A descriptive analysis of postmarketing requirement studies and clinical trials.

PURPOSE: Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA has the authority to require applicants to conduct postmarketing studies or clinical trials. These postmarketing requirements (PMRs) provide additional data on the safety of the drug product. The purpose of the study was to conduct a descriptive analysis of FDAAA PMRs and the resulting regulatory actions. METHODS: This study evaluated FDAAA PMRs established between 2013 and 2019. We used the Medical Dictionary for Regulatory Activities (MedDRA) to map preferred terms (PTs) for serious risks associated with the PMRs. Relevant documents available in the FDA's document archiving, reporting, and regulatory tracking system (DARRTS), including but not limited to internal letters and reviews, documents submitted by applicants, and publicly available data sources were assessed for data collection of study elements. RESULTS: Of the 1079 new FDAAA PMRs established between January 01, 2013, and December 31, 2019, 82% (n = 884) were associated with new drug applications (NDAs) and 18% (n = 195) with biologic license applications (BLAs). Most PMRs were established at the time of drug approval (73%, n = 789) compared to post-approval (27%, n = 290). The majority of PMRs had an open status (59%, n = 639) and 41% (n = 440) were closed. The median time from the PMR establishment date to submission of the results to the FDA was 690 days (interquartile range [IQR]: 748 days) for 167 completed clinical trials and 483 days (IQR: 603 days) for 241 completed studies. Approximately 53% (180/339) of fulfilled FDAAA PMRs resulted in labeling changes. CONCLUSIONS: FDAAA PMRs are useful in informing postmarket safety of drugs. Most FDAAA PMRs were established at the time of drug approval, reflecting safety signals identified during the review of the marketing application, and over half of fulfilled FDAAA PMRs resulted in regulatory action.

Carbohydrate balance predicts weight and fat gain in adults.

BACKGROUND: The prevention and treatment of obesity is a public health challenge. OBJECTIVE: We investigated the effects of dietary composition, insulin sensitivity (S(I)), and energy balance on predicted changes in body composition. DESIGN: In a randomized crossover design study, 39 normal-weight (n = 23), overweight (n = 8), and obese (n = 8) men and women (aged 25-36 y) each followed a 15-d isocaloric high-fat (HF; 50% fat) and high-carbohydrate [HC; 55% carbohydrate (CHO)] diet with a 4-6-wk washout period during the first year. During each treatment, energy balance was measured while the subjects were inactive by using indirect calorimetry on day 15, and S(I) was measured by using a euglycemic clamp study (40 mU . m(-2) . min(-1)) on day 16. Weight and body composition were then measured annually for 4 y. The outcomes for fat mass, percentage body fat, and weight were measured by using a linear 2-stage mixed model. RESULTS: CHO balance (day 15) and S(I) (day 16) on the HC diet were highly and significantly correlated (r = 0.55, P < 0.001). On the HC diet, the subjects who had a higher positive CHO balance (day 15) gained less fat mass (P < 0.001), percentage body fat (P = 0.006), and weight (P = 0.024) over time. When adjusted for S(I), CHO balance remained a significant predictor of changes in fat mass (P = 0.021) and percentage body fat (P = 0.025). CONCLUSIONS: On a HC diet, the subjects who had a higher positive CHO balance on day 15 while they were inactive gained less fat mass during 4 y, a predictive effect independent of S(I). As suggested in rodents, the capacity to expand the glycogen pool might reduce energy intake and protect against fat and weight gain.

Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction.

BACKGROUND: The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. METHODS AND RESULTS: The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56+/-4 mg/dL (P<0.0001) at day 7 and by an additional 8+/-3 mg/dL (P=0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo (P=0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] (P=0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. CONCLUSIONS: Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.

Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia.

OBJECTIVE: The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. METHODS AND RESULTS: Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P<0.001), total cholesterol (P<0.01), and apolipoprotein B (P<0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P<0.0001), nitroprusside (P<0.001), and verapamil (P<0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P<0.0001) and post-heparin (P<0.001) TG and tended to lower 24-hour (P=0.054) and post-heparin (P=0.028) FFA. CONCLUSIONS: Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

Effects of maintained weight loss on sleep dynamics and neck morphology in severely obese adults.

The goals of the study were to determine if moderate weight loss in severely obese adults resulted in (i) reduction in apnea/hypopnea index (AHI), (ii) improved pharyngeal patency, (iii) reduced total body oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) during sleep, and (iv) improved sleep quality. The main outcome was the change in AHI from before to after weight loss. Fourteen severely obese (BMI > 40 kg/m(2)) patients (3 males, 11 females) completed a highly controlled weight reduction program which included 3 months of weight loss and 3 months of weight maintenance. At baseline and postweight loss, patients underwent pulmonary function testing, polysomnography, and magnetic resonance imaging (MRI) to assess neck morphology. Weight decreased from 134 +/-6.6 kg to 118 +/- 6.1 kg (mean +/- s.e.m.; F = 113.763, P < 0.0001). There was a significant reduction in the AHI between baseline and postweight loss (subject, F = 11.11, P = 0.007). Moreover, patients with worse sleep-disordered breathing (SDB) at baseline had the greatest improvements in AHI (group, F = 9.00, P = 0.005). Reductions in VO(2) (285 +/- 12 to 234 +/-16 ml/min; F = 24.85, P < 0.0001) and VCO(2) (231 +/- 9 to 186 +/- 12 ml/min; F = 27.74, P < 0.0001) were also observed, and pulmonary function testing showed improvements in spirometry parameters. Sleep studies revealed improved minimum oxygen saturation (minSaO(2)) (83.4 +/- 61.9% to 89.1 +/- 1.2%; F = 7.59, P = 0.016), and mean SaO(2) (90.4 +/- 1.1% to 93.8 +/- 1.0%; F = 6.89, P = 0.022), and a significant increase in the number of arousals (8.1 +/- 1.4 at baseline, to 17.1 +/- 3.0 after weight loss; F = 18.13, P = 0.001). In severely obese patients, even moderate weight loss (approximately 10%) boasts substantial benefit in terms of the severity of SDB and sleep dynamics.

Impact of diet-induced weight loss on the cardiac autonomic nervous system in severe obesity.

OBJECTIVE: To determine the impact of diet-induced weight loss on cardiac autonomic nervous system modulation and arrhythmias in subjects with severe obesity and the influence of a high-fat or a high-carbohydrate diet regimen on heart rate variability in reduced-obese individuals. RESEARCH METHODS AND PROCEDURES: Eight severely obese subjects (BMI > or = 40.0 kg/m(2)) underwent a 3-month weight loss program followed by a 3-month reduced-weight maintenance regimen. Thereafter, each subject was admitted for an inpatient period of 17 days on two separate occasions. A high-carbohydrate (60%) or high-fat (55%) diet of appropriate energy content for weight maintenance was prescribed during each inpatient phase. Heart rate variability was derived from a 24-hour Holter monitoring system in all subjects during their inpatient stay. Cardiac Holter monitoring was performed at three occasions (baseline, diet phase I, and diet phase II), including the second night of a two overnight calorimetry chamber stay. RESULTS: After the diet regimen, there was a 10% decrease in weight. There were no significant changes in systolic and diastolic blood pressure, arrhythmias, glucose, insulin, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, respiratory exchange ratio, and resting energy expenditure between experiments. Mean heart rate was lower after weight loss compared with baseline (p < 0.001). After weight loss, there was an increase in the parasympathetic indices of heart rate variability showing an increase in cardiac vagal modulation (all p < 0.05). DISCUSSION: Weight loss is associated with significant improvement in autonomic cardiac modulation through enhancement of parasympathetic modulation, which clinically translates into a decrease in heart rate.