Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections.

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.

High-risk medical devices, children and the FDA: regulatory challenges facing pediatric mechanical circulatory support devices.

Pediatric mechanical circulatory support is a critical unmet need in the United States. Infant- and child-sized ventricular assist devices are currently being developed largely through federal contracts and grants through the National Heart, Lung, and Blood Institute (NHLBI). Human testing and marketing of high-risk devices for children raises epidemiologic and regulatory issues that will need to be addressed. Leaders from the US Food and Drug Administration (FDA), NHLBI, academic pediatric community, and industry convened in January 2006 for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices. The purpose was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges specific to the development and regulation of pediatric mechanical circulatory support devices. Pediatric mechanical circulatory support present significant epidemiologic, logistic, and financial challenges to industry, federal regulators, and the pediatric community. Early interactions with the FDA, shared appreciation of challenges, and careful planning will be critical to avoid unnecessary delays in making potentially life-saving devices available for children. Collaborative efforts to address these challenges are warranted.

Hemodynamic stresses and structural remodeling of anastomosing arteriolar networks: design principles of collateral arterioles.

OBJECTIVE: To investigate the potential influence of hemodynamic stresses on the development of the arcade arteriole (AA) network during normal maturation. METHODS: AA network data were collected from ink-filled Wistar-Kyoto rat gracilis muscles and used to construct hemodynamic computational models of the AA network at 7 (WKY(7)) and 13 (WKY(13)) weeks of age. RESULTS: Mean coefficients of variation for pressure, circumferential wall stress, and wall shear stress were 0.13, 0.12, and 0.48, respectively. Wall shear rate variability across bifurcations generated deviations in mean energy cost that were 9-30% above theoretical minimum, with many bifurcations exhibiting substantially higher energy costs. With the exception of the lowest pressure AA segments, the monotonic relationship between wall shear stress and pressure in the AAs was nearly identical from 7 to 13 weeks of age. CONCLUSIONS: Low coefficients of variation for computed AA pressures indicate that an even pressure head is maintained over the muscle during remodeling of the AA network. The anastomotic structure of the network creates high shear rate variability that, in turn, creates high-energy costs in some regions of the network. The results are consistent with the hypothesis that, during development, the maintenance of mean circumferential wall stress and the pressure-shear stress relationship are operative design principles for collateral arteriole development.