BackgroundPulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional β2-adrenergic receptors (β2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, β2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled β-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective β2AR agonist albuterol in individuals with CF.Methods18 CF and 30 control (CTL) subjects participated (ages 22 ± 2 versus 27 ± 2 and BSA = 1.7 ± 0.1 versus 1.8 ± 0.0 m2, both p < 0.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAP = DBP + 1/3(SBP–DBP); systemic vascular resistance (SVR) = (MAP/Q)•80; CP = Q•MAP; stroke work (SW) = SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI).ResultsAt baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (p < 0.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (p < 0.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (p < 0.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (p < 0.05).ConclusionsCardiac and peripheral hemodynamic responsiveness to acute β2AR stimulation via albuterol is attenuated in individuals with CF, suggesting β2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

On September 27‐28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence‐Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment.” The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development, with considerations for seeking regulatory endorsement for use in clinical trials. Biomarkers add value to drug development by improving patient selection criteria, safety monitoring, endpoint selection, and more. Regulatory endorsement through the FDA Biomarker Qualification Program encourages the use of biomarkers in drug development by instilling confidence and consistency in biomarker interpretation across trials. Public–private partnerships or consortia allow stakeholders to share expertise, resources, and data in pursuit of biomarker qualification. Biomarkers relevant to pretransplant risk assessment, early posttransplant care, and assessment of immune response, immunosuppressive drug efficacy, and graft function as discussed on day 1 of the workshop are described.

Introduction Patient-level data sharing has the potential to significantly impact the lives of patients by optimizing and improving the medical product development process. In the product development setting, successful data sharing is defined as data sharing that is actionable and facilitates decision making during the development and review of medical products. This often occurs through the creation of new product development tools or methodologies, such as novel clinical trial design and enrichment strategies, predictive pre-clinical and clinical models, clinical trial simulation tools, biomarkers, and clinical outcomes assessments, and more. Methods To be successful, extensive partnerships must be established between all relevant stakeholders, including industry, academia, research institutes and societies, patient-advocacy groups, and governmental agencies, and a neutral third-party convening organization that can provide a pre-competitive space for data sharing to occur. Conclusions Data sharing focused on identified regulatory deliverables that improve the medical product development process encounters significant challenges that are not seen with data sharing aimed at advancing clinical decision making and requires the commitment of all stakeholders. Regulatory data sharing challenges and solutions, as well as multiple examples of previous successful data sharing initiatives are presented and discussed in the context of medical product development.

Summary Background Although exercise is a vital component of the therapy prescribed to individuals with cystic fibrosis (CF), it is not a priority due to a finite amount of treatment time and the view that exercise is not as beneficial as pharmacological treatments by many individuals with CF. We sought to compare the therapeutic benefits of exercise and their prescribed bronchodilator albuterol. Methods CF (n = 14) and healthy (n = 16) subjects completed three visits, a baseline screening with VO2 max test and two treatment visits. On the two treatment visits, subjects completed spirometry and diffusing capacity of the lungs for nitric oxide (DLNO) maneuvers either at baseline, 60, and 110 min post-albuterol administration, or at baseline and the midway point of three separate 15 min exercise bouts at low, moderate and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). Results With moderate exercise the increase in DLNO was double (39 ± 8 vs 15 ±6% change) and the level of bronchodilation similar (23% change) when compared to 110 min post-albuterol in individuals with CF. During exercise FVC became reduced (−309 ± 66 mL with moderate exercise) and the increase in FEV1 was attenuated (103 ± 39 vs 236 ± 58 mL, exercise vs. albuterol) when compared with the response to albuterol in individuals with CF. Epinephrine (EPI) release increased 39, 72 and 144% change with low, moderate and vigorous intensity exercise respectively for individuals with CF, but this increase was blunted when compared to healthy subjects. Conclusion Our results suggest that moderate intensity exercise is the optimal intensity for individuals with CF, as low intensity exercise increases EPI less than 50% and vigorous intensity exercise is over taxing, such that airflow can be restricted. Although the duration of the beneficial effect is uncertain, exercise can promote greater improvements in gas diffusion and comparable bronchodilation when compared to albuterol.

The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time‐varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient‐level data from relevant observational studies, and (ii) used a model‐based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA‐2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis. The model quantifies presence of islet AA permutations as statistically significant predictors of the time‐varying probability of conversion to a diagnosis of T1D. Additional sources of variability that greatly improved the accuracy of quantifying the time‐varying probability of conversion to a T1D diagnosis included baseline age, sex, blood glucose measurements from the 120‐minute timepoints of oral glucose tolerance tests, and hemoglobin A1c. The developed models represented the underlying evidence to qualify islet AAs as enrichment biomarkers through the qualification of novel methodologies for drug development pathway at the European Medicines Agency (EMA). Additionally, the models are intended as the foundation of a fully functioning end‐user tool that will allow sponsors to optimize enrichment criteria for clinical trials in T1D prevention studies.