ABSTRACT
The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.
Subject(s)
Cardiovascular Agents/therapeutic use , Clinical Trials, Phase II as Topic/standards , Heart Failure/drug therapy , Research Design/standards , Cardiovascular Agents/adverse effects , Clinical Trials, Phase II as Topic/methods , Consensus , Heart Failure/diagnosis , Heart Failure/mortality , Heart Failure/physiopathology , Humans , Treatment Outcome , United States , United States Food and Drug AdministrationABSTRACT
The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting.
Subject(s)
Heart Failure/therapy , Hospitalization , Mortality , Patient Reported Outcome Measures , Stroke Volume , Congresses as Topic , Drug Approval , Drug Discovery , Exercise Test , Heart Failure/physiopathology , Humans , Outcome Assessment, Health Care , Oxygen Consumption , Quality of Life , United States , United States Food and Drug Administration , Walk TestABSTRACT
Preemptive analgesia is an important part of surgical management, but some NSAIDs can adversely affect platelet function or renal or hepatic status. Tepoxalin is approved in the United States for control of pain and inflammation associated with arthritis and in Europe for relief of pain caused by musculoskeletal disorders. In this study, no significant effects on indices of hemostasis or renal or hepatic function were detected when a single preoperative oral dose of tepoxalin was administered to young healthy dogs undergoing anesthesia and surgery.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Hemostasis/drug effects , Kidney/drug effects , Liver/drug effects , Preanesthetic Medication/veterinary , Pyrazoles/administration & dosage , Analgesia/methods , Analgesia/veterinary , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Dog Diseases/drug therapy , Dog Diseases/prevention & control , Dogs , Female , Hemostasis, Surgical , Kidney/physiology , Liver/physiology , Male , Pain/drug therapy , Pain/prevention & control , Pain/veterinary , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Random Allocation , Treatment OutcomeABSTRACT
Plasma and skin concentrations of orbifloxacin (Orbax tablets, Schering-Plough Animal Health) were assessed in 14 clinically normal dogs and 14 dogs with pyoderma following oral administration of the drug at 7.5 mg/kg once daily for 5 to 7 days. Skin biopsies and whole blood samples were obtained before dosing and at the time of the expected maximum concentration in skin (3 hours after dosing) on the first and on the fifth to seventh day of dosing. Skin biopsies and plasma were analyzed for orbifloxacin concentrations by high-performance liquid chromatography. Dogs with pyoderma had significantly higher mean skin concentrations of orbifloxacin within 3 hours of administration (Day 0: 7.80 +/- 3.40 mcg/g, Days 4 to 6: 9.47 +/- 6.23 mcg/g) than did dogs with normal skin (Day 0: 3.85 +/- 1.08 mcg/g, Days 4 to 6: 5.43 +/- 1.02 mcg/g). After dosing on Day 0 and after five to seven daily treatments, dogs with pyoderma had significantly higher mean orbifloxacin skin:plasma ratios (1.40 and 1.44, respectively) than did clinically normal dogs (0.81 and 0.96, respectively). The accumulation of orbifloxacin in diseased skin may contribute to the efficacy of this compound for the treatment of bacterial skin infections.