Clinical studies/trials reports

The overview should reference any specific FDA guidelines used and any FDA-sponsor discussions held on major issues, such as an end-of-phase 2 conference. The critical features of the trials should be explained, including duration, study design, and particular advantages or potential problems examined. If there is pertinent clinical literature (controlled or uncontrolled clinical studies or reports on patients), a review may be helpful. (The sponsor may want to comment on literature pertaining to closely related drugs that provide insight into potential problems or areas of special interest.)... 

At low doses, PUFAs provide protection against coronary heart disease and reduce the severity of cardiac arrhythmias at high doses, they lower blood cholesterol and triglycerides, reduce platelet aggregation, have antithrombotic activity, and reduce blood viscosity. Several clinical studies have reported beneficial effects of supplementation on mortality, sudden death, and arrhythmias. In the Diet and Reinfarction Trial (DART), the use of fatty fish or fish oil led to a 29% reduction in mortality, and the GlSSI-Preven-zione trial showed that consumption of 1 g n-3-PUFA daily resulted in a 20% decrease in mortality and 45%i reduction in sudden death. ° ... 

Since the publication our of initial hypothesis (Hibbeln and Salem, 1995), a series of clinical studies have reported that depressed patients have low tissue concentrations of EPA and/or DHA, and several supplementation trials have reported improvements in depressive or symptoms in the affective spectrum. Although initial reports described elevated plasma concentrations of DHA among subjects with some mixture of depressive... 

A robust database exists from observational studies, clinical studies/trials, animal studies, and in vitro studies demonstrating that fatty acids play a key role in chronic disease risk. Population studies show a positive correlation between coronary heart disease (CHD) risk and dietary SFA (Hu et al., 1997 Keys, 1970 Kromhout et al., 1995) and an inverse association with PUFA (Hu et al., 1997). The Nurses Health Study (Hu et al., 1997) reported an inverse relationship between the PUFA SFA ratio and CHD risk. By all estimates, replacing 5% of energy from SFA with PUFA or MUFA would reduce risk of CHD by -48 and 36%, respectively. The relationship between dietary fat intake and risk of CHD is illustrated in Figure 20.2. Tram fatty... 

Thoracic fluid is associated with decreased impedance between a ventricular lead and the pacing system generator. Two preliminary clinical studies have reported varying results on the clinical utility of thoracic impedance monitoring for predicting hemodynamic status. The Medtronic Impedance Diagnostics in Heart Failure Trial (MlD-HeFT) evaluated 33 patients with Class III or IV heart failure due to systolic dysfunction (n = 25) or diastolic dysfunction (n =... 

Coudert B, Anthoney A, Fiedler W, Droz JP, Dicaas V, Bomer M, Smyth JF, Morant R, de Vries MJ, Roelvink M, Fumoleau P (2001) Phase n trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLQ lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report. Eur J Cancer 37 2194-2198... 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Pre-approval safety and efficacy clinical studies involved product administration to 2500 adults with either type-1 or -2 diabetes. The primary efficacy parameter measured was glycaemic control (as measured by the reduction from baseline in haemoglobin Ale). Hypoglycaemia was the most commonly reported adverse effect. Trials also showed a greater decline in pulmonary function in the Exubera group, and product should not be administered to patients with underlying lung disease, or to smokers. Exubera was developed by Nektar Inc. and is marketed under licence by Pfizer. 

Quality of evidence I, evidence from >1 properly randomized, controlled trial II, evidence from <1 well-designed clinical trial, without randomization from cohort or case-controlled analytic studies (preferably from >1 center) or from multiple time-series III, evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. 

A number of studies in humans show that PUFAs can generate significant immunomodulatory effects. Generally, these studies have utilized considerably lower amounts of fish oil to treat subjects than found in most animal studies. Numerous clinical trials have examined the effects of fish oil on rheumatoid arthritis and many have reported statistically significant benefits such as decreased morning stiffness and numbers of tender joints [57]. Several other studies have reported that PUFAs can provide therapeutic benefits for patients with IgA nephropathy, the most common primary human glomerulonephritis... 

Clinical research coordinators (CRCs) are the research personnel who assist with pahent visits, and perform study-related procedures that do not require a physician (phlebotomy, vital signs, adverse event, and concomitant medicahon discussions, etc.). CRCs provide the PI or physician with data required for interpretation, medical decisions (inclusion/exclusion, dosage adjustment, patient withdrawal, adverse event causality, etc.), and trial oversight. In addition, CRCs are usually responsible for transcribing source documentation (medical records, clinic notes, laboratory reports, etc.) into case report forms (CRF) supplied by the study sponsor. 

Regulatory authorities play an important and active role to ensure regulatory compliance in the conduct of a clinical trial. Agencies such as the FDA inspect clinical studies. An inspection of a trial may reveal that the protocol is not being followed strictly, the Investigator may not be involved with the project as much as is expected, there may be a lack of patient care, changes to the protocol may not have been relayed to the IRB, and so on. In such cases, corrective actions have to be implemented immediately and the FDA must be satished before the trial can continue. Deficiencies found are reported on Form 583. 

Efficacy Nine topic headings—Clinical Safety, Clinical Study Reports, Dose-Response Studies, Ethnic Factors, GCP, Clinical Trials, Clinical Evaluation by Therapeutic Category, Clinical Evaluation, Pharmacogenomics total of 18 guidelines... 

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