinical and research purposes. DHTs are suitable tools presenting an important measurement opportunity to assess and evaluate occurrence, frequency, and other parameters of nocturnal scratching as a disease biomarker or COA of treatment efficacy.