A proposed multi-domain, digital model for capturing functional status and health-related quality of life in oncology.

Whereas traditional oncology clinical trial endpoints remain key for assessing novel treatments, capturing patients' functional status is increasingly recognized as an important aspect for supporting clinical decisions and assessing outcomes in clinical trials. Existing functional status assessments suffer from various limitations, some of which may be addressed by adopting digital health technologies (DHTs) as a means of collecting both objective and self-reported outcomes. In this mini-review, we propose a device-agnostic multi-domain model for oncology capturing functional status, which includes physical activity data, vital signs, sleep variables, and measures related to health-related quality of life enabled by connected digital tools. By using DHTs for all aspects of data collection, our proposed model allows for high-resolution measurement of objective data as patients navigate their daily lives outside of the hospital setting. This is complemented by electronic questionnaires administered at intervals appropriate for each instrument. Preliminary testing and practical considerations to address before adoption are also discussed. Finally, we highlight multi-institutional pre-competitive collaborations as a means of successfully transitioning the proposed digitally enabled data collection model from feasibility studies to interventional trials and care management.

Study protocol: A comparison of mobile and clinic-based spirometry for capturing the treatment effect in moderate asthma.

Several inefficiencies in drug development trial implementation may be improved by moving data collection from the clinic to mobile, allowing for more frequent measurements and therefore increased statistical power while aligning to a patient-centric approach to trial design. Sensor-based digital health technologies such as mobile spirometry (mSpirometry) are comparable to clinic spirometry for capturing outcomes, such as forced expiratory volume in 1 s (FEV1); however, the impact of remote spirometry measurements on the detection of treatment effect has not been investigated. A protocol for a multicenter, single-arm, open-label interventional trial of long-acting beta agonist (LABA) therapy among 60 participants with uncontrolled moderate asthma is described. Participants will complete twice-daily mSpirometry at home and clinic spirometry during weekly visits, alongside continuous use of a wrist-worn wearable and regular completion of several diaries capturing asthma symptoms as well as participant- and site-reported satisfaction and ease of use of mSpirometry. The co-primary objectives of this study are (A) to quantify the treatment effect of LABA therapy among participants with moderate asthma, using both clinical spirometry (FEV1c ) and mSpirometry (FEV1m ); and (B) to investigate whether FEV1m is as accurate as FEV1c in detecting the treatment effect using a mixed-effect model for repeated measures. Study results will help inform whether the deployment of mSpirometry and a wrist-worn wearable for remote data collection are feasible in a multicenter setting among participants with moderate asthma, which may then be generalizable to other populations with respiratory disease.

Significance of the Ontological/Utilitarian Distinction Among Measures of Individualism and Collectivism.

A meta-analysis reported in this article compared the effects of ontological and utilitarian measures of individualism and collectivism on the findings of published research. Ontological differences in individualism and collectivism concern the degree to which either individuals or collectivities are interpreted as the primary entities comprising social reality. Reflecting these differences are measures that include subjects such as the degree of permanence and sense of collective obligation associated with interpersonal, group, or community relationships. Utilitarian distinctions in individualism and collectivism involve beliefs that either individuals or collectivities are instrumental in the pursuit of valued outcomes. Related measures include items concerning the attractiveness or consequences of working alone versus working in a group. Results of the meta-analysis indicated that ontological and utilitarian measures have produced differing findings in several notable instances, with utilitarian measures producing larger effects.

The nervous system: Orchestra conductor in cancer, regeneration, inflammation and immunity.

Although the role of nerves in stimulating cellular growth and dissemination has long been described in tissue regeneration studies, until recently a similar trophic role of nerves in disease was not well recognized. However, recent studies in oncology have demonstrated that the growth and dissemination of cancers also requires the infiltration of nerves in the tumor microenvironment. Nerves generate various neurosignaling pathways, which orchestrate cancer initiation, progression, and metastases. Similarly, nerves are increasingly implicated for their regulatory functions in immunity and inflammation. This orchestrator role of nerves in cellular and molecular interactions during regeneration, cancer, immunity, and inflammation offers new possibilities for targeting or enhancing neurosignaling in human health and diseases.

Remote Cardiac Safety Monitoring through the Lens of the FDA Biomarker Qualification Evidentiary Criteria Framework: A Case Study Analysis.

Clinical safety findings remain one of the reasons for attrition of drug candidates during clinical development. Cardiovascular liabilities are not consistently detected in early-stage clinical trials and often become apparent when drugs are administered chronically for extended periods of time. Vital sign data collection outside of the clinic offers an opportunity for deeper physiological characterization of drug candidates and earlier safety signal detection. A working group representing expertise from biopharmaceutical and technology sectors, US Food and Drug Administration (FDA) public-private partnerships, academia, and regulators discussed and presented a remote cardiac monitoring case study at the FNIH Biomarkers Consortium Remote Digital Monitoring for Medical Product Development workshop to examine applicability of the biomarker qualification evidentiary framework by the FDA. This use case examined the components of the framework, including the statement of need, the context of use, the state of the evidence, and the benefit/risk profile. Examination of results from 2 clinical trials deploying 510(k)-cleared devices for remote cardiac data collection demonstrated the need for analytical and clinical validity irrespectively of the regulatory status of a device of interest, emphasizing the importance of data collection method assessment in the context of intended use. Additionally, collection of large amounts of ambulatory data also highlighted the need for new statistical methods and contextual information to enable data interpretation. A wider adoption of this approach for drug development purposes will require collaborations across industry, academia, and regulatory agencies to establish methodologies and supportive data sets to enable data interpretation and decision-making.

Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.

BACKGROUND & AIMS: Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology. METHODS: In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence. RESULTS: All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. CONCLUSIONS: Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.

Fit-for-Purpose Biometric Monitoring Technologies: Leveraging the Laboratory Biomarker Experience.

Biometric monitoring technologies (BioMeTs) are becoming increasingly common to aid data collection in clinical trials and practice. The state of BioMeTs, and associated digitally measured biomarkers, is highly reminiscent of the field of laboratory biomarkers 2 decades ago. In this review, we have summarized and leveraged historical perspectives, and lessons learned from laboratory biomarkers as they apply to BioMeTs. Both categories share common features, including goals and roles in biomedical research, definitions, and many elements of the biomarker qualification framework. They can also be classified based on the underlying technology, each with distinct features and performance characteristics, which require bench and human experimentation testing phases. In contrast to laboratory biomarkers, digitally measured biomarkers require prospective data collection for purposes of analytical validation in human subjects, lack well-established and widely accepted performance characteristics, require human factor testing, and, for many applications, access to raw (sample-level) data. Novel methods to handle large volumes of data, as well as security and data rights requirements add to the complexity of this emerging field. Our review highlights the need for a common framework with appropriate vocabulary and standardized approaches to evaluate digitally measured biomarkers, including defining performance characteristics and acceptance criteria. Additionally, the need for human factor testing drives early patient engagement during technology development. Finally, use of BioMeTs requires a relatively high degree of technology literacy among both study participants and healthcare professionals. Transparency of data generation and the need for novel analytical and statistical tools creates opportunities for precompetitive collaborations.

Ubrogepant Is Not Associated With Clinically Meaningful Elevations of Alanine Aminotransferase in Healthy Adult Males.

Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (tmax ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.

Continuous Monitoring Using a Wearable Device Detects Activity-Induced Heart Rate Changes After Administration of Amphetamine.

Wearable digital devices offer potential advantages over traditional methods for the collection of health-related information, including continuous collection of dense data while study subjects are ambulatory or in remote settings. We assessed the utility of collecting continuous actigraphy and cardiac monitoring by deploying two US Food and Drug Administration (FDA) 510(k)-cleared devices in a phase I clinical trial of a novel compound, which included the use of an amphetamine challenge. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep. The Preventice BodyGuardian (BodyGuardian) was used for monitoring heart rate (HR) and respiratory rate (RR), via single-lead electrocardiogram (ECG) recordings, together with physical activity. We measured data collection rates, compared device readouts with conventional measures, and monitored changes in HR measures during the amphetamine challenge. Completeness of data collection was good for the Actiwatch (96%) and lower for the BodyGuardian (80%). A good correlation was observed between device and in-clinic measures for HR (r = 0.99; P < 0.001), but was poor for RR (r = 0.39; P = 0.004). Manual reviews of selected ECG strips corresponding to HR measures below, within, and above the normal range were consistent with BodyGuardian measurements. The BodyGuardian device detected clear HR responses after amphetamine administration while subjects were physically active, whereas conventional measures collected at predefined timepoints while subjects were resting and supine did not. Wearable digital technology shows promise for monitoring human subjects for physiologic changes and pharmacologic responses, although fit-for-purpose evaluation and validation continues to be important prior to the wider deployment of these devices.

What Can Be Learned From Crowdsourced Population Asparagus Urinary Odor Kinetics?

Asparagus consumption is associated with the production of malodorous urine. Interindividual variability was previously characterized by an American Society for Clinical Pharmacology and Therapeutics crowdsourced study. To further characterize urinary odor kinetics, we conducted a study with consenting participants from Takeda Pharmaceutical International Company. The participants were randomized to consume a specified number of asparagus spears and asked to record urine odor. A kinetic-pharmacodynamic model characterized the data from both the newly conducted Takeda study (N = 42) and the previously analyzed American Society for Clinical Pharmacology and Therapeutics studies (total N = 139). The updated model included the identification of an absorption process with a half-life of 25 minutes. We estimated the elimination half-life of the asparagus effect on malodorous urine to be 7.2 hours, which was 44% longer in our study. We built on previous experience using an improved R-Shiny app for conducting the crowdsourcing experiment, further demonstrating the utility of this population kinetics approach in organizational and educational settings.

Evaluation of Wearable Digital Devices in a Phase I Clinical Trial.

We assessed the performance of two US Food and Drug Administration (FDA) 510(k)-cleared wearable digital devices and the operational feasibility of deploying them to augment data collection in a 10-day residential phase I clinical trial. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep, and the Vitalconnect HealthPatch MD (HealthPatch) was used for monitoring heart rate (HR), respiratory rate (RR), and surface skin temperature (ST). We measured data collection rates, compared device readouts with anticipated readings and conventional in-clinic measures, investigated data limitations, and assessed user acceptability. Six of nine study participants consented; completeness of data collection was adequate (> 90% for four of six subjects). A good correlation was observed between the HealthPatch device derived and in-clinic measures for HR (Pearson r = 0.71; P = 2.2e-16) but this was poor for RR (r = 0.08; P = 0.44) and ST (r = 0.14; P = 0.14). Manual review of electrocardiogram strips recorded during reported episodes of tachycardia > 180 beats/min showed that these were artefacts. The HealthPatch was judged to be not fit-for-purpose because of artefacts and the need for time-consuming manual review. The Actiwatch device was suitable for monitoring mobility, collecting derived sleep data, and facilitating the interpretation of vital sign data. These results suggest the need for fit-for-purpose evaluation of wearable devices prior to their deployment in drug development studies.

The Foundation for the National Institutes of Health Biomarkers Consortium: Past Accomplishments and New Strategic Direction.

The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium (BC) is a public-private partnership that aims to facilitate drug development with biomarkers across a range of therapeutic areas. The BC is organized to address specific precompetitive biomarker projects, giving participating stakeholders a role in the design and conduct of projects and making the results freely public. Ultimately, the goals of the BC are to accelerate the development of new medicines, inform regulatory decision making, and improve patient care. Here, we describe how the BC works and briefly highlight its accomplishments. The BC has had many notable successful biomarker projects in the past 12 years, including I-SPY2, which has improved clinical trials and biomarker use for breast cancer, and an evidentiary framework for biomarker qualification. Recently, the BC has undergone a strategic expansion of its scope to include related drug development tools along the lines of the Biomarkers, Endpoints, and other Tools (BEST) resource.