Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US an Europe From 2007 to 2021

IMPORTANCE: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. OBJECTIVES: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. RESULTS: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. CONCLUSIONS AND RELEVANCE: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways

Effects of Hypohydration on Muscular Performance in Females: An Ongoing Study

Dehydration (~3%) has been shown to negatively affect anaerobic performance. A majority of this research has been conducted using male participants. Like males, females have been shown to underestimate sweat loss, which could lead to insufficient rehydration and thus hypohydration. Additionally, due to differences in thermoregulation, it is possible that females respond to hypohydration differently than males. To date, no research has examined the effects of previous night dehydration on muscular performance in females. PURPOSE: The purpose of this ongoing study was to determine the effects of previous night dehydration on muscular strength, muscular endurance, lower body power, and perceptual measures in resistance trained females. METHODS: Healthy, resistance trained females (n = 7) completed two bouts of resistance exercise, either dehydrated (~3% body weight) (DT) or heat exposed with fluid replacement (HT). Each exercise bout consisted of one rep maximum (1RM) for bench press followed by 5 sets to failure of 75% of 1RM, 1RM for leg press followed by 5 sets to failure of 75% of 1RM, and vertical jump assessment. Participants estimated ratings of perceived exertion (RPE) after each exercise. Session RPE (SRPE) was estimated 5 minutes following completion of the protocol and estimations for feelings of recovery (PRS), perceived readiness to exercise (PR), thirst, and sleep quality were estimated prior to workouts. RESULTS: Analysis revealed a bench press 1RM (p = 0.05) and leg press 1RM (p = 0.03) were significantly lower for DT (bench: 95.0 ± 34.0; leg press: 461.4 ± 141.7) compared to HT (bench: 97.9 ± 34.3; leg press: 500.0 ± 141.0). There was no difference in total reps completed for bench press (p = 0.32) or leg press (p = 0.37) for DT (bench press: 31.0 ± 6.7; leg press: 47.9 ± 21.6) compared to HT (bench press: 31.7 ± 5.0; leg press: 49.6 ± 22.8). There was no significant difference (p = 0.15) for vertical jump height (DT: 17.6 ± 2.2, HT: 18.1 ± 2.6). RPE was not significantly different following bench press (p = 0.5) (DT: 7.1 ± 1.1, HT: 7.1 ± 0.9) or leg press (p = 0.41) (DT: 6.7 ± 0.5, HT: 6.9 ± 1.7). SRPE was significantly higher (p = 0.05) for DT (6.6 ± 0.5) vs HT (5.9 ± 0.7). Significant differences for PRS (p = 0.03) (DT: 5.4 ± 2.2, HT: 7.05 ± 1.3) and PR (p = 0.01) (DT: 3.9 ± 0.9, HT: 2.6 ± 0.5) indicate participants expected impaired performance during DT. Feelings of thirst were significantly higher (p = 0.001) for DT (6.5 ± 2.5) vs HT (2.1 ± 2.3). Estimations of sleep quality were significantly lower (p = 0.05) for DT (4.3 ± 3.3) vs HT (7.2 ± 2.1). CONCLUSION: Even though only preliminary data from a presently ongoing study, the current results suggest that previous night dehydration has a negative influence on both performance and perceptual measures in resistance trained females

Flavor Ratios of Astrophysical Neutrinos: Implications for Precision Measurements

We discuss flavor-mixing probabilities and flavor ratios of high energy astrophysical neutrinos. In the first part of this paper, we expand the neutrino flavor-fluxes in terms of the small parameters U_{e3} and pi/4 - theta_{23}, and show that there are universal first and second order corrections. The second order term can exceed the first order term, and so should be included in any analytic study. We also investigate the probabilities and ratios after a further expansion around the tribimaximal value of sin^2 theta_{12} = 1/3. In the second part of the paper, we discuss implications of deviations of initial flavor ratios from the usually assumed, idealized flavor compositions for pion, muon-damped, and neutron beam sources, viz., (1 : 2 : 0), (0 : 1 : 0), and (1 : 0 : 0), respectively. We show that even small deviations have significant consequences for the observed flavor ratios at Earth. If initial flavor deviations are not taken into account in analyses, then false inferences for the values in the PMNS matrix elements (angles and phase) may result.Comment: 32 pages, 15 figures. Minor changes, matches version in JHE

Ubiquitin Proteasome System Activity is Suppressed by Curcumin Following Exercise-Induced Muscle Damage in Human Skeletal Muscle

PURPOSE: Curcumin is a natural polyphenolic compound with antioxidant and anti-inflammatory properties. In vitro and in vivo animal studies have demonstrated that exposure to curcumin leads to dysregulation of the ubiquitin-proteasome system (UPS). However, to date, no study has investigated curcumin’s ability to influence UPS activity in a human model. Therefore, the purpose of this study was to investigate the effects of curcumin supplementation on markers of UPS activity in the presence of elevations in UPS activity due to exercise-induced muscle damage. METHODS: Twenty-three recreationally active male and female participants between the ages of 18-30 were randomized into a curcumin (CUR; n=11) or placebo (PLA; n=12) group. Both groups were instructed to consume 2 g of their respective supplement and 20 mg of piperine for 11 consecutive days. Following 8 consecutive days of supplementation, participants performed a 45 minute eccentrically-biased muscle damaging treadmill protocol at 60% VO2max. Muscle biopsies and delayed onset muscle soreness (DOMS) analyses were performed 30 minutes prior and 3, 24, 48, and 72 hours following exercise-induced muscle damage. Skeletal muscle ubiquitin, MAFbx/Atrogin-1, ubiquitin specific peptidase 19 (USP19), and chymotrypsin-like protease concentrations were measured using ELISA. A 3-way repeated measures ANOVA with pairwise comparisons was conducted with significance set at p≤0.05. RESULTS: Both groups had a significant time effect for DOMS (p \u3c .001). Pairwise comparisons indicated DOMS was significantly greater from baseline at all time points except 72 hours following muscle damage. No significant differences were found for USP19 between groups. Regardless of time, a significant main effect for condition was observed for ubiquitin (p=.016) and MAFbx/Atrogin-1 (p=.006) where CUR was significantly lower than PLA. Additionally, a significant main effect for gender was observed for MAFbx/Atrogin-1 (p=.013) where females were greater than males. A significant group x gender interaction was found for chymotrypsin-like protease (p = .049) where males had lower values with curcumin supplementation while females had slightly higher. CONCLUSION: Curcumin supplementation in humans does appear to dysregulate UPS activity in the presence of exercise-induced muscle damage. Specifically, curcumin’s ability to suppress protein ubiquination provides preliminary evidence of curcumin supplementation’s potential therapeutic role in decreasing protein degradation associated with skeletal muscle damage and perhaps other atrophic scenarios

Coverage of new drugs in medicare Part D

Context: Medicare Part D is an outpatient prescription drug benefit for older Americans covering over 46 million beneficiaries. Except for mandatory coverage for essentially all drugs in six “protected classes”, plans have substantial flexibility in how they design their formularies: which drugs are covered, which drugs are subject to restrictions, and what factors determine formulary placement. Our objective in this paper was to document the extent to which Part D plans limit coverage of newly approved drugs. Methods: We examined the formulary design of 4,582 Part D plans from 2014 through 2018 and measured (1) the decision to cover newly approved drugs in non-protected classes, (2)nuse of utilization management tools in protected and non-protected classes, and (3) the association between plan design and drug-level characteristics such as 30-day cost, therapeutic benefit, and the US Food and Drug Administration (FDA) expedited regulatory pathway. Findings: The FDA approved 109 new drugs predominantly used in outpatient settings between 2013 and 2017. Of these, 75 fell outside of the six protected drug classes. One-fifth of drugs in non-protected classes (15 out of 75) were covered by more than half of plans during the first year after approval. Coverage was often conditional on utilization management strategies in both protected and non-protected classes: only 7 drugs (6 percent) were covered without prior authorization requirements in more than half of plans. Higher 30-day drug costs were associated with more widespread coverage in non-protected classes: drugs that cost less than $150 for a 30-day course were covered by fewer than 20 percent of plans while those that cost over$30,000 per 30 days were covered by more than 50 percent of plans. Plans were also more likely to implement utilization management tools on high-cost drugs in both protected and non-protected classes. A higher proportion of plans implemented utilization management strategies on covered drugs with first-in-class status than drugs that were not first-in-class. Other drug characteristics, including availability of added therapeutic benefit and inclusion in FDA expedited regulatory approval, were not consistently associated with plan coverage or formulary restrictions. Conclusions: Newly approved drugs are frequently subject to formulary exclusions and restrictions in Medicare Part D. Ensuring that formulary design in Part D is linked closely to the therapeutic value of newly approved drugs would improve patients’ welfare

Quality of weight loss advice on internet forums.

BACKGROUND: Adults use the Internet for weight loss information, sometimes by participating in discussion forums. Our purpose was to analyze the quality of advice exchanged on these forums. METHODS: This was a retrospective analysis of messages posted to 18 Internet weight loss forums during 1 month in 2006. Advice was evaluated for congruence with clinical guidelines; potential for causing harm; and subsequent correction when it was contradictory to guidelines (erroneous) or potentially harmful. Message- and forum-specific characteristics were evaluated as predictors of advice quality and self-correction. RESULTS: Of 3368 initial messages, 266 (7.9%) were requests for advice. Of 654 provisions of advice, 56 (8.6%) were erroneous and 19 of these 56 (34%) were subsequently corrected. Forty-three (6.6%) provisions of advice were harmful, and 12 of these 43 (28%) were subsequently corrected. Messages from low-activity forums (fewer messages) were more likely than those from high-activity forums to be erroneous (10.6% vs 2.4%, P \u3c .001) or harmful (8.4% vs 1.2%, P \u3c .001). In high-activity forums, 2 of 4 (50%) erroneous provisions of advice and 2 of 2 (100%) potentially harmful provisions of advice were corrected by subsequent postings. Compared with general weight loss advice, medication-related advice was more likely to be erroneous (P = .02) or harmful (P = .01). CONCLUSIONS: Most advice posted on highly active Internet weight loss forums is not erroneous or harmful. However, clinical and research strategies are needed to address the quality of medication-related advice