User login
Cardiac biomarkers refine antihypertensive drug initiation decisions
PHILADELPHIA – Incorporation of cardiac biomarkers into current guideline-based decision-making regarding initiation of antihypertensive medication in patients with previously untreated mild or moderate high blood pressure leads to more appropriate and selective matching of intensive blood pressure control with true patient risk, Ambarish Pandey, MD, reported at the American Heart Association scientific sessions.
That’s because the 2017 American College of Cardiology/AHA blood pressure guidelines recommend incorporating the ACC/AHA 10-Year Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator into decision making as to whether to start antihypertensive drug therapy in patients with stage 1 hypertension (130-139/80-89 mm Hg), but the risk calculator doesn’t account for the risk of heart failure.
Yet by far the greatest benefit of intensive BP lowering is in reducing the risk of developing heart failure, as demonstrated in the landmark SPRINT trial, which showed that intensive BP lowering achieved much greater risk reduction in new-onset heart failure than in atherosclerotic cardiovascular events.
Thus, there’s a need for better strategies to guide antihypertensive therapy. And therein lies the rationale for incorporating into the risk assessment an individual’s values for N-terminal pro–brain natriuretic peptide (NT-proBNP), which reflects chronic myocardial stress, and high-sensitivity cardiac troponin T (hs-cTnT), which when elevated signals myocardial injury.
“Cardiac biomarkers are intermediate phenotypes from hypertension to future cardiovascular events. They can identify individuals at increased risk for atherosclerotic events, and at even higher risk for heart failure events,” explained Dr. Pandey, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
He presented a study of 12,987 participants in three major U.S. cohort studies: the Atherosclerosis Risk In Communities (ARIC) study, the Multi-Ethnic Study of Atherosclerosis (MESA), and the Dallas Heart Study. At baseline, none of the participants were on antihypertensive therapy or had known cardiovascular disease. During 10 years of prospective follow-up, 825 of them experienced a first cardiovascular disease event: 251 developed heart failure and 574 had an MI, stroke, or cardiovascular death. Dr. Pandey and his coworkers calculated the cardiovascular event incidence rate and number-needed-to-treat with intensive antihypertensive drug therapy to prevent a first cardiovascular disease event on the basis of whether patients in the various BP categories were positive or negative for one or more biomarkers.
The results
Fifty-four percent of subjects had normal BP, defined in the guidelines as less than 120/80 mm Hg. Another 3% had BP in excess of 160/100 mm Hg. No controversy exists regarding pharmacotherapy in either of these groups: It’s not warranted in the former, essential in the latter.
Another 3,000 individuals had what the ACC/AHA guidelines define as elevated BP, meaning 120-129/<80 mm Hg, or low-risk stage 1 hypertension of 130-139/80-89 mm Hg and a 10-year ASCVD risk score of less than 10%. Initiation of antihypertensive medication in these groups is not recommended in the guidelines. Yet 36% of these individuals had at least one positive cardiac biomarker. And here’s the eye-opening finding: Notably, the 10-year cardiovascular event incidence rate in this biomarker group not currently recommended for antihypertensive pharmacotherapy was 11%, more than double the 4.6% rate in the biomarker-negative group, which in turn was comparable to the 3.8% in the normal BP participants.
Antihypertensive therapy was recommended according to the guidelines in 20% of the total study population, comprising patients with stage 1 hypertension who had an ASCVD risk score of 10% or more as well as those with stage 2 hypertension, defined as BP greater than 140/90 mm Hg but less than 160/100 mm Hg. Forty-eight percent of these subjects were positive for at least one biomarker. Their cardiovascular incidence rate was 15.1%, compared to the 7.9% rate in biomarker-negative individuals.
The estimated number-needed-to-treat (NNT) with intensive blood pressure–lowering therapy to a target systolic BP of less than 120 mm Hg, as in SPRINT, to prevent one cardiovascular event in individuals not currently guideline-recommended for antihypertensive medications was 86 in those who were biomarker-negative. The NNT dropped to 36 in the biomarker-positive subgroup, a far more attractive figure that suggests a reasonable likelihood of benefit from intensive blood pressure control, in Dr. Pandey’s view.
Similarly, among individuals currently recommended for pharmacotherapy initiation, the NNTs were 49 if biomarker-negative, improving to 26 in those positive for one or both biomarkers, which was comparable to the NNT of 22 in the group with blood pressures greater than 160/100 mm Hg. The NNT of 49 in the biomarker-negative subgroup is in a borderline gray zone warranting individualized shared decision-making regarding pharmacotherapy, Dr. Pandey said.
In this study, an elevated hs-cTnT was defined as 6 ng/L or more, while an elevated NT-proBNP was considered to be at least 100 pg/mL.
“It’s noteworthy that the degree of elevation in hs-cTnT and NT-proBNP which were observed in our study were pretty subtle and much below the threshold used for diagnosis of ischemic events or heart failure. Thus, these elevations were largely representative of subtle chronic injury and not acute events,” according to the cardiologist.
One audience member asked if the elevated biomarkers could simply be a surrogate for longer duration of exposure of the heart to high BP. Sure, Dr. Pandey replied, pointing to the 6-year greater average age of the biomarker-positive participants.
“It is likely that biomarker-positive status is capturing the culmination of longstanding exposure. But the thing about hypertension is there are no symptoms that can signal to the patient or the doctor that they have this disease, so testing for the biomarkers can actually capture the high-risk group that may have had hypertension for a long duration but now needs to be treated in order to prevent the advance of downstream adverse events,” he said.
Dr. Pandey reported having no financial conflicts of interest regarding his study, conducted free of commercial support.
SOURCE: Pandey A. AHA 2019 Abstract EP.AOS.521.141
PHILADELPHIA – Incorporation of cardiac biomarkers into current guideline-based decision-making regarding initiation of antihypertensive medication in patients with previously untreated mild or moderate high blood pressure leads to more appropriate and selective matching of intensive blood pressure control with true patient risk, Ambarish Pandey, MD, reported at the American Heart Association scientific sessions.
That’s because the 2017 American College of Cardiology/AHA blood pressure guidelines recommend incorporating the ACC/AHA 10-Year Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator into decision making as to whether to start antihypertensive drug therapy in patients with stage 1 hypertension (130-139/80-89 mm Hg), but the risk calculator doesn’t account for the risk of heart failure.
Yet by far the greatest benefit of intensive BP lowering is in reducing the risk of developing heart failure, as demonstrated in the landmark SPRINT trial, which showed that intensive BP lowering achieved much greater risk reduction in new-onset heart failure than in atherosclerotic cardiovascular events.
Thus, there’s a need for better strategies to guide antihypertensive therapy. And therein lies the rationale for incorporating into the risk assessment an individual’s values for N-terminal pro–brain natriuretic peptide (NT-proBNP), which reflects chronic myocardial stress, and high-sensitivity cardiac troponin T (hs-cTnT), which when elevated signals myocardial injury.
“Cardiac biomarkers are intermediate phenotypes from hypertension to future cardiovascular events. They can identify individuals at increased risk for atherosclerotic events, and at even higher risk for heart failure events,” explained Dr. Pandey, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
He presented a study of 12,987 participants in three major U.S. cohort studies: the Atherosclerosis Risk In Communities (ARIC) study, the Multi-Ethnic Study of Atherosclerosis (MESA), and the Dallas Heart Study. At baseline, none of the participants were on antihypertensive therapy or had known cardiovascular disease. During 10 years of prospective follow-up, 825 of them experienced a first cardiovascular disease event: 251 developed heart failure and 574 had an MI, stroke, or cardiovascular death. Dr. Pandey and his coworkers calculated the cardiovascular event incidence rate and number-needed-to-treat with intensive antihypertensive drug therapy to prevent a first cardiovascular disease event on the basis of whether patients in the various BP categories were positive or negative for one or more biomarkers.
The results
Fifty-four percent of subjects had normal BP, defined in the guidelines as less than 120/80 mm Hg. Another 3% had BP in excess of 160/100 mm Hg. No controversy exists regarding pharmacotherapy in either of these groups: It’s not warranted in the former, essential in the latter.
Another 3,000 individuals had what the ACC/AHA guidelines define as elevated BP, meaning 120-129/<80 mm Hg, or low-risk stage 1 hypertension of 130-139/80-89 mm Hg and a 10-year ASCVD risk score of less than 10%. Initiation of antihypertensive medication in these groups is not recommended in the guidelines. Yet 36% of these individuals had at least one positive cardiac biomarker. And here’s the eye-opening finding: Notably, the 10-year cardiovascular event incidence rate in this biomarker group not currently recommended for antihypertensive pharmacotherapy was 11%, more than double the 4.6% rate in the biomarker-negative group, which in turn was comparable to the 3.8% in the normal BP participants.
Antihypertensive therapy was recommended according to the guidelines in 20% of the total study population, comprising patients with stage 1 hypertension who had an ASCVD risk score of 10% or more as well as those with stage 2 hypertension, defined as BP greater than 140/90 mm Hg but less than 160/100 mm Hg. Forty-eight percent of these subjects were positive for at least one biomarker. Their cardiovascular incidence rate was 15.1%, compared to the 7.9% rate in biomarker-negative individuals.
The estimated number-needed-to-treat (NNT) with intensive blood pressure–lowering therapy to a target systolic BP of less than 120 mm Hg, as in SPRINT, to prevent one cardiovascular event in individuals not currently guideline-recommended for antihypertensive medications was 86 in those who were biomarker-negative. The NNT dropped to 36 in the biomarker-positive subgroup, a far more attractive figure that suggests a reasonable likelihood of benefit from intensive blood pressure control, in Dr. Pandey’s view.
Similarly, among individuals currently recommended for pharmacotherapy initiation, the NNTs were 49 if biomarker-negative, improving to 26 in those positive for one or both biomarkers, which was comparable to the NNT of 22 in the group with blood pressures greater than 160/100 mm Hg. The NNT of 49 in the biomarker-negative subgroup is in a borderline gray zone warranting individualized shared decision-making regarding pharmacotherapy, Dr. Pandey said.
In this study, an elevated hs-cTnT was defined as 6 ng/L or more, while an elevated NT-proBNP was considered to be at least 100 pg/mL.
“It’s noteworthy that the degree of elevation in hs-cTnT and NT-proBNP which were observed in our study were pretty subtle and much below the threshold used for diagnosis of ischemic events or heart failure. Thus, these elevations were largely representative of subtle chronic injury and not acute events,” according to the cardiologist.
One audience member asked if the elevated biomarkers could simply be a surrogate for longer duration of exposure of the heart to high BP. Sure, Dr. Pandey replied, pointing to the 6-year greater average age of the biomarker-positive participants.
“It is likely that biomarker-positive status is capturing the culmination of longstanding exposure. But the thing about hypertension is there are no symptoms that can signal to the patient or the doctor that they have this disease, so testing for the biomarkers can actually capture the high-risk group that may have had hypertension for a long duration but now needs to be treated in order to prevent the advance of downstream adverse events,” he said.
Dr. Pandey reported having no financial conflicts of interest regarding his study, conducted free of commercial support.
SOURCE: Pandey A. AHA 2019 Abstract EP.AOS.521.141
PHILADELPHIA – Incorporation of cardiac biomarkers into current guideline-based decision-making regarding initiation of antihypertensive medication in patients with previously untreated mild or moderate high blood pressure leads to more appropriate and selective matching of intensive blood pressure control with true patient risk, Ambarish Pandey, MD, reported at the American Heart Association scientific sessions.
That’s because the 2017 American College of Cardiology/AHA blood pressure guidelines recommend incorporating the ACC/AHA 10-Year Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator into decision making as to whether to start antihypertensive drug therapy in patients with stage 1 hypertension (130-139/80-89 mm Hg), but the risk calculator doesn’t account for the risk of heart failure.
Yet by far the greatest benefit of intensive BP lowering is in reducing the risk of developing heart failure, as demonstrated in the landmark SPRINT trial, which showed that intensive BP lowering achieved much greater risk reduction in new-onset heart failure than in atherosclerotic cardiovascular events.
Thus, there’s a need for better strategies to guide antihypertensive therapy. And therein lies the rationale for incorporating into the risk assessment an individual’s values for N-terminal pro–brain natriuretic peptide (NT-proBNP), which reflects chronic myocardial stress, and high-sensitivity cardiac troponin T (hs-cTnT), which when elevated signals myocardial injury.
“Cardiac biomarkers are intermediate phenotypes from hypertension to future cardiovascular events. They can identify individuals at increased risk for atherosclerotic events, and at even higher risk for heart failure events,” explained Dr. Pandey, a cardiologist at the University of Texas Southwestern Medical Center, Dallas.
He presented a study of 12,987 participants in three major U.S. cohort studies: the Atherosclerosis Risk In Communities (ARIC) study, the Multi-Ethnic Study of Atherosclerosis (MESA), and the Dallas Heart Study. At baseline, none of the participants were on antihypertensive therapy or had known cardiovascular disease. During 10 years of prospective follow-up, 825 of them experienced a first cardiovascular disease event: 251 developed heart failure and 574 had an MI, stroke, or cardiovascular death. Dr. Pandey and his coworkers calculated the cardiovascular event incidence rate and number-needed-to-treat with intensive antihypertensive drug therapy to prevent a first cardiovascular disease event on the basis of whether patients in the various BP categories were positive or negative for one or more biomarkers.
The results
Fifty-four percent of subjects had normal BP, defined in the guidelines as less than 120/80 mm Hg. Another 3% had BP in excess of 160/100 mm Hg. No controversy exists regarding pharmacotherapy in either of these groups: It’s not warranted in the former, essential in the latter.
Another 3,000 individuals had what the ACC/AHA guidelines define as elevated BP, meaning 120-129/<80 mm Hg, or low-risk stage 1 hypertension of 130-139/80-89 mm Hg and a 10-year ASCVD risk score of less than 10%. Initiation of antihypertensive medication in these groups is not recommended in the guidelines. Yet 36% of these individuals had at least one positive cardiac biomarker. And here’s the eye-opening finding: Notably, the 10-year cardiovascular event incidence rate in this biomarker group not currently recommended for antihypertensive pharmacotherapy was 11%, more than double the 4.6% rate in the biomarker-negative group, which in turn was comparable to the 3.8% in the normal BP participants.
Antihypertensive therapy was recommended according to the guidelines in 20% of the total study population, comprising patients with stage 1 hypertension who had an ASCVD risk score of 10% or more as well as those with stage 2 hypertension, defined as BP greater than 140/90 mm Hg but less than 160/100 mm Hg. Forty-eight percent of these subjects were positive for at least one biomarker. Their cardiovascular incidence rate was 15.1%, compared to the 7.9% rate in biomarker-negative individuals.
The estimated number-needed-to-treat (NNT) with intensive blood pressure–lowering therapy to a target systolic BP of less than 120 mm Hg, as in SPRINT, to prevent one cardiovascular event in individuals not currently guideline-recommended for antihypertensive medications was 86 in those who were biomarker-negative. The NNT dropped to 36 in the biomarker-positive subgroup, a far more attractive figure that suggests a reasonable likelihood of benefit from intensive blood pressure control, in Dr. Pandey’s view.
Similarly, among individuals currently recommended for pharmacotherapy initiation, the NNTs were 49 if biomarker-negative, improving to 26 in those positive for one or both biomarkers, which was comparable to the NNT of 22 in the group with blood pressures greater than 160/100 mm Hg. The NNT of 49 in the biomarker-negative subgroup is in a borderline gray zone warranting individualized shared decision-making regarding pharmacotherapy, Dr. Pandey said.
In this study, an elevated hs-cTnT was defined as 6 ng/L or more, while an elevated NT-proBNP was considered to be at least 100 pg/mL.
“It’s noteworthy that the degree of elevation in hs-cTnT and NT-proBNP which were observed in our study were pretty subtle and much below the threshold used for diagnosis of ischemic events or heart failure. Thus, these elevations were largely representative of subtle chronic injury and not acute events,” according to the cardiologist.
One audience member asked if the elevated biomarkers could simply be a surrogate for longer duration of exposure of the heart to high BP. Sure, Dr. Pandey replied, pointing to the 6-year greater average age of the biomarker-positive participants.
“It is likely that biomarker-positive status is capturing the culmination of longstanding exposure. But the thing about hypertension is there are no symptoms that can signal to the patient or the doctor that they have this disease, so testing for the biomarkers can actually capture the high-risk group that may have had hypertension for a long duration but now needs to be treated in order to prevent the advance of downstream adverse events,” he said.
Dr. Pandey reported having no financial conflicts of interest regarding his study, conducted free of commercial support.
SOURCE: Pandey A. AHA 2019 Abstract EP.AOS.521.141
REPORTING FROM AHA 2019
Value analysis of JAK inhibitors for RA hampered by limited data
Adequate evidence shows that adding a Janus kinase (JAK) inhibitor to conventional disease-modifying antirheumatic drug therapy provides a net health benefit for patients with rheumatoid arthritis, compared with conventional drugs alone, according to a report by an independent research institute. But the long-term economic value of JAK inhibitors for rheumatoid arthritis is less clear, the report by the Institute for Clinical and Economic Review (ICER) indicates.
ICER on Jan. 9 released a finalized report and policy recommendations on JAK inhibitors and biosimilars for rheumatoid arthritis. The report reviews current evidence for JAK inhibitors for adults with moderately active to severely active rheumatoid arthritis.
Since the nonprofit’s 2017 review of targeted immune modulators for rheumatoid arthritis, two JAK inhibitors, baricitinib (Olumiant) and upadacitinib (Rinvoq), were approved by the Food and Drug Administration. At a December 2019 public meeting of the California Technology Assessment Forum (CTAF), one of ICER’s independent evidence appraisal committees, panelists reviewed recent evidence.
A pricey comparator
In ICER’s analysis, the JAK inhibitor upadacitinib reached common thresholds for cost-effectiveness when compared with adalimumab (Humira). Nevertheless, the 14 members of the independent evidence appraisal committee voted that upadacitinib’s long-term economic value was “low” (8 votes) or “intermediate” (6 votes). Concerns about the generalizability of phase 3 clinical trial data to patients in the real world were among the reservations noted by panelists. Furthermore, “legitimate questions remain about whether or not adalimumab, launched 17 years ago, is fairly priced to begin with,” Pamela Bradt, MD, MPH, ICER’s chief scientific officer, said in a news release.
The panel did not vote on the economic value of tofacitinib (Xeljanz) or baricitinib, the two other JAK inhibitors that are approved for rheumatoid arthritis, because head-to-head evidence against adalimumab was insufficient, ICER said.
“Rheumatoid arthritis is a progressively disabling condition, and patients are fortunate to have multiple therapy options – including biosimilars – that effectively slow disease progression,” Dr. Bradt said. “Many economists might expect medicines to become more affordable in an increasingly crowded therapeutic class; however, because the current rebate structure has erected barriers between patients and several emerging RA therapies, traditional market dynamics have been unable to drive down prices.”
Weighing efficacy and cost
Panelists found that the net health benefit provided by upadacitinib is superior to that provided by adalimumab. At the same time, they said that there is insufficient head-to-head evidence to distinguish between the net health benefit of upadacitinib and tofacitinib or to demonstrate that tofacitinib is superior to adalimumab. Evidence comparing baricitinib to adalimumab does not exist.
CTAF members unanimously agreed that adequate evidence demonstrates that the biosimilar infliximab-dyyb (Inflectra) is clinically equivalent to its reference biologic, infliximab (Remicade).
Economic modeling demonstrated that upadacitinib plus a conventional drug achieves marginally higher quality of life than adalimumab plus a conventional drug does, at similar costs. “Based on this comparison with adalimumab, ICER’s value-based price benchmark range for upadacitinib is between $44,000 and $45,000,” according to the ICER news release. “This benchmark represents a 25% discount off of upadacitinib’s annual list price of $59,860, a suggested discount that is consistent with the rebates we assume the manufacturer is currently offering.”
After the voting session, various experts, including clinicians, patient advocates, and representatives from manufacturers and insurance companies, made the following policy recommendations:
- Regulatory intervention may be needed to ensure that drug prices do not continue to increase further from reasonable alignment with added benefits for patients.
- Insurers, pharmacy benefit managers, and employers should increase transparency around the role of discounts and rebates in formulary design.
- Policymakers should aim to create a system that rewards lower-priced biosimilar treatment options.
The findings of the clinical review by the Institute for Clinical and Economic Review (ICER) are generally in line with our clinical perceptions. We have an increasing number of treatment options for our RA patients, and the results of this review support the efficacy of tofacitinib and upadacitinib, compared with currently available biologic treatments. While ICER’s voting panel did find the data supported the superiority of upadacitinib over adalimumab, the cost analysis notes a WAC (wholesale acquisition cost) for upadacitinib of $59,860. While at expected discounted rates it is felt to be cost effective when compared with adalimumab, it is difficult to know what this means since ICER found adalimumab itself not to be cost effective, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in its 2017 review.
ICER’s focus is drug pricing and cost effectiveness, so obviously our biologic drugs are in the institute’s crosshairs. This review provided context for a policy roundtable discussion that included patient, payer, and manufacturer input, as well as American College of Rheumatology (ACR) input. We are thankful that ACR had a seat at the table, and thankful ICER is attempting to bring light to the important issues and barriers that perpetuate high drug prices in our marketplace. The discussion was wide ranging but focused on step-edit policies, the role of pharmacy benefit managers (PBMs) in perpetuating high drug prices and the relatively slow uptake of biosimilars in our marketplace.
These issues are critical to every practicing rheumatologist because we each deal daily with the hassles of step-edit/fail-first policies, which hijack our otherwise thoughtful and evidence-based decision making regarding the best treatments for our patients. We know how much (unreimbursed) time it takes our staff to sort through these step edits and prior authorizations, and we have seen recent data regarding how these policies delay care and harm patients. We were thankful to see ICER validate these concerns and note that their suggested guidelines for rational step therapy somewhat mirror those in the Safe Step Act, which ACR supports on a federal legislative level. ACR continues to vigorously support the grandfathering of any patient on an effective treatment, regardless of changes in insurance or formulary; this was an issue of robust debate at their meeting, and this patient-centric position is not uniformly held among policymakers, unfortunately.
ACR agrees with ICER’s conclusion that transparency in the PBM system regarding rebates should be promoted and that opaque rebate negotiations between PBMs and manufacturers both incentivize higher prices and block access to the marketplace for cheaper biosimilar options.
Additionally, ICER and ACR agree about the critical role that biosimilar uptake will play in controlling drug costs. While we do not yet have any biosimilars that have been deemed interchangeable by the Food and Drug Administration, we agree with ICER that data regarding comparable efficacy and safety of biosimilars to their originator products is very reassuring. While the decision to switch to a biosimilar should be an individual decision between a provider and patient, and while we recognize with frustration that many FDA-approved biosimilars are not commercially available because of patent law, it is clear that the current costs of our biologic drugs are not sustainable and the uptake of biosimilars will be critical if we hope our health care economy can continue to support coverage of these life-changing drugs in years to come. We agree with ICER that it is incumbent upon prescribers to reassure our patients regarding the safety and efficacy of these drugs.
Christopher Phillips, MD , is a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the ACR, under the guidance of the Committee on Rheumatologic Care. He attended the initial ICER rheumatoid arthritis review meeting in 2017 on behalf of ACR. In 2019, Dr. Phillips served as a reviewer and clinical expert to the ICER panel and participated in the policy roundtable discussion.
The findings of the clinical review by the Institute for Clinical and Economic Review (ICER) are generally in line with our clinical perceptions. We have an increasing number of treatment options for our RA patients, and the results of this review support the efficacy of tofacitinib and upadacitinib, compared with currently available biologic treatments. While ICER’s voting panel did find the data supported the superiority of upadacitinib over adalimumab, the cost analysis notes a WAC (wholesale acquisition cost) for upadacitinib of $59,860. While at expected discounted rates it is felt to be cost effective when compared with adalimumab, it is difficult to know what this means since ICER found adalimumab itself not to be cost effective, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in its 2017 review.
ICER’s focus is drug pricing and cost effectiveness, so obviously our biologic drugs are in the institute’s crosshairs. This review provided context for a policy roundtable discussion that included patient, payer, and manufacturer input, as well as American College of Rheumatology (ACR) input. We are thankful that ACR had a seat at the table, and thankful ICER is attempting to bring light to the important issues and barriers that perpetuate high drug prices in our marketplace. The discussion was wide ranging but focused on step-edit policies, the role of pharmacy benefit managers (PBMs) in perpetuating high drug prices and the relatively slow uptake of biosimilars in our marketplace.
These issues are critical to every practicing rheumatologist because we each deal daily with the hassles of step-edit/fail-first policies, which hijack our otherwise thoughtful and evidence-based decision making regarding the best treatments for our patients. We know how much (unreimbursed) time it takes our staff to sort through these step edits and prior authorizations, and we have seen recent data regarding how these policies delay care and harm patients. We were thankful to see ICER validate these concerns and note that their suggested guidelines for rational step therapy somewhat mirror those in the Safe Step Act, which ACR supports on a federal legislative level. ACR continues to vigorously support the grandfathering of any patient on an effective treatment, regardless of changes in insurance or formulary; this was an issue of robust debate at their meeting, and this patient-centric position is not uniformly held among policymakers, unfortunately.
ACR agrees with ICER’s conclusion that transparency in the PBM system regarding rebates should be promoted and that opaque rebate negotiations between PBMs and manufacturers both incentivize higher prices and block access to the marketplace for cheaper biosimilar options.
Additionally, ICER and ACR agree about the critical role that biosimilar uptake will play in controlling drug costs. While we do not yet have any biosimilars that have been deemed interchangeable by the Food and Drug Administration, we agree with ICER that data regarding comparable efficacy and safety of biosimilars to their originator products is very reassuring. While the decision to switch to a biosimilar should be an individual decision between a provider and patient, and while we recognize with frustration that many FDA-approved biosimilars are not commercially available because of patent law, it is clear that the current costs of our biologic drugs are not sustainable and the uptake of biosimilars will be critical if we hope our health care economy can continue to support coverage of these life-changing drugs in years to come. We agree with ICER that it is incumbent upon prescribers to reassure our patients regarding the safety and efficacy of these drugs.
Christopher Phillips, MD , is a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the ACR, under the guidance of the Committee on Rheumatologic Care. He attended the initial ICER rheumatoid arthritis review meeting in 2017 on behalf of ACR. In 2019, Dr. Phillips served as a reviewer and clinical expert to the ICER panel and participated in the policy roundtable discussion.
The findings of the clinical review by the Institute for Clinical and Economic Review (ICER) are generally in line with our clinical perceptions. We have an increasing number of treatment options for our RA patients, and the results of this review support the efficacy of tofacitinib and upadacitinib, compared with currently available biologic treatments. While ICER’s voting panel did find the data supported the superiority of upadacitinib over adalimumab, the cost analysis notes a WAC (wholesale acquisition cost) for upadacitinib of $59,860. While at expected discounted rates it is felt to be cost effective when compared with adalimumab, it is difficult to know what this means since ICER found adalimumab itself not to be cost effective, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in its 2017 review.
ICER’s focus is drug pricing and cost effectiveness, so obviously our biologic drugs are in the institute’s crosshairs. This review provided context for a policy roundtable discussion that included patient, payer, and manufacturer input, as well as American College of Rheumatology (ACR) input. We are thankful that ACR had a seat at the table, and thankful ICER is attempting to bring light to the important issues and barriers that perpetuate high drug prices in our marketplace. The discussion was wide ranging but focused on step-edit policies, the role of pharmacy benefit managers (PBMs) in perpetuating high drug prices and the relatively slow uptake of biosimilars in our marketplace.
These issues are critical to every practicing rheumatologist because we each deal daily with the hassles of step-edit/fail-first policies, which hijack our otherwise thoughtful and evidence-based decision making regarding the best treatments for our patients. We know how much (unreimbursed) time it takes our staff to sort through these step edits and prior authorizations, and we have seen recent data regarding how these policies delay care and harm patients. We were thankful to see ICER validate these concerns and note that their suggested guidelines for rational step therapy somewhat mirror those in the Safe Step Act, which ACR supports on a federal legislative level. ACR continues to vigorously support the grandfathering of any patient on an effective treatment, regardless of changes in insurance or formulary; this was an issue of robust debate at their meeting, and this patient-centric position is not uniformly held among policymakers, unfortunately.
ACR agrees with ICER’s conclusion that transparency in the PBM system regarding rebates should be promoted and that opaque rebate negotiations between PBMs and manufacturers both incentivize higher prices and block access to the marketplace for cheaper biosimilar options.
Additionally, ICER and ACR agree about the critical role that biosimilar uptake will play in controlling drug costs. While we do not yet have any biosimilars that have been deemed interchangeable by the Food and Drug Administration, we agree with ICER that data regarding comparable efficacy and safety of biosimilars to their originator products is very reassuring. While the decision to switch to a biosimilar should be an individual decision between a provider and patient, and while we recognize with frustration that many FDA-approved biosimilars are not commercially available because of patent law, it is clear that the current costs of our biologic drugs are not sustainable and the uptake of biosimilars will be critical if we hope our health care economy can continue to support coverage of these life-changing drugs in years to come. We agree with ICER that it is incumbent upon prescribers to reassure our patients regarding the safety and efficacy of these drugs.
Christopher Phillips, MD , is a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the ACR, under the guidance of the Committee on Rheumatologic Care. He attended the initial ICER rheumatoid arthritis review meeting in 2017 on behalf of ACR. In 2019, Dr. Phillips served as a reviewer and clinical expert to the ICER panel and participated in the policy roundtable discussion.
Adequate evidence shows that adding a Janus kinase (JAK) inhibitor to conventional disease-modifying antirheumatic drug therapy provides a net health benefit for patients with rheumatoid arthritis, compared with conventional drugs alone, according to a report by an independent research institute. But the long-term economic value of JAK inhibitors for rheumatoid arthritis is less clear, the report by the Institute for Clinical and Economic Review (ICER) indicates.
ICER on Jan. 9 released a finalized report and policy recommendations on JAK inhibitors and biosimilars for rheumatoid arthritis. The report reviews current evidence for JAK inhibitors for adults with moderately active to severely active rheumatoid arthritis.
Since the nonprofit’s 2017 review of targeted immune modulators for rheumatoid arthritis, two JAK inhibitors, baricitinib (Olumiant) and upadacitinib (Rinvoq), were approved by the Food and Drug Administration. At a December 2019 public meeting of the California Technology Assessment Forum (CTAF), one of ICER’s independent evidence appraisal committees, panelists reviewed recent evidence.
A pricey comparator
In ICER’s analysis, the JAK inhibitor upadacitinib reached common thresholds for cost-effectiveness when compared with adalimumab (Humira). Nevertheless, the 14 members of the independent evidence appraisal committee voted that upadacitinib’s long-term economic value was “low” (8 votes) or “intermediate” (6 votes). Concerns about the generalizability of phase 3 clinical trial data to patients in the real world were among the reservations noted by panelists. Furthermore, “legitimate questions remain about whether or not adalimumab, launched 17 years ago, is fairly priced to begin with,” Pamela Bradt, MD, MPH, ICER’s chief scientific officer, said in a news release.
The panel did not vote on the economic value of tofacitinib (Xeljanz) or baricitinib, the two other JAK inhibitors that are approved for rheumatoid arthritis, because head-to-head evidence against adalimumab was insufficient, ICER said.
“Rheumatoid arthritis is a progressively disabling condition, and patients are fortunate to have multiple therapy options – including biosimilars – that effectively slow disease progression,” Dr. Bradt said. “Many economists might expect medicines to become more affordable in an increasingly crowded therapeutic class; however, because the current rebate structure has erected barriers between patients and several emerging RA therapies, traditional market dynamics have been unable to drive down prices.”
Weighing efficacy and cost
Panelists found that the net health benefit provided by upadacitinib is superior to that provided by adalimumab. At the same time, they said that there is insufficient head-to-head evidence to distinguish between the net health benefit of upadacitinib and tofacitinib or to demonstrate that tofacitinib is superior to adalimumab. Evidence comparing baricitinib to adalimumab does not exist.
CTAF members unanimously agreed that adequate evidence demonstrates that the biosimilar infliximab-dyyb (Inflectra) is clinically equivalent to its reference biologic, infliximab (Remicade).
Economic modeling demonstrated that upadacitinib plus a conventional drug achieves marginally higher quality of life than adalimumab plus a conventional drug does, at similar costs. “Based on this comparison with adalimumab, ICER’s value-based price benchmark range for upadacitinib is between $44,000 and $45,000,” according to the ICER news release. “This benchmark represents a 25% discount off of upadacitinib’s annual list price of $59,860, a suggested discount that is consistent with the rebates we assume the manufacturer is currently offering.”
After the voting session, various experts, including clinicians, patient advocates, and representatives from manufacturers and insurance companies, made the following policy recommendations:
- Regulatory intervention may be needed to ensure that drug prices do not continue to increase further from reasonable alignment with added benefits for patients.
- Insurers, pharmacy benefit managers, and employers should increase transparency around the role of discounts and rebates in formulary design.
- Policymakers should aim to create a system that rewards lower-priced biosimilar treatment options.
Adequate evidence shows that adding a Janus kinase (JAK) inhibitor to conventional disease-modifying antirheumatic drug therapy provides a net health benefit for patients with rheumatoid arthritis, compared with conventional drugs alone, according to a report by an independent research institute. But the long-term economic value of JAK inhibitors for rheumatoid arthritis is less clear, the report by the Institute for Clinical and Economic Review (ICER) indicates.
ICER on Jan. 9 released a finalized report and policy recommendations on JAK inhibitors and biosimilars for rheumatoid arthritis. The report reviews current evidence for JAK inhibitors for adults with moderately active to severely active rheumatoid arthritis.
Since the nonprofit’s 2017 review of targeted immune modulators for rheumatoid arthritis, two JAK inhibitors, baricitinib (Olumiant) and upadacitinib (Rinvoq), were approved by the Food and Drug Administration. At a December 2019 public meeting of the California Technology Assessment Forum (CTAF), one of ICER’s independent evidence appraisal committees, panelists reviewed recent evidence.
A pricey comparator
In ICER’s analysis, the JAK inhibitor upadacitinib reached common thresholds for cost-effectiveness when compared with adalimumab (Humira). Nevertheless, the 14 members of the independent evidence appraisal committee voted that upadacitinib’s long-term economic value was “low” (8 votes) or “intermediate” (6 votes). Concerns about the generalizability of phase 3 clinical trial data to patients in the real world were among the reservations noted by panelists. Furthermore, “legitimate questions remain about whether or not adalimumab, launched 17 years ago, is fairly priced to begin with,” Pamela Bradt, MD, MPH, ICER’s chief scientific officer, said in a news release.
The panel did not vote on the economic value of tofacitinib (Xeljanz) or baricitinib, the two other JAK inhibitors that are approved for rheumatoid arthritis, because head-to-head evidence against adalimumab was insufficient, ICER said.
“Rheumatoid arthritis is a progressively disabling condition, and patients are fortunate to have multiple therapy options – including biosimilars – that effectively slow disease progression,” Dr. Bradt said. “Many economists might expect medicines to become more affordable in an increasingly crowded therapeutic class; however, because the current rebate structure has erected barriers between patients and several emerging RA therapies, traditional market dynamics have been unable to drive down prices.”
Weighing efficacy and cost
Panelists found that the net health benefit provided by upadacitinib is superior to that provided by adalimumab. At the same time, they said that there is insufficient head-to-head evidence to distinguish between the net health benefit of upadacitinib and tofacitinib or to demonstrate that tofacitinib is superior to adalimumab. Evidence comparing baricitinib to adalimumab does not exist.
CTAF members unanimously agreed that adequate evidence demonstrates that the biosimilar infliximab-dyyb (Inflectra) is clinically equivalent to its reference biologic, infliximab (Remicade).
Economic modeling demonstrated that upadacitinib plus a conventional drug achieves marginally higher quality of life than adalimumab plus a conventional drug does, at similar costs. “Based on this comparison with adalimumab, ICER’s value-based price benchmark range for upadacitinib is between $44,000 and $45,000,” according to the ICER news release. “This benchmark represents a 25% discount off of upadacitinib’s annual list price of $59,860, a suggested discount that is consistent with the rebates we assume the manufacturer is currently offering.”
After the voting session, various experts, including clinicians, patient advocates, and representatives from manufacturers and insurance companies, made the following policy recommendations:
- Regulatory intervention may be needed to ensure that drug prices do not continue to increase further from reasonable alignment with added benefits for patients.
- Insurers, pharmacy benefit managers, and employers should increase transparency around the role of discounts and rebates in formulary design.
- Policymakers should aim to create a system that rewards lower-priced biosimilar treatment options.
Are providers asking about menstrual bleeding before/during anticoagulant therapy?
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
REPORTING FROM ASH 2019
Medicaid spending on MS drugs rose despite introduction of generic glatiramer
Prescription pricing is a primary reason why Medicaid spending on multiple sclerosis disease-modifying therapies (DMTs) has more than doubled between 2011 and 2017 and the introduction of a generic glatiramer acetate is having nominal effect on pricing and utilization within the class, new research is showing.
“Gross spending on self-administered and infusible MS DMTs in the Medicaid program increased 2.9-fold from $453 million in 2011 to $1.32 billion in 2017,” Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues wrote in a research report published Jan. 15 in Neurology. Net spending after accounting for rebates during this period showed a doubling of spending from $278 million per year to $600 million per year.
Use of MS DMTs during this period overall remained stable, but there was a shift from injectable DMTs to oral DMTs during this time window, the researchers found, with the plurality of utilization attributed to glatiramer acetate.
Sandoz began marketing a generic version of glatiramer acetate 20 mg in the second quarter of 2015, which led to an immediate increase in the cost per prescription of $441 for the branded version of glatiramer acetate 20 mg, although that cost has come down gradually by $52 per prescription over time. Other DMTs saw minimal price changes at that time, Dr. Hartung and his colleagues noted.
The researchers attributed the increased Medicaid spending to rising prices of DMTs.
“Although some of this increase is attributable to the 2014 Medicaid expansion, the primary driver was rising DMT costs per prescription, which doubled over the period,” the researchers wrote. “Thus, we assert that rising prices, not increasing use, are the primary driver of spending for DMTs in the Medicaid program.”
In addition, the introduction of the first generic DMT “appeared to have little effect on the overall trajectory of DMT costs,” they continued. “In fact, the cost of Teva’s 20-mg glatiramer acetate increased significantly following the release of Sandoz’s generic. ... The increase possibly signified efforts to both retain revenue and further push market share to the 40-mg version. Although the costs for generic glatiramer acetate declined over time, its introduction appears not to have fundamentally affected the overall trend in DMT costs.”
Indeed, the researchers’ examination of utilization trends found that Teva executed a successful preemptive strategy of converting 20-mg users of glatiramer acetate to 40-mg users, something that is not interchangeable with the generic product.
“Low generic penetration is also due to the fact that Sandoz’s product was only 15% less expensive than branded glatiramer acetate 20 mg and approximately the same cost as the 40-mg version at launch,” Dr. Hartung and his colleagues stated. “This difference may have been further diminished by rebates that Teva may have provided to maintain preferred status on state Medicaid formularies.”
These factors reflect an “urgent need for robust generic competition within the DMT class,” the authors wrote.
The study was supported by the National Multiple Sclerosis Society. Lead author Dr. Hartung reported receiving research support from AbbVie.
SOURCE: Hartung D et al. Neurology. Jan 15. doi: 10.1212/WNL.0000000000008936.
Prescription pricing is a primary reason why Medicaid spending on multiple sclerosis disease-modifying therapies (DMTs) has more than doubled between 2011 and 2017 and the introduction of a generic glatiramer acetate is having nominal effect on pricing and utilization within the class, new research is showing.
“Gross spending on self-administered and infusible MS DMTs in the Medicaid program increased 2.9-fold from $453 million in 2011 to $1.32 billion in 2017,” Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues wrote in a research report published Jan. 15 in Neurology. Net spending after accounting for rebates during this period showed a doubling of spending from $278 million per year to $600 million per year.
Use of MS DMTs during this period overall remained stable, but there was a shift from injectable DMTs to oral DMTs during this time window, the researchers found, with the plurality of utilization attributed to glatiramer acetate.
Sandoz began marketing a generic version of glatiramer acetate 20 mg in the second quarter of 2015, which led to an immediate increase in the cost per prescription of $441 for the branded version of glatiramer acetate 20 mg, although that cost has come down gradually by $52 per prescription over time. Other DMTs saw minimal price changes at that time, Dr. Hartung and his colleagues noted.
The researchers attributed the increased Medicaid spending to rising prices of DMTs.
“Although some of this increase is attributable to the 2014 Medicaid expansion, the primary driver was rising DMT costs per prescription, which doubled over the period,” the researchers wrote. “Thus, we assert that rising prices, not increasing use, are the primary driver of spending for DMTs in the Medicaid program.”
In addition, the introduction of the first generic DMT “appeared to have little effect on the overall trajectory of DMT costs,” they continued. “In fact, the cost of Teva’s 20-mg glatiramer acetate increased significantly following the release of Sandoz’s generic. ... The increase possibly signified efforts to both retain revenue and further push market share to the 40-mg version. Although the costs for generic glatiramer acetate declined over time, its introduction appears not to have fundamentally affected the overall trend in DMT costs.”
Indeed, the researchers’ examination of utilization trends found that Teva executed a successful preemptive strategy of converting 20-mg users of glatiramer acetate to 40-mg users, something that is not interchangeable with the generic product.
“Low generic penetration is also due to the fact that Sandoz’s product was only 15% less expensive than branded glatiramer acetate 20 mg and approximately the same cost as the 40-mg version at launch,” Dr. Hartung and his colleagues stated. “This difference may have been further diminished by rebates that Teva may have provided to maintain preferred status on state Medicaid formularies.”
These factors reflect an “urgent need for robust generic competition within the DMT class,” the authors wrote.
The study was supported by the National Multiple Sclerosis Society. Lead author Dr. Hartung reported receiving research support from AbbVie.
SOURCE: Hartung D et al. Neurology. Jan 15. doi: 10.1212/WNL.0000000000008936.
Prescription pricing is a primary reason why Medicaid spending on multiple sclerosis disease-modifying therapies (DMTs) has more than doubled between 2011 and 2017 and the introduction of a generic glatiramer acetate is having nominal effect on pricing and utilization within the class, new research is showing.
“Gross spending on self-administered and infusible MS DMTs in the Medicaid program increased 2.9-fold from $453 million in 2011 to $1.32 billion in 2017,” Daniel Hartung, PharmD, of Oregon Health and Science University, Portland, and his colleagues wrote in a research report published Jan. 15 in Neurology. Net spending after accounting for rebates during this period showed a doubling of spending from $278 million per year to $600 million per year.
Use of MS DMTs during this period overall remained stable, but there was a shift from injectable DMTs to oral DMTs during this time window, the researchers found, with the plurality of utilization attributed to glatiramer acetate.
Sandoz began marketing a generic version of glatiramer acetate 20 mg in the second quarter of 2015, which led to an immediate increase in the cost per prescription of $441 for the branded version of glatiramer acetate 20 mg, although that cost has come down gradually by $52 per prescription over time. Other DMTs saw minimal price changes at that time, Dr. Hartung and his colleagues noted.
The researchers attributed the increased Medicaid spending to rising prices of DMTs.
“Although some of this increase is attributable to the 2014 Medicaid expansion, the primary driver was rising DMT costs per prescription, which doubled over the period,” the researchers wrote. “Thus, we assert that rising prices, not increasing use, are the primary driver of spending for DMTs in the Medicaid program.”
In addition, the introduction of the first generic DMT “appeared to have little effect on the overall trajectory of DMT costs,” they continued. “In fact, the cost of Teva’s 20-mg glatiramer acetate increased significantly following the release of Sandoz’s generic. ... The increase possibly signified efforts to both retain revenue and further push market share to the 40-mg version. Although the costs for generic glatiramer acetate declined over time, its introduction appears not to have fundamentally affected the overall trend in DMT costs.”
Indeed, the researchers’ examination of utilization trends found that Teva executed a successful preemptive strategy of converting 20-mg users of glatiramer acetate to 40-mg users, something that is not interchangeable with the generic product.
“Low generic penetration is also due to the fact that Sandoz’s product was only 15% less expensive than branded glatiramer acetate 20 mg and approximately the same cost as the 40-mg version at launch,” Dr. Hartung and his colleagues stated. “This difference may have been further diminished by rebates that Teva may have provided to maintain preferred status on state Medicaid formularies.”
These factors reflect an “urgent need for robust generic competition within the DMT class,” the authors wrote.
The study was supported by the National Multiple Sclerosis Society. Lead author Dr. Hartung reported receiving research support from AbbVie.
SOURCE: Hartung D et al. Neurology. Jan 15. doi: 10.1212/WNL.0000000000008936.
FROM NEUROLOGY
Key clinical point: Medicaid spending on MS DMTs continues to rise in spite of generic introduction.
Major finding: Cost is the major factor in spending as utilization has remained stable.
Study details: Researchers examined quarterly Medicaid State Drug Utilization Data from 2011 to 2017, examining spending, utilization and cost per prescription for 15 MS DMTs, including brand and generic versions of glatiramer acetate.
Disclosures: The study was supported by the National Multiple Sclerosis Society. Lead author Dr. Hartung reported receiving research support from AbbVie.
Source: Hartung D et al. Neurology. Jan 15. doi: 10.1212/WNL.0000000000008936.
FDA committee rejects oxycodegol, new opioid designed for less abuse
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
A Food and Drug Administration advisory committee voted 27-0 on Jan. 14 against recommending agency approval of oxycodegol, a new type of opioid molecule designed to slow passage of the drug through the blood-brain barrier and hence cause less of a “high” and potentially blunt the drug’s abuse potential.
But the panel, which includes members from both the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, unanimously shared the opinion that the data submitted by the drug developer, Nektar, failed to clearly demonstrate the drug’s safety and efficacy.
“There was a lot of ambiguity [in the data] about safety and efficacy, and this is too important an issue to have so much ambiguity,” summed up Ronald S. Litman, DO, professor of anesthesiology and critical care at the University of Pennsylvania in Philadelphia and chair of the combined committee.
“The subliminal message” that would surround oxycodegol if it received FDA approval would be that it is a “safer” opioid, “and that would make it a blockbuster drug, and for that to happen you need data that [prove] the benefits outweigh risks, but we didn’t see those data. It was all speculation, and we can’t approve a potential blockbuster opioid in the middle of a public health opioid crisis based on speculation,” commented Steve B. Meisel, PharmD, system director of medication safety for Fairview Health Services in Minneapolis and a committee member.
According to Nektar, oxycodegol is a new molecular entity that combines a morphinan pharmacophore, oxycodol, with a six-unit chain of polyethylene glycol, a design that slows movement of the drug into the brain by about an hour after an oral dose when compared with oxycodone. It works as a full mu opioid receptor agonist that inhibits the nociceptive pathways while it reduces reinforcing or euphoric effects and other negative CNS-mediated side effects because of its slowed entry into the central nervous system.
But, as became apparent during the course of the day’s presentations and questions, while the clinical evidence in general supported this mechanism, the data were flawed by many limitations and caveats. FDA staffers critiqued the company’s data set for a variety of issues, including testing dosages that were “arbitrary and flawed,” evidence for “high oral abuse potential” in one study, including “a high rate of euphoria” of 17% even at the recommended dosage level (and a higher euphoria incidence at a higher dosage), limited information on additional pain medications that enrolled patients had used both before enrollment and during the study, and possible enrollment bias. Many panel members also raised concerns that included the efficacy data coming from a single randomized study, incomplete data on possible hepatic toxicity, no data to address potential abuse via injection or inhalation, a very modest demonstrated increment in pain relief, and abuse potential studies that relied on a single dose of the drug.
On the other hand, many committee members, and others in the pain field, applauded the general concept behind oxycodegol and urged the developer to run additional studies and collect more data for a future FDA application.
There has been “a lot of controversy” about oxycodegol, often centered on the question “why do we need another opioid,” commented Steven P. Cohen, MD, professor of anesthesiology, neurology, and pain medicine and chief of pain medicine at Johns Hopkins Health in Baltimore. “Having another opioid on the market with a different pain indication and possibly lower abuse potential” would be welcome and “almost certainly would not result in more prescriptions or abuse,” said Dr. Cohen, who was not a committee member but addressed in an interview the need for new and effective pain medications that offer an alternative to conventional opioids. “Patients who might otherwise be prescribed a different opioid might receive oxycodegol instead,” he suggested. But first, the developing company will need to collect a lot more clinical data than it has reported so far.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
FDA warns of possible cancer risk with lorcaserin
after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.
“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.
The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.
“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.
Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.
Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.
Lorcaserin is distributed by Eisai.*
*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin.
after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.
“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.
The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.
“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.
Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.
Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.
Lorcaserin is distributed by Eisai.*
*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin.
after results from a clinical trial assessing the drug’s safety showed a possible increased risk of cancer.
“At this time, the cause of the cancer is uncertain, and we cannot conclude that lorcaserin contributes to the cancer risk. However, we wanted to make the public aware of this potential risk,” the agency said in a press release.
The agency advised that health care providers consider whether the benefits of taking lorcaserin outweighed the potential cancer risk, and that patients currently taking the medication should talk to their providers about the risks.
“We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review,” the FDA noted in the statement.
Lorcaserin, a serotonin 2C receptor agonist, was approved by the FDA in 2012 at a dosage of 20 mg once daily for use with a reduced-calorie diet and increased physical activity as a means to improve weight loss in adults who are obese or overweight and have at least one weight-related medical problem, such as such as hypertension, type 2 diabetes, or dyslipidemia. In July 2016, the agency approved a New Drug Application for an extended-release, once-daily formulation.
Headache, dizziness, fatigue, nausea, dry mouth, and constipation are the more common adverse effects in patients without diabetes, whereas hypoglycemia, headache, back pain, cough, and fatigue are more common in patients with diabetes. The treatment is contraindicated for pregnancy.
Lorcaserin is distributed by Eisai.*
*Correction, 1/15/2020: An earlier version of this story misstated the manufacturer of lorcaserin.
Expedited review programs not shortening drug development
Drug development times are not showing any signs of decreasing even though application review times at the Food and Drug Administration are improving, new research has shown.
“Despite the accumulation of expedited programs that have reduced FDA review times, overall clinical development times have not become shorter, although it is not possible to know what role these programs may have played in preventing an increase in development times,” Jonathan Darrow of Harvard Medical School, Boston, and colleagues wrote in a study published Jan. 14 in JAMA.
Researchers noted that FDA approval times declined from more than 3 years in 1983 to less than 1 year in 2017, although total time from the authorization of clinical testing to approval has remained steady across that period at about 8 years.
“The resistance of total development times to efforts to shorten them could be the result of more submissions of applications for rare disease drugs, which can sometimes pose trial recruitment challenges; a shifting emphasis to more challenging therapeutic categories, such as central nervous system disorder treatments; longer time horizons needed to establish efficacy when early intervention is important (e.g., cancer); or other factors,” wrote Mr. Darrow and colleagues.
The authors also note that the value of the expanded review toolbox the FDA now employs is “unclear” as “the number of new drug approvals has not increased substantially over the past three decades.” This observation does not count biologics or generic approvals.
Research revealed that the mean annual number of new drug approvals (including biologics) was 34 from 1990 to 1999, 25 from 2000 to 2009, and 41 from 2010 to 2018. In addition, while the number of new drug approvals has remained at or below 60 per year, the portion of drugs using at least one expedited review program increased over time, with more than 80% of the 59 new drugs approved in 2018 being subject to at least one expedited review program.
“Although the FDA has on average applied its expedited programs to drugs offering larger health gains, it is difficult to assess whether these programs have incentivized greater therapeutic innovation or merely allowed more appropriate agency prioritization,” noted Mr. Darrow and colleagues.
And while it may be hard to truly understand the impact of the many expedited review programs that have been introduced at the FDA, there is still room for improvement in the process.
In an editorial published in JAMA, Joshua Sharfstein, MD, of Johns Hopkins University, Baltimore, suggested four reforms the FDA could examine.
“First, Congress and the FDA should rationalize the various programs for expedited review,” he wrote, noting that companies are using the Orphan Drug Act to prevent competition. “Fixing the system requires, at a minimum, promoting meaningful competition for non-orphan uses.”
Second, he wrote, the FDA needs to strengthen oversight of postmarket safety though more diligence in the operation of its Risk Evaluation and Management Strategies (REMS) program.
“Third, Congress should recalibrate the programs that provide companies with special marketing protections,” added Dr. Sharfstein, former FDA principal deputy commissioner. “One place to look is pediatric exclusivity, which has been estimated to cost the health care system more than $6 for every $1 spent by a company on a pediatric trial.”
And finally, “Congress should use patent and pricing incentives to accelerate the generation of definitive evidence under accelerated approval,” citing proposals to limit pricing or market exclusivity until companies complete studies that assess clinically relevant endpoints.
“These changes would reflect an evolution, not a revolution, of the FDA’s approach to new drug approval,” Dr. Sharfstein said. “These reforms could also bring greater order and thoughtfulness to the regulation of important new therapies, while enhancing safety and creating greater capability to afford truly transformative medical products.”
SOURCE: Jonathan Darrow et al. JAMA 2020 Jan 14. doi: 10.1001/jama.2019.20288.
Drug development times are not showing any signs of decreasing even though application review times at the Food and Drug Administration are improving, new research has shown.
“Despite the accumulation of expedited programs that have reduced FDA review times, overall clinical development times have not become shorter, although it is not possible to know what role these programs may have played in preventing an increase in development times,” Jonathan Darrow of Harvard Medical School, Boston, and colleagues wrote in a study published Jan. 14 in JAMA.
Researchers noted that FDA approval times declined from more than 3 years in 1983 to less than 1 year in 2017, although total time from the authorization of clinical testing to approval has remained steady across that period at about 8 years.
“The resistance of total development times to efforts to shorten them could be the result of more submissions of applications for rare disease drugs, which can sometimes pose trial recruitment challenges; a shifting emphasis to more challenging therapeutic categories, such as central nervous system disorder treatments; longer time horizons needed to establish efficacy when early intervention is important (e.g., cancer); or other factors,” wrote Mr. Darrow and colleagues.
The authors also note that the value of the expanded review toolbox the FDA now employs is “unclear” as “the number of new drug approvals has not increased substantially over the past three decades.” This observation does not count biologics or generic approvals.
Research revealed that the mean annual number of new drug approvals (including biologics) was 34 from 1990 to 1999, 25 from 2000 to 2009, and 41 from 2010 to 2018. In addition, while the number of new drug approvals has remained at or below 60 per year, the portion of drugs using at least one expedited review program increased over time, with more than 80% of the 59 new drugs approved in 2018 being subject to at least one expedited review program.
“Although the FDA has on average applied its expedited programs to drugs offering larger health gains, it is difficult to assess whether these programs have incentivized greater therapeutic innovation or merely allowed more appropriate agency prioritization,” noted Mr. Darrow and colleagues.
And while it may be hard to truly understand the impact of the many expedited review programs that have been introduced at the FDA, there is still room for improvement in the process.
In an editorial published in JAMA, Joshua Sharfstein, MD, of Johns Hopkins University, Baltimore, suggested four reforms the FDA could examine.
“First, Congress and the FDA should rationalize the various programs for expedited review,” he wrote, noting that companies are using the Orphan Drug Act to prevent competition. “Fixing the system requires, at a minimum, promoting meaningful competition for non-orphan uses.”
Second, he wrote, the FDA needs to strengthen oversight of postmarket safety though more diligence in the operation of its Risk Evaluation and Management Strategies (REMS) program.
“Third, Congress should recalibrate the programs that provide companies with special marketing protections,” added Dr. Sharfstein, former FDA principal deputy commissioner. “One place to look is pediatric exclusivity, which has been estimated to cost the health care system more than $6 for every $1 spent by a company on a pediatric trial.”
And finally, “Congress should use patent and pricing incentives to accelerate the generation of definitive evidence under accelerated approval,” citing proposals to limit pricing or market exclusivity until companies complete studies that assess clinically relevant endpoints.
“These changes would reflect an evolution, not a revolution, of the FDA’s approach to new drug approval,” Dr. Sharfstein said. “These reforms could also bring greater order and thoughtfulness to the regulation of important new therapies, while enhancing safety and creating greater capability to afford truly transformative medical products.”
SOURCE: Jonathan Darrow et al. JAMA 2020 Jan 14. doi: 10.1001/jama.2019.20288.
Drug development times are not showing any signs of decreasing even though application review times at the Food and Drug Administration are improving, new research has shown.
“Despite the accumulation of expedited programs that have reduced FDA review times, overall clinical development times have not become shorter, although it is not possible to know what role these programs may have played in preventing an increase in development times,” Jonathan Darrow of Harvard Medical School, Boston, and colleagues wrote in a study published Jan. 14 in JAMA.
Researchers noted that FDA approval times declined from more than 3 years in 1983 to less than 1 year in 2017, although total time from the authorization of clinical testing to approval has remained steady across that period at about 8 years.
“The resistance of total development times to efforts to shorten them could be the result of more submissions of applications for rare disease drugs, which can sometimes pose trial recruitment challenges; a shifting emphasis to more challenging therapeutic categories, such as central nervous system disorder treatments; longer time horizons needed to establish efficacy when early intervention is important (e.g., cancer); or other factors,” wrote Mr. Darrow and colleagues.
The authors also note that the value of the expanded review toolbox the FDA now employs is “unclear” as “the number of new drug approvals has not increased substantially over the past three decades.” This observation does not count biologics or generic approvals.
Research revealed that the mean annual number of new drug approvals (including biologics) was 34 from 1990 to 1999, 25 from 2000 to 2009, and 41 from 2010 to 2018. In addition, while the number of new drug approvals has remained at or below 60 per year, the portion of drugs using at least one expedited review program increased over time, with more than 80% of the 59 new drugs approved in 2018 being subject to at least one expedited review program.
“Although the FDA has on average applied its expedited programs to drugs offering larger health gains, it is difficult to assess whether these programs have incentivized greater therapeutic innovation or merely allowed more appropriate agency prioritization,” noted Mr. Darrow and colleagues.
And while it may be hard to truly understand the impact of the many expedited review programs that have been introduced at the FDA, there is still room for improvement in the process.
In an editorial published in JAMA, Joshua Sharfstein, MD, of Johns Hopkins University, Baltimore, suggested four reforms the FDA could examine.
“First, Congress and the FDA should rationalize the various programs for expedited review,” he wrote, noting that companies are using the Orphan Drug Act to prevent competition. “Fixing the system requires, at a minimum, promoting meaningful competition for non-orphan uses.”
Second, he wrote, the FDA needs to strengthen oversight of postmarket safety though more diligence in the operation of its Risk Evaluation and Management Strategies (REMS) program.
“Third, Congress should recalibrate the programs that provide companies with special marketing protections,” added Dr. Sharfstein, former FDA principal deputy commissioner. “One place to look is pediatric exclusivity, which has been estimated to cost the health care system more than $6 for every $1 spent by a company on a pediatric trial.”
And finally, “Congress should use patent and pricing incentives to accelerate the generation of definitive evidence under accelerated approval,” citing proposals to limit pricing or market exclusivity until companies complete studies that assess clinically relevant endpoints.
“These changes would reflect an evolution, not a revolution, of the FDA’s approach to new drug approval,” Dr. Sharfstein said. “These reforms could also bring greater order and thoughtfulness to the regulation of important new therapies, while enhancing safety and creating greater capability to afford truly transformative medical products.”
SOURCE: Jonathan Darrow et al. JAMA 2020 Jan 14. doi: 10.1001/jama.2019.20288.
FROM JAMA
APPRENTICE registry: Wide variation exists in acute pancreatitis treatment, outcomes
Etiologies, demographics, management, and outcomes vary widely among patients with acute pancreatitis around the world, according to an analysis of data from the prospective, international APPRENTICE patient registry.
In some cases – particularly in regard to therapeutic interventions – the differences are “strikingly divergent” and demonstrate a “lag behind current evidence,” Bassem Matta, MD, of the University of Pittsburgh Medical Center, and colleagues reported in Clinical Gastroenterology and Hepatology.
Findings of a disproportionately higher rate of opioid prescribing during hospitalization and at discharge at North American sites are especially alarming, the investigators said.
Demographics and etiologies
The most common etiologies among 1,612 patients in the registry, which collects data from individuals with acute pancreatitis at six centers in Europe, three centers in India, five centers in Latin America, and eight centers in North America, were biliary (45%) and alcoholic (21%), and severity was mild in 65% of patients, moderate in 23%, and severe in 12%, they noted.
The predominant etiology in Latin America was biliary (78%), whereas the predominant etiology in India was alcoholic (45%).
The mean age of patients in Europe was 58 years, which is older than the mean age of 46 years for all regions represented in the registry, and comorbid conditions were also more common among patients in Europe (73% vs. 50% overall), the investigators found.
In addition to age differences, significant geographic differences were seen with respect to sex, ethnicity, and race distributions. Patients from Indian sites, for example, were mostly men (75%), were younger in age (median, 39 years), and were more likely to have alcoholic etiology (45% vs. 14% in the other areas). Most of the Latin American patients were women (67%), were young (median, 43 years), and most often had biliary etiology (78% vs. 37% elsewhere).
In contrast, European and North American subjects had a relatively equal sex distribution and an overall older age (median, 58 years).
“Observed differences in etiology and demographics likely reflect a tight interconnection between age, sex, and etiology,” the investigators wrote.
Management
Analgesic utilization was “markedly variable” across the world, they said, explaining that nonsteroidal anti-inflammatory drugs (NSAIDs) were the mainstay of pain management in Europe (68%), whereas Indian sites used tramadol in 91% of patients.
Latin American centers frequently used opioids (59%), NSAIDs (48%), and tramadol (34%).
However, opioid analgesics were used in 93% of patients in North America, compared with 27% of patients in the other regions, and 64% vs. 2.7% of patients in North American vs. the other regions were discharged on opioid analgesics.
This is of particular concern in light of a meta-analysis showing no difference in efficacy between opioids and nonsteroidal anti-inflammatory drugs for pain control in acute pancreatitis, the investigators said, noting that “[i]t is not entirely clear why such divergences exist between North American centers compared to the rest of the world.
“Notably, no clear statements are included in the current societal guidelines addressing optimal strategies for analgesia in [acute pancreatitis],” they added.
Also of note, the rate of endoscopic retrograde cholangiopancreatography (ERCP) – which guidelines based on strong evidence say should be limited to urgent cases among biliary acute pancreatitis patients with suspected cholangitis or biliary obstruction – was much higher at North American sites (44.7% vs. 21.9% overall) and post-ERCP pancreatitis was significantly more common at North American sites (19% vs. 2.8% in the other geographic areas), they said.
However, these differences were mostly driven by two North American sites, which classified 50 out of 90 and 22 out of 62 enrolled patients, respectively, as having post-ERCP pancreatitis.
Further, cholecystectomies were performed at the time of hospital admission in 60% of patients in Latin America, compared with 15% overall.
Another notable difference in management related to intravenous fluid use; similar amounts were administered during the first 24 hours in India and Latin America (3-3.2 liters), but in Europe the average was 2.5 liters, and while lactated Ringers and normal saline were the main types of fluid used, lactated Ringers was the dominant type used in India (92%), but was rarely used in Latin America (7%).
Outcomes
The overall median length of stay was 8 days, and overall mortality during hospitalization was 2.8%. In patients with mild disease, the shortest lengths of stay were in North America (4 vs. 7 days in other regions), and severe disease was more common in India (23% vs. 9% elsewhere).
Intensive care unit admissions were highest at Indian centers, and in-hospital mortality was highest in Europe (5.7%), compared with 3.3% in India, 2.3% in Latin America, and 0.6% in North America, they said.
Mortality during the initial hospital stay among patients with severe acute pancreatitis was 44% in Europe, compared with 15% in the other three regions.
Multivariable regression analyses adjusting for potential confounders such as age, sex, body mass index, Charlson score, etiology, and transfer status showed that the odds of severe acute pancreatitis were 11.2 times higher in Europe, 7 times higher in India, and 5.6 times higher in Latin America, compared with North America.
The odds ratios for mortality during hospitalization among patients with severe disease were 10.4 in Europe, 4.2 in India, and 8.3 in Latin America, compared with North America.
Implications of the findings
Around the world, acute pancreatitis is a leading cause of gastrointestinal-related hospital admissions, and incidence is reportedly increasing in the United States and Europe, the investigators said, noting that about 20% of patients develop severe disease with relatively high morbidity and mortality.
Multiple advances in management have emerged over the last decade, but it is unclear whether those recent advances have gained traction worldwide, they added.
The APPRENTICE registry was created as a response to the lack of prospective, multinational data and the current study aimed to assess the geographic differences in patient characteristics, management, and outcomes across four geographic areas.
The findings, which represent “a bird’s eye view” of regional variation, underscore a need for “adequately powered, multicenter, randomized controlled trials comparing the efficacy of different fluid resuscitation protocols” in acute pancreatitis patients, the investigators said.
Further, “the interventions specific to each region are in certain aspects strikingly divergent, and in many occasions lag behind current evidence,” they wrote, noting the largely variable length-of-stay outcomes and mortality rates.
“In addition to depicting key features of [acute pancreatitis], the results from this study may serve as a reference guide for designing future clinical trials,” they concluded.
The authors reported having no disclosures.
SOURCE: Matt B et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.11.017.
Etiologies, demographics, management, and outcomes vary widely among patients with acute pancreatitis around the world, according to an analysis of data from the prospective, international APPRENTICE patient registry.
In some cases – particularly in regard to therapeutic interventions – the differences are “strikingly divergent” and demonstrate a “lag behind current evidence,” Bassem Matta, MD, of the University of Pittsburgh Medical Center, and colleagues reported in Clinical Gastroenterology and Hepatology.
Findings of a disproportionately higher rate of opioid prescribing during hospitalization and at discharge at North American sites are especially alarming, the investigators said.
Demographics and etiologies
The most common etiologies among 1,612 patients in the registry, which collects data from individuals with acute pancreatitis at six centers in Europe, three centers in India, five centers in Latin America, and eight centers in North America, were biliary (45%) and alcoholic (21%), and severity was mild in 65% of patients, moderate in 23%, and severe in 12%, they noted.
The predominant etiology in Latin America was biliary (78%), whereas the predominant etiology in India was alcoholic (45%).
The mean age of patients in Europe was 58 years, which is older than the mean age of 46 years for all regions represented in the registry, and comorbid conditions were also more common among patients in Europe (73% vs. 50% overall), the investigators found.
In addition to age differences, significant geographic differences were seen with respect to sex, ethnicity, and race distributions. Patients from Indian sites, for example, were mostly men (75%), were younger in age (median, 39 years), and were more likely to have alcoholic etiology (45% vs. 14% in the other areas). Most of the Latin American patients were women (67%), were young (median, 43 years), and most often had biliary etiology (78% vs. 37% elsewhere).
In contrast, European and North American subjects had a relatively equal sex distribution and an overall older age (median, 58 years).
“Observed differences in etiology and demographics likely reflect a tight interconnection between age, sex, and etiology,” the investigators wrote.
Management
Analgesic utilization was “markedly variable” across the world, they said, explaining that nonsteroidal anti-inflammatory drugs (NSAIDs) were the mainstay of pain management in Europe (68%), whereas Indian sites used tramadol in 91% of patients.
Latin American centers frequently used opioids (59%), NSAIDs (48%), and tramadol (34%).
However, opioid analgesics were used in 93% of patients in North America, compared with 27% of patients in the other regions, and 64% vs. 2.7% of patients in North American vs. the other regions were discharged on opioid analgesics.
This is of particular concern in light of a meta-analysis showing no difference in efficacy between opioids and nonsteroidal anti-inflammatory drugs for pain control in acute pancreatitis, the investigators said, noting that “[i]t is not entirely clear why such divergences exist between North American centers compared to the rest of the world.
“Notably, no clear statements are included in the current societal guidelines addressing optimal strategies for analgesia in [acute pancreatitis],” they added.
Also of note, the rate of endoscopic retrograde cholangiopancreatography (ERCP) – which guidelines based on strong evidence say should be limited to urgent cases among biliary acute pancreatitis patients with suspected cholangitis or biliary obstruction – was much higher at North American sites (44.7% vs. 21.9% overall) and post-ERCP pancreatitis was significantly more common at North American sites (19% vs. 2.8% in the other geographic areas), they said.
However, these differences were mostly driven by two North American sites, which classified 50 out of 90 and 22 out of 62 enrolled patients, respectively, as having post-ERCP pancreatitis.
Further, cholecystectomies were performed at the time of hospital admission in 60% of patients in Latin America, compared with 15% overall.
Another notable difference in management related to intravenous fluid use; similar amounts were administered during the first 24 hours in India and Latin America (3-3.2 liters), but in Europe the average was 2.5 liters, and while lactated Ringers and normal saline were the main types of fluid used, lactated Ringers was the dominant type used in India (92%), but was rarely used in Latin America (7%).
Outcomes
The overall median length of stay was 8 days, and overall mortality during hospitalization was 2.8%. In patients with mild disease, the shortest lengths of stay were in North America (4 vs. 7 days in other regions), and severe disease was more common in India (23% vs. 9% elsewhere).
Intensive care unit admissions were highest at Indian centers, and in-hospital mortality was highest in Europe (5.7%), compared with 3.3% in India, 2.3% in Latin America, and 0.6% in North America, they said.
Mortality during the initial hospital stay among patients with severe acute pancreatitis was 44% in Europe, compared with 15% in the other three regions.
Multivariable regression analyses adjusting for potential confounders such as age, sex, body mass index, Charlson score, etiology, and transfer status showed that the odds of severe acute pancreatitis were 11.2 times higher in Europe, 7 times higher in India, and 5.6 times higher in Latin America, compared with North America.
The odds ratios for mortality during hospitalization among patients with severe disease were 10.4 in Europe, 4.2 in India, and 8.3 in Latin America, compared with North America.
Implications of the findings
Around the world, acute pancreatitis is a leading cause of gastrointestinal-related hospital admissions, and incidence is reportedly increasing in the United States and Europe, the investigators said, noting that about 20% of patients develop severe disease with relatively high morbidity and mortality.
Multiple advances in management have emerged over the last decade, but it is unclear whether those recent advances have gained traction worldwide, they added.
The APPRENTICE registry was created as a response to the lack of prospective, multinational data and the current study aimed to assess the geographic differences in patient characteristics, management, and outcomes across four geographic areas.
The findings, which represent “a bird’s eye view” of regional variation, underscore a need for “adequately powered, multicenter, randomized controlled trials comparing the efficacy of different fluid resuscitation protocols” in acute pancreatitis patients, the investigators said.
Further, “the interventions specific to each region are in certain aspects strikingly divergent, and in many occasions lag behind current evidence,” they wrote, noting the largely variable length-of-stay outcomes and mortality rates.
“In addition to depicting key features of [acute pancreatitis], the results from this study may serve as a reference guide for designing future clinical trials,” they concluded.
The authors reported having no disclosures.
SOURCE: Matt B et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.11.017.
Etiologies, demographics, management, and outcomes vary widely among patients with acute pancreatitis around the world, according to an analysis of data from the prospective, international APPRENTICE patient registry.
In some cases – particularly in regard to therapeutic interventions – the differences are “strikingly divergent” and demonstrate a “lag behind current evidence,” Bassem Matta, MD, of the University of Pittsburgh Medical Center, and colleagues reported in Clinical Gastroenterology and Hepatology.
Findings of a disproportionately higher rate of opioid prescribing during hospitalization and at discharge at North American sites are especially alarming, the investigators said.
Demographics and etiologies
The most common etiologies among 1,612 patients in the registry, which collects data from individuals with acute pancreatitis at six centers in Europe, three centers in India, five centers in Latin America, and eight centers in North America, were biliary (45%) and alcoholic (21%), and severity was mild in 65% of patients, moderate in 23%, and severe in 12%, they noted.
The predominant etiology in Latin America was biliary (78%), whereas the predominant etiology in India was alcoholic (45%).
The mean age of patients in Europe was 58 years, which is older than the mean age of 46 years for all regions represented in the registry, and comorbid conditions were also more common among patients in Europe (73% vs. 50% overall), the investigators found.
In addition to age differences, significant geographic differences were seen with respect to sex, ethnicity, and race distributions. Patients from Indian sites, for example, were mostly men (75%), were younger in age (median, 39 years), and were more likely to have alcoholic etiology (45% vs. 14% in the other areas). Most of the Latin American patients were women (67%), were young (median, 43 years), and most often had biliary etiology (78% vs. 37% elsewhere).
In contrast, European and North American subjects had a relatively equal sex distribution and an overall older age (median, 58 years).
“Observed differences in etiology and demographics likely reflect a tight interconnection between age, sex, and etiology,” the investigators wrote.
Management
Analgesic utilization was “markedly variable” across the world, they said, explaining that nonsteroidal anti-inflammatory drugs (NSAIDs) were the mainstay of pain management in Europe (68%), whereas Indian sites used tramadol in 91% of patients.
Latin American centers frequently used opioids (59%), NSAIDs (48%), and tramadol (34%).
However, opioid analgesics were used in 93% of patients in North America, compared with 27% of patients in the other regions, and 64% vs. 2.7% of patients in North American vs. the other regions were discharged on opioid analgesics.
This is of particular concern in light of a meta-analysis showing no difference in efficacy between opioids and nonsteroidal anti-inflammatory drugs for pain control in acute pancreatitis, the investigators said, noting that “[i]t is not entirely clear why such divergences exist between North American centers compared to the rest of the world.
“Notably, no clear statements are included in the current societal guidelines addressing optimal strategies for analgesia in [acute pancreatitis],” they added.
Also of note, the rate of endoscopic retrograde cholangiopancreatography (ERCP) – which guidelines based on strong evidence say should be limited to urgent cases among biliary acute pancreatitis patients with suspected cholangitis or biliary obstruction – was much higher at North American sites (44.7% vs. 21.9% overall) and post-ERCP pancreatitis was significantly more common at North American sites (19% vs. 2.8% in the other geographic areas), they said.
However, these differences were mostly driven by two North American sites, which classified 50 out of 90 and 22 out of 62 enrolled patients, respectively, as having post-ERCP pancreatitis.
Further, cholecystectomies were performed at the time of hospital admission in 60% of patients in Latin America, compared with 15% overall.
Another notable difference in management related to intravenous fluid use; similar amounts were administered during the first 24 hours in India and Latin America (3-3.2 liters), but in Europe the average was 2.5 liters, and while lactated Ringers and normal saline were the main types of fluid used, lactated Ringers was the dominant type used in India (92%), but was rarely used in Latin America (7%).
Outcomes
The overall median length of stay was 8 days, and overall mortality during hospitalization was 2.8%. In patients with mild disease, the shortest lengths of stay were in North America (4 vs. 7 days in other regions), and severe disease was more common in India (23% vs. 9% elsewhere).
Intensive care unit admissions were highest at Indian centers, and in-hospital mortality was highest in Europe (5.7%), compared with 3.3% in India, 2.3% in Latin America, and 0.6% in North America, they said.
Mortality during the initial hospital stay among patients with severe acute pancreatitis was 44% in Europe, compared with 15% in the other three regions.
Multivariable regression analyses adjusting for potential confounders such as age, sex, body mass index, Charlson score, etiology, and transfer status showed that the odds of severe acute pancreatitis were 11.2 times higher in Europe, 7 times higher in India, and 5.6 times higher in Latin America, compared with North America.
The odds ratios for mortality during hospitalization among patients with severe disease were 10.4 in Europe, 4.2 in India, and 8.3 in Latin America, compared with North America.
Implications of the findings
Around the world, acute pancreatitis is a leading cause of gastrointestinal-related hospital admissions, and incidence is reportedly increasing in the United States and Europe, the investigators said, noting that about 20% of patients develop severe disease with relatively high morbidity and mortality.
Multiple advances in management have emerged over the last decade, but it is unclear whether those recent advances have gained traction worldwide, they added.
The APPRENTICE registry was created as a response to the lack of prospective, multinational data and the current study aimed to assess the geographic differences in patient characteristics, management, and outcomes across four geographic areas.
The findings, which represent “a bird’s eye view” of regional variation, underscore a need for “adequately powered, multicenter, randomized controlled trials comparing the efficacy of different fluid resuscitation protocols” in acute pancreatitis patients, the investigators said.
Further, “the interventions specific to each region are in certain aspects strikingly divergent, and in many occasions lag behind current evidence,” they wrote, noting the largely variable length-of-stay outcomes and mortality rates.
“In addition to depicting key features of [acute pancreatitis], the results from this study may serve as a reference guide for designing future clinical trials,” they concluded.
The authors reported having no disclosures.
SOURCE: Matt B et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.11.017.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
NCCN guidelines highlight ‘complicated’ treatment for pediatric lymphomas
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
Gout rates reduced with SGLT2 inhibitors
The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.
Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.
The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.
Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.
The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.
The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.
SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.
The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.
Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.
The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.
Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.
The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.
The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.
SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.
The incidence of gout was approximately 40% lower in diabetes patients who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2) than it was in those who were prescribed glucagonlike peptide–1 receptor (GLP-1) agonists in a population-based new-user cohort study.
Hyperuricemia is a known cause of gout and common in type 2 diabetes patients. SGLT2 inhibitors may reduce the risk of gout by preventing the reabsorption of glucose and lowering serum uric acid levels; however, the impact on gout risk remains uncertain, wrote Michael Fralick, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
In a study published in the Annals of Internal Medicine, the researchers compared SGLT2 inhibitors and GLP-1 agonists in patients with type 2 diabetes to assess protection against gout.
The study population included adults with type 2 diabetes mellitus who had a new prescription for an SGTL2 inhibitor or GLP-1 agonist. The average age of the patients was 54 years; approximately half were women. Baseline characteristics were similar between the groups.
Overall, the researchers found a relative risk reduction of approximately 40% and an absolute risk reduction of approximately three fewer cases per 1,000 person-years in patients who received SGLT2 inhibitors, compared with those who received GLP-1 agonists. The incidence rate for gout in the SGLT2 and GLP-1 groups were 4.9 per 1,000 person-years and 7.8 per 1,000 person-years, respectively.
The study findings were limited by the investigators’ inability to measure potential confounding variables such as body mass index, alcohol use, and high purine diet; incomplete lab data on creatinine and hemoglobin A; and a low baseline risk for gout in the study population, the researchers noted. However, the results persisted across sensitivity analysis and, if replicated, suggest that “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” they wrote.
The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.
SOURCE: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: Sodium-glucose cotransporter 2 (SGLT2) inhibitor use was associated with lower rates of gout in type 2 diabetes patients compared with glucagonlike peptide–1 (GLP-1) agonist use.
Major finding: The incidence of gout was 4.9 per 1,000 person-years in patients on SGLT2 inhibitors and 7.8 per 1,000 person-years in patients on GLP1 agonists.
Study details: The data come from a population-based cohort study of 295,907 adults with type 2 diabetes.
Disclosures: The study was supported in part by Brigham and Women’s Hospital; lead author Dr. Fralick disclosed funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research.
Source: Fralick M et al. Ann Intern Med. 2020 Jan 14. doi: 10.7326/M19-2610.