Actigraphy Study Endpoints to Reduce Sample Size and Facilitate Drug Development for Pediatric Pulmonary Arterial Hypertension.

Objective: To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to 6-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process.

Study Design: We conducted a prospective, multicenter, noninterventional study in pediatric PAH patients and healthy children. Actiheart and Fitbit Charge 2 recorded pA and heart rate data.

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015-2020.

Pediatric extrapolation plays a key role in the availability of reliable pediatric use information in approved drug labeling. This review examined the use of pediatric extrapolation in studies submitted to the US Food and Drug Administration and assessed changes in extrapolation approaches over time. Pediatric studies of 125 drugs submitted to the US Food and Drug Administration that led to subsequent pediatric information in drug labeling between 2015 and 2020 were reviewed.

Using Historical Data to Support Approval of Drug Products for Ophthalmia Neonatorum: Innovative Approach Toward Evidence-Based Medicine.

Importance: Off-label treatment was common for ophthalmia neonatorum because only erythromycin ointment had been approved by the US Food and Drug Administration (FDA) for this indication. Ophthalmia neonatorum was previously considered a different indication from bacterial conjunctivitis in older children and adults because of uncertain similarities in the cause of disease and the treatment course between the 2 populations. Prospective therapeutic clinical studies were required to demonstrate the effectiveness of treatment for ophthalmia neonatorum.

Surrogate Endpoints in Pediatric Studies Submitted to the US FDA.

The 21 Century Cures Act was passed in December, 2016, and included a number of provisions to facilitate drug approval. Considerable discussion was generated related to some aspects of the Act, especially to the use of surrogate endpoints (SEs) as a means to shorten the time required prior to receiving US Food and Drug Administration (FDA) approval. The objective of this analysis was to identify the use and outcomes of SEs and clinical endpoints in pediatric drug development trials.

Extrapolation of Efficacy in Pediatric Drug Development and Evidence-based Medicine: Progress and Lessons Learned.

Background: "Complete Extrapolation" of efficacy from adult or other pediatric data, to the pediatric population, is an important scientific tool that reduces the need for pediatric efficacy trials. Dose finding and safety studies in pediatrics are still needed. "No Extrapolation" requires 2 pediatric efficacy trials.

Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration.

Objective: There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD.

Methods: Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015.

The Role of Biomarkers and Surrogate End Points in Drug Development for Neonatal Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease in newborns, infants, and children. It is associated with significant morbidity and mortality, but has limited treatment options. Except for inhaled nitric oxide, which is approved for persistent pulmonary hypertension of the newborn (PPHN), no drug is approved for the treatment of newborns, infants, and children with PAH.

Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development.

Objectives: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD).

Methods: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development.

Results: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 2: data extrapolation, trial design, and pharmacokinetics.

Objectives: To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development.

Methods: Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature.

Results: Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 1: efficacy endpoints and disease outcome assessments.

Objectives: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally.

Alternate endpoints and clinical outcome assessments in pediatric ulcerative colitis registration trials.

Objectives: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC.

Methods: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed.

Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents.

OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011.

Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models.

Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.(1) Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,(2) in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After 2 weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.

Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer.

PURPOSE We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity.

Pulsed high-intensity focused ultrasound enhances uptake of radiolabeled monoclonal antibody to human epidermoid tumor in nude mice.

Unlabelled: The aim of this study was to determine if pulsed high-intensity focused ultrasound (HIFU) exposures could enhance tumor uptake of (111)In-MX-B3, a murine IgG1kappa monoclonal antibody directed against the Le(y) antigen.

Methods: MX-B3 was labeled with (111)In, purified, and confirmed for its binding to the antigen-positive A431 cell line. Groups of nude mice were inoculated subcutaneously with A431 tumor cells on both hind flanks.

Tumor imaging using 1-(2'-deoxy-2'-18F-fluoro-beta-D-arabinofuranosyl)thymine and PET.

Unlabelled: The kinetics of 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated.

Methods: Ten patients with brain (n = 4) or prostate (n = 6) tumors were imaged using (18)F-FMAU PET (mean dose, 369 MBq).

Biodistribution and radiation dosimetry estimates of 1-(2'-deoxy-2'-(18)F-Fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil: PET imaging studies in dogs.

Unlabelled: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis.

Methods: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism.

Imaging the pharmacokinetics of [F-18]FAU in patients with tumors: PET studies.

Purpose: FAU (1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl) uracil) can be phosphorylated by thymidine kinase, methylated by thymidylate synthase, followed by DNA incorporation and thus functions as a DNA synthesis inhibitor. This first-in-human study of [F-18]FAU was conducted in cancer patients to determine its suitability for imaging and also to understand its pharmacokinetics as a potential antineoplastic agent.

Methods: Six patients with colorectal (n = 3) or breast cancer (n = 3) were imaged with [F-18]FAU.

Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer.

Purpose: FMAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This first-in-human study of [18F]FMAU was conducted as a pilot in patients to determine its biodistribution and suitability for imaging DNA synthesis in tumors using positron emission tomography (PET).

Methods: Fourteen patients with diverse cancers (brain, prostate, colorectal, lung, and breast) were imaged with [18F]FMAU.

Imaging [18F]FAU [1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) uracil] in dogs.

We have studied the biodistribution of [(18)F]FAU [(1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil], which previous work has shown is incorporated into DNA and functions as an inhibitor of DNA synthesis. It is being tested as a potential antineoplastic agent and imaging agent for PET. We have produced [(18)F]FAU and injected the tracer into 3 normal dogs and imaged them for up to 4 hours and removed tissues along with blood and urine samples for HPLC and activity analysis.