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Regional differences in surgical outcomes could unfairly skew bundled payments
Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.
The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.
All hospitals with a minimum of 20 evaluable colorectal resection cases from the master data set regardless of coding quality were identified for comparative outcomes. For hospital analysis, the total number of patients with one or more adverse outcomes (AOs) was tabulated. The total predicted AOs were then set equal to the number of observed events for each hospital by multiplication of the hospital-specific predicted value by the ratio of observed-to-predicted events for the entire final hospital population of patients.
Hospitals were then sorted by the nine Census Bureau regions: region 1 (New England), region 2 (Middle Atlantic), region 3 (South Atlantic), region 4 (East South Central), region 5 (West South Central), region 6 (East North Central), region 7 (West North Central), region 8 (Mountain), and region 9 (Pacific).
Within each region, total patients, total observed AOs, and total predicted AOs were derived from the prediction models. Region-specific standard deviations (SDs) were computed and overall region z scores and risk-adjusted AO rates were calculated for comparison.
A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).
Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.
Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
What findings could mean for bundled payments
The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.
“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.
The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.
Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.
A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.
“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”
By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.
“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
Perspectives on the study
However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.
“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”
“The overall average adverse outcome in the study was 24.3%, but 16.8% of that 24% is due to readmissions,” he said in an interview. “Length of stay and readmissions are correlated – people who tend to have long lengths of stay tend to be readmitted. If you add those two rates together in the study, almost all of the outcome rate is the length of stay and readmissions. You could argue [that] mortality [should] be more heavily weighted than length of stay and readmissions.”
In regard to adjusting risk by region, there is good research that utilization of procedures varies dramatically by region and that some of this variation may have more to do with overutilization of procedures, Dr. Pitt added.
“I would think that risk adjusting for type of operation, diagnosis, and socioeconomic status –across the country – would be more appropriate than risk adjusting by region where there may be major differences in patient selection and indication for operation,” he said.
For example, there is currently an international debate about the management of diverticulitis, including whether and when to operate as well as what procedure(s) to perform.
“It may be in one region, there’s a very low threshold to operate, whereas in another region, there’s a high threshold to operate,” he said. “And the operations that are done may be very different in one region than another.”
Dr. Fry and his colleagues are planning future research in this area, and he said he hopes their studies will impact how the CMS rolls out its bundled payment programs in the future.
“What we’re trying to stimulate is for payment models to be nationally indexed and not regionally indexed,” he said. “CMS is doing that now with [Medicare Severity–Diagnosis Related Groups]. They are paying a price for a total joint replacement, a price for a colon resection, a price for a heart operation – and they do make adjustments based on the local wage and price index, but the core payment is linked to a national payment model, and that’s what we would like to see happen with the bundled payment initiative.”
[email protected]
On Twitter @legal_med
Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.
The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.
All hospitals with a minimum of 20 evaluable colorectal resection cases from the master data set regardless of coding quality were identified for comparative outcomes. For hospital analysis, the total number of patients with one or more adverse outcomes (AOs) was tabulated. The total predicted AOs were then set equal to the number of observed events for each hospital by multiplication of the hospital-specific predicted value by the ratio of observed-to-predicted events for the entire final hospital population of patients.
Hospitals were then sorted by the nine Census Bureau regions: region 1 (New England), region 2 (Middle Atlantic), region 3 (South Atlantic), region 4 (East South Central), region 5 (West South Central), region 6 (East North Central), region 7 (West North Central), region 8 (Mountain), and region 9 (Pacific).
Within each region, total patients, total observed AOs, and total predicted AOs were derived from the prediction models. Region-specific standard deviations (SDs) were computed and overall region z scores and risk-adjusted AO rates were calculated for comparison.
A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).
Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.
Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
What findings could mean for bundled payments
The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.
“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.
The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.
Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.
A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.
“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”
By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.
“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
Perspectives on the study
However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.
“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”
“The overall average adverse outcome in the study was 24.3%, but 16.8% of that 24% is due to readmissions,” he said in an interview. “Length of stay and readmissions are correlated – people who tend to have long lengths of stay tend to be readmitted. If you add those two rates together in the study, almost all of the outcome rate is the length of stay and readmissions. You could argue [that] mortality [should] be more heavily weighted than length of stay and readmissions.”
In regard to adjusting risk by region, there is good research that utilization of procedures varies dramatically by region and that some of this variation may have more to do with overutilization of procedures, Dr. Pitt added.
“I would think that risk adjusting for type of operation, diagnosis, and socioeconomic status –across the country – would be more appropriate than risk adjusting by region where there may be major differences in patient selection and indication for operation,” he said.
For example, there is currently an international debate about the management of diverticulitis, including whether and when to operate as well as what procedure(s) to perform.
“It may be in one region, there’s a very low threshold to operate, whereas in another region, there’s a high threshold to operate,” he said. “And the operations that are done may be very different in one region than another.”
Dr. Fry and his colleagues are planning future research in this area, and he said he hopes their studies will impact how the CMS rolls out its bundled payment programs in the future.
“What we’re trying to stimulate is for payment models to be nationally indexed and not regionally indexed,” he said. “CMS is doing that now with [Medicare Severity–Diagnosis Related Groups]. They are paying a price for a total joint replacement, a price for a colon resection, a price for a heart operation – and they do make adjustments based on the local wage and price index, but the core payment is linked to a national payment model, and that’s what we would like to see happen with the bundled payment initiative.”
[email protected]
On Twitter @legal_med
Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.
The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.
All hospitals with a minimum of 20 evaluable colorectal resection cases from the master data set regardless of coding quality were identified for comparative outcomes. For hospital analysis, the total number of patients with one or more adverse outcomes (AOs) was tabulated. The total predicted AOs were then set equal to the number of observed events for each hospital by multiplication of the hospital-specific predicted value by the ratio of observed-to-predicted events for the entire final hospital population of patients.
Hospitals were then sorted by the nine Census Bureau regions: region 1 (New England), region 2 (Middle Atlantic), region 3 (South Atlantic), region 4 (East South Central), region 5 (West South Central), region 6 (East North Central), region 7 (West North Central), region 8 (Mountain), and region 9 (Pacific).
Within each region, total patients, total observed AOs, and total predicted AOs were derived from the prediction models. Region-specific standard deviations (SDs) were computed and overall region z scores and risk-adjusted AO rates were calculated for comparison.
A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).
Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.
Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
What findings could mean for bundled payments
The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.
“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.
The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.
Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.
A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.
“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”
By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.
“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
Perspectives on the study
However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.
“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”
“The overall average adverse outcome in the study was 24.3%, but 16.8% of that 24% is due to readmissions,” he said in an interview. “Length of stay and readmissions are correlated – people who tend to have long lengths of stay tend to be readmitted. If you add those two rates together in the study, almost all of the outcome rate is the length of stay and readmissions. You could argue [that] mortality [should] be more heavily weighted than length of stay and readmissions.”
In regard to adjusting risk by region, there is good research that utilization of procedures varies dramatically by region and that some of this variation may have more to do with overutilization of procedures, Dr. Pitt added.
“I would think that risk adjusting for type of operation, diagnosis, and socioeconomic status –across the country – would be more appropriate than risk adjusting by region where there may be major differences in patient selection and indication for operation,” he said.
For example, there is currently an international debate about the management of diverticulitis, including whether and when to operate as well as what procedure(s) to perform.
“It may be in one region, there’s a very low threshold to operate, whereas in another region, there’s a high threshold to operate,” he said. “And the operations that are done may be very different in one region than another.”
Dr. Fry and his colleagues are planning future research in this area, and he said he hopes their studies will impact how the CMS rolls out its bundled payment programs in the future.
“What we’re trying to stimulate is for payment models to be nationally indexed and not regionally indexed,” he said. “CMS is doing that now with [Medicare Severity–Diagnosis Related Groups]. They are paying a price for a total joint replacement, a price for a colon resection, a price for a heart operation – and they do make adjustments based on the local wage and price index, but the core payment is linked to a national payment model, and that’s what we would like to see happen with the bundled payment initiative.”
[email protected]
On Twitter @legal_med
Pembrolizumab and Nivolumab May Cause Neurologic Events
Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.
Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.
—Amy Karon
Suggested Reading
Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].
Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.
Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.
—Amy Karon
Suggested Reading
Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].
Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.
Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.
—Amy Karon
Suggested Reading
Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].
Biosimilar matches rituximab in large follicular lymphoma trial
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
AT ESMO 2017
Key clinical point:
Major finding: The objective response rates were 87.1% and 87.5% for G-CVP and R-CVP.
Data source: Double-blind, multicenter randomized trial of 629 patients with previously untreated, advanced-stage follicular lymphoma.
Disclosures: Dr. Jurczak reported financial relationships with Sandoz.
Analysis: Actual cancer drug R&D costs are far less than widely publicized sum
Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.
The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.
Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.
Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.
Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).
Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.
The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.
“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”
Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.
Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.
[email protected]
On Twitter @legal_med
To counter increasing public alarm over high drug prices, industry leaders regularly assert that the substantial investment in researching and developing new products, and the riskiness of that enterprise, justify charging Americans the highest prices in the world for medicines.
To support the assertion, the industry’s trade group relies on an industry-funded study first produced in 1979 by the Tufts University Center for the Study of Drug Development. The most recent iteration of the study, updated in 2014, claims it takes more than 10 years and nearly $2.7 billion in capital to develop a single drug. In inflation-adjusted dollars, the study’s estimate for developing a new drug has more than doubled in the past decade and is more than 10 times the original 1979 figure.
In this issue of JAMA Internal Medicine, study authors Vinay Prasad, MD, MPH, and Sham Mailankody, MBBS, report that the actual cost of developing a new drug is approximately one-fourth the Tufts study estimate. The implications of the present study seem clear. Current pharmaceutical industry pricing policies are unrelated to the cost of research and development. Policymakers can safely take steps to rein in drug prices without fear of jeopardizing innovation.
Merrill Goozner is editor emeritus for Modern Healthcare in Chicago. He is also author of “The $800 Million Pill: The Truth Behind the Cost of New Drugs.” He made these remarks in an invited commentary accompanying the study (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.4997).
To counter increasing public alarm over high drug prices, industry leaders regularly assert that the substantial investment in researching and developing new products, and the riskiness of that enterprise, justify charging Americans the highest prices in the world for medicines.
To support the assertion, the industry’s trade group relies on an industry-funded study first produced in 1979 by the Tufts University Center for the Study of Drug Development. The most recent iteration of the study, updated in 2014, claims it takes more than 10 years and nearly $2.7 billion in capital to develop a single drug. In inflation-adjusted dollars, the study’s estimate for developing a new drug has more than doubled in the past decade and is more than 10 times the original 1979 figure.
In this issue of JAMA Internal Medicine, study authors Vinay Prasad, MD, MPH, and Sham Mailankody, MBBS, report that the actual cost of developing a new drug is approximately one-fourth the Tufts study estimate. The implications of the present study seem clear. Current pharmaceutical industry pricing policies are unrelated to the cost of research and development. Policymakers can safely take steps to rein in drug prices without fear of jeopardizing innovation.
Merrill Goozner is editor emeritus for Modern Healthcare in Chicago. He is also author of “The $800 Million Pill: The Truth Behind the Cost of New Drugs.” He made these remarks in an invited commentary accompanying the study (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.4997).
To counter increasing public alarm over high drug prices, industry leaders regularly assert that the substantial investment in researching and developing new products, and the riskiness of that enterprise, justify charging Americans the highest prices in the world for medicines.
To support the assertion, the industry’s trade group relies on an industry-funded study first produced in 1979 by the Tufts University Center for the Study of Drug Development. The most recent iteration of the study, updated in 2014, claims it takes more than 10 years and nearly $2.7 billion in capital to develop a single drug. In inflation-adjusted dollars, the study’s estimate for developing a new drug has more than doubled in the past decade and is more than 10 times the original 1979 figure.
In this issue of JAMA Internal Medicine, study authors Vinay Prasad, MD, MPH, and Sham Mailankody, MBBS, report that the actual cost of developing a new drug is approximately one-fourth the Tufts study estimate. The implications of the present study seem clear. Current pharmaceutical industry pricing policies are unrelated to the cost of research and development. Policymakers can safely take steps to rein in drug prices without fear of jeopardizing innovation.
Merrill Goozner is editor emeritus for Modern Healthcare in Chicago. He is also author of “The $800 Million Pill: The Truth Behind the Cost of New Drugs.” He made these remarks in an invited commentary accompanying the study (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.4997).
Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.
The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.
Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.
Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.
Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).
Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.
The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.
“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”
Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.
Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.
[email protected]
On Twitter @legal_med
Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.
The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.
Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.
Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.
Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).
Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.
The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.
“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”
Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.
Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.
[email protected]
On Twitter @legal_med
FROM JAMA INTERNAL MEDICINE
Key clinical point:
Major finding: The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion.
Data source: A case study of U.S. Securities and Exchange Commission filings for drug companies that received approval by the Food and Drug Administration for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015.
Disclosures: Dr. Mailankody reported serving as principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush PacGrow Healthcare Conference 2016. No other disclosures were reported.
WHI hormone trials offer reassurance on long-term mortality risk
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
The findings from the Women’s Health Initiative hormone therapy trials as reported by Dr. Manson and her colleagues expand the understanding of the long-term risks and benefits of hormone therapy, which is an important issue for women around the world, Melissa A. McNeil, MD, wrote in an editorial.
The information will be helpful for counseling women considering whether to start hormone therapy, and “hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” she said, explaining that the effect of hormone therapy on cancer mortality, and especially on breast cancer mortality, has generated concern and reluctance to prescribe and take hormone therapy for troubling menopausal symptoms.
“The current report ... provides substantial reassurance for patients and physicians about this issue,” she said. “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious.”
While several questions remain, including about optimal duration of therapy, whether there is a difference in mortality by age and menopausal status at hormone therapy initiation, and if earlier initiation would provide additional benefits, the data “fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration,” she wrote.
Dr. McNeil is with the University of Pittsburgh. She reported having no financial disclosures. Her comments come from an accompanying editorial (JAMA. 2017 Sep;318[10]:911-13).
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.
All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.
For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).
Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.
An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.
The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.
“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”
They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”
The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
FROM JAMA
Key clinical point:
Major finding: All-cause mortality was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99).
Data source: The randomized, double-blind, placebo-controlled Women’s Health Initiative hormone therapy trials of 27,347 women.
Disclosures: The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.
Blood Test Accurately Detects GLUT1 Deficiency Syndrome
A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.
To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.
Analysis of Red Blood Cells
Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.
For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.
Age Did Not Affect Test Results
GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.
The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.
Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.
—Erik Greb
Suggested Reading
Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.
A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.
To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.
Analysis of Red Blood Cells
Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.
For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.
Age Did Not Affect Test Results
GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.
The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.
Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.
—Erik Greb
Suggested Reading
Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.
A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.
To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.
Analysis of Red Blood Cells
Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.
For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.
Age Did Not Affect Test Results
GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.
The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.
Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.
—Erik Greb
Suggested Reading
Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.
FDA advisory committee rejects opioids in children’s cough syrup
ROCKVILLE, MD – The majority of
The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.
On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.
This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years. 
For hydrocodone, the committee asked two questions: 1) Was the benefit versus risk favorable for pediatric patients aged 6 years to less than 12 years? and 2) Was the benefit versus risk favorable for pediatric patients aged 12 years to less than 18 years? On the vote for patients aged 6 years to less than 12 years, the committee voted 23 no, 1 yes with no abstention. For the patients aged 12 years to less than 18, the committee voted 23 no, 1 yes, with no abstention.
According to Sharon Levy, MD, MPH, adolescents are the most at-risk population for opioid misuse. This susceptibility is due to the developmental neurobiology of adolescent brains. A region of the brain associated with the reward pathway, nucleus accumbens, is developing in adolescents and plays a role in salience. Salience, or the differentiation between important vs. unimportant rewards, varies widely by age group. Young children show little salience with rewards, and treat rewards equivocally. Adults have a proportional response to rewards with accurate salience. Adolescents, on the other hand, are unhappy with small rewards, but receive a massive return with large rewards. This type of neurobiological feedback makes adolescents “vulnerable to develop substance use disorders.”
Dr. Levy also noted a correlation between prescribed opioid use and alcohol, marijuana, and tobacco use as contributing factors to opioid misuse. When opioids are prescribed for pain management, there is an adjusted odds ratio (AOR) of 1.33, indicating a high likelihood of misuse. Similar AORs are seen in adolescents who have used marijuana, cigarettes, and alcohol: 2.44, 1.25, and 1.23, respectively.
Sovereign pharmaceuticals representative Leonard Lawrence presented the findings of a pharmacokinetic study for hydrocodone and guaifenesin in 25-35 pediatric patients evenly divided into groups aged 6 years to less than 12 years, and 12 years to less than 18 years. According to Mr. Lawrence, codeine appears “to be a greater risk in children younger than 12 years, and should not be used” because of difficulty breathing. Mr Lawrence went on to say that these effects were exacerbated in obese children with lung disease or obstructive sleep apnea.
Victor S. Sloan, MD, of UCB in Brussels, presented an internal review of Tussionex, a combination cough medicine (hydrocodone/chlorpheniramine). This review took into account modern pharmacovigilance methods, changes in clinical practice, and a literature review. “Upon annual review, UCB determined that benefit risk balance for use of Tussionex for cough in children was no longer favorable,” said Dr. Sloan. Based on the results of the review, UCB has filed a label supplement to limit use of Tussionex to patients aged 18 years or older.
“Codeine, in particular, is an antiquated drug,” said Kathleen Neville, MD, pediatrics and clinical pharmacology section chief of Arkansas Children’s Hospital, Little Rock. Many of the committee members echoed Dr. Neville’s opinion.
The committee members had no relevant financial disclosures.
[email protected]
On Twitter @ilacy_19
ROCKVILLE, MD – The majority of
The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.
On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.
This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years.
For hydrocodone, the committee asked two questions: 1) Was the benefit versus risk favorable for pediatric patients aged 6 years to less than 12 years? and 2) Was the benefit versus risk favorable for pediatric patients aged 12 years to less than 18 years? On the vote for patients aged 6 years to less than 12 years, the committee voted 23 no, 1 yes with no abstention. For the patients aged 12 years to less than 18, the committee voted 23 no, 1 yes, with no abstention.
According to Sharon Levy, MD, MPH, adolescents are the most at-risk population for opioid misuse. This susceptibility is due to the developmental neurobiology of adolescent brains. A region of the brain associated with the reward pathway, nucleus accumbens, is developing in adolescents and plays a role in salience. Salience, or the differentiation between important vs. unimportant rewards, varies widely by age group. Young children show little salience with rewards, and treat rewards equivocally. Adults have a proportional response to rewards with accurate salience. Adolescents, on the other hand, are unhappy with small rewards, but receive a massive return with large rewards. This type of neurobiological feedback makes adolescents “vulnerable to develop substance use disorders.”
Dr. Levy also noted a correlation between prescribed opioid use and alcohol, marijuana, and tobacco use as contributing factors to opioid misuse. When opioids are prescribed for pain management, there is an adjusted odds ratio (AOR) of 1.33, indicating a high likelihood of misuse. Similar AORs are seen in adolescents who have used marijuana, cigarettes, and alcohol: 2.44, 1.25, and 1.23, respectively.
Sovereign pharmaceuticals representative Leonard Lawrence presented the findings of a pharmacokinetic study for hydrocodone and guaifenesin in 25-35 pediatric patients evenly divided into groups aged 6 years to less than 12 years, and 12 years to less than 18 years. According to Mr. Lawrence, codeine appears “to be a greater risk in children younger than 12 years, and should not be used” because of difficulty breathing. Mr Lawrence went on to say that these effects were exacerbated in obese children with lung disease or obstructive sleep apnea.
Victor S. Sloan, MD, of UCB in Brussels, presented an internal review of Tussionex, a combination cough medicine (hydrocodone/chlorpheniramine). This review took into account modern pharmacovigilance methods, changes in clinical practice, and a literature review. “Upon annual review, UCB determined that benefit risk balance for use of Tussionex for cough in children was no longer favorable,” said Dr. Sloan. Based on the results of the review, UCB has filed a label supplement to limit use of Tussionex to patients aged 18 years or older.
“Codeine, in particular, is an antiquated drug,” said Kathleen Neville, MD, pediatrics and clinical pharmacology section chief of Arkansas Children’s Hospital, Little Rock. Many of the committee members echoed Dr. Neville’s opinion.
The committee members had no relevant financial disclosures.
[email protected]
On Twitter @ilacy_19
ROCKVILLE, MD – The majority of
The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.
On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.
This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years.
For hydrocodone, the committee asked two questions: 1) Was the benefit versus risk favorable for pediatric patients aged 6 years to less than 12 years? and 2) Was the benefit versus risk favorable for pediatric patients aged 12 years to less than 18 years? On the vote for patients aged 6 years to less than 12 years, the committee voted 23 no, 1 yes with no abstention. For the patients aged 12 years to less than 18, the committee voted 23 no, 1 yes, with no abstention.
According to Sharon Levy, MD, MPH, adolescents are the most at-risk population for opioid misuse. This susceptibility is due to the developmental neurobiology of adolescent brains. A region of the brain associated with the reward pathway, nucleus accumbens, is developing in adolescents and plays a role in salience. Salience, or the differentiation between important vs. unimportant rewards, varies widely by age group. Young children show little salience with rewards, and treat rewards equivocally. Adults have a proportional response to rewards with accurate salience. Adolescents, on the other hand, are unhappy with small rewards, but receive a massive return with large rewards. This type of neurobiological feedback makes adolescents “vulnerable to develop substance use disorders.”
Dr. Levy also noted a correlation between prescribed opioid use and alcohol, marijuana, and tobacco use as contributing factors to opioid misuse. When opioids are prescribed for pain management, there is an adjusted odds ratio (AOR) of 1.33, indicating a high likelihood of misuse. Similar AORs are seen in adolescents who have used marijuana, cigarettes, and alcohol: 2.44, 1.25, and 1.23, respectively.
Sovereign pharmaceuticals representative Leonard Lawrence presented the findings of a pharmacokinetic study for hydrocodone and guaifenesin in 25-35 pediatric patients evenly divided into groups aged 6 years to less than 12 years, and 12 years to less than 18 years. According to Mr. Lawrence, codeine appears “to be a greater risk in children younger than 12 years, and should not be used” because of difficulty breathing. Mr Lawrence went on to say that these effects were exacerbated in obese children with lung disease or obstructive sleep apnea.
Victor S. Sloan, MD, of UCB in Brussels, presented an internal review of Tussionex, a combination cough medicine (hydrocodone/chlorpheniramine). This review took into account modern pharmacovigilance methods, changes in clinical practice, and a literature review. “Upon annual review, UCB determined that benefit risk balance for use of Tussionex for cough in children was no longer favorable,” said Dr. Sloan. Based on the results of the review, UCB has filed a label supplement to limit use of Tussionex to patients aged 18 years or older.
“Codeine, in particular, is an antiquated drug,” said Kathleen Neville, MD, pediatrics and clinical pharmacology section chief of Arkansas Children’s Hospital, Little Rock. Many of the committee members echoed Dr. Neville’s opinion.
The committee members had no relevant financial disclosures.
[email protected]
On Twitter @ilacy_19
AT AN FDA PEDIATRIC ADVISORY COMMITTEE MEETING
Ten-year outcomes support skipping axillary lymph node dissection with positive sentinel nodes
A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.
Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.
Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.
After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).
“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).
A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.
Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.
Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.
After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).
“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).
A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.
Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.
Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.
After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).
“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).
FROM JAMA
Microneedling With Stem Cells
Incidental hip CT scans could serve as osteoporosis screen
DENVER – Computed tomography (CT) scans that were taken for an unrelated purpose could potentially be used to screen for osteoporosis, according to a new study. Researchers analyzed data from CT scans that produced estimates of bone mineral density (BMD) and femoral strength, and these performed similarly to dual-energy X-ray absorptiometry (DXA) in predicting fracture risk.
“The neat thing is that there’s no additional burden to the patients, because they’ve already had the CT scan. There’s no additional radiation exposure, no additional trip to the office. Another advantage to this is there are so many more men who are getting CT scans than there are who are getting DXAs for osteoporosis, so it’s an opportunity to screen more men,” Annette Adams, PhD, research scientist at Kaiser Permanente of Southern California, said in an interview at the annual meeting of the American Society for Bone and Mineral Research.
To test the potential of the CT scans, the researchers conducted a case-control cohort analysis of patients aged 65 and over who were seen at 11 Kaiser Permanente Southern California (KPSC) hospitals. The patients had undergone abdominal or pelvic CT between 2006 and 2014. They had not experienced a fragility hip fracture before the CT scan was taken, but they had to have undergone a DXA within 3 years of the scan.
A total of 1,340 women and 619 men had a first hip fracture during the study period. They were compared to randomly selected subjects without hip fractures.
The researchers found associations between hip fractures and CT-based scores, and the relationships were stronger than those seen with DXA. In women, for each decrease in one standard deviation (SD) in hip BMD T-score, the hazard ratio (HR) for hip fracture was 2.18 (95% confidence interval [CI], 1.87-2.54). In men, the HR was 3.12 (2.35-4.14). The HRs for hip fracture based on DXA hip BMD T-score values were 1.80 (95% CI, 1.53-2.13) for women and 2.74 (95% CI, 2.15-3.49) for men.
CT-derived femoral strength values also performed well. In women, each one SD decrease in femoral strength seen in the CT-based scores was associated with an HR of 2.76 (95% CI, 2.25-3.39). In men, the value was HR 2.84 (95% CI, 2.20-3.66).
In a subanalysis of subjects who had not received osteoporosis treatment, for each one SD decrease in hip BMD T-score, the HR for hip fracture was 2.72 (95% CI, 2.24-3.32) in women and 3.93 (95% CI, 2.46-6.26) in men.
In untreated patients, each increase of one SD in femoral strength was tied to an HR in women of 3.81 (95% CI, 2.90-5.01) and 3.37 (95% CI, 2.27-5.01) in men.
The addition of established thresholds for osteoporosis (BMD T-score –2.5 or less) as well as fragile bone strength (3,000 Newtons or less in women, 3,500 Newtons or less in men) increased the 5-year sensitivity for hip fracture from 0.55 to 0.67 in women, and from 0.43 to 0.54 in men.
The technique is not yet ready for large-scale implementation because the process isn’t yet completely automated – it requires human review to eliminate some glitches, and that is likely to make it cost ineffective for now, Sally Warner, PhD, said in an interview. Dr. Warner is senior director of musculoskeletal imaging at Parexel, and was not involved in the study.
But she was nevertheless enthusiastic. “CT is such a great modality to be able to look at bone and interpret the density, the volume, the quality of the bone. It’s got great potential utility,” she said.
She said she thinks it will become cost-effective in time. “As long as the acquisition is standardized, I’m sure the automation could come a little bit more readily,” Dr. Warner said.
Amgen and Merck funded the study. Dr. Adams has received research funding from both companies. Dr. Warner reported having no financial disclosures.
DENVER – Computed tomography (CT) scans that were taken for an unrelated purpose could potentially be used to screen for osteoporosis, according to a new study. Researchers analyzed data from CT scans that produced estimates of bone mineral density (BMD) and femoral strength, and these performed similarly to dual-energy X-ray absorptiometry (DXA) in predicting fracture risk.
“The neat thing is that there’s no additional burden to the patients, because they’ve already had the CT scan. There’s no additional radiation exposure, no additional trip to the office. Another advantage to this is there are so many more men who are getting CT scans than there are who are getting DXAs for osteoporosis, so it’s an opportunity to screen more men,” Annette Adams, PhD, research scientist at Kaiser Permanente of Southern California, said in an interview at the annual meeting of the American Society for Bone and Mineral Research.
To test the potential of the CT scans, the researchers conducted a case-control cohort analysis of patients aged 65 and over who were seen at 11 Kaiser Permanente Southern California (KPSC) hospitals. The patients had undergone abdominal or pelvic CT between 2006 and 2014. They had not experienced a fragility hip fracture before the CT scan was taken, but they had to have undergone a DXA within 3 years of the scan.
A total of 1,340 women and 619 men had a first hip fracture during the study period. They were compared to randomly selected subjects without hip fractures.
The researchers found associations between hip fractures and CT-based scores, and the relationships were stronger than those seen with DXA. In women, for each decrease in one standard deviation (SD) in hip BMD T-score, the hazard ratio (HR) for hip fracture was 2.18 (95% confidence interval [CI], 1.87-2.54). In men, the HR was 3.12 (2.35-4.14). The HRs for hip fracture based on DXA hip BMD T-score values were 1.80 (95% CI, 1.53-2.13) for women and 2.74 (95% CI, 2.15-3.49) for men.
CT-derived femoral strength values also performed well. In women, each one SD decrease in femoral strength seen in the CT-based scores was associated with an HR of 2.76 (95% CI, 2.25-3.39). In men, the value was HR 2.84 (95% CI, 2.20-3.66).
In a subanalysis of subjects who had not received osteoporosis treatment, for each one SD decrease in hip BMD T-score, the HR for hip fracture was 2.72 (95% CI, 2.24-3.32) in women and 3.93 (95% CI, 2.46-6.26) in men.
In untreated patients, each increase of one SD in femoral strength was tied to an HR in women of 3.81 (95% CI, 2.90-5.01) and 3.37 (95% CI, 2.27-5.01) in men.
The addition of established thresholds for osteoporosis (BMD T-score –2.5 or less) as well as fragile bone strength (3,000 Newtons or less in women, 3,500 Newtons or less in men) increased the 5-year sensitivity for hip fracture from 0.55 to 0.67 in women, and from 0.43 to 0.54 in men.
The technique is not yet ready for large-scale implementation because the process isn’t yet completely automated – it requires human review to eliminate some glitches, and that is likely to make it cost ineffective for now, Sally Warner, PhD, said in an interview. Dr. Warner is senior director of musculoskeletal imaging at Parexel, and was not involved in the study.
But she was nevertheless enthusiastic. “CT is such a great modality to be able to look at bone and interpret the density, the volume, the quality of the bone. It’s got great potential utility,” she said.
She said she thinks it will become cost-effective in time. “As long as the acquisition is standardized, I’m sure the automation could come a little bit more readily,” Dr. Warner said.
Amgen and Merck funded the study. Dr. Adams has received research funding from both companies. Dr. Warner reported having no financial disclosures.
DENVER – Computed tomography (CT) scans that were taken for an unrelated purpose could potentially be used to screen for osteoporosis, according to a new study. Researchers analyzed data from CT scans that produced estimates of bone mineral density (BMD) and femoral strength, and these performed similarly to dual-energy X-ray absorptiometry (DXA) in predicting fracture risk.
“The neat thing is that there’s no additional burden to the patients, because they’ve already had the CT scan. There’s no additional radiation exposure, no additional trip to the office. Another advantage to this is there are so many more men who are getting CT scans than there are who are getting DXAs for osteoporosis, so it’s an opportunity to screen more men,” Annette Adams, PhD, research scientist at Kaiser Permanente of Southern California, said in an interview at the annual meeting of the American Society for Bone and Mineral Research.
To test the potential of the CT scans, the researchers conducted a case-control cohort analysis of patients aged 65 and over who were seen at 11 Kaiser Permanente Southern California (KPSC) hospitals. The patients had undergone abdominal or pelvic CT between 2006 and 2014. They had not experienced a fragility hip fracture before the CT scan was taken, but they had to have undergone a DXA within 3 years of the scan.
A total of 1,340 women and 619 men had a first hip fracture during the study period. They were compared to randomly selected subjects without hip fractures.
The researchers found associations between hip fractures and CT-based scores, and the relationships were stronger than those seen with DXA. In women, for each decrease in one standard deviation (SD) in hip BMD T-score, the hazard ratio (HR) for hip fracture was 2.18 (95% confidence interval [CI], 1.87-2.54). In men, the HR was 3.12 (2.35-4.14). The HRs for hip fracture based on DXA hip BMD T-score values were 1.80 (95% CI, 1.53-2.13) for women and 2.74 (95% CI, 2.15-3.49) for men.
CT-derived femoral strength values also performed well. In women, each one SD decrease in femoral strength seen in the CT-based scores was associated with an HR of 2.76 (95% CI, 2.25-3.39). In men, the value was HR 2.84 (95% CI, 2.20-3.66).
In a subanalysis of subjects who had not received osteoporosis treatment, for each one SD decrease in hip BMD T-score, the HR for hip fracture was 2.72 (95% CI, 2.24-3.32) in women and 3.93 (95% CI, 2.46-6.26) in men.
In untreated patients, each increase of one SD in femoral strength was tied to an HR in women of 3.81 (95% CI, 2.90-5.01) and 3.37 (95% CI, 2.27-5.01) in men.
The addition of established thresholds for osteoporosis (BMD T-score –2.5 or less) as well as fragile bone strength (3,000 Newtons or less in women, 3,500 Newtons or less in men) increased the 5-year sensitivity for hip fracture from 0.55 to 0.67 in women, and from 0.43 to 0.54 in men.
The technique is not yet ready for large-scale implementation because the process isn’t yet completely automated – it requires human review to eliminate some glitches, and that is likely to make it cost ineffective for now, Sally Warner, PhD, said in an interview. Dr. Warner is senior director of musculoskeletal imaging at Parexel, and was not involved in the study.
But she was nevertheless enthusiastic. “CT is such a great modality to be able to look at bone and interpret the density, the volume, the quality of the bone. It’s got great potential utility,” she said.
She said she thinks it will become cost-effective in time. “As long as the acquisition is standardized, I’m sure the automation could come a little bit more readily,” Dr. Warner said.
Amgen and Merck funded the study. Dr. Adams has received research funding from both companies. Dr. Warner reported having no financial disclosures.
AT ASBMR
Key clinical point: Use of existing abdominal or pelvic CT scans may serve as a way to screen for osteoporosis without the need for dual-energy x-ray absorptiometry.
Major finding: For each decrease in one standard deviation in CT-derived hip BMD T-score, the hazard ratio for hip fracture was 2.18 in women and 3.12 in men.
Data source: A case-control study of 1,340 women and 619 men at 11 California centers.
Disclosures: Amgen and Merck funded the study. Dr. Adams has received research funding from both companies. Dr. Warner reported having no financial disclosures.