Purchase viagra

Serum levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity are associated purchase viagra with the presence of CAVS. However, it has been unclear whether this association is due to a cause–effect relationship. In this issue of Heart, Perrot and colleagues1 used genetic association studies from eight cohorts to show that CAVS was not associated with any of four single nucleotide polymorphisms that are associated with Lp-PLA2 activity or mass. These findings suggest that although Lp-PLA2 activity is a biomarker for CAVS unfortunately, it is unlikely to be a therapeutic purchase viagra target (figure 1).Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study.

CAVS, calcific aortic valve stenosis. Lp-PLA2, lipoprotein-associated phospholipase A2." data-icon-position data-hide-link-title="0">Figure 1 Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study. CAVS, calcific purchase viagra aortic valve stenosis. Lp-PLA2, lipoprotein-associated phospholipase A2.In an editorial, Zheng and Dweck2 discuss this article, summarise current ongoing trials of medical therapy for CAVS (table 1) and comment.

€˜Strong evidence points towards elevated Lp(a) levels and its associated oxidised phospholipids (OxPL) as causal risk factors for CAVS, suggesting that targeting this lipid-driven, inflammatory pathway has a real chance to translate into therapy capable of mitigating disease. The current study suggests that this association is not mediated by Lp-PLA2 and underlines the importance of scrutinising whether biological factors within pathophysiological pathways are merely biomarkers or actually represent a feasible and causal target.’View this table:Table 1 Ongoing randomised clinical trials of medical therapies in aortic stenosisRheumatic heart disease purchase viagra (RHD) remains the primary cause of valve disease worldwide and contributes significantly to maternal and fetal morbidity and mortality. In a study by Baghel and colleagues3 of 681 pregnant women with RHD, adverse cardiovascular evens occurred in about 15% of pregnancies. Multivariable predictors of adverse outcomes during pregnancy were prior adverse cardiovascular events, lack of appropriate medical therapy, severity of mitral stenosis, valve replacement and pulmonary hypertension.

Based on this analysis, the authors propose a risk score from pregnant women with RHD (table 2).View this table:Table 2 New prognostic score (DEVI’s score) to predict composite adverse cardiac outcome in pregnant women with rheumatic valvular heart diseaseCommenting on this paper, Elkayam and Shmueli4 purchase viagra point out that in about one-fourth of women, the diagnosis of RHD was not known prior to pregnancy and that a late diagnosis often was associated with adverse outcomes. Their editorial provides a concise summary of optimal management of pregnant women with RHD. They conclude ‘With proper evaluation and risk stratification prior to pregnancy, a close multidisciplinary follow-up during pregnancy, and close monitoring during labour and delivery as well as the early postpartum period most complications can be prevented.’The importance of psychosocial factors in cardiovascular disease (CVD) prevalence and outcomes is increasingly recognised. Using data from the English Longitudinal Study of Ageing, Bu and colleagues5 found that loneliness was associated with CVD, independent of possible confounders and other risk factors, with a 30% higher risk of a new CVD diagnosis in the most lonely people compared purchase viagra with the least lonely people.

As O’Keefe and colleagues6 point out, this data is especially important now in the context of social distancing and stay-at-home recommendations and they offer several approaches to mitigating loneliness during the erectile dysfunction treatment viagra.The Education in Heart article7 in this issue focuses on the clinical use and prognostic implications of echocardiographic speckle tracking measurements of global longitudinal strain to detect and quantify early systolic dysfunction of the left ventricle (figure 2).Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy and cardiac amyloidosis. (A) Apical four-chamber view of a 66-year-old patient known with mutation-positive hypertrophic cardiomyopathy. The thickness of the septum was 28 mm and the left ventricular ejection fraction was purchase viagra 55%. (B) The polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal strain is impaired (−13.6%).

(C) Apical four-chamber view of a 75-year-old patient diagnosed with light chain amyloidosis. There is concentric purchase viagra hypertrophy of the left ventricle and the ejection fraction is 56%. Based on speckle tracking echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the apical segments (D). ANT, anterior.

ANT SEPT, anteroseptal purchase viagra. GS, global strain. INF, inferior. LAT, lateral purchase viagra.

POST, posterior. SEPT, septal." data-icon-position data-hide-link-title="0">Figure 2 Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy and cardiac amyloidosis. (A) Apical four-chamber view of a purchase viagra 66-year-old patient known with mutation-positive hypertrophic cardiomyopathy. The thickness of the septum was 28 mm and the left ventricular ejection fraction was 55%.

(B) The polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal strain is impaired (−13.6%). (C) Apical four-chamber view purchase viagra of a 75-year-old patient diagnosed with light chain amyloidosis. There is concentric hypertrophy of the left ventricle and the ejection fraction is 56%. Based on speckle tracking echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the apical segments (D).

ANT, anterior purchase viagra. ANT SEPT, anteroseptal. GS, global strain. INF, inferior purchase viagra.

LAT, lateral. POST, posterior. SEPT, septal.Our Cardiology-in-Focus article by Hudson and Pettit8 provides a clear-eyed but brief discussion and outstanding purchase viagra graphic of the challenges in reconciling the varying definitions of the ‘normal’ values for left ventricular ejection fraction, as stated in different guidelines (figure 3).Categories of left ventricular ejection fraction. EF, ejection fraction.

HF, heart failure. LVEF, left ventricular ejection fraction." data-icon-position data-hide-link-title="0">Figure 3 Categories of left purchase viagra ventricular ejection fraction. EF, ejection fraction. HF, heart failure.

How to get a viagra prescription from your doctor

	Viagra	Sildigra	Levitra with dapoxetine	Viagra soft flavored	Viagra sublingual
Best price in Australia	No	Canadian Pharmacy	No	Pharmacy	No
Female dosage	No	No	No	Online	No
Can you get a sample	No	No	No	Yes	No

Patients Figure how to get a viagra prescription from your doctor Cheap cialis 1. Figure 1. Enrollment and how to get a viagra prescription from your doctor Randomization. Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the how to get a viagra prescription from your doctor remdesivir group and 522 to the placebo group (Figure 1).

Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) how to get a viagra prescription from your doctor or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned. Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day how to get a viagra prescription from your doctor 29, recovered, or died.

Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. There were 132 patients in how to get a viagra prescription from your doctor the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at how to get a viagra prescription from your doctor the time of the database freeze. Table 1.

Table 1 how to get a viagra prescription from your doctor. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1). On the basis of the evolving epidemiology of erectile dysfunction treatment during the trial, 79.8% of patients were enrolled at how to get a viagra prescription from your doctor sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported.

249 (23.4%) were Hispanic how to get a viagra prescription from your doctor or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days how to get a viagra prescription from your doctor between symptom onset and randomization was 9 (interquartile range, 6 to 12). Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category how to get a viagra prescription from your doctor 5, and 127 (11.9%) category 4.

There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. Primary Outcome how to get a viagra prescription from your doctor Figure 2. Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries how to get a viagra prescription from your doctor.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with a baseline score of 5 (receiving how to get a viagra prescription from your doctor oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with how to get a viagra prescription from your doctor a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E).

Table 2. Table 2 how to get a viagra prescription from your doctor. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 how to get a viagra prescription from your doctor. Figure 3.

Time to how to get a viagra prescription from your doctor Recovery According to Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and how to get a viagra prescription from your doctor ethnic group were reported by the patients. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32.

95% confidence interval how to get a viagra prescription from your doctor [CI], 1.12 to 1.55. P<0.001. 1059 patients how to get a viagra prescription from your doctor (Figure 2 and Table 2). Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) how to get a viagra prescription from your doctor and 1.20 (95% CI, 0.79 to 1.81), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), how to get a viagra prescription from your doctor the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant. An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect how to get a viagra prescription from your doctor estimate (rate ratio for recovery, 1.31.

95% CI, 1.12 to 1.54. 1017 patients) how to get a viagra prescription from your doctor. Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate how to get a viagra prescription from your doctor ratio for recovery of 1.28 (95% CI, 1.05 to 1.57. 664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81.

380 patients) how to get a viagra prescription from your doctor (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50. 95% CI, 1.18 to 1.91. P=0.001. 844 patients) (Table 2 and Fig.

S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04. 1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2).

The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits. An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients).

Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]).

Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Trial Population Table 1. Table 1.

Characteristics of the Participants in the mRNA-1273 Trial at Enrollment. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected erectile dysfunction treatment while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits.

The demographic characteristics of participants at enrollment are provided in Table 1. treatment Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1. Figure 1.

Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2). Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination.

After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3).

erectile dysfunction Binding Antibody Responses Table 2. Table 2. Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens. Figure 2. Figure 2.

erectile dysfunction Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live viagra PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants.

Red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay.

The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A).

Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens. The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). erectile dysfunction Neutralization Responses No participant had detectable PsVNA responses before vaccination.

After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]. Figure 2C, Fig. S8, and Table 2. 80% inhibitory dilution [ID80]. Fig.

S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens.

Before vaccination, no participant had detectable 80% live-viagra neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type viagra–neutralizing activity capable of reducing erectile dysfunction infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay. Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273.

erectile dysfunction T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig.

S11).Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with erectile dysfunction treatment at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network. (Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed erectile dysfunction and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020.

Pregnant or breast-feeding women were eligible. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net.

The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment.

Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial. For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician. Patients and local members of the trial staff were aware of the assigned treatments.

Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months.

Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the erectile dysfunction treatment viagra. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients.

For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio. Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization.

For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio. Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support. Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1).

To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk.

(One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest. Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle. The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to erectile dysfunction treatment.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo.

Participants had known exposure (by participant report) to a person with laboratory-confirmed erectile dysfunction treatment, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days. Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for erectile dysfunction, with the eligibility window extended to within 4 days after exposure.

This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application. In Canada, the trial was approved by Health Canada. Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed erectile dysfunction treatment at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org).

Persons with symptoms of erectile dysfunction treatment or with PCR-proven erectile dysfunction were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early . Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms. Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent.

We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status.

Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants. Only pharmacies had access to the randomization sequence.

Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total). If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the erectile dysfunction in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased.

Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, erectile dysfunction treatment–related symptoms. We assumed that health care workers would have access to erectile dysfunction treatment testing if symptomatic. However, access to testing was limited throughout the trial period. erectile dysfunction treatment–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for erectile dysfunction on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria.

Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for erectile dysfunction treatment or death, the incidence of PCR-confirmed erectile dysfunction , the incidence of erectile dysfunction treatment symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]). Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text. Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible erectile dysfunction treatment–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report. Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org.

Sample Size We anticipated that illness compatible with erectile dysfunction treatment would develop in 10% of close contacts exposed to erectile dysfunction treatment.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic s, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group. We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic erectile dysfunction treatment after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new s in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic s.

Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome. A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility. At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of s in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue.

Statistical Analysis We assessed the incidence of erectile dysfunction treatment disease by day 14 with Fisher’s exact test. Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test. Among participants in whom incident illness compatible with erectile dysfunction treatment developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05. For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event.

Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the erectile dysfunction treatment viagra by advancing development, manufacturing, and distribution of treatments, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S. Government typically supports product development and treatment distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for erectile dysfunction treatment countermeasure research and development across the U.S.

Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR). One of us (M.S.) serves as OWS chief advisor. We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a erectile dysfunction treatment — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S.

Population — beginning at the end of 2020 and to have as many as 300 million doses of such treatments available and deployed by mid-2021. The pace and scope of such a treatment effort are unprecedented. The 2014 West African Ebola viagra epidemic spurred rapid treatment development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. erectile dysfunction treatment development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July.

Our objectives are based on advances in treatment platform technology, improved understanding of safe and efficacious treatment design, and similarities between the SARS-CoV-1 and erectile dysfunction disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected treatments. The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder treatment development or deployment.OWS selected treatment candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy. Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the viagra, to deliver efficacy outcomes by the end of 2020 or the first half of 2021.

Candidates had to be based on treatment-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021. Finally, candidates had to use one of four treatment-platform technologies that we believe are the most likely to yield a safe and effective treatment against erectile dysfunction treatment. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two treatment candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best treatment platform for each subpopulation at risk for contracting or transmitting erectile dysfunction treatment, including older adults, frontline and essential workers, young adults, and pediatric populations.

In addition, advancing eight treatments in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate treatment program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate treatment.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA.

To permit appropriate comparisons among the treatment candidates and to optimize treatment utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the erectile dysfunction Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their treatments are in preclinical or very early clinical stages. To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each treatment candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of treatment doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate treatment development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each treatment for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit treatment administration before all BLA procedures are completed.Of the eight treatments in OWS’s portfolio, six have been announced and partnerships executed with the companies.

Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein). These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA treatment in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA treatment also produced encouraging phase 1 results2 and started its phase 3 trial on July 27. The ChAdOx replication-defective live-vector treatment developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S.

Phase 3 trials in August.3 The Janssen Ad26 erectile dysfunction treatment replication-defective live-vector treatment has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27. It should be in phase 3 trials in mid-September. Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein treatment in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA treatments are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for treatment distribution, subpopulation prioritization, financing, and logistic support.

We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues. We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive treatment doses once they are ready. Prioritization will also depend on the relative performance of each treatment and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these treatments will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor..

Patients Figure purchase viagra Cheap cialis 1. Figure 1. Enrollment and purchase viagra Randomization.

Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 purchase viagra to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned.

Forty-nine patients had remdesivir treatment discontinued before day purchase viagra 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned. Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2).

As of April 28, 2020, a total of 391 patients in the purchase viagra remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed purchase viagra the day 29 follow-up visit.

The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline purchase viagra data were available at the time of the database freeze. Table 1.

Table 1 purchase viagra. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1).

On the basis of the evolving epidemiology of purchase viagra erectile dysfunction treatment during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported. 249 (23.4%) were Hispanic or Latino purchase viagra.

Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, purchase viagra 6 to 12). Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix.

272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and purchase viagra 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group.

Primary Outcome purchase viagra Figure 2. Figure 2. Kaplan–Meier Estimates purchase viagra of Cumulative Recoveries.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in purchase viagra those with a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation.

Panel D), and in those with purchase viagra a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E). Table 2.

Table 2 purchase viagra. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 purchase viagra.

Figure 3. Time to Recovery According purchase viagra to Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects.

Race and ethnic group were reported by the patients purchase viagra. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32.

95% confidence purchase viagra interval [CI], 1.12 to 1.55. P<0.001. 1059 patients (Figure 2 purchase viagra and Table 2).

Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and purchase viagra those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7.

272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42) purchase viagra. A test of interaction of treatment with baseline score on the ordinal scale was not significant. An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome.

This adjusted analysis produced a similar treatment-effect purchase viagra estimate (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.54. 1017 patients) purchase viagra.

Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio purchase viagra for recovery of 1.28 (95% CI, 1.05 to 1.57. 664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81.

380 patients) purchase viagra (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50. 95% CI, 1.18 to 1.91.

P=0.001. 844 patients) (Table 2 and Fig. S5).

Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04. 1059 patients).

The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits. An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10).

Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients).

Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4).

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]). Pyrexia (27 events [5.0%], as compared with 17 [3.3%]).

Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Trial Population Table 1.

Table 1. Characteristics of the Participants in the mRNA-1273 Trial at Enrollment. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig.

S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected erectile dysfunction treatment while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits.

The demographic characteristics of participants at enrollment are provided in Table 1. treatment Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination.

Figure 1. Figure 1. Systemic and Local Adverse Events.

The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2). Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.

None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe.

(Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3).

erectile dysfunction Binding Antibody Responses Table 2. Table 2. Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens.

Figure 2. Figure 2. erectile dysfunction Antibody and Neutralization Responses.

Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live viagra PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

The convalescent serum panel includes specimens from 41 participants. Red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel.

In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay.

The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A). Dose-dependent responses to the first and second vaccinations were evident.

Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens. The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]).

erectile dysfunction Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]. Figure 2C, Fig.

S8, and Table 2. 80% inhibitory dilution [ID80]. Fig.

S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43.

The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens. Before vaccination, no participant had detectable 80% live-viagra neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay.

At day 43, wild-type viagra–neutralizing activity capable of reducing erectile dysfunction infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay. Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs.

S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. erectile dysfunction T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >.

Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig.

S11).Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with erectile dysfunction treatment at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network. (Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma.

Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed erectile dysfunction and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible.

Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee.

The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication.

The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment.

Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial. For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report.

The randomly assigned treatment was prescribed by the treating clinician. Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first.

Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization.

Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation.

Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the erectile dysfunction treatment viagra. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients.

For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio. Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days.

Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio.

Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support.

Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent.

Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk.

(One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest. Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing.

All analyses were performed according to the intention-to-treat principle. The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to erectile dysfunction treatment.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo. Participants had known exposure (by participant report) to a person with laboratory-confirmed erectile dysfunction treatment, whether as a household contact, a health care worker, or a person with other occupational exposures.

Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days. Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests.

However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for erectile dysfunction, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application. In Canada, the trial was approved by Health Canada.

Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed erectile dysfunction treatment at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org).

Persons with symptoms of erectile dysfunction treatment or with PCR-proven erectile dysfunction were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early . Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms. Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta.

Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent. We sent follow-up e-mail surveys on days 1, 5, 10, and 14.

A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status.

When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country.

A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants. Only pharmacies had access to the randomization sequence.

Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total). If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses.

We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the erectile dysfunction in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased. Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, erectile dysfunction treatment–related symptoms.

We assumed that health care workers would have access to erectile dysfunction treatment testing if symptomatic. However, access to testing was limited throughout the trial period. erectile dysfunction treatment–related symptoms were based on U.S.

Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for erectile dysfunction on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for erectile dysfunction treatment or death, the incidence of PCR-confirmed erectile dysfunction , the incidence of erectile dysfunction treatment symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]). Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text.

Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible erectile dysfunction treatment–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report. Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org.

Sample Size We anticipated that illness compatible with erectile dysfunction treatment would develop in 10% of close contacts exposed to erectile dysfunction treatment.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic s, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group. We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial.

Because the estimates for both incident symptomatic erectile dysfunction treatment after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new s in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic s. Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up.

Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome. A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility. At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of s in the control group.

At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of erectile dysfunction treatment disease by day 14 with Fisher’s exact test. Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test.

Among participants in whom incident illness compatible with erectile dysfunction treatment developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05. For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event.

Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the erectile dysfunction treatment viagra by advancing development, manufacturing, and distribution of treatments, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S.

Government typically supports product development and treatment distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for erectile dysfunction treatment countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR).

One of us (M.S.) serves as OWS chief advisor. We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives.

To deliver tens of millions of doses of a erectile dysfunction treatment — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S. Population — beginning at the end of 2020 and to have as many as 300 million doses of such treatments available and deployed by mid-2021. The pace and scope of such a treatment effort are unprecedented.

The 2014 West African Ebola viagra epidemic spurred rapid treatment development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. erectile dysfunction treatment development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July.

Our objectives are based on advances in treatment platform technology, improved understanding of safe and efficacious treatment design, and similarities between the SARS-CoV-1 and erectile dysfunction disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected treatments. The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder treatment development or deployment.OWS selected treatment candidates on the basis of four criteria.

We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy. Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the viagra, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on treatment-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021.

Finally, candidates had to use one of four treatment-platform technologies that we believe are the most likely to yield a safe and effective treatment against erectile dysfunction treatment. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two treatment candidates based on each of the four platform technologies.

Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best treatment platform for each subpopulation at risk for contracting or transmitting erectile dysfunction treatment, including older adults, frontline and essential workers, young adults, and pediatric populations. In addition, advancing eight treatments in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate treatment program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel.

Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate treatment.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA.

To permit appropriate comparisons among the treatment candidates and to optimize treatment utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the erectile dysfunction Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their treatments are in preclinical or very early clinical stages. To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each treatment candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of treatment doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate treatment development without curtailing the critical steps required by sound science and regulatory standards.

The FDA recently reissued guidance and standards that will be used to assess each treatment for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit treatment administration before all BLA procedures are completed.Of the eight treatments in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein).

These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA treatment in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA treatment also produced encouraging phase 1 results2 and started its phase 3 trial on July 27.

The ChAdOx replication-defective live-vector treatment developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S. Phase 3 trials in August.3 The Janssen Ad26 erectile dysfunction treatment replication-defective live-vector treatment has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27.

It should be in phase 3 trials in mid-September. Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein treatment in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA treatments are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for treatment distribution, subpopulation prioritization, financing, and logistic support.

We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues. We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive treatment doses once they are ready. Prioritization will also depend on the relative performance of each treatment and its suitability for particular populations.

Because some technologies have limited previous data on safety in humans, the long-term safety of these treatments will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor..

What may interact with Viagra?

Do not take Viagra with any of the following:

• cisapride
• methscopolamine nitrate
• nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin
• nitroprusside
• other sildenafil products (Revatio)

Viagra may also interact with the following:

• certain drugs for high blood pressure
• certain drugs for the treatment of HIV or AIDS
• certain drugs used for fungal or yeast s, like fluconazole, itraconazole, ketoconazole, and voriconazole
• cimetidine
• erythromycin
• rifampin

This list may not describe all possible interactions. Give your health care providers a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Viagra 200mg

About This TrackerThis tracker provides the number of confirmed cases and deaths from novel erectile dysfunction by country, the trend in confirmed case and death counts by country, and viagra 200mg a global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) erectile dysfunction Resource Center’s erectile dysfunction treatment Map and the World Health Organization’s viagra 200mg (WHO) erectile dysfunction Disease (erectile dysfunction treatment-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About erectile dysfunction treatment erectile dysfunctionIn late 2019, a new erectile dysfunction emerged in central China to cause disease in humans. Cases of this disease, known as erectile dysfunction treatment, have since been reported across around viagra 200mg the globe.

On January 30, 2020, the World Health Organization (WHO) declared the viagra represents a public health emergency of international concern, and on January 31, 2020, the U.S viagra 200mg. Department of Health and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that erectile dysfunction poses to children and their role in transmission of the disease.A new KFF brief examines the latest available data and evidence about the issues around erectile dysfunction treatment and children and what they suggest about the risks posed for reopening classrooms. The review concludes that while children are much less likely than adults to become severely ill, viagra 200mg they can transmit the viagra. Key findings include:Disease severity viagra 200mg is significantly less in children, though rarely some do get very sick.

Children under age 18 account for 22% of the population but account for just 7% of the more than 4 million erectile dysfunction treatment cases and less than 1% of deaths.The evidence is mixed about whether children are less likely than adults to become infected when exposed. While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the viagra, other studies find children and adults viagra 200mg are about equally likely to have antibodies that develop after a erectile dysfunction treatment .While children do transmit to others, more evidence is needed on the frequency and extent of that transmission. A number of studies find children are less likely than adults to be the source of s in households and other settings, though this could occur because of differences in testing, the severity of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but viagra 200mg almost all had significantly lower rates of community transmission. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education.A United Airlines passenger jet takes off with New York City as a backdrop, at Newark Liberty International Airport, New Jersey.Chris Helgren | ReutersIt's time to say goodbye to the $200 ticket-change fee.United Airlines on Sunday said that it will permanently scrap fees to change domestic flights, a big bet that more flexible policies will win over much-needed customers as the pain from the erectile dysfunction viagra's impact on air travel continue to mount.It's a page from the playbook of rival Southwest Airlines, which doesn't charge customers fees to change their flights."Following previous tough times, airlines made difficult decisions to survive, sometimes at the expense of customer service," said United CEO Scott Kirby in a news release.

"United Airlines won't be following that same playbook as we come out of this viagra 200mg crisis. Instead, we're taking a completely different approach – and looking at new ways to serve our customers better."United's announcement that it will no longer charge travelers the $200 fee comes as airlines are scrambling to viagra 200mg find ways to revitalize their businesses, which have been battered by the viagra. This summer, Transportation Security Administration screenings at U.S. Airports are hovering around 30% of last year's levels, as airlines go without much-needed revenue during the peak summer travel season.Customers with standard economy tickets or premium-class tickets will be able to change their flights without paying the viagra 200mg fee but they will be responsible for a difference in fare.

The new policy does not apply to basic economy tickets, which do not permit changes, but United has extended its change-fee waiver on all tickets through the end of the year.The Chicago-based airline in January will also allow customers who want to depart earlier or later the same day to fly viagra 200mg standby without paying a $75 same-day change fee.The measures could ramp up pressure on rivals to make similar policy changes.The end of the ticket-change costs is a departure from the myriad add-ons and other fees that airlines spent years rolling out. Last year, U.S. Carriers brought in $2.8 billion in ticket-change and cancellation fees, according to the Department of viagra 200mg Transportation.Scott Gottlieb, former Commissioner of the FDAAdam Jeffery | CNBCDr. Scott Gottlieb, former FDA chief under President Donald Trump, said on Sunday that the new guidance from the Centers for Disease Control and Prevention to viagra 200mg not test asymptomatic people for erectile dysfunction treatment was "unfortunate" because those people could be at high risk of contracting the .

"We should be testing those people to make sure they haven't become infected and aren't asymptomatic carriers because we know that they can spread the ," Gottlieb said in an interview on CBS' "Face the Nation." "They're less likely to spread the , but they can still spread the ."Earlier this month, the CDC quietly revised its guidance on erectile dysfunction testing and dropped its previous recommendation to test everyone who has come into close contact with an infected person, even those who don't have symptoms.The move drew immediate criticism from medical groups and allegations of political motivation. Two federal health officials reportedly said the CDC was pressured into changing viagra 200mg the guidance by top officials at the White House and Department of Health and Human Services.Medical experts and lawmakers say that early and widespread testing of people without symptoms can help mitigate the spread of the viagra. Gottlieb said that one reason for the CDC's decision could be that businesses were requiring people to test negative for viagra 200mg the viagra before they can return to work. He said he doesn't think the new guidance will likely be followed by states.

"If that's the case and that was a concern, there were more targeted ways to address that and speak to that problem, as opposed to making this very broad, sweeping change in the recommendations, which I think could be misinterpreted by the general public viagra 200mg and certainly by public health agencies within states," Gottlieb said. "And so I don't think this changed guidance is likely to be followed by many states." "I think it's prudent that viagra 200mg we test people who might be at high risk of contracting the ," Gottlieb added. — CNBC's Will Feuer contributed reporting.

About This TrackerThis tracker provides the number of confirmed cases and deaths from novel erectile dysfunction by country, the trend in confirmed case and death counts by country, and a global map showing which purchase viagra countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) erectile dysfunction Resource Center’s erectile dysfunction treatment purchase viagra Map and the World Health Organization’s (WHO) erectile dysfunction Disease (erectile dysfunction treatment-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About erectile dysfunction treatment erectile dysfunctionIn late 2019, a new erectile dysfunction emerged in central China to cause disease in humans.

Cases of this disease, known as erectile dysfunction treatment, have since been purchase viagra reported across around the globe. On January 30, 2020, the World purchase viagra Health Organization (WHO) declared the viagra represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that erectile dysfunction poses to children and their role in transmission of the disease.A new KFF brief examines the latest available data and evidence about the issues around erectile dysfunction treatment and children and what they suggest about the risks posed for reopening classrooms.

The review concludes that while children are much less likely purchase viagra than adults to become severely ill, they can transmit the viagra. Key findings include:Disease severity is significantly less in children, though purchase viagra rarely some do get very sick. Children under age 18 account for 22% of the population but account for just 7% of the more than 4 million erectile dysfunction treatment cases and less than 1% of deaths.The evidence is mixed about whether children are less likely than adults to become infected when exposed.

While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the viagra, other studies find children and adults are about equally likely to have antibodies that develop after a erectile dysfunction treatment .While children do transmit to others, more evidence is needed on purchase viagra the frequency and extent of that transmission. A number of studies find children are less likely than adults to be the source of s in households and other settings, though this could occur because of differences in testing, the severity purchase viagra of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but almost all had significantly lower rates of community transmission. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education.A United Airlines passenger jet takes off with New York City as a backdrop, at Newark Liberty International Airport, New Jersey.Chris Helgren | ReutersIt's time to say goodbye to the $200 ticket-change fee.United Airlines on Sunday said that it will permanently scrap fees to change domestic flights, a big bet that more flexible policies will win over much-needed customers as the pain from the erectile dysfunction viagra's impact on air travel continue to mount.It's a page from the playbook of rival Southwest Airlines, which doesn't charge customers fees to change their flights."Following previous tough times, airlines made difficult decisions to survive, sometimes at the expense of customer service," said United CEO Scott Kirby in a news release.

"United Airlines won't be following that same playbook purchase viagra as we come out of this crisis. Instead, we're taking a purchase viagra completely different approach – and looking at new ways to serve our customers better."United's announcement that it will no longer charge travelers the $200 fee comes as airlines are scrambling to find ways to revitalize their businesses, which have been battered by the viagra. This summer, Transportation Security Administration screenings at U.S.

Airports are hovering around 30% of last year's levels, as airlines go without much-needed revenue during the purchase viagra peak summer travel season.Customers with standard economy tickets or premium-class tickets will be able to change their flights without paying the fee but they will be responsible for a difference in fare. The new policy does not apply to basic economy tickets, which do not permit changes, but United has extended its change-fee waiver on all tickets through the end of the year.The Chicago-based airline in January will also allow customers who want to depart earlier or later the same day to fly standby without paying purchase viagra a $75 same-day change fee.The measures could ramp up pressure on rivals to make similar policy changes.The end of the ticket-change costs is a departure from the myriad add-ons and other fees that airlines spent years rolling out. Last year, U.S.

Carriers brought in $2.8 billion in purchase viagra ticket-change and cancellation fees, according to the Department of Transportation.Scott Gottlieb, former Commissioner of the FDAAdam Jeffery | CNBCDr. Scott Gottlieb, former FDA chief under President Donald Trump, said on Sunday that purchase viagra the new guidance from the Centers for Disease Control and Prevention to not test asymptomatic people for erectile dysfunction treatment was "unfortunate" because those people could be at high risk of contracting the . "We should be testing those people to make sure they haven't become infected and aren't asymptomatic carriers because we know that they can spread the ," Gottlieb said in an interview on CBS' "Face the Nation." "They're less likely to spread the , but they can still spread the ."Earlier this month, the CDC quietly revised its guidance on erectile dysfunction testing and dropped its previous recommendation to test everyone who has come into close contact with an infected person, even those who don't have symptoms.The move drew immediate criticism from medical groups and allegations of political motivation.

Two federal health officials reportedly said the CDC was pressured into changing the guidance by top officials at the White House purchase viagra and Department of Health and Human Services.Medical experts and lawmakers say that early and widespread testing of people without symptoms can help mitigate the spread of the viagra. Gottlieb said that one reason for the CDC's decision could be that purchase viagra businesses were requiring people to test negative for the viagra before they can return to work. He said he doesn't think the new guidance will likely be followed by states.

"If that's the case and that was a concern, there purchase viagra were more targeted ways to address that and speak to that problem, as opposed to making this very broad, sweeping change in the recommendations, which I think could be misinterpreted by the general public and certainly by public health agencies within states," Gottlieb said. "And so I don't think this changed guidance is likely to be followed by many states." "I think it's prudent that we test people who might be purchase viagra at high risk of contracting the ," Gottlieb added. — CNBC's Will Feuer contributed reporting.

How viagra works

This document http://www.snackoverflow.uk/2017/10/delayed-gbbo-bakes/ is unpublished how viagra works. It is scheduled to be published on 09/18/2020. Once it is published it will be available on this page in an how viagra works official form.

Until then, you can download the unpublished PDF version. Although we make a concerted effort to reproduce the original document in full on our Public Inspection pages, in some cases graphics may not be displayed, and non-substantive markup language may appear alongside substantive text. If you are using public inspection listings for legal research, you should verify the contents of documents how viagra works against a final, official edition of the Federal Register.

Only official editions of the Federal Register provide legal notice to the public and judicial notice to the courts under 44 U.S.C. 1503 & how viagra works. 1507.

Learn more here.Start Preamble Centers for Medicare &. Medicaid Services (CMS), how viagra works HHS. Proposed rule.

This proposed rule would establish a Medicare coverage pathway to provide Medicare beneficiaries nationwide with faster access to new, innovative medical devices designated as breakthrough by the Food and Drug Administration (FDA). After the final rule is effective, the Medicare Coverage of Innovative Technology (MCIT) pathway would begin national Medicare coverage on how viagra works the date of FDA market authorization and would continue for 4 years. We are also proposing regulatory standards to be used in making reasonable and necessary determinations under section Start Printed Page 543281862(a)(1)(A) of the Social Security Act (the Act) for items and services that are furnished under Part A and Part B.

To be assured consideration, how viagra works comments must be received at one of the addresses provided below, no later than 5 p.m. On November 2, 2020. In commenting, please refer to file code CMS-3372-P.

Because of how viagra works staff and resource limitations, we cannot accept comments by facsimile (FAX) transmission. You may submit comments in one of three ways (please choose only one of the ways listed). 1.

Electronically. You may submit electronic comments on this regulation to http://www.regulations.gov. Follow the “Submit a comment” instructions.

2. By regular mail. You may mail written comments to the following address ONLY.

Centers for Medicare &. Medicaid Services, Department of Health and Human Services, Attention. CMS-3372-P, P.O.

Box 8013, Baltimore, MD 21244-8013. Please allow sufficient time for mailed comments to be received before the close of the comment period. 3.

By express or overnight mail. You may send written comments to the following address ONLY. Centers for Medicare &.

Medicaid Services, Department of Health and Human Services, Attention. CMS-3372-P, Mail Stop C4-26-05, 7500 Security Boulevard, Baltimore, MD 21244-1850. For information on viewing public comments, see the beginning of the SUPPLEMENTARY INFORMATION section.

Start Further Info Linda Gousis or JoAnna Baldwin, (410) 786-2281 or CAGinquiries@cms.hhs.gov. End Further Info End Preamble Start Supplemental Information Inspection of Public Comments. All comments received before the close of the comment period are available for viewing by the public, including any personally identifiable or confidential business information that is included in a comment.

We post all comments received before the close of the comment period on the following website as soon as possible after they have been received. Http://www.regulations.gov. Follow the search instructions on that website to view public comments.

Comments received timely will also be available for public inspection as they are received, generally beginning approximately 3 weeks after publication of a document, at the headquarters of the Centers for Medicare &. Medicaid Services, 7500 Security Boulevard, Baltimore, Maryland 21244, Monday through Friday of each week from 8:30 a.m. To 4 p.m.

To schedule an appointment to view public comments, phone 1-800-743-3951. I. Background The Administration is committed to ensuring Medicare beneficiaries have access to new cures and technologies that improve health outcomes.

Section 6 of the October 3, 2019 Executive Order 13890 (E.O. 13890) “Executive Order on Protecting and Improving Medicare for Our Nation's Seniors,” [] directs the Secretary to “propose regulatory and sub-regulatory changes to the Medicare program to encourage innovation for patients” including by “streamlining the approval, coverage, and coding process”.[] The E.O. 13890 explicitly includes making coverage of breakthrough medical devices “widely available, consistent with the principles of patient safety, market-based policies, and value for patients.” [] The E.O.

Also directs the Secretary to “clarify the application of coverage standards.” [] We are responding directly to these directives by proposing a definition of the term “reasonable and necessary” to clarify coverage standards and proposing the Medicare Coverage of Innovative Technology (MCIT) pathway to accelerate the coverage of new, innovative breakthrough devices to Medicare beneficiaries. To date, the factors used in making “reasonable and necessary” determinations based on section 1862(a)(1)(A) of the Act have not been established in regulations for Medicare coverage purposes. The Secretary has authority to determine whether a particular medical item or service is “reasonable and necessary” under section 1862(a)(1)(A) of the Act.

(See Heckler v. Ringer, 466 U.S. 602, 617 (1984).) When making coverage determinations, our policies have long considered whether the item or service is safe and effective, not experimental or investigational, and appropriate.

(For more information see the January 30, 1989 notice of proposed rulemaking (54 FR 4307)). These factors are found in Chapter 13 of the Medicare Program Integrity Manual (PIM) at section 13.5.4—Reasonable and Necessary Provisions in LCDs as instructions for Medicare contractors. We are proposing to codify in regulations the Program Integrity Manual definition of “reasonable and necessary” with modifications, including to add a reference to Medicare patients and a reference to commercial health insurer coverage policies.

We propose that an item or service would be considered “reasonable and necessary” if it is—(1) safe and effective. (2) not experimental or investigational. And (3) appropriate for Medicare patients, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it is— Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member.

Furnished in a setting appropriate to the patient's medical needs and condition. Ordered and furnished by qualified personnel. One that meets, but does not exceed, the patient's medical need.

And At least as beneficial as an existing and available medically appropriate alternative. We also propose that an item or service would be “appropriate for Medicare patients” under (3) if it is covered in the commercial insurance market, except where evidence supports that there are clinically relevant differences between Medicare beneficiaries and commercially insured individuals. An item or service deemed appropriate for Medicare coverage based on commercial coverage would be covered on that basis without also having to satisfy the bullets listed above.

We believe this definition is a significant step in meeting the E.O.'s directive to bring clarity to coverage standards. Stakeholders have expressed interest in codifying a definition of “reasonable and necessary” for many years. This proposed definition is familiar and functional, can satisfy that interest and meet the E.O.'s ask, while also aligning with the goals of MCIT by providing clarity and predictability for innovation, including for beneficiaries and innovators.

The proposed MCIT coverage pathway is specifically for Medicare coverage of devices that are designated as part of the Food and Drug Administration's (FDA) Breakthrough Devices Program (hereafter referred to as “breakthrough devices”) and are FDA market authorized. The MCIT pathway would be voluntary and device manufacturers would notify CMS if they want to utilize this coverage option. We propose that national Medicare coverage under the MCIT pathway would begin immediately upon the date of FDA market authorization (that is, the Start Printed Page 54329date the medical device receives Premarket Approval (PMA).

510(k) clearance. Or the granting of a De Novo classification request) for the breakthrough device. This coverage would occur unless the device does not have a Medicare benefit category or is otherwise excluded from coverage by statute (that is, the Medicare statute does not allow for coverage of the particular device.) This coverage pathway delivers on the Administration's commitment to give Medicare beneficiaries access to the newest innovations on the market, consistent with the statutory definitions of Medicare benefits.

Because Medicare is a defined benefit program, devices that do not fit within the statutory definitions may not be considered for MCIT. As an example, medical equipment for home use by the beneficiary must be durable (that is, withstand repeated use) for it to be coverable by Medicare (as defined in statutes and regulations by the Secretary). At this time, we are limiting MCIT to medical devices because that is a category of products explicitly identified in E.O.

13890, and we have identified that breakthrough devices can experience variable coverage across the nation shortly after market authorization. We propose this MCIT pathway because the prescribed statutory timeframes for the National Coverage Determination (NCD) process limit CMS' ability to institute immediate national coverage policies for new, innovative medical devices. NCDs and Local Coverage Determinations (LCD) take, on average, 9 to 12 months to finalize.

Because of this length of time, there may be coverage uncertainty between the period of FDA market authorization and CMS finalization of an NCD or a Medicare Administrative Contractor's (MACs) finalization of an LCD. During this time period shortly after market authorization, MACs make coverage determinations on a case-by-case (individual beneficiary) basis, but those decisions do not usually establish agency policies for future claims because a case-by-case decision is for a particular beneficiary and their health circumstances. Over the past few years, CMS has heard concerns from stakeholders that breakthrough devices are not automatically covered nationally by Medicare once they are FDA market authorized.

Variation in coverage from one jurisdiction to another is also a concern. To date, 16 breakthrough devices have also been market authorized. The majority of these breakthrough devices (10 devices) experience variability in coverage for two reasons.

One reason is because the breakthrough devices are coverable at MAC discretion, like many other item and services, on a case-by-case basis (that is, the breakthrough device may be covered for one patient, but not for another within the same jurisdiction). The other reason is because breakthrough devices are used by a hospital or other provider that operates under a bundled payment system (such as a diagnosis related group (DRG) system), so there may be no separate coverage policy for each item or service that may be included in the bundled payment. Another example of variable coverage is for one breakthrough device that is non-covered by a local policy in Florida, but coverable at MAC discretion on a case-by-case basis in other jurisdictions.

One breakthrough device has national coverage through an NCD. One breakthrough device has uniform coverage because the same LCD has been adopted in all jurisdictions. There are three breakthrough devices that do not have a Medicare benefit category (for example, certain wearable devices).

Therefore, those breakthrough devices cannot be covered by the Medicare program. In contrast to varied local coverage, the proposed MCIT would create a pathway for immediate national Medicare coverage of any FDA-market authorized breakthrough device if the device meets criteria outlined in this proposal. A.

Statutory Authority We are also proposing to establish in regulations the factors we have historically used in making “reasonable and necessary” determinations under section 1862(a)(1)(A) of the Act, with some modification. To summarize, this section explains that Medicare payment may be made under part A or part B for any expenses incurred for items or services that are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Thus, with some exceptions, section 1862(a)(1)(A) of the Act requires that an item or service be “reasonable and necessary” to be covered by Medicare.

The courts have recognized that the Secretary has significant authority to determine whether a particular item or service is “reasonable and necessary.” (Heckler v. Ringer, 466 U.S. 602, 617 (1984).

See also, Yale-New Haven Hospital v. Leavitt, 470 F.3d 71, 84 (2d Cir. 2006).

3d 98, 110 (D.C. 2016) (The statute vests substantial authority in the Secretary.)) So even though section 1862(a)(1)(A) of the Act limits the scope of Medicare coverage, the Secretary has discretion to revise his/her interpretation of the statute in order to ensure adequate coverage for items and services under Part A and Part B. This proposal would provide national Medicare coverage for breakthrough devices that are FDA market-authorized and used consistent with the FDA approved or cleared indication for use (also referred to as the “FDA-required labeling”).[] This device coverage under the MCIT pathway is reasonable and necessary under section 1862(a)(1)(A) of the Act because the device has met the unique criteria of the FDA Breakthrough Devices Program.

B. FDA Breakthrough Devices Program Under the proposed MCIT coverage pathway, CMS would coordinate with FDA and manufacturers as medical devices move through the FDA regulatory process for Breakthrough Devices to ensure seamless Medicare coverage on the date of FDA market authorization unless CMS determines those devices do not have a Medicare benefit category. The Breakthrough Devices Program is an evolution of the Expedited Access Pathway Program and the Priority Review Program (section 515B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)), 21 U.S.C.

360e-3. See also final guidance for industry entitled, “Breakthrough Devices Program,” https://www.fda.gov/​downloads/​MedicalDevices/​DeviceRegulationandGuidance/​GuidanceDocuments/​UCM581664.pdf). The FDA's Breakthrough Devices Program is not for all new medical devices.

Rather, it is only for those that the FDA determines meet the standards for breakthrough device designation. In accordance with section 3051 of the 21st Century Cures Act (21 U.S.C. 360e-3),[] the Breakthrough Devices Program is for medical devices and device-led combination products that meet two criteria.

The first criterion is that the device provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions. The second criterion is that the device must satisfy one of the following elements. It Start Printed Page 54330represents a breakthrough technology.

No approved or cleared alternatives exist. It offers significant advantages over existing approved or cleared alternatives, including additional considerations outlined in the statute. Or device availability is in the best interest of patients (for more information see 21 U.S.C.

360e-3(b)(2)). These criteria make breakthrough designated devices unique among all other medical devices.[] The parameters of the breakthrough devices program focus on innovations for patients, in turn, MCIT, focuses on these breakthrough devices consistent with E.O. 13890 and in order to streamline coverage of innovative medical devices.

C. Current Medicare Coverage Pathways Currently, we utilize several coverage pathways for items and services, which includes medical devices. None of the coverage pathways described in this section offer immediate, predictable coverage concurrently with FDA market authorization like the proposed MCIT pathway would do.

We summarize the other coverage pathways here to provide context for MCIT. National Coverage Determinations (NCDs). Section 1862(l)(6)(A) of the Act defines the term national coverage determination as “a determination by the Secretary with respect to whether or not a particular item or service is covered nationally under this title.” In general, NCDs are national policy statements published to identify the circumstances under which particular items and services will be considered covered by Medicare.

Traditionally, CMS relies heavily on health outcomes data to make NCDs. Most NCDs have involved determinations under section 1862(a)(1)(A) of the Act, but NCDs can be made based on other provisions of the Act, and includes a determination that the item or service under consideration has a Medicare benefit category. The NCD pathway, which has statutorily prescribed timeframes, generally takes 9 to 12 months to complete.[] Local Coverage Determinations (LCDs).

Medicare contractors develop LCDs based on section 1862(a)(1)(A) of the Act that apply only within their geographic jurisdictions. (Sections 1862(l)(6)(B) and 1869(f)(2)(B) of the Act.) MACs will not need to develop LCDs for breakthrough devices when they are nationally covered through MCIT. The MACs follow specific guidance for developing LCDs for Medicare coverage in the CMS Program Integrity Manual, and in some instances, an LCD can also take 9 to12 months to develop (MACs must finalize proposed LCDs within 365 days from opening per Chapter 13—Local Coverage Determinations of the (PIM) 13.5.1).

We note that the MCIT pathway will not alter the existing coverage standards in Chapter 13—Local Coverage Determinations of the PIM.[] That chapter will continue to be used in making determinations under section 1862(a)(1)(A) of the Act for other items and services at the local level. Claim-by-claim Adjudication. In the absence of an NCD or LCD, MACs would make coverage decisions under section 1862(a)(1)(A) of the Act and may cover or not cover items and services on a claim-by-claim basis.

The majority of claims are handled through the claim adjudication process. Clinical Trial Policy (CTP) NCD 310.1. The CTP pathway can be used for coverage of routine care items and services (but generally not the technology under investigation) in a clinical study that is supported by certain Federal agencies.

The CTP coverage pathway was developed in 2000.[] This coverage pathway has not generally been utilized by device manufacturers because they usually seek coverage of the device, which is not included in this pathway. Parallel Review. Parallel Review is a mechanism for FDA and CMS to simultaneously review the submitted clinical data to help decrease the time between FDA's approval of a premarket application or granting of a de novo classification and the subsequent CMS NCD.

Parallel Review has two stages. (1) FDA and CMS meet with the manufacturer to provide feedback on the proposed pivotal clinical trial within the FDA pre-submission process. And (2) FDA and CMS concurrently review (“in parallel”) the clinical trial results submitted in the PMA, or De Novo request.

FDA and CMS independently review the data to determine whether it meets their respective Agency's standards and communicate with the manufacturer during their respective reviews. This program is most successful for devices that have a significant amount of clinical evidence. (Candidates for parallel review would not be appropriate for simultaneous MCIT consideration.) Even though CMS has multiple coverage pathways, at this time none are readily available to provide immediate national coverage for new breakthrough devices with a Medicare benefit category at the same time as FDA market authorization.

Further, some of these new breakthrough devices are likely to have limited or developing bodies of clinical evidence because of the newness of the device. Therefore, the MCIT pathway can support manufacturers that are interested in combining coverage with their own clinical study to augment clinical evidence of improved health outcomes, particularly for Medicare patients. Given this summary of existing coverage pathways, we seek comment from the public regarding if any of these existing pathways should be modified to achieve the goals set out by E.O.

13890. D. MCIT Pathway We propose that the MCIT pathway would provide immediate national coverage for breakthrough devices beginning on the date of FDA market authorization and continue for up to 4 years, unless we determine the device does not have a Medicare benefit category as determined by us as part of the MCIT pathway process.

The MCIT pathway is voluntary (that is, manufacturers would affirmatively opt-in), and would be initiated when a manufacturer notifies CMS of its intention to utilize the MCIT pathway. (This notification process is described further in section III. Of this proposed rule.) We would subsequently coordinate with the manufacturer regarding steps that need to be taken for MCIT implementation purposes.

The frequency of subsequent engagement will be largely driven by whether the manufacturer has questions for CMS, or CMS and FDA. The timing of coverage will depend upon the timing of the FDA's market authorization decision. Engagements can take place in the form of in-person meetings, phone calls, emails, etc.

We intend to put devices that are covered through the MCIT pathway on the CMS website so that all stakeholders will be aware of what is covered through the MCIT pathway. Manufacturers of breakthrough devices will not be obligated or mandated by CMS to conduct clinical studies during Start Printed Page 54331coverage under the proposed MCIT pathway. However, we seek comment as to whether CMS should require or incentivize manufacturers to provide data about outcomes or should be obligated to enter into a clinical study similar to CMS's Coverage with Evidence Development (CED) paradigm.[] We are aware some manufacturers may be required by the FDA to conduct post market data collection as a condition of market authorization, and nothing in this proposed rule would alter that FDA requirement.

Manufacturers are encouraged to develop the clinical evidence base needed for one of the other coverage pathways after the MCIT pathway ends. This evidence is encouraged not only for CMS and private commercial health insurer coverage policies but also to better inform the clinical community and the public generally about the risks and benefits of treatment. CMS encourages early manufacturer engagement, both before and after FDA market authorization, for manufacturers to receive feedback from CMS on potential clinical study designs and clinical endpoints that may produce the evidence needed for a definitive coverage determination after MCIT.

This feedback would not involve CMS predicting specific coverage or non-coverage. In order to further the goals of E.O. 13890, CMS proposes to rely on FDA's breakthrough device designation and market authorization of those devices to define the universe of devices eligible for MCIT, except for those particular devices CMS determines do not have a Medicare benefit category or are statutorily excluded from coverage under Part A or Part B.

In order to provide immediate national coverage to innovative medical devices, we propose to establish a time limit on how long a breakthrough device can be eligible for MCIT (that is, considered a breakthrough device for coverage purposes). MCIT has a time limit on newness similar to our New Technology Add-on Payment (NTAP) policy. Eligibility for the NTAP is also time limited and this time limit applies to all new technologies, including breakthrough devices, for which an application for additional payment is submitted.

Additionally, the time-limited characteristic of MCIT will drive some manufacturers to leverage this period of coverage to demonstrate the value of their device in the competitive marketplace. The 4-year coverage period is particularly important for manufacturers of breakthrough devices that choose to further develop the clinical evidence basis on which the FDA granted marketing authorization. From our experience with clinical studies conducted as part of an NCD, 4 years is approximately the amount of time it takes to complete a study.

At the end of the 4-year MCIT pathway, coverage of the breakthrough device would be subject to one of these possible outcomes. (1) NCD (affirmative coverage, which may include facility or patient criteria). (2) NCD (non-coverage).

Or (3) MAC discretion (claim-by-claim adjudication or LCD). Manufacturers that are interested in a NCD are encouraged to submit a NCD request during the third year of MCIT to allow for sufficient time for NCD development. We seek public comment on whether CMS should open a national coverage analysis if a MAC has not issued an LCD for a breakthrough device within 6 months of the expiration date of the 4-year MCIT period.

In our analysis of the current coverage landscape to determine opportunities for innovation and efficiencies, we also considered modifying the coverage process for non-breakthrough devices (for example, PMAs because they are also new to the market), but ultimately determined that it was the unique characteristics of FDA designated breakthrough devices and their ability to serve unmet needs that resonated most with the E.O.'s direction to encourage innovation for patients. We also considered expedited coverage of newly market authorized and breakthrough devices when used in a clinical study. We seek public comment on the proposed MCIT pathway, the considerations described, whether any of the existing coverage pathways should be modified to achieve the goals set out by the E.O., and alternatives to these proposals.

We specifically seek public comment on whether the MCIT pathway should also include diagnostics, drugs and/or biologics that utilize breakthrough or expedited approaches at the FDA (for example, Breakthrough Therapy, Fast Track, Priority Review, Accelerated Approval) [] or all diagnostics, drugs and/or biologics. We seek data to support including these additional item categories in the MCIT pathway. Also, we specifically seek manufacturer input on whether an opt-in or opt-out approach would work best for utilizing the MCIT pathway.

We believe manufactures will welcome this new coverage pathway. We want to preserve manufacturers' business judgment and not assume which Medicare coverage pathway a given manufacturer of a breakthrough device would prefer (if any). Therefore, we have proposed an opt-in approach with an email to CMS to indicate affirmative interest in coverage.

We are interested in whether an opt-out approach would be less burdensome for stakeholders. If so, we encourage public comment on a process for stakeholders to opt-out of MCIT that would not be burdensome. Also, we seek public comment on whether, once a manufacturer has opted-out of coverage, it can subsequently opt-in to MCIT.

II. Provision of Proposed Regulations A. Defining “Reasonable and Necessary” As described in section I.

Of this proposed rule, the Secretary has authority to determine the meaning of “reasonable and necessary” under section 1862(a)(1)(A) of the Act. We are proposing to codify the longstanding Program Integrity Manual definition of “reasonable and necessary” into our regulations at 42 CFR 405.201(b), with modification. Under the current definition, an item or service is considered “reasonable and necessary” if it is (1) safe and effective.

(2) not experimental or investigational. And (3) appropriate, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it is— Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member. Furnished in a setting appropriate to the patient's medical needs and condition.

Ordered and furnished by qualified personnel. One that meets, but does not exceed, the patient's medical need. And At least as beneficial as an existing and available medically appropriate alternative.

In addition to codifying the above criteria, we propose to include a separate basis under which an item or service would be appropriate under (3) above that is based on commercial health insurers' coverage policies (that is, non-governmental entities that sponsor health insurance plans). The Start Printed Page 54332commercial market analysis would be initiated if an item/service fails to fulfill the existing factor (3) criteria defining appropriate for Medicare patients but fulfills (1) safe and effective and (2) not experimental or investigational. By considering commercial health insurer coverage policies, CMS would bring together the expertise of private payers and CMS.

For example, in a recent NCD on acupuncture for chronic low back pain, CMS considered the technology assessments and coverage criteria among commercial health insurer coverage policies.[] We believe that this approach would be in line with E.O. 13890 that directs us to make technologies “widely available, consistent with the principles of patient safety, market-based policies, and value for patients.” Under this separate basis, we propose that an item or service would satisfy factor (3) if it is covered under a plan(s) coverage policy if offered in the commercial insurance market, unless evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant. Under our proposal, we would exclude Medicaid managed care, Medicare Advantage, and other government administered healthcare coverage programs from the types of coverage CMS would consider, as these enrollees are not in the commercial market.

In the following paragraphs, we seek comment on this proposal and on how best to implement this mechanism. We solicit comments on sources of data that could be used to implement this policy, and whether CMS should make this information public and transparent. We seek public comment on the most appropriate source(s) for these coverage policies and the best way to determine which commercial plan(s) we would rely on for Medicare coverage.

We seek comment on whether beneficiaries, providers, innovators, or others wishing to gain coverage for an item or service demonstrate that the item or service is covered by at least one commercial insurance plan policy. If they can provide CMS with evidence of commercial coverage or if CMS or its MACs identify such coverage from its review of compilations of health insurance offerings or data from other sources, CMS would consider factor (3) to be satisfied. We solicit comment on whether we should limit our consideration of commercial plan offerings or covered lives to a subset of the commercial market in the interest of simplicity, including looking at geographic subsets, subsets based on number of enrollees, subsets based on plan type (HMO, PPO, etc.), or other subsets of plans—including utilizing a singular plan.

We also seek comment on whether, given considerations such the variation and distribution of coverage policies and access to innovations, we should only cover an item or service if it is covered for a majority, or a different proportion such as a plurality, of covered lives amongst plans or a majority, plurality, or some other proportion of plan offerings in the commercial market. (A plan offering is a contract an insurer offers to its enrollees, and a single insurance company may provide many different offerings.) We also recognize that plan offerings may impose certain coverage restrictions on an item or service, e.g. Related to clinical criteria, disease stage, or number and frequency of treatment.

As greater access to innovative treatments provides beneficiaries with more opportunity to improve health and drive decisions, we would, when coverage is afforded on the basis of commercial coverage, adopt the least restrictive coverage policy for the item or service amongst the offerings we examine. However, given potential unreasonable or unnecessary utilization, we also solicit comment on whether we should instead adopt the most restrictive coverage policy. We are further considering, as another variation, that if coverage restrictions are largely similar and present across the majority of offerings, CMS would adopt these in its coverage policies.

We note that such coverage restrictions include the basic requirement for medical necessity at the level of individual patients. Medicare will still only pay for an item or service received by a beneficiary if it is medically necessary for the beneficiary. We seek comment on whether, if we were to take this approach, we should instead use a proportion other than a majority, as low as any offering and as high as all offerings, as a sufficient threshold.

As a final variation, we could defer, in the absence of an NCD or national policy, to the MACs to tailor the restrictions on coverage based on what they observe in the commercial market, just as we rely on MACs with regards to the current definition. We further solicit comment on whether to grant coverage for an item or service to the extent it meets the first and second factors and the commercial coverage basis for the third factor. Under this approach, we would only use the current definition of “appropriate” from the current PIM when the exception for clinically relevant differences between Medicare beneficiaries and commercially insured individuals applies (or if the commercial coverage basis is determined by a proportion like a majority and there is insufficient commercial coverage information available).

We note that referring to commercial coverage in this way may expand or narrow the circumstances under which we will cover a particular item or service and therefore solicit comment on whether, under such an approach, we should grandfather our current coverage policies for items and services. We also emphasize that the MACs will continue to make judgements in evaluating individual claims for reimbursement, such that a decision by CMS that an item or service is reasonable and necessary in general does not mean that it is reasonable and necessary in all circumstances with respect to individual claims for reimbursement. We seek public comment on the most appropriate source(s) for these coverage policies.

Further, under our proposal, each MAC would be responsible for reviewing commercial offerings to inform their LCDs or claim by claim decisions, which would include individual medical necessity decisions. We may also allow the MACs to develop approaches to address any or all of the considerations outlined above, parallel to their current practice of making coverage decisions in the absence of an NCD or national policy. We solicit comment on the best role of the MACs, along these lines or otherwise.

We also solicit comment on whether the discretion to use the current criteria in the PIM when there is evidence to believe Medicare beneficiaries have different clinical needs should be exercised through the NCD process or in other ways, as well as what quantum of evidence should be sufficient. In sum, we are proposing to define the term “reasonable and necessary” based on the factors currently found in the PIM, plus an alternative basis for meeting factor (3) based on any coverage in the commercial market. We are also soliciting comment on an alternative under whether an item or service satisfies the commercial coverage basis for factor (3) is determined by how it is treated across a majority of covered lives amongst commercial plan offerings, as well as an alternative whereby an item or service would be appropriate for Medicare patients to the extent it is covered in the commercial market.

Start Printed Page 54333When evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant, we would rely on the criteria in the current PIM. We would continue relying on local administration of the program by MACs (including coverage on a claim by claim basis and LCDs) and maintain our discretion to issue NCDs based on the final rule. We solicit comment on this proposed definition of reasonable and necessary, and alternatives outlined above, as well as other mechanisms or definitions we could establish for the term “reasonable and necessary”, and the merits and drawbacks associated with each, including the potential impact on Medicare program expenses or complexity.

We may finalize any variation or outgrowth of the policies described in this proposal, or some combination of these options in lieu of or in conjunction with our proposed definition. B. Application of the “Reasonable and Necessary” Standard to the MCIT Pathway We are proposing that, under the proposed MCIT pathway, an item or service that receives a breakthrough device designation from the FDA would be considered “reasonable and necessary” under section 1862(a)(1)(A) of the Act because breakthrough devices have met the FDA's unique breakthrough devices criteria, and they are innovations that serve unmet needs.

While other devices are still considered new to the market, for example, PMAs and even some 510(k)s, the devices designated by the FDA as breakthrough are representative of true innovations in the marketplace. This application of the “reasonable and necessary” standard in this way would ensure that the MCIT pathway can provide a fast-track to Medicare coverage of innovative devices that may more effectively treat or diagnose life-threatening or irreversibly debilitating human disease or conditions. MCIT would improve healthcare for Medicare beneficiaries by providing national Medicare coverage for devices receiving the FDA breakthrough device designation, which are FDA market-authorized and used consistent with the FDA approved or cleared indication for use (also referred to as the “FDA required labeling”),[] so long as the breakthrough device is described in an appropriate Medicare benefit category under Part A or Part B and is not specifically excluded by statute.

We believe the criteria for qualification as a breakthrough device, as defined in section 515B(b) of the Food, Drug and Cosmetic Act (21 U.S.C. 360e-3(b)) is sufficient to satisfy the elements of the “reasonable and necessary” standard. The first breakthrough device designation criterion is that a device must “provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions” (21 U.S.C.

360e-3(b)(1)). The second criterion is that the device must satisfy one of the following elements. It represents a breakthrough technology.

There are no approved or cleared alternatives. It offers significant advantages over existing approved or cleared alternatives, including additional considerations outlined in the statute. Or availability of the device is in the best interest of patients (21 U.S.C.

360e-3(b)(2)). Thus, breakthrough devices are those that HHS has determined may provide better health outcomes for patients facing life-threatening or irreversibly debilitating human disease or conditions. We believe that a device meeting these criteria, once also FDA market authorized, is “reasonable and necessary” for purposes of Medicare coverage.

This proposed rule recognizes that the FDA market authorization of breakthrough devices warrants immediate coverage under the “reasonable and necessary” clause in section 1862(a)(1)(A) of the Act. We previously stated that FDA https://www.moneyspace.com/how-to-pick-the-best-life-insurance-to-protect-your-loved-ones/ determinations were not controlling determinations for Medicare coverage purposes under section 1862(a)(1)(A) of the Act. (For more information see the January 30, 1989 Federal Register (54 FR 4307) (“FDA approval for the marketing of a medical device will not necessarily lead to a favorable coverage recommendation.

. . €) and the August 7, 2013 Federal Register (78 FR 48165) (“However, FDA approval or clearance alone does not entitle that technology to Medicare coverage.”) Under the Secretary's broad authority to interpret section 1862(a)(1)(A) of the Act (supra section I.A.), we are revising our interpretation of the statute because of the practical concerns that our current standards have delayed access to a unique set of innovative devices that FDA has found to be safe and effective, and we believe are “reasonable and necessary” for purposes of Medicare coverage.

In light of E.O. 13890, the Secretary has determined that application of the current standards for making “reasonable and necessary” determinations may take too long following FDA market authorization of breakthrough devices. More importantly, the existing standard has not always provided Medicare beneficiaries adequate access to certain breakthrough medical devices when needed to improve health outcomes.

We are proposing that breakthrough devices per se meet the reasonable and necessary standard in order to increase access and to reduce the delay from FDA market authorization to Medicare coverage. C. MCIT Pathway We are proposing the MCIT pathway to deliver on the Administration's commitment to provide access to breakthrough devices to Medicare beneficiaries.

The MCIT pathway provides up to 4 years of national coverage to newly FDA market authorized breakthrough devices. We are aware that this coverage may also facilitate evidence development on devices for the Medicare population because manufacturers can gather additional data on utilization of the device during the MCIT coverage period. 1.

Definitions In § 405.601(a) we are proposing that the MCIT pathway is voluntary. Operationally, we propose that manufacturers of breakthrough devices notify CMS of their intention to elect MCIT shortly after receiving notice from the FDA of being granted the breakthrough device designation. Ideally, this notification would be sent to CMS within 2 weeks of receiving breakthrough designation.

However, entities would not be penalized for notifying CMS after that time. Alternatively, submitting a notification to CMS shortly before or concurrently with the date of the FDA marketing submission should also afford CMS sufficient time to operationalize MCIT for the device. The CMS Coverage and Analysis Group would establish an email box for these inquires.

This notification alerts CMS to offer guidance to manufacturers about the MCIT pathway and point to resources for coding and payment, which are key conversations to effectuate coverage upon FDA market authorization. We intend to utilize the existing coverage implementation processes to be prepared to offer coverage immediately upon the FDA market authorization. In § 405.601(b), we propose the following definitions for the purposes of 42 CFR part 405.

We propose to define Start Printed Page 54334“breakthrough device” as a medical device that receives such designation by the FDA (section 515B(d)(1) of the FD&C Act (21 U.S.C. 360e-3(d)(1))). We also propose to define, for the sake of clarity in the rule, that the acronym MCIT stands for Medicare Coverage of Innovative Technology.

2. MCIT Pathway Device Eligibility In § 405.603(a) we propose that the pathway is available to devices that meet the definitions proposed in § 405.601. Based on the explicit mention of devices in E.O.

13890 and our interaction and feedback from stakeholders who expressed their concern that there is more uncertainty of coverage for devices than for other items and services (for example, diagnostics, drugs and biologics), this proposed policy is for devices only. We propose in § 405.603(b) that the breakthrough devices that received FDA market authorization no more than 2 calendar years prior to the effective date of this subpart (the date the final rule is finalized) and thereafter will be eligible for coverage for claims submitted on or after the effective date of this rule. Claims for breakthrough devices with dates of service that occurred before the effective date of this rule would not be covered through MCIT.

For example, a hypothetical breakthrough device that was FDA market authorized on October 1, 2018, and utilized on January 1, 2020 would not be eligible for coverage under MCIT because on January 1, 2020, the date of service, the final MCIT rule was not yet legally in effect. In contrast, a claim for utilization of the same hypothetical breakthrough device with a date of service on January 1, 2021 might be eligible for coverage if the claim occurred after the effective date of the rule (assuming that the effective date of the rule was prior to January 1, 2021). Breakthrough devices market authorized prior to the effective date of this rule will not be eligible for all 4 years of coverage.

The 4-year period starts on the date of FDA market authorization. For example, a breakthrough device market authorized on October 1, 2018 would have claims covered through MCIT from the effective date of the final rule until October 1, 2022. If a manufacturer initially chooses to not utilize the MCIT pathway, and then chooses to do so some time after the breakthrough device's market authorization, coverage still only lasts 4 years from the date of FDA market authorization.

We seek comment on this eligibility criterion for devices and specifically the 2 year lookback. We propose in § 405.603(c) that to be part of the MCIT pathway, the device must be used according to its FDA approved or cleared indication for use. We propose that the device is only covered for use consistent with its FDA approved or cleared indication for use because that is the indication and conditions for use that were reviewed by the FDA and authorized for marketing.

Data are unlikely to be available to support extending beyond the FDA required labeling for breakthrough devices on the date of marketing authorization. Use of the device for a condition or population that is not labeled (“off-label”) will not be covered as that use would not be FDA authorized. We specifically seek comment on whether off-label use of breakthrough devices should be covered and, if so, under what specific circumstances and/or evidentiary support.

In § 405.603(d) and (e), we additionally propose limitations to what is coverable under the Act. In § 405.603(e), we are proposing that if CMS has issued an NCD on a particular breakthrough device, that breakthrough device is not eligible for MCIT. We are proposing this because, once the device has been reviewed by CMS for the FDA required approved or cleared indication for use.

CMS has made a coverage determination based on the available evidence for that technology. We believe this would happen rarely because breakthrough devices are new technologies that are not likely to have been previously reviewed through the NCD process. In § 405.603(f), we acknowledge that devices in the MCIT pathway may be excluded due to statute or regulation (for example, 42 CFR 411.15, Particular services excluded from coverage) and, like other items and services coverable by Medicare, the device must fall within the scope of a Medicare benefit category under section 1861 of the Act and the implementing regulations.

If the device does not fall within a Medicare benefit category as outlined in the statute and implementing regulations, the device is not eligible for Medicare coverage. Therefore, the device would not be eligible for the MCIT pathway. 3.

General Coverage of Items and Services under the MCIT Pathway We propose in § 405.605 that devices covered under the MCIT pathway are covered no differently from devices that are covered outside of MCIT. In other words, provided the items and services are otherwise coverable (that is, not specifically excluded and not found by CMS to be outside the scope of a Medicare benefit category), covered items and services could include the device, reasonable and necessary surgery to implant the device, if implantable, related care and services costs of the device (for example, replacing reasonable and necessary parts of the device such as a battery), and coverage of any reasonable and necessary treatments due to complications arising from use of the device. What the MCIT pathway offers compared to other pathways is predictable national coverage simultaneous with FDA market authorization that will generally last for a set time period.

The proposed MCIT pathway would support and accelerate beneficiary access to certain innovative devices. CMS encourages manufacturers that have breakthrough devices covered under MCIT to develop additional data for the healthcare community. 4.

MCIT Pathway for Breakthrough Devices. 4 Years of Coverage In § 405.607(a), we propose that the MCIT pathway for coverage would begin on the same date the device receives FDA market authorization. We propose this point in time to ensure there is no gap between Medicare coverage and FDA market authorization.

This supports the MCIT pathway's focus of ensuring beneficiaries have a predictable access to new devices. We propose in § 405.607(b)(1) that the MCIT pathway for breakthrough devices ends 4 years from the date the device received FDA market authorization. We propose this 4 year time period because it could allow manufacturers to develop clinical evidence and data regarding the benefit of the use of their device in a real world setting.

For example, we believe 4 years would allow most manufacturers sufficient time to complete FDA required post-approval or other real-world data collection studies that may have been a condition of FDA market authorization. This assumption is based upon our historical experience with studies conducted through coverage with evidence development (CED). Further, this time period allows Medicare to support manufacturers that, whether required by the FDA or not, have an interest in better understanding the health outcomes of their device in the Medicare population, including impacts on patient-reported and longer-term outcomes.

Further, § 405.607(b) proposes reasons that the MCIT pathway may end prior to 4 years. This includes circumstances whereby the device becomes subject to an NCD, regulation, statute, or if the device can no longer be lawfully marketed.Start Printed Page 54335 D. Summary In summary, the MCIT pathway would provide immediate Medicare coverage of newly FDA market authorized breakthrough devices for 4 years.

We seek public comment on all of our proposals. In particular, we seek feedback on whether the proposed 4 year coverage period is sufficient. We also look to stakeholders and the public to determine the level of interest and expected use of the proposed MCIT pathway so the agency can begin to estimate the level of needed resources to support successful implementation.

We are also seeking public comments on our proposal to codify in regulations the standards we have historically used in making reasonable and necessary decisions under Part A and Part B under section 1862(a)(1)(A) of the Act. After considering public comments we would prepare a final rule that we expect would be effective 60 days after publication of the final rule. III.

Collection of Information Requirements Under the Paperwork Reduction Act of 1995, we are required to provide 60-day notice in the Federal Register and solicit public comment before a collection of information requirement is submitted to the Office of Management and Budget (OMB) for review and approval. In order to fairly evaluate whether an information collection should be approved by OMB, section 3506(c)(2)(A) of the Paperwork Reduction Act of 1995 requires that we solicit comment on the following issues. The need for the information collection and its usefulness in carrying out the proper functions of our agency.

The accuracy of our estimate of the information collection burden. The quality, utility, and clarity of the information to be collected. Recommendations to minimize the information collection burden on the affected public, including automated collection techniques.

We are soliciting public comment on each of the section 3506(c)(2)(A)-required issues for the following sections of this document that contain information collection requirements (ICRs). To derive average costs, we used data from the U.S. Bureau of Labor Statistics' May 2018 National Occupational Employment and Wage Estimates for all salary estimates (https://www.bls.gov/​oes/​current/​oes131041.htm, released May 2019).

In this regard, the table that follows presents the mean hourly wage, the cost of fringe benefits (calculated at 100 percent of salary), and the adjusted hourly wage. Table 1—National Occupational Employment and Wage Estimates for MCITOccupation titleOccupation codeMean hourly wage ($/hr)Fringe benefit ($/hr)Adjusted hourly wage ($/hr)Compliance Officer13-104134.8634.8669.72 As indicated, we are adjusting our employee hourly wage estimates by a factor of 100 percent. This is necessarily a rough adjustment, both because fringe benefits and overhead costs vary significantly from employer to employer.

Nonetheless, there is no practical alternative and we believe that doubling the hourly wage to estimate total cost is a reasonably accurate estimation method. This proposed coverage pathway allows for a voluntary participation and therefore necessitates that manufacturers of breakthrough devices notify CMS of their intent to enter the MCIT pathway. Therefore, the burden associated with notifying CMS is the time and effort it would take for each of the organizations to send CMS an email or letter.

We anticipate two MCIT pathway participants in the first year based upon the number of medical devices that received FY2020 NTAP and were non-covered in at least one MAC jurisdiction by LCDs and related articles. We estimate notifying CMS of intent to participate in MCIT would involve 15 minutes at $69.72 per hour by a compliance officer. In this regard, we estimate 15 mins per notification at a cost of $17.43 per organization (0.25 hours × $69.72).

In aggregate, we estimate 0.5 hours (0.25 hours × 2 submissions) at $34.86 ($17.43 × 2 submissions). After the anticipated initial 2 submitters, over the next 3 years we expect 3 submitters in year 2, 4 submitters in year 3, and 5 submitters in year 4 to notify CMS of interested in the MCIT pathway. We expect this increase in submitters each year to level off at this point.

In this regard, we estimate the same 0.25 hours per submission at a cost of $17.43 per organization. Similarly, in aggregate, we estimate, for year 2 (0.75 hours at $52.29 an hour), for year 3 (1.0 hour at $69.72 an hour), and for year 4 (1.25 hours at $87.15 an hour). The proposed requirements and burden will be submitted to OMB under control number 0938-NEW.

We are requesting public comments on these information collection and recordkeeping requirements. If you comment on these information collection and recordkeeping requirements, please do either of the following. 1.

Submit your comments electronically as specified in the ADDRESSES section of this proposed rule. Or 2. Submit your comments to the Office of Information and Regulatory Affairs, Office of Management and Budget, Attention.

CMS Desk Officer, CMS-3372-P, Fax. (202) 395-6974. Or Email.

OIRA_submission@omb.eop.gov. Comments must be received on/by November 2, 2020. IV.

Regulatory Impact Statement This proposed rule makes Medicare coverage policy updates pursuant to the authority at section 1862(a)(1)(A) of the Act. We are using regulatory action per the October 3, 2019 “Executive Order on Protecting and Improving Medicare for Our Nation's Seniors” to address the increasing need for a swift Medicare coverage mechanism to allow beneficiaries across the nation to access breakthrough devices faster after FDA market authorization. This proposed rule addresses that need by establishing a coverage pathway that will allow immediate beneficiary access to FDA market authorized breakthrough devices.

We have examined the impact of this proposed rule as required by Executive Order 12866 on Regulatory Planning and Review (September 30, 1993), Executive Order 13563 on Improving Regulation and Regulatory Review (January 18, 2011), the Regulatory Flexibility Act (RFA) (September 19, 1980, Pub. L. 96-354), section 1102(b) of the Social Security Act, section 202 of the Unfunded Mandates Reform Act of 1995 (March 22, 1995.

Pub. L. 104-4), Start Printed Page 54336Executive Order 13132 on Federalism (August 4, 1999), the Congressional Review Act (5 U.S.C.

804(2)), and Executive Order 13771 on Reducing Regulation and Controlling Regulatory Costs (January 30, 2017). Executive Orders 12866 and 13563 direct agencies to assess all costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety effects, distributive impacts, and equity). A regulatory impact analysis (RIA) must be prepared for major rules with economically significant effects ($100 million or more in any 1 year).

This proposed rule does reach the economic threshold and thus is considered a major rule. Regulatory alternatives to this proposed rule were to combine Medicare coverage with clinical evidence development under section 1862(a)(1)(E) of the Act, to take no regulatory action at this time, or to adjust the duration of the MCIT pathway. Combining coverage with clinical evidence development would have met the E.O.

13890 overarching goal of beneficiary access to breakthrough devices. However, this alternative did not meet the other E.O. 13890 aims of minimizing time between FDA market authorization and Medicare coverage and wide availability.

The timing of coverage would depend upon the manufacturer being able to initiate a clinical study and the wide availability of coverage could be an issue if providers did not have the infrastructure necessary to participate in the clinical study. CMS chose to not to pursue combining coverage with evidence development for breakthrough devices because we wanted to meet the timing and wide availability aims of E.O. 13890.

CMS also considered taking no regulatory action and trying to leverage the existing Medicare coverage pathways or proposing sub-regulatory policies to achieve the streamlined coverage process described in E.O. 13890. Taking no action would not have resulted in the desired national coverage and access envisioned in E.O.

13890 because, as described in this preamble, the existing coverage pathways do not consistently provide swift, national beneficiary access to innovative devices. As discussed elsewhere in the preamble, the nature of the problem being addressed by this proposed regulation is a potential delay between a milestone such as FDA market authorization and CMS coverage. As such, we request comment on a policy option of shortening of the duration of the MCIT pathway from the proposed 4 years to 1 year.

In addition to the alternatives just discussed, there are various possibilities regarding how to change the definition of “reasonable and necessary”—for example, whether to include a new aspect of the proposed definition that focuses on commercial insurance coverage practices. As noted earlier in the preamble, the goal of this revision is to expand coverage. However, the nuances of the definition would affect the magnitude of the impact and we request comment that would facilitate quantification of effects and comparison of alternatives at the final rule stage.

The impact of implementing the MCIT pathway is difficult to determine without knowing the specific technologies that would be covered. In addition, many of these technologies would be eligible for coverage in the absence of this rule, such as through a local or national coverage determination, so the impact for certain items may be the acceleration of coverage or adoption by just a few months. Furthermore, some of these devices would be covered immediately if the MACs decide to pay for them, which would result in no impact on Medicare spending for devices approved under this pathway.

However, it is possible that some of these innovative technologies would not otherwise be eligible for coverage in the absence of this rule. Because it is not known how these new technologies would otherwise come to market and be reimbursed, it is not possible to develop a point estimate of the impact. In general, we believe the MCIT coverage pathway would range in impact from having no impact on Medicare spending, to a temporary cost for innovations that are adopted under an accelerated basis.

The decision to enter the MCIT pathway is voluntary for the manufacturer. Because manufacturers typically join the Medicare coverage pathway that is most beneficial to them, this would result in selection against the existing program coverage pathways (to what degree is unknown at this point). In addition, the past trend of new technology costing more than existing technology could lead to a higher cost for Medicare if this trend continued for technologies enrolling in the MCIT pathway.

Nevertheless, new technology may also mitigate ongoing chronic health issues or improve efficiency of services thereby reducing some costs for Medicare. In order to demonstrate the potential impact on Medicare spending, the CMS Office of the Actuary (OACT) developed three hypothetical scenarios that illustrate the impact of implementing the proposed MCIT pathway. Scenarios two and three assume that the device would not have been eligible for coverage in the absence of this proposed rule.

(See Table 2) The illustration used the new devices that applied for a NTAP in FY 2020 as a proxy for the new devices that would utilize the MCIT pathway. The submitted cost and anticipated utilization for these devices was published in the Federal Register.[] In addition, we assumed that two manufacturers would elect to utilize the MCIT pathway in the first year, three manufacturers in the second year, four manufacturers in the third year, and five manufacturers in the fourth year each year for all three scenarios. This assumption is based on the number of medical devices that received FY 2020 NTAP and were non-covered in at least one MAC jurisdiction by LCDs and related articles and our impression from the FDA that the number of devices granted breakthrough status is increasing.

For the first scenario, the no-cost scenario, we assumed that all the devices would be eligible for coverage in the absence of the proposed rule. If the devices received payment nationally and at the same time then there would be no additional cost under this pathway. For the second scenario, the low-cost scenario, we assumed that the new technologies would have the average costs ($2,044) and utilization (2,322 patients) of similar technologies included in the FY 2020 NTAP application cycle.

Therefore, to estimate the first year of MCIT, we multiplied the add-on payment for a new device by the anticipated utilization for a new device by the number of anticipated devices in the pathway ($2,044 × 2,322 × 2 = $ 9.5 million). For the third scenario, the high-cost scenario, we assumed the new technologies would receive the maximum add-on payment from the FY 2020 NTAP application cycle ($22,425) and the highest utilization of a device (6,500 patients). Therefore, to estimate for the first year of MCIT, we estimated similarly ($22,425 × 6,500 patients × 2 = $ 291.5 million).

For subsequent years, we increased the number of anticipated devices in the pathway by three, four, and five in the last two scenarios until 2024.[] In addition to Start Printed Page 54337not taking into account inflation, the illustration does not reflect any offsets for the costs of these technologies that would be utilized through existing authorities nor the cost of other treatments (except as noted). It is not possible to explicitly quantify these offsetting costs but they could substantially reduce or eliminate the net program cost. However, by assuming that only two to five manufacturers will elect MCIT coverage, we have implicitly assumed that, while more manufacturers could potentially elect coverage under MCIT, the majority of devices would have been covered under a different coverage pathway.

Therefore, a substantial portion of the offsetting costs are implicitly reflected. Based on this analysis, there is a range of potential impacts of the proposed MCIT coverage pathway as shown in Table 2. The difference between the three estimates demonstrates how sensitive the impact is to the cost and utilization of these unknown devices.

Table 2—Illustrated Impact on the Medicare Program by Proposed MCIT Coverage Pathway Costs (in millions)FY 2021FY 2022FY 2023FY 2024No-cost Scenario$0$0$0$0Low-cost Scenario9.523.742.766.4High-cost Scenario291.5728.81,311.92,040.7 We believe the assumptions used in the three scenarios are reasonable to show the possible wide range of impacts for implementing this proposed pathway, in particular for a technology that would not have otherwise been eligible for coverage. The RFA requires agencies to analyze options for regulatory relief of small entities. For purposes of the RFA, small entities include small businesses, nonprofit organizations, and small governmental jurisdictions.

Some hospitals and other providers and suppliers are small entities, either by nonprofit status or by having revenues of less than $7.5 million to $38.5 million in any 1 year. Individuals and States are not included in the definition of a small entity. We reviewed the Small Business Administration's Table of Small Business Size Standards Matched to North American Industry Classification System (NAICS) Codes to determine the NAICS U.S.

Industry titles and size standards in millions of dollars and/or number of employees that apply to small businesses that could be impacted by this rule.[] We determined that small businesses potentially impacted may include surgical and medical instrument manufacturers (NAICS code 339112, dollars not provided/1,000 employees), Offices of Physicians (except Mental Health Specialists) (NAICS code 621111, $12 million/employees not provided), and Freestanding Ambulatory Surgical and Emergency Centers (NAICS code 621493, $16.5 million/employees not provided). During the first 4 years of MCIT, we anticipate approximately 14 surgical and medical instrument manufacturers may participate, and based off of U.S. Census data, the majority of this businesses type are small businesses with less than 1,000 employees (968 out of 1,093 businesses have less than 500 employees).[] As such, this proposed rule would impact less than 5 percent of these businesses, and the revenue impact, if any, would not be negative.

Rather, it would be a positive impact because MCIT would provide Medicare coverage (and subsequent payment) to providers who purchase the devices from these manufacturers. For Offices of Physicians (except Mental Health Specialists) and Freestanding Ambulatory Surgical and Emergency Centers that may be providing the breakthrough devices, the majority are small businesses with less than 1,000 employees (4,060 out of 4,385 and 160, 367 out of 161, 286 have less than 500 employees, respectively).[] Given that we estimate, at most in the high-cost scenario, that 6,500 beneficiaries would utilize breakthrough devices through MCIT per year, and even if each beneficiary were to access services at only one of these small businesses (that is, no two beneficiaries used the same office or center), still less than 5 percent of these small businesses would be impacted by MCIT. As such, the revenue impact, if any, would not be negative, rather, it would be a positive impact because MCIT would provide Medicare coverage (and subsequent payment) to providers.

Overall, this proposed rule results in a payment, not a reduction in revenue. We are not preparing a further analysis for the RFA because we have determined, and the Secretary certifies, that this proposed rule will not have a significant negative economic impact on a substantial number of small entities because small entities are not being asked to undertake additional effort or take on additional costs outside of the ordinary course of business through this proposed rule. Rather, for small entities that develop or provide breakthrough devices to patients, this proposed rule is a means for the device to be covered through the Medicare program, which does not detract from revenue and could be viewed as a positive economic impact.

With the limited information we had to base this estimate, we solicit public comment on improvements to this estimate for the final rule. In addition, section 1102(b) of the Act requires us to prepare a regulatory impact analysis if a rule may have a significant impact on the operations of a substantial number of small rural hospitals. This analysis must conform to the provisions of section 603 of the RFA.

For purposes of section 1102(b) of the Act, we define a small rural hospital Start Printed Page 54338as a hospital that is located outside of a Metropolitan Statistical Area for Medicare payment regulations and has fewer than 100 beds. We are not preparing an analysis for section 1102(b) of the Act because we have determined, and the Secretary certifies, that this proposed rule would not have a significant impact on the operations of a substantial number of small rural hospitals because small rural hospitals are not being asked to undertake additional effort or take on additional costs outside of the ordinary course of business through this proposed rule. Obtaining breakthrough devices for patients is at the discretion of providers.

We are not requiring the purchase and use of breakthrough devices. Providers should continue to work with their patients to choose the best treatment. For small rural hospitals that provide breakthrough devices to their patients, this proposed rule is a means for the device to be covered through the Medicare program.

Section 202 of the Unfunded Mandates Reform Act of 1995 also requires that agencies assess anticipated costs and benefits before issuing any rule whose mandates require spending in any 1 year of $100 million in 1995 dollars, updated annually for inflation. In 2020, that threshold was approximately $156 million. This proposed rule would have no consequential effect on State, local, or tribal governments or on the private sector.

Executive Order 13132 establishes certain requirements that an agency must meet when it promulgates a proposed rule (and subsequent final rule) that imposes substantial direct requirement costs on State and local governments, preempts State law, or otherwise has Federalism implications. Since this regulation does not impose any costs on State or local governments, the requirements of Executive Order 13132 are not applicable. Executive Order 13771 (E.O.

13771), titled Reducing Regulation and Controlling Regulatory Costs, was issued on January 30, 2017. This proposed rule, if finalized as proposed, is expected to impose no more than de minimis costs and thus be neither an E.O. 13771 regulatory action nor an E.O.

13771 deregulatory action. In accordance with the provisions of Executive Order 12866, this proposed rule was reviewed by the Office of Management and Budget. V.

Response to Comments Because of the large number of public comments we normally receive on Federal Register documents, we are not able to acknowledge or respond to them individually. We will consider all comments we receive by the date and time specified in the DATES section of this preamble, and, when we proceed with a subsequent document, we will respond to the comments in the preamble to that document. Start List of Subjects Administrative practice and procedureDiseasesHealth facilitiesHealth professionsMedical devicesMedicareReporting and recordkeeping requirementsRural areasX-rays End List of Subjects For the reasons set forth in the preamble, the Centers for Medicare &.

Medicaid Services proposes to amend 42 CFR chapter IV as set forth below. Start Part End Part Start Amendment Part1. The authority for part 405 continues to read as follows.

End Amendment Part Start Authority 42 U.S.C. 263a, 405(a), 1302, 1320b-12, 1395x, 1395y(a), 1395ff, 1395hh, 1395kk, 1395rr, and 1395ww(k). End Authority Start Amendment Part2.

Section 405.201 is amended in paragraph (b) by adding the definition of “Reasonable and necessary” in alphabetical order to read as follows. End Amendment Part Scope of subpart and definitions. * * * * * (b) * * * Reasonable and necessary means that an item or service is considered— (1) Safe and effective.

(2) Except as set forth in § 411.15(o)) of this chapter, not experimental or investigational. And (3) Appropriate for Medicare patients, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it (i) Meets all of the following criteria. (A) Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member.

(B) Furnished in a setting appropriate to the patient's medical needs and condition. (C) Ordered and furnished by qualified personnel. (D) One that meets, but does not exceed, the patient's medical need.

And (E) At least as beneficial as an existing and available medically appropriate alternative. Or (ii) Is covered by commercial insurers, unless evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant. * * * * * Start Amendment Part3.

Subpart F, consisting of §§ 405.601-405.607, is added to read as follows. End Amendment Part 405.601 Medicare coverage of innovative technology. 405.603 Medical device eligibility.

405.605 Coverage of items and services. 405.607 Coverage period. Medicare coverage of innovative technology.

(a) Basis and scope. Medicare coverage of innovative technology (MCIT) is a program that provides national, time-limited coverage under section 1862(a)(1)(A) of the Act for certain breakthrough medical devices. Manufacturer participation in the pathway for breakthrough device coverage is voluntary.

(b) Definitions. For the purposes of this subpart, the following definitions are applicable. Breakthrough device means a device that receives such designation by the Food and Drug Administration (FDA) (section 515B(d)(1) of the FD&C Act (21 U.S.C.

360e-3(d)(1)). MCIT stands for Medicare coverage of innovative technology. Medical device eligibility.

The MCIT pathway is available only to medical devices that meet all of the following. (a) That are FDA-designated breakthrough devices. (b) That are FDA market authorized at most [date 2 years prior to effective date of final rule] and thereafter.

(c) That are used according to their FDA approved or cleared indication for use. (d) That are within a Medicare benefit category. (e) That are not the subject of a Medicare national coverage determination.

(f) That are not otherwise excluded from coverage through law or regulation. Coverage of items and services. Covered items and services furnished within the MCIT pathway may include any of the following, if not otherwise excluded from coverage.

(a) The breakthrough device. (b) Any reasonable and necessary procedures to implant the breakthrough device.Start Printed Page 54339 (c) Reasonable and necessary costs to maintain the breakthrough device. (d) Related care and services for the breakthrough device.

(e) Reasonable and necessary services to treat complications arising from use of the breakthrough device. Coverage period. (a) Start of the period.

The MCIT pathway begins on the date the breakthrough device receives FDA market authorization. (b) End of the period. The MCIT pathway for a breakthrough device ends as follows.

(1) No later than 4 years from the date the breakthrough device received FDA market authorization. (2) Prior to 4 years if a manufacturer withdraws the breakthrough device from the MCIT pathway. (3) Prior to 4 years if the breakthrough device becomes the subject of a national coverage determination or otherwise becomes noncovered through law or regulation.

Start Signature Dated. May 4, 2020. Seema Verma, Administrator, Centers for Medicare &.

Alex M. Azar II, Secretary, Department of Health and Human Services. End Signature End Supplemental Information [FR Doc.

2020-19289 Filed 8-31-20. 8:45 am]BILLING CODE 4120-01-P.

This document https://www.moneyspace.com/how-to-pick-the-best-life-insurance-to-protect-your-loved-ones/ is purchase viagra unpublished. It is scheduled to be published on 09/18/2020. Once it is purchase viagra published it will be available on this page in an official form. Until then, you can download the unpublished PDF version.

Although we make a concerted effort to reproduce the original document in full on our Public Inspection pages, in some cases graphics may not be displayed, and non-substantive markup language may appear alongside substantive text. If you are using public inspection listings for legal research, you should verify the contents of documents purchase viagra against a final, official edition of the Federal Register. Only official editions of the Federal Register provide legal notice to the public and judicial notice to the courts under 44 U.S.C. 1503 & purchase viagra.

1507. Learn more here.Start Preamble Centers for Medicare &. Medicaid Services purchase viagra (CMS), HHS. Proposed rule.

This proposed rule would establish a Medicare coverage pathway to provide Medicare beneficiaries nationwide with faster access to new, innovative medical devices designated as breakthrough by the Food and Drug Administration (FDA). After the final rule is effective, the Medicare Coverage of Innovative Technology (MCIT) pathway purchase viagra would begin national Medicare coverage on the date of FDA market authorization and would continue for 4 years. We are also proposing regulatory standards to be used in making reasonable and necessary determinations under section Start Printed Page 543281862(a)(1)(A) of the Social Security Act (the Act) for items and services that are furnished under Part A and Part B. To be assured consideration, comments must be received at one of the addresses provided below, no later than purchase viagra 5 p.m.

On November 2, 2020. In commenting, please refer to file code CMS-3372-P. Because of staff and purchase viagra resource limitations, we cannot accept comments by facsimile (FAX) transmission. You may submit comments in one of three ways (please choose only one of the ways listed).

1. Electronically. You may submit electronic comments on this regulation to http://www.regulations.gov. Follow the “Submit a comment” instructions.

2. By regular mail. You may mail written comments to the following address ONLY. Centers for Medicare &.

Medicaid Services, Department of Health and Human Services, Attention. CMS-3372-P, P.O. Box 8013, Baltimore, MD 21244-8013. Please allow sufficient time for mailed comments to be received before the close of the comment period.

3. By express or overnight mail. You may send written comments to the following address ONLY. Centers for Medicare &.

Medicaid Services, Department of Health and Human Services, Attention. CMS-3372-P, Mail Stop C4-26-05, 7500 Security Boulevard, Baltimore, MD 21244-1850. For information on viewing public comments, see the beginning of the SUPPLEMENTARY INFORMATION section. Start Further Info Linda Gousis or JoAnna Baldwin, (410) 786-2281 or CAGinquiries@cms.hhs.gov.

End Further Info End Preamble Start Supplemental Information Inspection of Public Comments. All comments received before the close of the comment period are available for viewing by the public, including any personally identifiable or confidential business information that is included in a comment. We post all comments received before the close of the comment period on the following website as soon as possible after they have been received. Http://www.regulations.gov.

Follow the search instructions on that website to view public comments. Comments received timely will also be available for public inspection as they are received, generally beginning approximately 3 weeks after publication of a document, at the headquarters of the Centers for Medicare &. Medicaid Services, 7500 Security Boulevard, Baltimore, Maryland 21244, Monday through Friday of each week from 8:30 a.m. To 4 p.m.

To schedule an appointment to view public comments, phone 1-800-743-3951. I. Background The Administration is committed to ensuring Medicare beneficiaries have access to new cures and technologies that improve health outcomes. Section 6 of the October 3, 2019 Executive Order 13890 (E.O.

13890) “Executive Order on Protecting and Improving Medicare for Our Nation's Seniors,” [] directs the Secretary to “propose regulatory and sub-regulatory changes to the Medicare program to encourage innovation for patients” including by “streamlining the approval, coverage, and coding process”.[] The E.O. 13890 explicitly includes making coverage of breakthrough medical devices “widely available, consistent with the principles of patient safety, market-based policies, and value for patients.” [] The E.O. Also directs the Secretary to “clarify the application of coverage standards.” [] We are responding directly to these directives by proposing a definition of the term “reasonable and necessary” to clarify coverage standards and proposing the Medicare Coverage of Innovative Technology (MCIT) pathway to accelerate the coverage of new, innovative breakthrough devices to Medicare beneficiaries. To date, the factors used in making “reasonable and necessary” determinations based on section 1862(a)(1)(A) of the Act have not been established in regulations for Medicare coverage purposes.

The Secretary has authority to determine whether a particular medical item or service is “reasonable and necessary” under section 1862(a)(1)(A) of the Act. (See Heckler v. Ringer, 466 U.S. 602, 617 (1984).) When making coverage determinations, our policies have long considered whether the item or service is safe and effective, not experimental or investigational, and appropriate.

(For more information see the January 30, 1989 notice of proposed rulemaking (54 FR 4307)). These factors are found in Chapter 13 of the Medicare Program Integrity Manual (PIM) at section 13.5.4—Reasonable and Necessary Provisions in LCDs as instructions for Medicare contractors. We are proposing to codify in regulations the Program Integrity Manual definition of “reasonable and necessary” with modifications, including to add a reference to Medicare patients and a reference to commercial health insurer coverage policies. We propose that an item or service would be considered “reasonable and necessary” if it is—(1) safe and effective.

(2) not experimental or investigational. And (3) appropriate for Medicare patients, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it is— Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member. Furnished in a setting appropriate to the patient's medical needs and condition. Ordered and furnished by qualified personnel.

One that meets, but does not exceed, the patient's medical need. And At least as beneficial as an existing and available medically appropriate alternative. We also propose that an item or service would be “appropriate for Medicare patients” under (3) if it is covered in the commercial insurance market, except where evidence supports that there are clinically relevant differences between Medicare beneficiaries and commercially insured individuals. An item or service deemed appropriate for Medicare coverage based on commercial coverage would be covered on that basis without also having to satisfy the bullets listed above.

We believe this definition is a significant step in meeting the E.O.'s directive to bring clarity to coverage standards. Stakeholders have expressed interest in codifying a definition of “reasonable and necessary” for many years. This proposed definition is familiar and functional, can satisfy that interest and meet the E.O.'s ask, while also aligning with the goals of MCIT by providing clarity and predictability for innovation, including for beneficiaries and innovators. The proposed MCIT coverage pathway is specifically for Medicare coverage of devices that are designated as part of the Food and Drug Administration's (FDA) Breakthrough Devices Program (hereafter referred to as “breakthrough devices”) and are FDA market authorized.

The MCIT pathway would be voluntary and device manufacturers would notify CMS if they want to utilize this coverage option. We propose that national Medicare coverage under the MCIT pathway would begin immediately upon the date of FDA market authorization (that is, the Start Printed Page 54329date the medical device receives Premarket Approval (PMA). 510(k) clearance. Or the granting of a De Novo classification request) for the breakthrough device.

This coverage would occur unless the device does not have a Medicare benefit category or is otherwise excluded from coverage by statute (that is, the Medicare statute does not allow for coverage of the particular device.) This coverage pathway delivers on the Administration's commitment to give Medicare beneficiaries access to the newest innovations on the market, consistent with the statutory definitions of Medicare benefits. Because Medicare is a defined benefit program, devices that do not fit within the statutory definitions may not be considered for MCIT. As an example, medical equipment for home use by the beneficiary must be durable (that is, withstand repeated use) for it to be coverable by Medicare (as defined in statutes and regulations by the Secretary). At this time, we are limiting MCIT to medical devices because that is a category of products explicitly identified in E.O.

13890, and we have identified that breakthrough devices can experience variable coverage across the nation shortly after market authorization. We propose this MCIT pathway because the prescribed statutory timeframes for the National Coverage Determination (NCD) process limit CMS' ability to institute immediate national coverage policies for new, innovative medical devices. NCDs and Local Coverage Determinations (LCD) take, on average, 9 to 12 months to finalize. Because of this length of time, there may be coverage uncertainty between the period of FDA market authorization and CMS finalization of an NCD or a Medicare Administrative Contractor's (MACs) finalization of an LCD.

During this time period shortly after market authorization, MACs make coverage determinations on a case-by-case (individual beneficiary) basis, but those decisions do not usually establish agency policies for future claims because a case-by-case decision is for a particular beneficiary and their health circumstances. Over the past few years, CMS has heard concerns from stakeholders that breakthrough devices are not automatically covered nationally by Medicare once they are FDA market authorized. Variation in coverage from one jurisdiction to another is also a concern. To date, 16 breakthrough devices have also been market authorized.

The majority of these breakthrough devices (10 devices) experience variability in coverage for two reasons. One reason is because the breakthrough devices are coverable at MAC discretion, like many other item and services, on a case-by-case basis (that is, the breakthrough device may be covered for one patient, but not for another within the same jurisdiction). The other reason is because breakthrough devices are used by a hospital or other provider that operates under a bundled payment system (such as a diagnosis related group (DRG) system), so there may be no separate coverage policy for each item or service that may be included in the bundled payment. Another example of variable coverage is for one breakthrough device that is non-covered by a local policy in Florida, but coverable at MAC discretion on a case-by-case basis in other jurisdictions.

One breakthrough device has national coverage through an NCD. One breakthrough device has uniform coverage because the same LCD has been adopted in all jurisdictions. There are three breakthrough devices that do not have a Medicare benefit category (for example, certain wearable devices). Therefore, those breakthrough devices cannot be covered by the Medicare program.

In contrast to varied local coverage, the proposed MCIT would create a pathway for immediate national Medicare coverage of any FDA-market authorized breakthrough device if the device meets criteria outlined in this proposal. A. Statutory Authority We are also proposing to establish in regulations the factors we have historically used in making “reasonable and necessary” determinations under section 1862(a)(1)(A) of the Act, with some modification. To summarize, this section explains that Medicare payment may be made under part A or part B for any expenses incurred for items or services that are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Thus, with some exceptions, section 1862(a)(1)(A) of the Act requires that an item or service be “reasonable and necessary” to be covered by Medicare. The courts have recognized that the Secretary has significant authority to determine whether a particular item or service is “reasonable and necessary.” (Heckler v. Ringer, 466 U.S. 602, 617 (1984).

See also, Yale-New Haven Hospital v. Leavitt, 470 F.3d 71, 84 (2d Cir. 2006). Kort v.

Burwell, 209 F. Supp. 3d 98, 110 (D.C. 2016) (The statute vests substantial authority in the Secretary.)) So even though section 1862(a)(1)(A) of the Act limits the scope of Medicare coverage, the Secretary has discretion to revise his/her interpretation of the statute in order to ensure adequate coverage for items and services under Part A and Part B.

This proposal would provide national Medicare coverage for breakthrough devices that are FDA market-authorized and used consistent with the FDA approved or cleared indication for use (also referred to as the “FDA-required labeling”).[] This device coverage under the MCIT pathway is reasonable and necessary under section 1862(a)(1)(A) of the Act because the device has met the unique criteria of the FDA Breakthrough Devices Program. B. FDA Breakthrough Devices Program Under the proposed MCIT coverage pathway, CMS would coordinate with FDA and manufacturers as medical devices move through the FDA regulatory process for Breakthrough Devices to ensure seamless Medicare coverage on the date of FDA market authorization unless CMS determines those devices do not have a Medicare benefit category. The Breakthrough Devices Program is an evolution of the Expedited Access Pathway Program and the Priority Review Program (section 515B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)), 21 U.S.C.

360e-3. See also final guidance for industry entitled, “Breakthrough Devices Program,” https://www.fda.gov/​downloads/​MedicalDevices/​DeviceRegulationandGuidance/​GuidanceDocuments/​UCM581664.pdf). The FDA's Breakthrough Devices Program is not for all new medical devices. Rather, it is only for those that the FDA determines meet the standards for breakthrough device designation.

In accordance with section 3051 of the 21st Century Cures Act (21 U.S.C. 360e-3),[] the Breakthrough Devices Program is for medical devices and device-led combination products that meet two criteria. The first criterion is that the device provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions. The second criterion is that the device must satisfy one of the following elements.

It Start Printed Page 54330represents a breakthrough technology. No approved or cleared alternatives exist. It offers significant advantages over existing approved or cleared alternatives, including additional considerations outlined in the statute. Or device availability is in the best interest of patients (for more information see 21 U.S.C.

360e-3(b)(2)). These criteria make breakthrough designated devices unique among all other medical devices.[] The parameters of the breakthrough devices program focus on innovations for patients, in turn, MCIT, focuses on these breakthrough devices consistent with E.O. 13890 and in order to streamline coverage of innovative medical devices. C.

Current Medicare Coverage Pathways Currently, we utilize several coverage pathways for items and services, which includes medical devices. None of the coverage pathways described in this section offer immediate, predictable coverage concurrently with FDA market authorization like the proposed MCIT pathway would do. We summarize the other coverage pathways here to provide context for MCIT. National Coverage Determinations (NCDs).

Section 1862(l)(6)(A) of the Act defines the term national coverage determination as “a determination by the Secretary with respect to whether or not a particular item or service is covered nationally under this title.” In general, NCDs are national policy statements published to identify the circumstances under which particular items and services will be considered covered by Medicare. Traditionally, CMS relies heavily on health outcomes data to make NCDs. Most NCDs have involved determinations under section 1862(a)(1)(A) of the Act, but NCDs can be made based on other provisions of the Act, and includes a determination that the item or service under consideration has a Medicare benefit category. The NCD pathway, which has statutorily prescribed timeframes, generally takes 9 to 12 months to complete.[] Local Coverage Determinations (LCDs).

Medicare contractors develop LCDs based on section 1862(a)(1)(A) of the Act that apply only within their geographic jurisdictions. (Sections 1862(l)(6)(B) and 1869(f)(2)(B) of the Act.) MACs will not need to develop LCDs for breakthrough devices when they are nationally covered through MCIT. The MACs follow specific guidance for developing LCDs for Medicare coverage in the CMS Program Integrity Manual, and in some instances, an LCD can also take 9 to12 months to develop (MACs must finalize proposed LCDs within 365 days from opening per Chapter 13—Local Coverage Determinations of the (PIM) 13.5.1). We note that the MCIT pathway will not alter the existing coverage standards in Chapter 13—Local Coverage Determinations of the PIM.[] That chapter will continue to be used in making determinations under section 1862(a)(1)(A) of the Act for other items and services at the local level.

Claim-by-claim Adjudication. In the absence of an NCD or LCD, MACs would make coverage decisions under section 1862(a)(1)(A) of the Act and may cover or not cover items and services on a claim-by-claim basis. The majority of claims are handled through the claim adjudication process. Clinical Trial Policy (CTP) NCD 310.1.

The CTP pathway can be used for coverage of routine care items and services (but generally not the technology under investigation) in a clinical study that is supported by certain Federal agencies. The CTP coverage pathway was developed in 2000.[] This coverage pathway has not generally been utilized by device manufacturers because they usually seek coverage of the device, which is not included in this pathway. Parallel Review. Parallel Review is a mechanism for FDA and CMS to simultaneously review the submitted clinical data to help decrease the time between FDA's approval of a premarket application or granting of a de novo classification and the subsequent CMS NCD.

Parallel Review has two stages. (1) FDA and CMS meet with the manufacturer to provide feedback on the proposed pivotal clinical trial within the FDA pre-submission process. And (2) FDA and CMS concurrently review (“in parallel”) the clinical trial results submitted in the PMA, or De Novo request. FDA and CMS independently review the data to determine whether it meets their respective Agency's standards and communicate with the manufacturer during their respective reviews.

This program is most successful for devices that have a significant amount of clinical evidence. (Candidates for parallel review would not be appropriate for simultaneous MCIT consideration.) Even though CMS has multiple coverage pathways, at this time none are readily available to provide immediate national coverage for new breakthrough devices with a Medicare benefit category at the same time as FDA market authorization. Further, some of these new breakthrough devices are likely to have limited or developing bodies of clinical evidence because of the newness of the device. Therefore, the MCIT pathway can support manufacturers that are interested in combining coverage with their own clinical study to augment clinical evidence of improved health outcomes, particularly for Medicare patients.

Given this summary of existing coverage pathways, we seek comment from the public regarding if any of these existing pathways should be modified to achieve the goals set out by E.O. 13890. D. MCIT Pathway We propose that the MCIT pathway would provide immediate national coverage for breakthrough devices beginning on the date of FDA market authorization and continue for up to 4 years, unless we determine the device does not have a Medicare benefit category as determined by us as part of the MCIT pathway process.

The MCIT pathway is voluntary (that is, manufacturers would affirmatively opt-in), and would be initiated when a manufacturer notifies CMS of its intention to utilize the MCIT pathway. (This notification process is described further in section III. Of this proposed rule.) We would subsequently coordinate with the manufacturer regarding steps that need to be taken for MCIT implementation purposes. The frequency of subsequent engagement will be largely driven by whether the manufacturer has questions for CMS, or CMS and FDA.

The timing of coverage will depend upon the timing of the FDA's market authorization decision. Engagements can take place in the form of in-person meetings, phone calls, emails, etc. We intend to put devices that are covered through the MCIT pathway on the CMS website so that all stakeholders will be aware of what is covered through the MCIT pathway. Manufacturers of breakthrough devices will not be obligated or mandated by CMS to conduct clinical studies during Start Printed Page 54331coverage under the proposed MCIT pathway.

However, we seek comment as to whether CMS should require or incentivize manufacturers to provide data about outcomes or should be obligated to enter into a clinical study similar to CMS's Coverage with Evidence Development (CED) paradigm.[] We are aware some manufacturers may be required by the FDA to conduct post market data collection as a condition of market authorization, and nothing in this proposed rule would alter that FDA requirement. Manufacturers are encouraged to develop the clinical evidence base needed for one of the other coverage pathways after the MCIT pathway ends. This evidence is encouraged not only for CMS and private commercial health insurer coverage policies but also to better inform the clinical community and the public generally about the risks and benefits of treatment. CMS encourages early manufacturer engagement, both before and after FDA market authorization, for manufacturers to receive feedback from CMS on potential clinical study designs and clinical endpoints that may produce the evidence needed for a definitive coverage determination after MCIT.

This feedback would not involve CMS predicting specific coverage or non-coverage. In order to further the goals of E.O. 13890, CMS proposes to rely on FDA's breakthrough device designation and market authorization of those devices to define the universe of devices eligible for MCIT, except for those particular devices CMS determines do not have a Medicare benefit category or are statutorily excluded from coverage under Part A or Part B. In order to provide immediate national coverage to innovative medical devices, we propose to establish a time limit on how long a breakthrough device can be eligible for MCIT (that is, considered a breakthrough device for coverage purposes).

MCIT has a time limit on newness similar to our New Technology Add-on Payment (NTAP) policy. Eligibility for the NTAP is also time limited and this time limit applies to all new technologies, including breakthrough devices, for which an application for additional payment is submitted. Additionally, the time-limited characteristic of MCIT will drive some manufacturers to leverage this period of coverage to demonstrate the value of their device in the competitive marketplace. The 4-year coverage period is particularly important for manufacturers of breakthrough devices that choose to further develop the clinical evidence basis on which the FDA granted marketing authorization.

From our experience with clinical studies conducted as part of an NCD, 4 years is approximately the amount of time it takes to complete a study. At the end of the 4-year MCIT pathway, coverage of the breakthrough device would be subject to one of these possible outcomes. (1) NCD (affirmative coverage, which may include facility or patient criteria). (2) NCD (non-coverage).

Or (3) MAC discretion (claim-by-claim adjudication or LCD). Manufacturers that are interested in a NCD are encouraged to submit a NCD request during the third year of MCIT to allow for sufficient time for NCD development. We seek public comment on whether CMS should open a national coverage analysis if a MAC has not issued an LCD for a breakthrough device within 6 months of the expiration date of the 4-year MCIT period. In our analysis of the current coverage landscape to determine opportunities for innovation and efficiencies, we also considered modifying the coverage process for non-breakthrough devices (for example, PMAs because they are also new to the market), but ultimately determined that it was the unique characteristics of FDA designated breakthrough devices and their ability to serve unmet needs that resonated most with the E.O.'s direction to encourage innovation for patients.

We also considered expedited coverage of newly market authorized and breakthrough devices when used in a clinical study. We seek public comment on the proposed MCIT pathway, the considerations described, whether any of the existing coverage pathways should be modified to achieve the goals set out by the E.O., and alternatives to these proposals. We specifically seek public comment on whether the MCIT pathway should also include diagnostics, drugs and/or biologics that utilize breakthrough or expedited approaches at the FDA (for example, Breakthrough Therapy, Fast Track, Priority Review, Accelerated Approval) [] or all diagnostics, drugs and/or biologics. We seek data to support including these additional item categories in the MCIT pathway.

Also, we specifically seek manufacturer input on whether an opt-in or opt-out approach would work best for utilizing the MCIT pathway. We believe manufactures will welcome this new coverage pathway. We want to preserve manufacturers' business judgment and not assume which Medicare coverage pathway a given manufacturer of a breakthrough device would prefer (if any). Therefore, we have proposed an opt-in approach with an email to CMS to indicate affirmative interest in coverage.

We are interested in whether an opt-out approach would be less burdensome for stakeholders. If so, we encourage public comment on a process for stakeholders to opt-out of MCIT that would not be burdensome. Also, we seek public comment on whether, once a manufacturer has opted-out of coverage, it can subsequently opt-in to MCIT. II.

Provision of Proposed Regulations A. Defining “Reasonable and Necessary” As described in section I. Of this proposed rule, the Secretary has authority to determine the meaning of “reasonable and necessary” under section 1862(a)(1)(A) of the Act. We are proposing to codify the longstanding Program Integrity Manual definition of “reasonable and necessary” into our regulations at 42 CFR 405.201(b), with modification.

Under the current definition, an item or service is considered “reasonable and necessary” if it is (1) safe and effective. (2) not experimental or investigational. And (3) appropriate, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it is— Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member. Furnished in a setting appropriate to the patient's medical needs and condition.

Ordered and furnished by qualified personnel. One that meets, but does not exceed, the patient's medical need. And At least as beneficial as an existing and available medically appropriate alternative. In addition to codifying the above criteria, we propose to include a separate basis under which an item or service would be appropriate under (3) above that is based on commercial health insurers' coverage policies (that is, non-governmental entities that sponsor health insurance plans).

The Start Printed Page 54332commercial market analysis would be initiated if an item/service fails to fulfill the existing factor (3) criteria defining appropriate for Medicare patients but fulfills (1) safe and effective and (2) not experimental or investigational. By considering commercial health insurer coverage policies, CMS would bring together the expertise of private payers and CMS. For example, in a recent NCD on acupuncture for chronic low back pain, CMS considered the technology assessments and coverage criteria among commercial health insurer coverage policies.[] We believe that this approach would be in line with E.O. 13890 that directs us to make technologies “widely available, consistent with the principles of patient safety, market-based policies, and value for patients.” Under this separate basis, we propose that an item or service would satisfy factor (3) if it is covered under a plan(s) coverage policy if offered in the commercial insurance market, unless evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant.

Under our proposal, we would exclude Medicaid managed care, Medicare Advantage, and other government administered healthcare coverage programs from the types of coverage CMS would consider, as these enrollees are not in the commercial market. In the following paragraphs, we seek comment on this proposal and on how best to implement this mechanism. We solicit comments on sources of data that could be used to implement this policy, and whether CMS should make this information public and transparent. We seek public comment on the most appropriate source(s) for these coverage policies and the best way to determine which commercial plan(s) we would rely on for Medicare coverage.

We seek comment on whether beneficiaries, providers, innovators, or others wishing to gain coverage for an item or service demonstrate that the item or service is covered by at least one commercial insurance plan policy. If they can provide CMS with evidence of commercial coverage or if CMS or its MACs identify such coverage from its review of compilations of health insurance offerings or data from other sources, CMS would consider factor (3) to be satisfied. We solicit comment on whether we should limit our consideration of commercial plan offerings or covered lives to a subset of the commercial market in the interest of simplicity, including looking at geographic subsets, subsets based on number of enrollees, subsets based on plan type (HMO, PPO, etc.), or other subsets of plans—including utilizing a singular plan. We also seek comment on whether, given considerations such the variation and distribution of coverage policies and access to innovations, we should only cover an item or service if it is covered for a majority, or a different proportion such as a plurality, of covered lives amongst plans or a majority, plurality, or some other proportion of plan offerings in the commercial market.

(A plan offering is a contract an insurer offers to its enrollees, and a single insurance company may provide many different offerings.) We also recognize that plan offerings may impose certain coverage restrictions on an item or service, e.g. Related to clinical criteria, disease stage, or number and frequency of treatment. As greater access to innovative treatments provides beneficiaries with more opportunity to improve health and drive decisions, we would, when coverage is afforded on the basis of commercial coverage, adopt the least restrictive coverage policy for the item or service amongst the offerings we examine. However, given potential unreasonable or unnecessary utilization, we also solicit comment on whether we should instead adopt the most restrictive coverage policy.

We are further considering, as another variation, that if coverage restrictions are largely similar and present across the majority of offerings, CMS would adopt these in its coverage policies. We note that such coverage restrictions include the basic requirement for medical necessity at the level of individual patients. Medicare will still only pay for an item or service received by a beneficiary if it is medically necessary for the beneficiary. We seek comment on whether, if we were to take this approach, we should instead use a proportion other than a majority, as low as any offering and as high as all offerings, as a sufficient threshold.

As a final variation, we could defer, in the absence of an NCD or national policy, to the MACs to tailor the restrictions on coverage based on what they observe in the commercial market, just as we rely on MACs with regards to the current definition. We further solicit comment on whether to grant coverage for an item or service to the extent it meets the first and second factors and the commercial coverage basis for the third factor. Under this approach, we would only use the current definition of “appropriate” from the current PIM when the exception for clinically relevant differences between Medicare beneficiaries and commercially insured individuals applies (or if the commercial coverage basis is determined by a proportion like a majority and there is insufficient commercial coverage information available). We note that referring to commercial coverage in this way may expand or narrow the circumstances under which we will cover a particular item or service and therefore solicit comment on whether, under such an approach, we should grandfather our current coverage policies for items and services.

We also emphasize that the MACs will continue to make judgements in evaluating individual claims for reimbursement, such that a decision by CMS that an item or service is reasonable and necessary in general does not mean that it is reasonable and necessary in all circumstances with respect to individual claims for reimbursement. We seek public comment on the most appropriate source(s) for these coverage policies. Further, under our proposal, each MAC would be responsible for reviewing commercial offerings to inform their LCDs or claim by claim decisions, which would include individual medical necessity decisions. We may also allow the MACs to develop approaches to address any or all of the considerations outlined above, parallel to their current practice of making coverage decisions in the absence of an NCD or national policy.

We solicit comment on the best role of the MACs, along these lines or otherwise. We also solicit comment on whether the discretion to use the current criteria in the PIM when there is evidence to believe Medicare beneficiaries have different clinical needs should be exercised through the NCD process or in other ways, as well as what quantum of evidence should be sufficient. In sum, we are proposing to define the term “reasonable and necessary” based on the factors currently found in the PIM, plus an alternative basis for meeting factor (3) based on any coverage in the commercial market. We are also soliciting comment on an alternative under whether an item or service satisfies the commercial coverage basis for factor (3) is determined by how it is treated across a majority of covered lives amongst commercial plan offerings, as well as an alternative whereby an item or service would be appropriate for Medicare patients to the extent it is covered in the commercial market.

Start Printed Page 54333When evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant, we would rely on the criteria in the current PIM. We would continue relying on local administration of the program by MACs (including coverage on a claim by claim basis and LCDs) and maintain our discretion to issue NCDs based on the final rule. We solicit comment on this proposed definition of reasonable and necessary, and alternatives outlined above, as well as other mechanisms or definitions we could establish for the term “reasonable and necessary”, and the merits and drawbacks associated with each, including the potential impact on Medicare program expenses or complexity. We may finalize any variation or outgrowth of the policies described in this proposal, or some combination of these options in lieu of or in conjunction with our proposed definition.

B. Application of the “Reasonable and Necessary” Standard to the MCIT Pathway We are proposing that, under the proposed MCIT pathway, an item or service that receives a breakthrough device designation from the FDA would be considered “reasonable and necessary” under section 1862(a)(1)(A) of the Act because breakthrough devices have met the FDA's unique breakthrough devices criteria, and they are innovations that serve unmet needs. While other devices are still considered new to the market, for example, PMAs and even some 510(k)s, the devices designated by the FDA as breakthrough are representative of true innovations in the marketplace. This application of the “reasonable and necessary” standard in this way would ensure that the MCIT pathway can provide a fast-track to Medicare coverage of innovative devices that may more effectively treat or diagnose life-threatening or irreversibly debilitating human disease or conditions.

MCIT would improve healthcare for Medicare beneficiaries by providing national Medicare coverage for devices receiving the FDA breakthrough device designation, which are FDA market-authorized and used consistent with the FDA approved or cleared indication for use (also referred to as the “FDA required labeling”),[] so long as the breakthrough device is described in an appropriate Medicare benefit category under Part A or Part B and is not specifically excluded by statute. We believe the criteria for qualification as a breakthrough device, as defined in section 515B(b) of the Food, Drug and Cosmetic Act (21 U.S.C. 360e-3(b)) is sufficient to satisfy the elements of the “reasonable and necessary” standard. The first breakthrough device designation criterion is that a device must “provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions” (21 U.S.C.

360e-3(b)(1)). The second criterion is that the device must satisfy one of the following elements. It represents a breakthrough technology. There are no approved or cleared alternatives.

It offers significant advantages over existing approved or cleared alternatives, including additional considerations outlined in the statute. Or availability of the device is in the best interest of patients (21 U.S.C. 360e-3(b)(2)). Thus, breakthrough devices are those that HHS has determined may provide better health outcomes for patients facing life-threatening or irreversibly debilitating human disease or conditions.

We believe that a device meeting these criteria, once also FDA market authorized, is “reasonable and necessary” for purposes of Medicare coverage. This proposed rule recognizes that the FDA market authorization of breakthrough devices warrants immediate coverage under the “reasonable and necessary” clause in section 1862(a)(1)(A) of the Act. We previously stated that FDA determinations were not controlling determinations for Medicare how to buy viagra coverage purposes under section 1862(a)(1)(A) of the Act. (For more information see the January 30, 1989 Federal Register (54 FR 4307) (“FDA approval for the marketing of a medical device will not necessarily lead to a favorable coverage recommendation.

. . €) and the August 7, 2013 Federal Register (78 FR 48165) (“However, FDA approval or clearance alone does not entitle that technology to Medicare coverage.”) Under the Secretary's broad authority to interpret section 1862(a)(1)(A) of the Act (supra section I.A.), we are revising our interpretation of the statute because of the practical concerns that our current standards have delayed access to a unique set of innovative devices that FDA has found to be safe and effective, and we believe are “reasonable and necessary” for purposes of Medicare coverage. In light of E.O.

13890, the Secretary has determined that application of the current standards for making “reasonable and necessary” determinations may take too long following FDA market authorization of breakthrough devices. More importantly, the existing standard has not always provided Medicare beneficiaries adequate access to certain breakthrough medical devices when needed to improve health outcomes. We are proposing that breakthrough devices per se meet the reasonable and necessary standard in order to increase access and to reduce the delay from FDA market authorization to Medicare coverage. C.

MCIT Pathway We are proposing the MCIT pathway to deliver on the Administration's commitment to provide access to breakthrough devices to Medicare beneficiaries. The MCIT pathway provides up to 4 years of national coverage to newly FDA market authorized breakthrough devices. We are aware that this coverage may also facilitate evidence development on devices for the Medicare population because manufacturers can gather additional data on utilization of the device during the MCIT coverage period. 1.

Definitions In § 405.601(a) we are proposing that the MCIT pathway is voluntary. Operationally, we propose that manufacturers of breakthrough devices notify CMS of their intention to elect MCIT shortly after receiving notice from the FDA of being granted the breakthrough device designation. Ideally, this notification would be sent to CMS within 2 weeks of receiving breakthrough designation. However, entities would not be penalized for notifying CMS after that time.

Alternatively, submitting a notification to CMS shortly before or concurrently with the date of the FDA marketing submission should also afford CMS sufficient time to operationalize MCIT for the device. The CMS Coverage and Analysis Group would establish an email box for these inquires. This notification alerts CMS to offer guidance to manufacturers about the MCIT pathway and point to resources for coding and payment, which are key conversations to effectuate coverage upon FDA market authorization. We intend to utilize the existing coverage implementation processes to be prepared to offer coverage immediately upon the FDA market authorization.

In § 405.601(b), we propose the following definitions for the purposes of 42 CFR part 405. We propose to define Start Printed Page 54334“breakthrough device” as a medical device that receives such designation by the FDA (section 515B(d)(1) of the FD&C Act (21 U.S.C. 360e-3(d)(1))). We also propose to define, for the sake of clarity in the rule, that the acronym MCIT stands for Medicare Coverage of Innovative Technology.

2. MCIT Pathway Device Eligibility In § 405.603(a) we propose that the pathway is available to devices that meet the definitions proposed in § 405.601. Based on the explicit mention of devices in E.O. 13890 and our interaction and feedback from stakeholders who expressed their concern that there is more uncertainty of coverage for devices than for other items and services (for example, diagnostics, drugs and biologics), this proposed policy is for devices only.

We propose in § 405.603(b) that the breakthrough devices that received FDA market authorization no more than 2 calendar years prior to the effective date of this subpart (the date the final rule is finalized) and thereafter will be eligible for coverage for claims submitted on or after the effective date of this rule. Claims for breakthrough devices with dates of service that occurred before the effective date of this rule would not be covered through MCIT. For example, a hypothetical breakthrough device that was FDA market authorized on October 1, 2018, and utilized on January 1, 2020 would not be eligible for coverage under MCIT because on January 1, 2020, the date of service, the final MCIT rule was not yet legally in effect. In contrast, a claim for utilization of the same hypothetical breakthrough device with a date of service on January 1, 2021 might be eligible for coverage if the claim occurred after the effective date of the rule (assuming that the effective date of the rule was prior to January 1, 2021).

Breakthrough devices market authorized prior to the effective date of this rule will not be eligible for all 4 years of coverage. The 4-year period starts on the date of FDA market authorization. For example, a breakthrough device market authorized on October 1, 2018 would have claims covered through MCIT from the effective date of the final rule until October 1, 2022. If a manufacturer initially chooses to not utilize the MCIT pathway, and then chooses to do so some time after the breakthrough device's market authorization, coverage still only lasts 4 years from the date of FDA market authorization.

We seek comment on this eligibility criterion for devices and specifically the 2 year lookback. We propose in § 405.603(c) that to be part of the MCIT pathway, the device must be used according to its FDA approved or cleared indication for use. We propose that the device is only covered for use consistent with its FDA approved or cleared indication for use because that is the indication and conditions for use that were reviewed by the FDA and authorized for marketing. Data are unlikely to be available to support extending beyond the FDA required labeling for breakthrough devices on the date of marketing authorization.

Use of the device for a condition or population that is not labeled (“off-label”) will not be covered as that use would not be FDA authorized. We specifically seek comment on whether off-label use of breakthrough devices should be covered and, if so, under what specific circumstances and/or evidentiary support. In § 405.603(d) and (e), we additionally propose limitations to what is coverable under the Act. In § 405.603(e), we are proposing that if CMS has issued an NCD on a particular breakthrough device, that breakthrough device is not eligible for MCIT.

We are proposing this because, once the device has been reviewed by CMS for the FDA required approved or cleared indication for use. CMS has made a coverage determination based on the available evidence for that technology. We believe this would happen rarely because breakthrough devices are new technologies that are not likely to have been previously reviewed through the NCD process. In § 405.603(f), we acknowledge that devices in the MCIT pathway may be excluded due to statute or regulation (for example, 42 CFR 411.15, Particular services excluded from coverage) and, like other items and services coverable by Medicare, the device must fall within the scope of a Medicare benefit category under section 1861 of the Act and the implementing regulations.

If the device does not fall within a Medicare benefit category as outlined in the statute and implementing regulations, the device is not eligible for Medicare coverage. Therefore, the device would not be eligible for the MCIT pathway. 3. General Coverage of Items and Services under the MCIT Pathway We propose in § 405.605 that devices covered under the MCIT pathway are covered no differently from devices that are covered outside of MCIT.

In other words, provided the items and services are otherwise coverable (that is, not specifically excluded and not found by CMS to be outside the scope of a Medicare benefit category), covered items and services could include the device, reasonable and necessary surgery to implant the device, if implantable, related care and services costs of the device (for example, replacing reasonable and necessary parts of the device such as a battery), and coverage of any reasonable and necessary treatments due to complications arising from use of the device. What the MCIT pathway offers compared to other pathways is predictable national coverage simultaneous with FDA market authorization that will generally last for a set time period. The proposed MCIT pathway would support and accelerate beneficiary access to certain innovative devices. CMS encourages manufacturers that have breakthrough devices covered under MCIT to develop additional data for the healthcare community.

4. MCIT Pathway for Breakthrough Devices. 4 Years of Coverage In § 405.607(a), we propose that the MCIT pathway for coverage would begin on the same date the device receives FDA market authorization. We propose this point in time to ensure there is no gap between Medicare coverage and FDA market authorization.

This supports the MCIT pathway's focus of ensuring beneficiaries have a predictable access to new devices. We propose in § 405.607(b)(1) that the MCIT pathway for breakthrough devices ends 4 years from the date the device received FDA market authorization. We propose this 4 year time period because it could allow manufacturers to develop clinical evidence and data regarding the benefit of the use of their device in a real world setting. For example, we believe 4 years would allow most manufacturers sufficient time to complete FDA required post-approval or other real-world data collection studies that may have been a condition of FDA market authorization.

This assumption is based upon our historical experience with studies conducted through coverage with evidence development (CED). Further, this time period allows Medicare to support manufacturers that, whether required by the FDA or not, have an interest in better understanding the health outcomes of their device in the Medicare population, including impacts on patient-reported and longer-term outcomes. Further, § 405.607(b) proposes reasons that the MCIT pathway may end prior to 4 years. This includes circumstances whereby the device becomes subject to an NCD, regulation, statute, or if the device can no longer be lawfully marketed.Start Printed Page 54335 D.

Summary In summary, the MCIT pathway would provide immediate Medicare coverage of newly FDA market authorized breakthrough devices for 4 years. We seek public comment on all of our proposals. In particular, we seek feedback on whether the proposed 4 year coverage period is sufficient. We also look to stakeholders and the public to determine the level of interest and expected use of the proposed MCIT pathway so the agency can begin to estimate the level of needed resources to support successful implementation.

We are also seeking public comments on our proposal to codify in regulations the standards we have historically used in making reasonable and necessary decisions under Part A and Part B under section 1862(a)(1)(A) of the Act. After considering public comments we would prepare a final rule that we expect would be effective 60 days after publication of the final rule. III. Collection of Information Requirements Under the Paperwork Reduction Act of 1995, we are required to provide 60-day notice in the Federal Register and solicit public comment before a collection of information requirement is submitted to the Office of Management and Budget (OMB) for review and approval.

In order to fairly evaluate whether an information collection should be approved by OMB, section 3506(c)(2)(A) of the Paperwork Reduction Act of 1995 requires that we solicit comment on the following issues. The need for the information collection and its usefulness in carrying out the proper functions of our agency. The accuracy of our estimate of the information collection burden. The quality, utility, and clarity of the information to be collected.

Recommendations to minimize the information collection burden on the affected public, including automated collection techniques. We are soliciting public comment on each of the section 3506(c)(2)(A)-required issues for the following sections of this document that contain information collection requirements (ICRs). To derive average costs, we used data from the U.S. Bureau of Labor Statistics' May 2018 National Occupational Employment and Wage Estimates for all salary estimates (https://www.bls.gov/​oes/​current/​oes131041.htm, released May 2019).

In this regard, the table that follows presents the mean hourly wage, the cost of fringe benefits (calculated at 100 percent of salary), and the adjusted hourly wage. Table 1—National Occupational Employment and Wage Estimates for MCITOccupation titleOccupation codeMean hourly wage ($/hr)Fringe benefit ($/hr)Adjusted hourly wage ($/hr)Compliance Officer13-104134.8634.8669.72 As indicated, we are adjusting our employee hourly wage estimates by a factor of 100 percent. This is necessarily a rough adjustment, both because fringe benefits and overhead costs vary significantly from employer to employer. Nonetheless, there is no practical alternative and we believe that doubling the hourly wage to estimate total cost is a reasonably accurate estimation method.

This proposed coverage pathway allows for a voluntary participation and therefore necessitates that manufacturers of breakthrough devices notify CMS of their intent to enter the MCIT pathway. Therefore, the burden associated with notifying CMS is the time and effort it would take for each of the organizations to send CMS an email or letter. We anticipate two MCIT pathway participants in the first year based upon the number of medical devices that received FY2020 NTAP and were non-covered in at least one MAC jurisdiction by LCDs and related articles. We estimate notifying CMS of intent to participate in MCIT would involve 15 minutes at $69.72 per hour by a compliance officer.

In this regard, we estimate 15 mins per notification at a cost of $17.43 per organization (0.25 hours × $69.72). In aggregate, we estimate 0.5 hours (0.25 hours × 2 submissions) at $34.86 ($17.43 × 2 submissions). After the anticipated initial 2 submitters, over the next 3 years we expect 3 submitters in year 2, 4 submitters in year 3, and 5 submitters in year 4 to notify CMS of interested in the MCIT pathway. We expect this increase in submitters each year to level off at this point.

In this regard, we estimate the same 0.25 hours per submission at a cost of $17.43 per organization. Similarly, in aggregate, we estimate, for year 2 (0.75 hours at $52.29 an hour), for year 3 (1.0 hour at $69.72 an hour), and for year 4 (1.25 hours at $87.15 an hour). The proposed requirements and burden will be submitted to OMB under control number 0938-NEW. We are requesting public comments on these information collection and recordkeeping requirements.

If you comment on these information collection and recordkeeping requirements, please do either of the following. 1. Submit your comments electronically as specified in the ADDRESSES section of this proposed rule. Or 2.

Submit your comments to the Office of Information and Regulatory Affairs, Office of Management and Budget, Attention. CMS Desk Officer, CMS-3372-P, Fax. (202) 395-6974. Or Email.

OIRA_submission@omb.eop.gov. Comments must be received on/by November 2, 2020. IV. Regulatory Impact Statement This proposed rule makes Medicare coverage policy updates pursuant to the authority at section 1862(a)(1)(A) of the Act.

We are using regulatory action per the October 3, 2019 “Executive Order on Protecting and Improving Medicare for Our Nation's Seniors” to address the increasing need for a swift Medicare coverage mechanism to allow beneficiaries across the nation to access breakthrough devices faster after FDA market authorization. This proposed rule addresses that need by establishing a coverage pathway that will allow immediate beneficiary access to FDA market authorized breakthrough devices. We have examined the impact of this proposed rule as required by Executive Order 12866 on Regulatory Planning and Review (September 30, 1993), Executive Order 13563 on Improving Regulation and Regulatory Review (January 18, 2011), the Regulatory Flexibility Act (RFA) (September 19, 1980, Pub. L.

96-354), section 1102(b) of the Social Security Act, section 202 of the Unfunded Mandates Reform Act of 1995 (March 22, 1995. Pub. L. 104-4), Start Printed Page 54336Executive Order 13132 on Federalism (August 4, 1999), the Congressional Review Act (5 U.S.C.

804(2)), and Executive Order 13771 on Reducing Regulation and Controlling Regulatory Costs (January 30, 2017). Executive Orders 12866 and 13563 direct agencies to assess all costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety effects, distributive impacts, and equity). A regulatory impact analysis (RIA) must be prepared for major rules with economically significant effects ($100 million or more in any 1 year). This proposed rule does reach the economic threshold and thus is considered a major rule.

Regulatory alternatives to this proposed rule were to combine Medicare coverage with clinical evidence development under section 1862(a)(1)(E) of the Act, to take no regulatory action at this time, or to adjust the duration of the MCIT pathway. Combining coverage with clinical evidence development would have met the E.O. 13890 overarching goal of beneficiary access to breakthrough devices. However, this alternative did not meet the other E.O.

13890 aims of minimizing time between FDA market authorization and Medicare coverage and wide availability. The timing of coverage would depend upon the manufacturer being able to initiate a clinical study and the wide availability of coverage could be an issue if providers did not have the infrastructure necessary to participate in the clinical study. CMS chose to not to pursue combining coverage with evidence development for breakthrough devices because we wanted to meet the timing and wide availability aims of E.O. 13890.

CMS also considered taking no regulatory action and trying to leverage the existing Medicare coverage pathways or proposing sub-regulatory policies to achieve the streamlined coverage process described in E.O. 13890. Taking no action would not have resulted in the desired national coverage and access envisioned in E.O. 13890 because, as described in this preamble, the existing coverage pathways do not consistently provide swift, national beneficiary access to innovative devices.

As discussed elsewhere in the preamble, the nature of the problem being addressed by this proposed regulation is a potential delay between a milestone such as FDA market authorization and CMS coverage. As such, we request comment on a policy option of shortening of the duration of the MCIT pathway from the proposed 4 years to 1 year. In addition to the alternatives just discussed, there are various possibilities regarding how to change the definition of “reasonable and necessary”—for example, whether to include a new aspect of the proposed definition that focuses on commercial insurance coverage practices. As noted earlier in the preamble, the goal of this revision is to expand coverage.

However, the nuances of the definition would affect the magnitude of the impact and we request comment that would facilitate quantification of effects and comparison of alternatives at the final rule stage. The impact of implementing the MCIT pathway is difficult to determine without knowing the specific technologies that would be covered. In addition, many of these technologies would be eligible for coverage in the absence of this rule, such as through a local or national coverage determination, so the impact for certain items may be the acceleration of coverage or adoption by just a few months. Furthermore, some of these devices would be covered immediately if the MACs decide to pay for them, which would result in no impact on Medicare spending for devices approved under this pathway.

However, it is possible that some of these innovative technologies would not otherwise be eligible for coverage in the absence of this rule. Because it is not known how these new technologies would otherwise come to market and be reimbursed, it is not possible to develop a point estimate of the impact. In general, we believe the MCIT coverage pathway would range in impact from having no impact on Medicare spending, to a temporary cost for innovations that are adopted under an accelerated basis. The decision to enter the MCIT pathway is voluntary for the manufacturer.

Because manufacturers typically join the Medicare coverage pathway that is most beneficial to them, this would result in selection against the existing program coverage pathways (to what degree is unknown at this point). In addition, the past trend of new technology costing more than existing technology could lead to a higher cost for Medicare if this trend continued for technologies enrolling in the MCIT pathway. Nevertheless, new technology may also mitigate ongoing chronic health issues or improve efficiency of services thereby reducing some costs for Medicare. In order to demonstrate the potential impact on Medicare spending, the CMS Office of the Actuary (OACT) developed three hypothetical scenarios that illustrate the impact of implementing the proposed MCIT pathway.

Scenarios two and three assume that the device would not have been eligible for coverage in the absence of this proposed rule. (See Table 2) The illustration used the new devices that applied for a NTAP in FY 2020 as a proxy for the new devices that would utilize the MCIT pathway. The submitted cost and anticipated utilization for these devices was published in the Federal Register.[] In addition, we assumed that two manufacturers would elect to utilize the MCIT pathway in the first year, three manufacturers in the second year, four manufacturers in the third year, and five manufacturers in the fourth year each year for all three scenarios. This assumption is based on the number of medical devices that received FY 2020 NTAP and were non-covered in at least one MAC jurisdiction by LCDs and related articles and our impression from the FDA that the number of devices granted breakthrough status is increasing.

For the first scenario, the no-cost scenario, we assumed that all the devices would be eligible for coverage in the absence of the proposed rule. If the devices received payment nationally and at the same time then there would be no additional cost under this pathway. For the second scenario, the low-cost scenario, we assumed that the new technologies would have the average costs ($2,044) and utilization (2,322 patients) of similar technologies included in the FY 2020 NTAP application cycle. Therefore, to estimate the first year of MCIT, we multiplied the add-on payment for a new device by the anticipated utilization for a new device by the number of anticipated devices in the pathway ($2,044 × 2,322 × 2 = $ 9.5 million).

For the third scenario, the high-cost scenario, we assumed the new technologies would receive the maximum add-on payment from the FY 2020 NTAP application cycle ($22,425) and the highest utilization of a device (6,500 patients). Therefore, to estimate for the first year of MCIT, we estimated similarly ($22,425 × 6,500 patients × 2 = $ 291.5 million). For subsequent years, we increased the number of anticipated devices in the pathway by three, four, and five in the last two scenarios until 2024.[] In addition to Start Printed Page 54337not taking into account inflation, the illustration does not reflect any offsets for the costs of these technologies that would be utilized through existing authorities nor the cost of other treatments (except as noted). It is not possible to explicitly quantify these offsetting costs but they could substantially reduce or eliminate the net program cost.

However, by assuming that only two to five manufacturers will elect MCIT coverage, we have implicitly assumed that, while more manufacturers could potentially elect coverage under MCIT, the majority of devices would have been covered under a different coverage pathway. Therefore, a substantial portion of the offsetting costs are implicitly reflected. Based on this analysis, there is a range of potential impacts of the proposed MCIT coverage pathway as shown in Table 2. The difference between the three estimates demonstrates how sensitive the impact is to the cost and utilization of these unknown devices.

Table 2—Illustrated Impact on the Medicare Program by Proposed MCIT Coverage Pathway Costs (in millions)FY 2021FY 2022FY 2023FY 2024No-cost Scenario$0$0$0$0Low-cost Scenario9.523.742.766.4High-cost Scenario291.5728.81,311.92,040.7 We believe the assumptions used in the three scenarios are reasonable to show the possible wide range of impacts for implementing this proposed pathway, in particular for a technology that would not have otherwise been eligible for coverage. The RFA requires agencies to analyze options for regulatory relief of small entities. For purposes of the RFA, small entities include small businesses, nonprofit organizations, and small governmental jurisdictions. Some hospitals and other providers and suppliers are small entities, either by nonprofit status or by having revenues of less than $7.5 million to $38.5 million in any 1 year.

Individuals and States are not included in the definition of a small entity. We reviewed the Small Business Administration's Table of Small Business Size Standards Matched to North American Industry Classification System (NAICS) Codes to determine the NAICS U.S. Industry titles and size standards in millions of dollars and/or number of employees that apply to small businesses that could be impacted by this rule.[] We determined that small businesses potentially impacted may include surgical and medical instrument manufacturers (NAICS code 339112, dollars not provided/1,000 employees), Offices of Physicians (except Mental Health Specialists) (NAICS code 621111, $12 million/employees not provided), and Freestanding Ambulatory Surgical and Emergency Centers (NAICS code 621493, $16.5 million/employees not provided). During the first 4 years of MCIT, we anticipate approximately 14 surgical and medical instrument manufacturers may participate, and based off of U.S.

Census data, the majority of this businesses type are small businesses with less than 1,000 employees (968 out of 1,093 businesses have less than 500 employees).[] As such, this proposed rule would impact less than 5 percent of these businesses, and the revenue impact, if any, would not be negative. Rather, it would be a positive impact because MCIT would provide Medicare coverage (and subsequent payment) to providers who purchase the devices from these manufacturers. For Offices of Physicians (except Mental Health Specialists) and Freestanding Ambulatory Surgical and Emergency Centers that may be providing the breakthrough devices, the majority are small businesses with less than 1,000 employees (4,060 out of 4,385 and 160, 367 out of 161, 286 have less than 500 employees, respectively).[] Given that we estimate, at most in the high-cost scenario, that 6,500 beneficiaries would utilize breakthrough devices through MCIT per year, and even if each beneficiary were to access services at only one of these small businesses (that is, no two beneficiaries used the same office or center), still less than 5 percent of these small businesses would be impacted by MCIT. As such, the revenue impact, if any, would not be negative, rather, it would be a positive impact because MCIT would provide Medicare coverage (and subsequent payment) to providers.

Overall, this proposed rule results in a payment, not a reduction in revenue. We are not preparing a further analysis for the RFA because we have determined, and the Secretary certifies, that this proposed rule will not have a significant negative economic impact on a substantial number of small entities because small entities are not being asked to undertake additional effort or take on additional costs outside of the ordinary course of business through this proposed rule. Rather, for small entities that develop or provide breakthrough devices to patients, this proposed rule is a means for the device to be covered through the Medicare program, which does not detract from revenue and could be viewed as a positive economic impact. With the limited information we had to base this estimate, we solicit public comment on improvements to this estimate for the final rule.

In addition, section 1102(b) of the Act requires us to prepare a regulatory impact analysis if a rule may have a significant impact on the operations of a substantial number of small rural hospitals. This analysis must conform to the provisions of section 603 of the RFA. For purposes of section 1102(b) of the Act, we define a small rural hospital Start Printed Page 54338as a hospital that is located outside of a Metropolitan Statistical Area for Medicare payment regulations and has fewer than 100 beds. We are not preparing an analysis for section 1102(b) of the Act because we have determined, and the Secretary certifies, that this proposed rule would not have a significant impact on the operations of a substantial number of small rural hospitals because small rural hospitals are not being asked to undertake additional effort or take on additional costs outside of the ordinary course of business through this proposed rule.

Obtaining breakthrough devices for patients is at the discretion of providers. We are not requiring the purchase and use of breakthrough devices. Providers should continue to work with their patients to choose the best treatment. For small rural hospitals that provide breakthrough devices to their patients, this proposed rule is a means for the device to be covered through the Medicare program.

Section 202 of the Unfunded Mandates Reform Act of 1995 also requires that agencies assess anticipated costs and benefits before issuing any rule whose mandates require spending in any 1 year of $100 million in 1995 dollars, updated annually for inflation. In 2020, that threshold was approximately $156 million. This proposed rule would have no consequential effect on State, local, or tribal governments or on the private sector. Executive Order 13132 establishes certain requirements that an agency must meet when it promulgates a proposed rule (and subsequent final rule) that imposes substantial direct requirement costs on State and local governments, preempts State law, or otherwise has Federalism implications.

Since this regulation does not impose any costs on State or local governments, the requirements of Executive Order 13132 are not applicable. Executive Order 13771 (E.O. 13771), titled Reducing Regulation and Controlling Regulatory Costs, was issued on January 30, 2017. This proposed rule, if finalized as proposed, is expected to impose no more than de minimis costs and thus be neither an E.O.

13771 regulatory action nor an E.O. 13771 deregulatory action. In accordance with the provisions of Executive Order 12866, this proposed rule was reviewed by the Office of Management and Budget. V.

Response to Comments Because of the large number of public comments we normally receive on Federal Register documents, we are not able to acknowledge or respond to them individually. We will consider all comments we receive by the date and time specified in the DATES section of this preamble, and, when we proceed with a subsequent document, we will respond to the comments in the preamble to that document. Start List of Subjects Administrative practice and procedureDiseasesHealth facilitiesHealth professionsMedical devicesMedicareReporting and recordkeeping requirementsRural areasX-rays End List of Subjects For the reasons set forth in the preamble, the Centers for Medicare &. Medicaid Services proposes to amend 42 CFR chapter IV as set forth below.

Start Part End Part Start Amendment Part1. The authority for part 405 continues to read as follows. End Amendment Part Start Authority 42 U.S.C. 263a, 405(a), 1302, 1320b-12, 1395x, 1395y(a), 1395ff, 1395hh, 1395kk, 1395rr, and 1395ww(k).

End Authority Start Amendment Part2. Section 405.201 is amended in paragraph (b) by adding the definition of “Reasonable and necessary” in alphabetical order to read as follows. End Amendment Part Scope of subpart and definitions. * * * * * (b) * * * Reasonable and necessary means that an item or service is considered— (1) Safe and effective.

(2) Except as set forth in § 411.15(o)) of this chapter, not experimental or investigational. And (3) Appropriate for Medicare patients, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it (i) Meets all of the following criteria. (A) Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient's condition or to improve the function of a malformed body member. (B) Furnished in a setting appropriate to the patient's medical needs and condition.

(C) Ordered and furnished by qualified personnel. (D) One that meets, but does not exceed, the patient's medical need. And (E) At least as beneficial as an existing and available medically appropriate alternative. Or (ii) Is covered by commercial insurers, unless evidence supports that differences between Medicare beneficiaries and commercially insured individuals are clinically relevant.

* * * * * Start Amendment Part3. Subpart F, consisting of §§ 405.601-405.607, is added to read as follows. End Amendment Part 405.601 Medicare coverage of innovative technology. 405.603 Medical device eligibility.

405.605 Coverage of items and services. 405.607 Coverage period. Medicare coverage of innovative technology. (a) Basis and scope.

Medicare coverage of innovative technology (MCIT) is a program that provides national, time-limited coverage under section 1862(a)(1)(A) of the Act for certain breakthrough medical devices. Manufacturer participation in the pathway for breakthrough device coverage is voluntary. (b) Definitions. For the purposes of this subpart, the following definitions are applicable.

Breakthrough device means a device that receives such designation by the Food and Drug Administration (FDA) (section 515B(d)(1) of the FD&C Act (21 U.S.C. 360e-3(d)(1)). MCIT stands for Medicare coverage of innovative technology. Medical device eligibility.

The MCIT pathway is available only to medical devices that meet all of the following. (a) That are FDA-designated breakthrough devices. (b) That are FDA market authorized at most [date 2 years prior to effective date of final rule] and thereafter. (c) That are used according to their FDA approved or cleared indication for use.

(d) That are within a Medicare benefit category. (e) That are not the subject of a Medicare national coverage determination. (f) That are not otherwise excluded from coverage through law or regulation. Coverage of items and services.

Covered items and services furnished within the MCIT pathway may include any of the following, if not otherwise excluded from coverage. (a) The breakthrough device. (b) Any reasonable and necessary procedures to implant the breakthrough device.Start Printed Page 54339 (c) Reasonable and necessary costs to maintain the breakthrough device. (d) Related care and services for the breakthrough device.

(e) Reasonable and necessary services to treat complications arising from use of the breakthrough device. Coverage period. (a) Start of the period. The MCIT pathway begins on the date the breakthrough device receives FDA market authorization.

(b) End of the period. The MCIT pathway for a breakthrough device ends as follows. (1) No later than 4 years from the date the breakthrough device received FDA market authorization. (2) Prior to 4 years if a manufacturer withdraws the breakthrough device from the MCIT pathway.

(3) Prior to 4 years if the breakthrough device becomes the subject of a national coverage determination or otherwise becomes noncovered through law or regulation. Start Signature Dated. May 4, 2020. Seema Verma, Administrator, Centers for Medicare &.

Medicaid Services. Dated. June 11, 2020. Alex M.

Azar II, Secretary, Department of Health and Human Services. End Signature End Supplemental Information [FR Doc. 2020-19289 Filed 8-31-20. 8:45 am]BILLING CODE 4120-01-P.

Viagra gif

The erectile dysfunction treatment viagra continues to negatively impact population health by indirect effects on viagra gif patient and healthcare systems, in addition Get More Information to the direct effects of erectile dysfunction treatment itself. Accurate and quantitative information about the indirect effects of the erectile dysfunction treatment viagra on cardiovascular disease (CVD) services and outcomes will allow better public health planning. Ball and colleagues1 aim to ‘design and implement a simple tool for monitoring and viagra gif visualising trends in CVD hospital services in the UK’ and towards that end they present pilot data from a preliminary cohort of nine UK hospitals in this issue of Heart. Comparing 6 months in 2019–2020 (that include the erectile dysfunction treatment lockdown in the UK) to the same time period in 2018–2019, there was a 57.9% decrease in total hospital admissions and a 52.9% decrease in emergency department visits (figure 1).

In addition, there was a 31%–88% decline during lockdown in procedures for treatment of cardiac, cerebrovascular and other vascular conditions.Overall hospital activity (admissions, ED attendances and erectile dysfunction treatment admissions) between 31 October 2019 and 10 May 2020 compared with the same weeks from 2018 to 2019. Lines describe the viagra gif mean hospital activities in 2019–2020 (solid) and 2018–2019 (dotted). Shading represents 95% CI of the respective hospital activity. The first case of erectile dysfunction treatment was on 31 January 2020 and lockdown started on 23 March 2020.

ED, emergency department." data-icon-position data-hide-link-title="0">Figure 1 Overall hospital viagra gif activity (admissions, ED attendances and erectile dysfunction treatment admissions) between 31 October 2019 and 10 May 2020 compared with the same weeks from 2018 to 2019. Lines describe the mean hospital activities in 2019–2020 (solid) and 2018–2019 (dotted). Shading represents 95% CI of the respective hospital activity. The first viagra gif case of erectile dysfunction treatment was on 31 January 2020 and lockdown started on 23 March 2020.

ED, emergency department.From the other side of the world, Brant and colleagues2 report the number of cardiovascular deaths in the six Brazilian cities with the greatest number of erectile dysfunction treatment deaths. They conclude. €˜Excess cardiovascular mortality was greater in the less developed cities, possibly viagra gif associated with healthcare collapse. Specified cardiovascular deaths decreased in the most developed cities, in parallel with an increase in unspecified cardiovascular and home deaths, presumably as a result of misdiagnosis.

Conversely, specified cardiovascular deaths increased in cities with a healthcare collapse’ (figure 2).Per cent change with 95% CIs between the observed and expected number of deaths in 2020 for specified cardiovascular deaths (acute coronary syndromes and stroke) and unspecified cardiovascular diseases per selected six capital cities." data-icon-position data-hide-link-title="0">Figure 2 Per cent change with 95% CIs between the observed and expected number of deaths in 2020 for specified cardiovascular deaths (acute coronary syndromes and stroke) and unspecified cardiovascular diseases per selected six capital cities.In the accompanying editorial, Watkins3 notes that ‘Taken together, these two studies quantify what many readers of this journal have experienced firsthand. The restructuring of hospital services to cope with an influx of erectile dysfunction treatment cases, combined with social distancing measures, has severely limited access to cardiovascular care, adversely impacting patient outcomes.’ He then goes on to propose policy responses to reduce all-cause death among patients with CVD including deaths due to erectile dysfunction treatment or to disruptions to healthcare delivery associated with the viagra viagra gif (figure 3). His two key messages are. (1) ‘the global and national viagra responses cannot be separated from the cardiovascular health agenda’ and (2) ‘priorities for cardiovascular science must pivot, capitalising on lessons learnt during the viagra’.Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment.

The elements viagra gif proposed above can be modified to fit the resource levels and epidemiological contexts of different countries. Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality." data-icon-position data-hide-link-title="0">Figure 3 Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit the resource levels and viagra gif epidemiological contexts of different countries.

Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality.Other interesting papers in this issue of Heart include a study by Doris and colleagues4 showing that in adults with aortic stenosis CT quantitation of valve calcification is reproducible and demonstrates a greater rate of change in disease severity, compared with echocardiography. Guzzetti and Clavel5 point out that more precise measures of aortic stenosis (AS) severity will allow smaller viagra gif sample sizes in clinical trials of potential medical therapies, in addition to providing insights into the pathophysiology of disease progression (figure 4).Model of AS progression. Pathophysiological model of serial AS progression (‘aortic stenosis cascade’, in blue), along with imaging biomarkers targeting each phase (red) and potential disease-modifying treatments being currently tested in randomised clinical trials (green).

1South Korean PCSK9 inhibitors (NCT03051360). 2EAVaLL. Early aortic valve lipoprotein(a) lowering (NCT02109614). 3SALTIRE II.

Study investigating the effect of drugs used to treat osteoporosis on the progression of calcific aortic stenosis (NCT02132026). 4BASIK2. Bicuspid aortic valve stenosis and the effect of vitamin K2 on calcium metabolism on 18F-NaF PET/MRI (NCT02917525). 5EvoLVeD.

Early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with severe AS (NCT03094143). 6Early TAVR. Evaluation of transcatheter aortic valve replacement compared with surveillance for patients with asymptomatic severe aortic stenosis (NCT03042104). 18F-FDG, 18-fluorodeoxyglucose.

18F-NaF, 18-sodium fluoride. AS, aortic stenosis. AVC, aortic valve calcification. PET, positron emission tomography.

PCSK9, proprotein convertase subtilisin/kexin type 9. TAVR, transcatheter aortic valve replacement." data-icon-position data-hide-link-title="0">Figure 4 Model of AS progression. Pathophysiological model of serial AS progression (‘aortic stenosis cascade’, in blue), along with imaging biomarkers targeting each phase (red) and potential disease-modifying treatments being currently tested in randomised clinical trials (green). 1South Korean PCSK9 inhibitors (NCT03051360).

2EAVaLL. Early aortic valve lipoprotein(a) lowering (NCT02109614). 3SALTIRE II. Study investigating the effect of drugs used to treat osteoporosis on the progression of calcific aortic stenosis (NCT02132026).

4BASIK2. Bicuspid aortic valve stenosis and the effect of vitamin K2 on calcium metabolism on 18F-NaF PET/MRI (NCT02917525). 5EvoLVeD. Early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with severe AS (NCT03094143).

6Early TAVR. Evaluation of transcatheter aortic valve replacement compared with surveillance for patients with asymptomatic severe aortic stenosis (NCT03042104). 18F-FDG, 18-fluorodeoxyglucose. 18F-NaF, 18-sodium fluoride.

AS, aortic stenosis. AVC, aortic valve http://www.ec-schloessel-ostwald.ac-strasbourg.fr/?tribe_events=kilometre-solidarite calcification. PET, positron emission tomography. PCSK9, proprotein convertase subtilisin/kexin type 9.

TAVR, transcatheter aortic valve replacement.In a study of patients undergoing atrial fibrillation (AF) ablation, Piccini and colleagues6 found that almost 30% experienced recurrent atrial tachycardiac (AT) or AF within 3 months. However, although those without recurrent AT/AF had greater improvement in functional status, overall quality of life was similar in those with and without AT/AF recurrence. Sridhar and Colbert7 discuss the importance of patient-reported outcomes (PROs), not just ‘hard’ clinical endpoints in clinical trials. €˜As researchers and clinicians, our goals must align with those of the patients and what they value.

It is heartening to see that more and more clinical trials in cardiology and electrophysiology are incorporating PROs as important endpoints. A slow but definite paradigm shift is occurring to incorporate therapies with a focus on improving patients’ lives, not just their hearts.’The Education in Heart article in this issue discusses the diagnosis and management of familial hypercholesterolemia.8 Our Cardiology in Focus article ‘What to do when things go wrong’ provides a thoughtful discussion of the key steps in dealing with medical error.9 The Image Challenge in this issue10 provides a concise review of a sophisticated set of possible diagnoses to consider in a patient with a new murmur and classic echocardiographic images. Be sure to look at our online Image Challenge archive with over 150 image-based multiple choice questions and answers (https://heart.bmj.com/pages/collections/image_challenges/).Global trends in cardiovascular health have reached a worrisome inflection point. Decades of innovation led to a slew of drugs, devices and programmes that translated into reduced mortality from cardiovascular diseases in many countries.

Unfortunately, progress on cardiovascular mortality since 2010 has slowed. In some countries, it has even reversed.1 Compounding the problem, political actions on cardiovascular health have been inadequate, and health systems across many low-income and middle-income countries are woefully under-resourced to scale up basic cardiovascular services. These factors could increase global health inequalities in coming decades.2erectile dysfunction treatment threatens to derail progress on cardiovascular health even furtherCardiovascular practitioners are now under greater pressure to deliver the same or better care in the context of a viagra. erectile dysfunction treatment has hit cardiovascular care particularly hard.

WHO surveys recently found that cardiovascular services have been partially or completely disrupted in nearly half of countries with community spread of erectile dysfunction treatment, raising the chance of increased cardiovascular mortality in these locations.3Two studies published in this issue of Heart shed more light on the specific effects of erectile dysfunction treatment on health systems in Brazil and the UK. Brant et al looked at cardiovascular mortality in six Brazilian capital cities.4 Ball et al tracked disruptions in acute cardiovascular services across nine UK hospitals.5 Taken together, these two studies quantify what many readers of this Journal have experienced firsthand. The restructuring of hospital services to cope with an influx of erectile dysfunction treatment cases, combined with social distancing measures, has severely limited access to cardiovascular care, adversely impacting patient outcomes.Although Ball et al did not attempt to link reduced service delivery to mortality outcomes, other studies from the UK have estimated excess cardiovascular deaths during erectile dysfunction treatment.5 Brant et al posited that excess cardiovascular mortality in Brazil was partly due to avoidance of care (ie, increases cardiovascular deaths occurring at home).4 They also found that healthcare system collapse in more socioeconomically deprived states was associated with increased acute coronary syndrome and stroke deaths in these states, independent of the uptick in deaths at home.A comprehensive responseWhat can be done about these disruptions?. The relationship between erectile dysfunction treatment and cardiovascular health can be separated into two issues that require different responses.

First, persons living with cardiovascular diseases have worse outcomes when they acquire erectile dysfunction treatment. On the other hand, persons living with cardiovascular disease or major risk factors are also at increased risk of death from cardiovascular mechanisms (eg, thrombotic events or heart failure) when their access to acute care services is interrupted. Health systems, patients and patient-system interactions are implicated in both of these issues.Figure 1 illustrates how an appropriate policy response should consider all of the elements mentioned above, with the overarching goal being to reduce deaths from any cause (erectile dysfunction treatment or otherwise) among persons living with cardiovascular diseases or major risk factors. Importantly, the actions specified in the figure 1 can be adapted to all populations and countries, regardless of health system resource levels.

With such a framework in mind, practitioners and researchers could then structure their work and advocacy around two key messages.Message 1. The global and national viagra responses cannot be separated from the cardiovascular health agendaCritical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit the resource levels and epidemiological contexts of different countries. Areas marked in red are those likely to translate into the largest short-term mortality gains.

Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality." data-icon-position data-hide-link-title="0">Figure 1 Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit the resource levels and epidemiological contexts of different countries. Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality.Outcomes from infectious diseases are usually worse among patients with multimorbidity, and erectile dysfunction treatment is no different.

As cardiovascular practitioners, scientists and advocates, we need to articulate the substantial benefits of viagra mitigation efforts to persons living with cardiovascular diseases or risk factors. In parallel, accelerated investment in population-level prevention efforts would reduce the future burden of cardiovascular disease on health systems and reduce the number of persons at high risk of complications from future viagras or outbreaks.In much of the global health community, investments in acute care and in cardiovascular diseases are often perceived to be non-essential—or even anti-equity—and are almost never given serious consideration within health and development programmes. We need to forcefully push back on such short-sighted thinking. Collaborators on the Disease Control Priorities Project recently released guidance for low-income and middle-income and humanitarian settings, including a list of 120 essential health services to protect during the viagra.

On value-for-money grounds, basic cardiovascular disease prevention and care are just as ‘essential’ as immunisation programmes, maternal healthcare and screening and treatment of HIV .6At the same time, locations with advanced cardiovascular care systems need guidance on how to balance the need to treat severe cardiovascular disease against the need to adapt quickly to increased erectile dysfunction treatment caseloads. Ball et al found that emergency department visits and percutaneous coronary intervention procedure rates in UK hospitals had partially rebounded by the end of May 2020.5 Assuming the top objective is to maximise health, emergency cardiac care and interventional services should be brought back online before phasing in other semi-elective vascular procedures (even if the latter provide substantial revenues to hospitals). Critically, more must be done to encourage patients with acute cardiac or neurological symptoms to seek care even in the face of potential erectile dysfunction treatment exposure. Initiatives like the American Heart Association’s ‘Don’t Die of Doubt’ campaign7 should be examined, adapted and disseminated widely to complement supply-side efforts to improve access.Message 2.

Priorities for cardiovascular science must pivot, capitalising on lessons learnt during the viagraIt is increasingly clear that viagras and emerging s, driven by globalisation and climate change, will continue to threaten health systems in the coming decades. Cardiovascular research and development priorities must adapt to this emerging reality. We need new technologies, programmes and care systems that protect what is working during erectile dysfunction treatment and transform what is not. In addition, the viagra has illuminated—and in many cases magnified—inequalities in cardiovascular health.

Cardiovascular research funders should prioritise development of truly ‘global’ public goods that can immediately benefit the health of the world’s poorest as well as vulnerable populations in the global North.2How could the cardiovascular research community make this pivot?. Table 1 proposes several principles for cardiovascular research and development priorities amid and beyond the erectile dysfunction treatment viagra. Not every concept in table 1 will be directly applicable to every research initiative, but they could be used by funders as benchmarks for developing or revising their strategies and scoring proposals.View this table:Table 1 Proposed principles to guide cardiovascular research and development prioritiesManagement of acute coronary syndromes exemplifies the need for a research and development pivot. Our ability to reduce case fatality from acute coronary syndromes is based on prompt delivery of interventions or fibrinolysis.

Researchers and planners have worked for years to improve referral and triage systems to increase access to these life-saving technologies. Yet when viewed through the lens of erectile dysfunction treatment, it is problematic that the cornerstone of acute coronary syndrome management is early access to a referral hospital. We need new technologies, like home-based diagnostics and smartphone-based triage and referral processes, that can circumvent time and distance bottlenecks. We also need new drugs (available at home) that bridge to interventions or replace them entirely.

Such technologies are especially needed in low-income and middle-income countries, where systems are less advanced and timely access is more difficult to achieve (eg, in majority-rural countries).More generally, new technologies should ‘disrupt’ care systems in a way that makes cardiovascular care more patient-centred, community-facing and responsive to population needs. The notion that healthcare by default requires a physical building (separate from one’s home or work) should quickly become antiquated. The greater use of telemedicine during the viagra is a big step in this direction, but we have yet to hardness the full potential of mobile devices and wearables—technologies that are already widely available and will become ubiquitous in low-income and middle-income countries much more quickly than new clinics or hospitals. Innovators and health planners in resource-limited countries could collaborate to develop ‘leapfrog’ cardiovascular health programmes that do not rely on the inefficient, slow-to-adapt and labour-intensive models used in the global North.The future of cardiovascular health and researchIn the midst of the debate over the future of cardiovascular care, we should not to lose sight of the ‘endgame’.8 In the long term, it would be far better to live in a world where the prevalence of ideal cardiovascular health is high and the lifetime disease risk is low.

In such a world, the impact of another viagra on cardiovascular services and patients would be lessened greatly. Aggressive action is needed to fully implement policies and health services that we know can help achieve this goal in a cost-effective manner. Still, in order to accomplish the endgame, we need better evidence on how to design policy instruments that can minimise dietary risks and barriers to optimal physical activity—the most challenging of the risk factors to tackle.2erectile dysfunction treatment has left an indelible mark on human health. At the end of 2019, many of us in the cardiovascular health community were probably quite comfortable with business as usual and with incremental improvements in science and clinical practice.

The events of 2020 have raised the stakes, forcing us to become more accepting of disruptions (creative or otherwise). We must use this opportunity to think more boldly..

The erectile dysfunction treatment viagra continues to negatively impact population health by indirect effects on visit this web-site patient and healthcare purchase viagra systems, in addition to the direct effects of erectile dysfunction treatment itself. Accurate and quantitative information about the indirect effects of the erectile dysfunction treatment viagra on cardiovascular disease (CVD) services and outcomes will allow better public health planning. Ball and colleagues1 aim to ‘design and implement a simple tool for monitoring and visualising trends in CVD hospital services in the UK’ purchase viagra and towards that end they present pilot data from a preliminary cohort of nine UK hospitals in this issue of Heart.

Comparing 6 months in 2019–2020 (that include the erectile dysfunction treatment lockdown in the UK) to the same time period in 2018–2019, there was a 57.9% decrease in total hospital admissions and a 52.9% decrease in emergency department visits (figure 1). In addition, there was a 31%–88% decline during lockdown in procedures for treatment of cardiac, cerebrovascular and other vascular conditions.Overall hospital activity (admissions, ED attendances and erectile dysfunction treatment admissions) between 31 October 2019 and 10 May 2020 compared with the same weeks from 2018 to 2019. Lines describe the mean hospital activities in 2019–2020 (solid) and purchase viagra 2018–2019 (dotted).

Shading represents 95% CI of the respective hospital activity. The first case of erectile dysfunction treatment was on 31 January 2020 and lockdown started on 23 March 2020. ED, emergency department." data-icon-position data-hide-link-title="0">Figure 1 Overall hospital activity (admissions, ED attendances and erectile dysfunction treatment admissions) between purchase viagra 31 October 2019 and 10 May 2020 compared with the same weeks from 2018 to 2019.

Lines describe the mean hospital activities in 2019–2020 (solid) and 2018–2019 (dotted). Shading represents 95% CI of the respective hospital activity. The first case of erectile dysfunction treatment was on 31 purchase viagra January 2020 and lockdown started on 23 March 2020.

ED, emergency department.From the other side of the world, Brant and colleagues2 report the number of cardiovascular deaths in the six Brazilian cities with the greatest number of erectile dysfunction treatment deaths. They conclude. €˜Excess cardiovascular mortality was greater in the less developed purchase viagra cities, possibly associated with healthcare collapse.

Specified cardiovascular deaths decreased in the most developed cities, in parallel with an increase in unspecified cardiovascular and home deaths, presumably as a result of misdiagnosis. Conversely, specified cardiovascular deaths increased in cities with a healthcare collapse’ (figure 2).Per cent change with 95% CIs between the observed and expected number of deaths in 2020 for specified cardiovascular deaths (acute coronary syndromes and stroke) and unspecified cardiovascular diseases per selected six capital cities." data-icon-position data-hide-link-title="0">Figure 2 Per cent change with 95% CIs between the observed and expected number of deaths in 2020 for specified cardiovascular deaths (acute coronary syndromes and stroke) and unspecified cardiovascular diseases per selected six capital cities.In the accompanying editorial, Watkins3 notes that ‘Taken together, these two studies quantify what many readers of this journal have experienced firsthand. The restructuring of hospital services to cope with an influx of erectile dysfunction treatment cases, combined with social distancing measures, has severely limited access to cardiovascular care, adversely impacting patient outcomes.’ He then goes on to purchase viagra propose policy responses to reduce all-cause death among patients with CVD including deaths due to erectile dysfunction treatment or to disruptions to healthcare delivery associated with the viagra (figure 3).

His two key messages are. (1) ‘the global and national viagra responses cannot be separated from the cardiovascular health agenda’ and (2) ‘priorities for cardiovascular science must pivot, capitalising on lessons learnt during the viagra’.Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit purchase viagra the resource levels and epidemiological contexts of different countries.

Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality." data-icon-position data-hide-link-title="0">Figure 3 Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified purchase viagra to fit the resource levels and epidemiological contexts of different countries.

Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality.Other interesting papers in this issue of Heart include a study by Doris and colleagues4 showing that in adults with aortic stenosis CT quantitation of valve calcification is reproducible and demonstrates a greater rate of change in disease severity, compared with echocardiography. Guzzetti and purchase viagra Clavel5 point out that more precise measures of aortic stenosis (AS) severity will allow smaller sample sizes in clinical trials of potential medical therapies, in addition to providing insights into the pathophysiology of disease progression (figure 4).Model of AS progression.

Pathophysiological model of serial AS progression (‘aortic stenosis cascade’, in blue), along with imaging biomarkers targeting each phase (red) and potential disease-modifying treatments being currently tested in randomised clinical trials (green). 1South Korean PCSK9 inhibitors (NCT03051360). 2EAVaLL.

Early aortic valve lipoprotein(a) lowering (NCT02109614). 3SALTIRE II. Study investigating the effect of drugs used to treat osteoporosis on the progression of calcific aortic stenosis (NCT02132026).

4BASIK2. Bicuspid aortic valve stenosis and the effect of vitamin K2 on calcium metabolism on 18F-NaF PET/MRI (NCT02917525). 5EvoLVeD.

Early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with severe AS (NCT03094143). 6Early TAVR. Evaluation of transcatheter aortic valve replacement compared with surveillance for patients with asymptomatic severe aortic stenosis (NCT03042104).

18F-FDG, 18-fluorodeoxyglucose. 18F-NaF, 18-sodium fluoride. AS, aortic stenosis.

AVC, aortic valve calcification. PET, positron emission tomography. PCSK9, proprotein convertase subtilisin/kexin type 9.

TAVR, transcatheter aortic valve replacement." data-icon-position data-hide-link-title="0">Figure 4 Model of AS progression. Pathophysiological model of serial AS progression (‘aortic stenosis cascade’, in blue), along with imaging biomarkers targeting each phase (red) and potential disease-modifying treatments being currently tested in randomised clinical trials (green). 1South Korean PCSK9 inhibitors (NCT03051360).

2EAVaLL. Early aortic valve lipoprotein(a) lowering (NCT02109614). 3SALTIRE II.

Study investigating the effect of drugs used to treat osteoporosis on the progression of calcific aortic stenosis (NCT02132026). 4BASIK2. Bicuspid aortic valve stenosis and the effect of vitamin K2 on calcium metabolism on 18F-NaF PET/MRI (NCT02917525).

5EvoLVeD. Early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with severe AS (NCT03094143). 6Early TAVR.

Evaluation of transcatheter aortic valve replacement compared with surveillance for patients with asymptomatic severe aortic stenosis (NCT03042104). 18F-FDG, 18-fluorodeoxyglucose. 18F-NaF, 18-sodium fluoride.

AS, aortic stenosis. AVC, aortic valve calcification. PET, positron emission tomography.

PCSK9, proprotein convertase subtilisin/kexin type 9. TAVR, transcatheter aortic valve replacement.In a study of patients undergoing atrial fibrillation (AF) ablation, Piccini and colleagues6 found that almost 30% experienced recurrent atrial tachycardiac (AT) or AF within 3 months. However, although those without recurrent AT/AF had greater improvement in functional status, overall quality of life was similar in those with and without AT/AF recurrence.

Sridhar and Colbert7 discuss the importance of patient-reported outcomes (PROs), not just ‘hard’ clinical endpoints in clinical trials. €˜As researchers and clinicians, our goals must align with those of the patients and what they value. It is heartening to see that more and more clinical trials in cardiology and electrophysiology are incorporating PROs as important endpoints.

A slow but definite paradigm shift is occurring to incorporate therapies with a focus on improving patients’ lives, not just their hearts.’The Education in Heart article in this issue discusses the diagnosis and management of familial hypercholesterolemia.8 Our Cardiology in Focus article ‘What to do when things go wrong’ provides a thoughtful discussion of the key steps in dealing with medical error.9 The Image Challenge in this issue10 provides a concise review of a sophisticated set of possible diagnoses to consider in a patient with a new murmur and classic echocardiographic images. Be sure to look at our online Image Challenge archive with over 150 image-based multiple choice questions and answers (https://heart.bmj.com/pages/collections/image_challenges/).Global trends in cardiovascular health have reached a worrisome inflection point. Decades of innovation led to a slew of drugs, devices and programmes that translated into reduced mortality from cardiovascular diseases in many countries.

Unfortunately, progress on cardiovascular mortality since 2010 has slowed. In some countries, it has even reversed.1 Compounding the problem, political actions on cardiovascular health have been inadequate, and health systems across many low-income and middle-income countries are woefully under-resourced to scale up basic cardiovascular services. These factors could increase global health inequalities in coming decades.2erectile dysfunction treatment threatens to derail progress on cardiovascular health even furtherCardiovascular practitioners are now under greater pressure to deliver the same or better care in the context of a viagra.

erectile dysfunction treatment has hit cardiovascular care particularly hard. WHO surveys recently found that cardiovascular services have been partially or completely disrupted in nearly half of countries with community spread of erectile dysfunction treatment, raising the chance of increased cardiovascular mortality in these locations.3Two studies published in this issue of Heart shed more light on the specific effects of erectile dysfunction treatment on health systems in Brazil and the UK. Brant et al looked at cardiovascular mortality in six Brazilian capital cities.4 Ball et al tracked disruptions in acute cardiovascular services across nine UK hospitals.5 Taken together, these two studies quantify what many readers of this Journal have experienced firsthand.

The restructuring of hospital services to cope with an influx of erectile dysfunction treatment cases, combined with social distancing measures, has severely limited access to cardiovascular care, adversely impacting patient outcomes.Although Ball et al did not attempt to link reduced service delivery to mortality outcomes, other studies from the UK have estimated excess cardiovascular deaths during erectile dysfunction treatment.5 Brant et al posited that excess cardiovascular mortality in Brazil was partly due to avoidance of care (ie, increases cardiovascular deaths occurring at home).4 They also found that healthcare system collapse in more socioeconomically deprived states was associated with increased acute coronary syndrome and stroke deaths in these states, independent of the uptick in deaths at home.A comprehensive responseWhat can be done about these disruptions?. The relationship between erectile dysfunction treatment and cardiovascular health can be separated into two issues that require different responses. First, persons living with cardiovascular diseases have worse outcomes when they acquire erectile dysfunction treatment.

On the other hand, persons living with cardiovascular disease or major risk factors are also at increased risk of death from cardiovascular mechanisms (eg, thrombotic events or heart failure) when their access to acute care services is interrupted. Health systems, patients and patient-system interactions are implicated in both of these issues.Figure 1 illustrates how an appropriate policy response should consider all of the elements mentioned above, with the overarching goal being to reduce deaths from any cause (erectile dysfunction treatment or otherwise) among persons living with cardiovascular diseases or major risk factors. Importantly, the actions specified in the figure 1 can be adapted to all populations and countries, regardless of health system resource levels.

With such a framework in mind, practitioners and researchers could then structure their work and advocacy around two key messages.Message 1. The global and national viagra responses cannot be separated from the cardiovascular health agendaCritical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit the resource levels and epidemiological contexts of different countries.

Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality." data-icon-position data-hide-link-title="0">Figure 1 Critical elements of a comprehensive policy response to cardiovascular disease during erectile dysfunction treatment. The elements proposed above can be modified to fit the resource levels and epidemiological contexts of different countries.

Areas marked in red are those likely to translate into the largest short-term mortality gains. Areas marked in yellow or green, while important for prevention, health promotion or stewardship objectives, are less likely to reduce mortality.Outcomes from infectious diseases are usually worse among patients with multimorbidity, and erectile dysfunction treatment is no different. As cardiovascular practitioners, scientists and advocates, we need to articulate the substantial benefits of viagra mitigation efforts to persons living with cardiovascular diseases or risk factors.

In parallel, accelerated investment in population-level prevention efforts would reduce the future burden of cardiovascular disease on health systems and reduce the number of persons at high risk of complications from future viagras or outbreaks.In much of the global health community, investments in acute care and in cardiovascular diseases are often perceived to be non-essential—or even anti-equity—and are almost never given serious consideration within health and development programmes. We need to forcefully push back on such short-sighted thinking. Collaborators on the Disease Control Priorities Project recently released guidance for low-income and middle-income and humanitarian settings, including a list of 120 essential health services to protect during the viagra.

On value-for-money grounds, basic cardiovascular disease prevention and care are just as ‘essential’ as immunisation programmes, maternal healthcare and screening and treatment of HIV .6At the same time, locations with advanced cardiovascular care systems need guidance on how to balance the need to treat severe cardiovascular disease against the need to adapt quickly to increased erectile dysfunction treatment caseloads. Ball et al found that emergency department visits and percutaneous coronary intervention procedure rates in UK hospitals had partially rebounded by the end of May 2020.5 Assuming the top objective is to maximise health, emergency cardiac care and interventional services should be brought back online before phasing in other semi-elective vascular procedures (even if the latter provide substantial revenues to hospitals). Critically, more must be done to encourage patients with acute cardiac or neurological symptoms to seek care even in the face of potential erectile dysfunction treatment exposure.

Initiatives like the American Heart Association’s ‘Don’t Die of Doubt’ campaign7 should be examined, adapted and disseminated widely to complement supply-side efforts to improve access.Message 2. Priorities for cardiovascular science must pivot, capitalising on lessons learnt during the viagraIt is increasingly clear that viagras and emerging s, driven by globalisation and climate change, will continue to threaten health systems in the coming decades. Cardiovascular research and development priorities must adapt to this emerging reality.

We need new technologies, programmes and care systems that protect what is working during erectile dysfunction treatment and transform what is not. In addition, the viagra has illuminated—and in many cases magnified—inequalities in cardiovascular health. Cardiovascular research funders should prioritise development of truly ‘global’ public goods that can immediately benefit the health of the world’s poorest as well as vulnerable populations in the global North.2How could the cardiovascular research community make this pivot?.

Table 1 proposes several principles for cardiovascular research and development priorities amid and beyond the erectile dysfunction treatment viagra. Not every concept in table 1 will be directly applicable to every research initiative, but they could be used by funders as benchmarks for developing or revising their strategies and scoring proposals.View this table:Table 1 Proposed principles to guide cardiovascular research and development prioritiesManagement of acute coronary syndromes exemplifies the need for a research and development pivot. Our ability to reduce case fatality from acute coronary syndromes is based on prompt delivery of interventions or fibrinolysis.

Researchers and planners have worked for years to improve referral and triage systems to increase access to these life-saving technologies. Yet when viewed through the lens of erectile dysfunction treatment, it is problematic that the cornerstone of acute coronary syndrome management is early access to a referral hospital. We need new technologies, like home-based diagnostics and smartphone-based triage and referral processes, that can circumvent time and distance bottlenecks.

We also need new drugs (available at home) that bridge to interventions or replace them entirely. Such technologies are especially needed in low-income and middle-income countries, where systems are less advanced and timely access is more difficult to achieve (eg, in majority-rural countries).More generally, new technologies should ‘disrupt’ care systems in a way that makes cardiovascular care more patient-centred, community-facing and responsive to population needs. The notion that healthcare by default requires a physical building (separate from one’s home or work) should quickly become antiquated.

The greater use of telemedicine during the viagra is a big step in this direction, but we have yet to hardness the full potential of mobile devices and wearables—technologies that are already widely available and will become ubiquitous in low-income and middle-income countries much more quickly than new clinics or hospitals. Innovators and health planners in resource-limited countries could collaborate to develop ‘leapfrog’ cardiovascular health programmes that do not rely on the inefficient, slow-to-adapt and labour-intensive models used in the global North.The future of cardiovascular health and researchIn the midst of the debate over the future of cardiovascular care, we should not to lose sight of the ‘endgame’.8 In the long term, it would be far better to live in a world where the prevalence of ideal cardiovascular health is high and the lifetime disease risk is low. In such a world, the impact of another viagra on cardiovascular services and patients would be lessened greatly.

Aggressive action is needed to fully implement policies and health services that we know can help achieve this goal in a cost-effective manner. Still, in order to accomplish the endgame, we need better evidence on how to design policy instruments that can minimise dietary risks and barriers to optimal physical activity—the most challenging of the risk factors to tackle.2erectile dysfunction treatment has left an indelible mark on human health. At the end of 2019, many of us in the cardiovascular health community were probably quite comfortable with business as usual and with incremental improvements in science and clinical practice.

The events of 2020 have raised the stakes, forcing us to become more accepting of disruptions (creative or otherwise). We must use this opportunity to think more boldly..

Side effects of viagra in older men

Organizations are side effects of viagra in older men strongly encouraged to Cipro cheapest price submit a single response that reflects the views of their organization and their membership as a whole. This RFI is open for public comment for a period of five weeks. Comments must be received by 11:59:59 p.m.

(ET) on December 7, 2020 to ensure side effects of viagra in older men consideration. Start Printed Page 69336 All comments must be submitted electronically on the submission website, available at. Https://rfi.grants.nih.gov/​?.

S=​5f91a3efdb70000018003362. Start Further Info Please direct all inquiries to. Beth Walsh, nihstrategicplan@od.nih.gov, 301-496-4000.

End Further Info End Preamble Start Supplemental Information Urgent public health measures are needed to control the spread of the novel erectile dysfunction (erectile dysfunction) and the disease it causes, erectile dysfunction disease 2019, or erectile dysfunction treatment. Scientific research to improve basic understanding of erectile dysfunction and erectile dysfunction treatment, and to develop the necessary tools and approaches to better prevent, diagnose, and treat this disease is of paramount importance. The NIH-Wide Strategic Plan for erectile dysfunction treatment Research (available at.

Https://www.nih.gov/​research-training/​medical-research-initiatives/​nih-wide-strategic-plan-erectile dysfunction treatment-research), released on July 13, 2020, provides a framework for achieving this goal. It describes how NIH is rapidly mobilizing diverse stakeholders, including the biomedical research community, industry, and philanthropic organizations, through new programs and existing resources, to lead a swift, coordinated research response to this global viagra. The plan outlines how NIH is implementing five Priorities, guided by three Crosscutting Strategies.

Priorities Priority 1. Improve Fundamental Knowledge of erectile dysfunction and erectile dysfunction treatment ○ Objective 1.1. Advance fundamental research for erectile dysfunction and erectile dysfunction treatment ○ Objective 1.2.

Support research to develop preclinical models of erectile dysfunction and erectile dysfunction treatment ○ Objective 1.3. Advance the understanding of erectile dysfunction transmission and erectile dysfunction treatment dynamics at the population level ○ Objective 1.4. Understand erectile dysfunction treatment disease progression, recovery, and psychosocial and behavioral health consequences Priority 2.

Advance Detection and Diagnosis of erectile dysfunction treatment ○ Objective 2.1. Support research to develop and validate new diagnostic technologies ○ Objective 2.2. Retool existing diagnostics for detection of erectile dysfunction ○ Objective 2.3.

Support research to develop and validate serological assays Priority 3. Advance the Treatment of erectile dysfunction treatment ○ Objective 3.1. Identify and develop new or repurposed treatments for erectile dysfunction ○ Objective 3.2.

Evaluate new, repurposed, or existing treatments and treatment strategies for erectile dysfunction treatment ○ Objective 3.3. Investigate strategies for access to and implementation of erectile dysfunction treatments Priority 4. Improve Prevention of erectile dysfunction ○ Objective 4.1.

Develop novel treatments for the prevention of erectile dysfunction treatment ○ Objective 4.2. Develop and study other methods to prevent erectile dysfunction transmission ○ Objective 4.3. Develop effective implementation models for preventive measures Priority 5.

Prevent and Redress Poor erectile dysfunction treatment Outcomes in Health Disparity and Vulnerable Populations ○ Objective 5.1. Understand and address erectile dysfunction treatment as it relates to health disparities and erectile dysfunction treatment—vulnerable populations in the United States ○ Objective 5.2. Understand and address erectile dysfunction treatment maternal health and pregnancy outcomes ○ Objective 5.3.

Understand and address age-specific factors in erectile dysfunction treatment ○ Objective 5.4. Address global health research needs from erectile dysfunction treatment Crosscutting Strategies Partnering to promote collaborative science ○ Leverage existing NIH-funded global research networks and private sector, public, and non-profit relationships ○ Coordinate with Federal partners ○ Establish new public-private partnerships Supporting the research workforce and infrastructure ○ Conduct research to elucidate how erectile dysfunction treatment impacts the scientific workforce ○ Provide research resources ○ Leverage intramural infrastructure to support extramural researchers ○ Conduct virtual peer review processes Investing in data science ○ Create new data science resources and analytical tools ○ Develop shared metrics and terminologies NIH seeks comments on any or all of, but not limited to, the following topics. Significant research gaps or barriers not identified in the existing framework above.

Resources required or lacking or existing leverageable resources (e.g., existing partnerships, collaborations, or infrastructure) that could advance the strategic priorities. Emerging scientific advances or techniques in basic, diagnostic, therapeutic, or treatment research that may accelerate the research priorities detailed in the framework above. And Additional ideas for bold, innovative research initiatives, processes, or data-driven approaches that could advance the response to erectile dysfunction treatment.

NIH encourages organizations (e.g., patient advocacy groups, professional organizations) to submit a single response reflective of the views of the organization or membership as a whole. Responses to this RFI are voluntary and may be submitted anonymously. Please do not include any personally identifiable information or any information that you do not wish to make public.

Proprietary, classified, confidential, or sensitive information should not be included in your response. The Government will use the information submitted in response to this RFI at its discretion. The Government reserves the right to use any submitted information on public websites, in reports, in summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or cooperative agreement(s), or in the development of future funding opportunity announcements.

This RFI is for informational and planning purposes only and is not a solicitation for applications or an obligation on the part of the Government to provide support for any ideas identified in response to it. Please note that the Government will not pay for the preparation of any information submitted or for use of that information. We look forward to your input and hope that you will share this RFI opportunity with your colleagues.

Start Signature Dated. October 27, 2020. Lawrence A.

Tabak, Principal Deputy Director, National Institutes of Health. End Signature End Supplemental Information [FR Doc. 2020-24202 Filed 10-30-20.

8:45 am]BILLING CODE 4140-01-PSign up for our newsletter Explore full page map The language we’ve heard to describe erectile dysfunction treatment in rural America is evolving. Early in the viagra, healthcare professionals were concerned. Later, some were alarmed.

Now, what I hear sounds a lot like shock. In a story we published earlier today, Alan Morgan with the National Rural Health Association called the rural viagra a horror story. Carrie Henning-Smith with the University of Minnesota Rural Health Research Center has another word.

Ominous. That’s not the kind of comforting word we like to hear from our caregivers. But a cheerful bedside manner doesn’t seem to be doing the job with rural America.

€œI think that there was a chance early on to try to contain this, when we had this as a mostly urban phenomenon back in March and April,” said Henning-Smith, who is also an associate professor in the School of Public Health at the University of Minnesota. €œWe blew way past that. And now this has spread into virtually every county in the country, in metro and non-metro alike.” Welcome to the rural wave – the phase of the viagra that is swamping rural America with record numbers of erectile dysfunction treatment s.

Late this spring, we still had swaths of rural America – mostly in the Midwest and Great Plains – that went weeks without a single case. On June 1, nearly 9% of rural counties hadn’t reported any s. Today, only one county in the Lower 48 hasn’t reported a case of erectile dysfunction treatment.

For the rest of rural America, most of the news is bad. The rate of new s in rural counties is 65% higher than in urban counties. The number of new cases in rural America has set a record each of the last five weeks.

Seventy percent of rural counties are at risk of uncontrolled spread, what the White House erectile dysfunction Task Force calls the red zone. Something different is happening in rural America in this surge. The coastal and urban regions that bore the brunt of the summer surge look relatively contained now.

The trouble spots, as shown in the map above, are in the interior. Why is erectile dysfunction treatment surging now in these areas that got off relatively easy this summer?. Henning-Smith, who holds three master’s level degrees and a PhD, cited several possibilities.

The first may be “erectile dysfunction treatment fatigue.” “It took longer to get to rural areas and it’s hard to keep the public relentlessly engaged and being mindful and cautious as the viagra wears on,” she said. Another factor is politics, she said. €œThere are definitely some strong relationships where we’re seeing very, very mixed messaging at the highest levels of the federal government about even the most basic precautions for erectile dysfunction treatment.” And some of it is just the nature of the erectile dysfunction.

All things equal, the viagra spreads from one host to the next. Think of spreading peanut butter on toast. You won’t get it to a uniform thickness, but each swipe of the knife gets you closer.

€œ[The graphs] give every indication that rural areas will catch up to urban, and we’ll see proportional rates of erectile dysfunction treatment cases and erectile dysfunction treatment deaths in rural, relative to urban,” Henning-Smith said. Rural areas could even get worse than urban ones eventually, she said. A host of factors make that a possibility.

Rural employment may not be as suited for remote work. Services like online grocery ordering and delivery are less available in rural areas. Lack of broadband may mean rural people have to do more activities in person.

Contact tracing may not be as robust. Testing can be more challenging in less densely populated areas. Henning-Smith, whose research focuses on health equity, also said race is a factor in how erectile dysfunction treatment is spreading and what happens when it reaches a community.

€œI don’t think we’re talking enough about the intersection of [race and rurality], of the impact of structural racism among rural residents,” she said. Most people have a choice about whether to wear a mask. Fewer of us have a choice about other factors that contribute to the spread of erectile dysfunction treatment.

€œWho has the luxury of containing themselves to their household so they don’t get it?. € she said. €œWho lives in a house that’s not crowded, so they’re not spreading it to their family members?.

Who has access to healthcare, decent health insurance?. Who still has a hospital or a clinic in town to get the care that they need, if they need it?. € Tim Murphy contributed data analysis to this article.

Before You Go The Daily Yonder is a nonprofit news platform dedicated to reporting on rural people, places, and issues. Donations from readers like you makes it possible for us to fulfill this important mission. So far this year, we’ve helped readers understand where rural America fits in the erectile dysfunction treatment viagra, the 2020 election, and the fight for racial equity.

For the rest of 2020, you have a special opportunity to double your contribution to the Daily Yonder. Your gift will be matched dollar for dollar by NewsMatch, a nonprofit news funding program. All you have to do to help us get this extra support is make a gift, in any amount.

This Request for Information (RFI) is intended to gather broad purchase viagra public input on the National Institutes of Health More Info (NIH)-Wide Strategic Plan for erectile dysfunction treatment Research. Because of the urgency and evolving nature of the viagra, NIH intends this plan to be a living document, which will be continually updated to reflect new challenges presented by erectile dysfunction treatment. To ensure that it remains in step with public needs, this RFI invites stakeholders throughout the scientific research, advocacy, and clinical practice communities, as well as the general public to comment on the NIH-Wide Strategic Plan for erectile dysfunction treatment Research. Organizations are strongly encouraged to submit a single response that reflects the views of their organization and purchase viagra their membership as a whole.

This RFI is open for public comment for a period of five weeks. Comments must be received by 11:59:59 p.m. (ET) on December 7, purchase viagra 2020 to ensure consideration. Start Printed Page 69336 All comments must be submitted electronically on the submission website, available at.

Https://rfi.grants.nih.gov/​?. S=​5f91a3efdb70000018003362. Start Further Info Please direct all inquiries to. Beth Walsh, nihstrategicplan@od.nih.gov, 301-496-4000.

End Further Info End Preamble Start Supplemental Information Urgent public health measures are needed to control the spread of the novel erectile dysfunction (erectile dysfunction) and the disease it causes, erectile dysfunction disease 2019, or erectile dysfunction treatment. Scientific research to improve basic understanding of erectile dysfunction and erectile dysfunction treatment, and to develop the necessary tools and approaches to better prevent, diagnose, and treat this disease is of paramount importance. The NIH-Wide Strategic Plan for erectile dysfunction treatment Research (available at. Https://www.nih.gov/​research-training/​medical-research-initiatives/​nih-wide-strategic-plan-erectile dysfunction treatment-research), released on July 13, 2020, provides a framework for achieving this goal.

It describes how NIH is rapidly mobilizing diverse stakeholders, including the biomedical research community, industry, and philanthropic organizations, through new programs and existing resources, to lead a swift, coordinated research response to this global viagra. The plan outlines how NIH is implementing five Priorities, guided by three Crosscutting Strategies. Priorities Priority 1. Improve Fundamental Knowledge of erectile dysfunction and erectile dysfunction treatment ○ Objective 1.1.

Advance fundamental research for erectile dysfunction and erectile dysfunction treatment ○ Objective 1.2. Support research to develop preclinical models of erectile dysfunction and erectile dysfunction treatment ○ Objective 1.3. Advance the understanding of erectile dysfunction transmission and erectile dysfunction treatment dynamics at the population level ○ Objective 1.4. Understand erectile dysfunction treatment disease progression, recovery, and psychosocial and behavioral health consequences Priority 2.

Advance Detection and Diagnosis of erectile dysfunction treatment ○ Objective 2.1. Support research to develop and validate new diagnostic technologies ○ Objective 2.2. Retool existing diagnostics for detection of erectile dysfunction ○ Objective 2.3. Support research to develop and validate serological assays Priority 3.

Advance the Treatment of erectile dysfunction treatment ○ Objective 3.1. Identify and develop new or repurposed treatments for erectile dysfunction ○ Objective 3.2. Evaluate new, repurposed, or existing treatments and treatment strategies for erectile dysfunction treatment ○ Objective 3.3. Investigate strategies for access to and implementation of erectile dysfunction treatments Priority 4.

Improve Prevention of erectile dysfunction ○ Objective 4.1. Develop novel treatments for the prevention of erectile dysfunction treatment ○ Objective 4.2. Develop and study other methods to prevent erectile dysfunction transmission ○ Objective 4.3. Develop effective implementation models for preventive measures Priority 5.

Prevent and Redress Poor erectile dysfunction treatment Outcomes in Health Disparity and Vulnerable Populations ○ Objective 5.1. Understand and address erectile dysfunction treatment as it relates to health disparities and erectile dysfunction treatment—vulnerable populations in the United States ○ Objective 5.2. Understand and address erectile dysfunction treatment maternal health and pregnancy outcomes ○ Objective 5.3. Understand and address age-specific factors in erectile dysfunction treatment ○ Objective 5.4.

Address global health research needs from erectile dysfunction treatment Crosscutting Strategies Partnering to promote collaborative science ○ Leverage existing NIH-funded global research networks and private sector, public, and non-profit relationships ○ Coordinate with Federal partners ○ Establish new public-private partnerships Supporting the research workforce and infrastructure ○ Conduct research to elucidate how erectile dysfunction treatment impacts the scientific workforce ○ Provide research resources ○ Leverage intramural infrastructure to support extramural researchers ○ Conduct virtual peer review processes Investing in data science ○ Create new data science resources and analytical tools ○ Develop shared metrics and terminologies NIH seeks comments on any or all of, but not limited to, the following topics. Significant research gaps or barriers not identified in the existing framework above. Resources required or lacking or existing leverageable resources (e.g., existing partnerships, collaborations, or infrastructure) that could advance the strategic priorities. Emerging scientific advances or techniques in basic, diagnostic, therapeutic, or treatment research that may accelerate the research priorities detailed in the framework above.

And Additional ideas for bold, innovative research initiatives, processes, or data-driven approaches that could advance the response to erectile dysfunction treatment. NIH encourages organizations (e.g., patient advocacy groups, professional organizations) to submit a single response reflective of the views of the organization or membership as a whole. Responses to this RFI are voluntary and may be submitted anonymously. Please do not include any personally identifiable information or any information that you do not wish to make public.

Proprietary, classified, confidential, or sensitive information should not be included in your response. The Government will use the information submitted in response to this RFI at its discretion. The Government reserves the right to use any submitted information on public websites, in reports, in summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or cooperative agreement(s), or in the development of future funding opportunity announcements. This RFI is for informational and planning purposes only and is not a solicitation for applications or an obligation on the part of the Government to provide support for any ideas identified in response to it.

Please note that the Government will not pay for the preparation of any information submitted or for use of that information. We look forward to your input and hope that you will share this RFI opportunity with your colleagues. Start Signature Dated. October 27, 2020.

Lawrence A. Tabak, Principal Deputy Director, National Institutes of Health. End Signature End Supplemental Information [FR Doc. 2020-24202 Filed 10-30-20.

8:45 am]BILLING CODE 4140-01-PSign up for our newsletter Explore full page map The language we’ve heard to describe erectile dysfunction treatment in rural America is evolving. Early in the viagra, healthcare professionals were concerned. Later, some were alarmed. Now, what I hear sounds a lot like shock.

In a story we published earlier today, Alan Morgan with the National Rural Health Association called the rural viagra a horror story. Carrie Henning-Smith with the University of Minnesota Rural Health Research Center has another word. Ominous. That’s not the kind of comforting word we like to hear from our caregivers.

But a cheerful bedside manner doesn’t seem to be doing the job with rural America. €œI think that there was a chance early on to try to contain this, when we had this as a mostly urban phenomenon back in March and April,” said Henning-Smith, who is also an associate professor in the School of Public Health at the University of Minnesota. €œWe blew way past that. And now this has spread into virtually every county in the country, in metro and non-metro alike.” Welcome to the rural wave – the phase of the viagra that is swamping rural America with record numbers of erectile dysfunction treatment s.

Late this spring, we still had swaths of rural America – mostly in the Midwest and Great Plains – that went weeks without a single case. On June 1, nearly 9% of rural counties hadn’t reported any s. Today, only one county in the Lower 48 hasn’t reported a case of erectile dysfunction treatment. For the rest of rural America, most of the news is bad.

The rate of new s in rural counties is 65% higher than in urban counties. The number of new cases in rural America has set a record each of the last five weeks. Seventy percent of rural counties are at risk of uncontrolled spread, what the White House erectile dysfunction Task Force calls the red zone. Something different is happening in rural America in this surge.

The coastal and urban regions that bore the brunt of the summer surge look relatively contained now. The trouble spots, as shown in the map above, are in the interior. Why is erectile dysfunction treatment surging now in these areas that got off relatively easy this summer?. Henning-Smith, who holds three master’s level degrees and a PhD, cited several possibilities.

The first may be “erectile dysfunction treatment fatigue.” “It took longer to get to rural areas and it’s hard to keep the public relentlessly engaged and being mindful and cautious as the viagra wears on,” she said. Another factor is politics, she said. €œThere are definitely some strong relationships where we’re seeing very, very mixed messaging at the highest levels of the federal government about even the most basic precautions for erectile dysfunction treatment.” And some of it is just the nature of the erectile dysfunction. All things equal, the viagra spreads from one host to the next.

Think of spreading peanut butter on toast. You won’t get it to a uniform thickness, but each swipe of the knife gets you closer. €œ[The graphs] give every indication that rural areas will catch up to urban, and we’ll see proportional rates of erectile dysfunction treatment cases and erectile dysfunction treatment deaths in rural, relative to urban,” Henning-Smith said. Rural areas could even get worse than urban ones eventually, she said.

A host of factors make that a possibility. Rural employment may not be as suited for remote work. Services like online grocery ordering and delivery are less available in rural areas. Lack of broadband may mean rural people have to do more activities in person.

Contact tracing may not be as robust. Testing can be more challenging in less densely populated areas. Henning-Smith, whose research focuses on health equity, also said race is a factor in how erectile dysfunction treatment is spreading and what happens when it reaches a community. €œI don’t think we’re talking enough about the intersection of [race and rurality], of the impact of structural racism among rural residents,” she said.

Most people have a choice about whether to wear a mask. Fewer of us have a choice about other factors that contribute to the spread of erectile dysfunction treatment. €œWho has the luxury of containing themselves to their household so they don’t get it?. € she said.

€œWho lives in a house that’s not crowded, so they’re not spreading it to their family members?. Who has access to healthcare, decent health insurance?. Who still has a hospital or a clinic in town to get the care that they need, if they need it?. € Tim Murphy contributed data analysis to this article.

Before You Go The Daily Yonder is a nonprofit news platform dedicated to reporting on rural people, places, and issues. Donations from readers like you makes it possible for us to fulfill this important mission. So far this year, we’ve helped readers understand where rural America fits in the erectile dysfunction treatment viagra, the 2020 election, and the fight for racial equity. For the rest of 2020, you have a special opportunity to double your contribution to the Daily Yonder.