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Sacred cows
Within the academic pediatric community, there is little argument that the concepts “evidence based” and “early intervention” are gold standards against which we must measure our efforts.
It should be obvious to everyone that if we can intervene early in a child’s developmental trajectory, our chances of affecting his/her outcome are improved. And the earlier the better. If we aren’t supremely committed to prevention, then what sets pediatrics apart from the other specialties?
Likewise, if we aren’t willing to systematically measure our efforts at improving the health of our patients, we run the risk of simply spinning our wheels and even worse, squandering our patients’ time and their parents’ energies. However, a recent article in Pediatrics and a companion commentary suggest that we need to be more careful as we interpret the buzz that surrounds the terms “early intervention” and “evidence based.”
In their one-sentence conclusion of a paper reviewing 48 studies of early intervention in early childhood development, the authors observe, “Although several interventions resulted in improved child development outcomes age 0 to 3 years, comparison across studies and interventions is limited by the use of different outcome measures, time of evaluation, and variability of results” (“Primary Care Interventions for Early Childhood Development: A Systematic Review,” Peacock-Chambers et al. Pediatrics. 2017, Nov 14. doi: 10.1542/peds.2017-1661). Unless you are looking for another reason to slip further into an abyss of despair, I urge that you skip reading the details of the Peacock-Chambers paper and turn instead to Dr. Jack P. Shonkoff’s excellent commentary (“Rethinking the Definition of Evidence-Based Interventions to Promote Early Child Development,” Pediatrics. 2017, Dec. doi: 10.1542/peds.2017-3136).
Dr. Shonkoff observes that there is ample evidence to support the general concept of early intervention as it relates to childhood development. However, he acknowledges that the improvements observed generally have been small. And there has been little success in scaling these few successes to larger populations. It would seem that the sacred cow of early intervention remains standing, albeit on somewhat shaky legs.
Dr. Shonkoff points out that an obsession with statistical significance often has blinded some of us to the importance of the magnitude of (or the lack of) impact when interpreting studies of early intervention. As a result, we may have failed to realize how far research in early childhood development has fallen behind the other fields of biomedical research such as cancer, HIV, and AIDS. His plea is that we begin to leverage our successes in fields such as molecular biology, epigenetics, and neuroscience when designing future studies of early childhood development. He asserts that this kind of basic science – in concert with “on-the-ground experience” (that’s you and me) and “authentic parental engagement” – is more likely to result in greater scalable impact for our patients threatened by developmental delays.
It is refreshing and encouraging reading a critical consideration of the evidence-based sacred cow. Evidence can be viewed from a variety of perspectives. If we continue to filter all of our observations through a statistical significance filter, we run the risk of missing both the forest and the trees.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Within the academic pediatric community, there is little argument that the concepts “evidence based” and “early intervention” are gold standards against which we must measure our efforts.
It should be obvious to everyone that if we can intervene early in a child’s developmental trajectory, our chances of affecting his/her outcome are improved. And the earlier the better. If we aren’t supremely committed to prevention, then what sets pediatrics apart from the other specialties?
Likewise, if we aren’t willing to systematically measure our efforts at improving the health of our patients, we run the risk of simply spinning our wheels and even worse, squandering our patients’ time and their parents’ energies. However, a recent article in Pediatrics and a companion commentary suggest that we need to be more careful as we interpret the buzz that surrounds the terms “early intervention” and “evidence based.”
In their one-sentence conclusion of a paper reviewing 48 studies of early intervention in early childhood development, the authors observe, “Although several interventions resulted in improved child development outcomes age 0 to 3 years, comparison across studies and interventions is limited by the use of different outcome measures, time of evaluation, and variability of results” (“Primary Care Interventions for Early Childhood Development: A Systematic Review,” Peacock-Chambers et al. Pediatrics. 2017, Nov 14. doi: 10.1542/peds.2017-1661). Unless you are looking for another reason to slip further into an abyss of despair, I urge that you skip reading the details of the Peacock-Chambers paper and turn instead to Dr. Jack P. Shonkoff’s excellent commentary (“Rethinking the Definition of Evidence-Based Interventions to Promote Early Child Development,” Pediatrics. 2017, Dec. doi: 10.1542/peds.2017-3136).
Dr. Shonkoff observes that there is ample evidence to support the general concept of early intervention as it relates to childhood development. However, he acknowledges that the improvements observed generally have been small. And there has been little success in scaling these few successes to larger populations. It would seem that the sacred cow of early intervention remains standing, albeit on somewhat shaky legs.
Dr. Shonkoff points out that an obsession with statistical significance often has blinded some of us to the importance of the magnitude of (or the lack of) impact when interpreting studies of early intervention. As a result, we may have failed to realize how far research in early childhood development has fallen behind the other fields of biomedical research such as cancer, HIV, and AIDS. His plea is that we begin to leverage our successes in fields such as molecular biology, epigenetics, and neuroscience when designing future studies of early childhood development. He asserts that this kind of basic science – in concert with “on-the-ground experience” (that’s you and me) and “authentic parental engagement” – is more likely to result in greater scalable impact for our patients threatened by developmental delays.
It is refreshing and encouraging reading a critical consideration of the evidence-based sacred cow. Evidence can be viewed from a variety of perspectives. If we continue to filter all of our observations through a statistical significance filter, we run the risk of missing both the forest and the trees.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Within the academic pediatric community, there is little argument that the concepts “evidence based” and “early intervention” are gold standards against which we must measure our efforts.
It should be obvious to everyone that if we can intervene early in a child’s developmental trajectory, our chances of affecting his/her outcome are improved. And the earlier the better. If we aren’t supremely committed to prevention, then what sets pediatrics apart from the other specialties?
Likewise, if we aren’t willing to systematically measure our efforts at improving the health of our patients, we run the risk of simply spinning our wheels and even worse, squandering our patients’ time and their parents’ energies. However, a recent article in Pediatrics and a companion commentary suggest that we need to be more careful as we interpret the buzz that surrounds the terms “early intervention” and “evidence based.”
In their one-sentence conclusion of a paper reviewing 48 studies of early intervention in early childhood development, the authors observe, “Although several interventions resulted in improved child development outcomes age 0 to 3 years, comparison across studies and interventions is limited by the use of different outcome measures, time of evaluation, and variability of results” (“Primary Care Interventions for Early Childhood Development: A Systematic Review,” Peacock-Chambers et al. Pediatrics. 2017, Nov 14. doi: 10.1542/peds.2017-1661). Unless you are looking for another reason to slip further into an abyss of despair, I urge that you skip reading the details of the Peacock-Chambers paper and turn instead to Dr. Jack P. Shonkoff’s excellent commentary (“Rethinking the Definition of Evidence-Based Interventions to Promote Early Child Development,” Pediatrics. 2017, Dec. doi: 10.1542/peds.2017-3136).
Dr. Shonkoff observes that there is ample evidence to support the general concept of early intervention as it relates to childhood development. However, he acknowledges that the improvements observed generally have been small. And there has been little success in scaling these few successes to larger populations. It would seem that the sacred cow of early intervention remains standing, albeit on somewhat shaky legs.
Dr. Shonkoff points out that an obsession with statistical significance often has blinded some of us to the importance of the magnitude of (or the lack of) impact when interpreting studies of early intervention. As a result, we may have failed to realize how far research in early childhood development has fallen behind the other fields of biomedical research such as cancer, HIV, and AIDS. His plea is that we begin to leverage our successes in fields such as molecular biology, epigenetics, and neuroscience when designing future studies of early childhood development. He asserts that this kind of basic science – in concert with “on-the-ground experience” (that’s you and me) and “authentic parental engagement” – is more likely to result in greater scalable impact for our patients threatened by developmental delays.
It is refreshing and encouraging reading a critical consideration of the evidence-based sacred cow. Evidence can be viewed from a variety of perspectives. If we continue to filter all of our observations through a statistical significance filter, we run the risk of missing both the forest and the trees.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Minorities less likely to seek treatment for psoriasis
Black, Asian, and other non-Hispanic Americans are less likely than are whites to seek treatment for psoriasis, according to data on 842 patients, reported Alexander H. Fischer, MD, of the University of Pennsylvania, Philadelphia, and his colleagues.
Data from previous studies have shown that racial and ethnic minorities have more severe psoriasis and a lower quality of life as a result of the disease, compared with white patients, the researchers noted in a study published as a research letter in the Journal of the American Academy of Dermatology.
A total of 51% of non-Hispanic whites with psoriasis sought treatment from a dermatologist, compared with 47% of Hispanic whites and 38% of non-Hispanic minorities (blacks, Asians, native Hawaiians, Pacific Islanders, and others). In addition, non-Hispanic minorities had significantly fewer ambulatory visits for psoriasis per year than did whites (a mean of 1.30 visits vs. 2.69 visits). Black, Asian, and other non-Hispanic minorities were about 40% less likely than were non-Hispanic whites to seek care for psoriasis.
The number of psoriasis prescriptions obtained was not significantly different among the racial/ethnic groups, the researchers reported.
The study is important because of the lack of data on psoriasis in nonwhite populations, senior author Junko Takeshita, MD, PhD, also of the University of Pennsylvania, said in an interview.
“Based on a few existing studies, we know that psoriasis is less common among minorities, but minorities, particularly blacks, may have more severe disease,” she said. “Also, minorities report poorer quality of life due to psoriasis than whites, independent of psoriasis severity. Furthermore, we previously published a study among Medicare beneficiaries with psoriasis that revealed that blacks are about 70% less likely to receive biologic therapies than whites, independent of socioeconomic status and access to medical care,” she added.
“The take-home message for clinicians is that while psoriasis is less common among minorities than whites, minorities may suffer from a larger burden of disease, yet have fewer visits and are less likely to see a dermatologist for their psoriasis,” Dr. Takeshita said. “This disparity in health care utilization for psoriasis does not seem to be entirely explained by racial/ethnic differences in socioeconomic status and health insurance. It is yet unknown why this disparity exists, and I’m not sure that minority patients being ‘hesitant to pursue care’ is the entire answer, though it may be a contributing factor,” she noted.
The study findings were limited by several factors including the relatively small sample size and the use of self-reports.
Many factors could be contributing to the disparity, including patient, physician/other health care provider, and health care system factors, but “once we identify the major causes of the disparity, we can develop methods to address the causes and reduce the disparity,” said Dr. Takeshita, who is a dermatologist and an epidemiologist. In the meantime, she added, “some things I think that are important to ensure equitable care for psoriasis are making sure that clinicians/dermatologists are comfortable diagnosing and treating psoriasis in nonwhite individuals, and encouraging clinicians to help increase awareness of psoriasis by educating their minority patients that psoriasis is still a common skin disease among nonwhite individuals.”
The study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Takeshita has received a research grant from Pfizer; she and another author, Joel Gelfand, MD, have received payment for psoriasis-related continuing medical education work supported indirectly by Eli Lilly; Dr. Gelfand’s other disclosures included serving as a consultant for, and having received research grants from, several other pharmaceutical companies. Dr. Fischer, a medical student at Johns Hopkins University, Baltimore, at the time of the research, and a fourth author had no financial disclosures.
SOURCE: Fischer AH et al. J Am Acad Dermatol. 2018 Jan;78[1]:200-3. doi: 10.1016/j.jaad.2017.07.052.
Black, Asian, and other non-Hispanic Americans are less likely than are whites to seek treatment for psoriasis, according to data on 842 patients, reported Alexander H. Fischer, MD, of the University of Pennsylvania, Philadelphia, and his colleagues.
Data from previous studies have shown that racial and ethnic minorities have more severe psoriasis and a lower quality of life as a result of the disease, compared with white patients, the researchers noted in a study published as a research letter in the Journal of the American Academy of Dermatology.
A total of 51% of non-Hispanic whites with psoriasis sought treatment from a dermatologist, compared with 47% of Hispanic whites and 38% of non-Hispanic minorities (blacks, Asians, native Hawaiians, Pacific Islanders, and others). In addition, non-Hispanic minorities had significantly fewer ambulatory visits for psoriasis per year than did whites (a mean of 1.30 visits vs. 2.69 visits). Black, Asian, and other non-Hispanic minorities were about 40% less likely than were non-Hispanic whites to seek care for psoriasis.
The number of psoriasis prescriptions obtained was not significantly different among the racial/ethnic groups, the researchers reported.
The study is important because of the lack of data on psoriasis in nonwhite populations, senior author Junko Takeshita, MD, PhD, also of the University of Pennsylvania, said in an interview.
“Based on a few existing studies, we know that psoriasis is less common among minorities, but minorities, particularly blacks, may have more severe disease,” she said. “Also, minorities report poorer quality of life due to psoriasis than whites, independent of psoriasis severity. Furthermore, we previously published a study among Medicare beneficiaries with psoriasis that revealed that blacks are about 70% less likely to receive biologic therapies than whites, independent of socioeconomic status and access to medical care,” she added.
“The take-home message for clinicians is that while psoriasis is less common among minorities than whites, minorities may suffer from a larger burden of disease, yet have fewer visits and are less likely to see a dermatologist for their psoriasis,” Dr. Takeshita said. “This disparity in health care utilization for psoriasis does not seem to be entirely explained by racial/ethnic differences in socioeconomic status and health insurance. It is yet unknown why this disparity exists, and I’m not sure that minority patients being ‘hesitant to pursue care’ is the entire answer, though it may be a contributing factor,” she noted.
The study findings were limited by several factors including the relatively small sample size and the use of self-reports.
Many factors could be contributing to the disparity, including patient, physician/other health care provider, and health care system factors, but “once we identify the major causes of the disparity, we can develop methods to address the causes and reduce the disparity,” said Dr. Takeshita, who is a dermatologist and an epidemiologist. In the meantime, she added, “some things I think that are important to ensure equitable care for psoriasis are making sure that clinicians/dermatologists are comfortable diagnosing and treating psoriasis in nonwhite individuals, and encouraging clinicians to help increase awareness of psoriasis by educating their minority patients that psoriasis is still a common skin disease among nonwhite individuals.”
The study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Takeshita has received a research grant from Pfizer; she and another author, Joel Gelfand, MD, have received payment for psoriasis-related continuing medical education work supported indirectly by Eli Lilly; Dr. Gelfand’s other disclosures included serving as a consultant for, and having received research grants from, several other pharmaceutical companies. Dr. Fischer, a medical student at Johns Hopkins University, Baltimore, at the time of the research, and a fourth author had no financial disclosures.
SOURCE: Fischer AH et al. J Am Acad Dermatol. 2018 Jan;78[1]:200-3. doi: 10.1016/j.jaad.2017.07.052.
Black, Asian, and other non-Hispanic Americans are less likely than are whites to seek treatment for psoriasis, according to data on 842 patients, reported Alexander H. Fischer, MD, of the University of Pennsylvania, Philadelphia, and his colleagues.
Data from previous studies have shown that racial and ethnic minorities have more severe psoriasis and a lower quality of life as a result of the disease, compared with white patients, the researchers noted in a study published as a research letter in the Journal of the American Academy of Dermatology.
A total of 51% of non-Hispanic whites with psoriasis sought treatment from a dermatologist, compared with 47% of Hispanic whites and 38% of non-Hispanic minorities (blacks, Asians, native Hawaiians, Pacific Islanders, and others). In addition, non-Hispanic minorities had significantly fewer ambulatory visits for psoriasis per year than did whites (a mean of 1.30 visits vs. 2.69 visits). Black, Asian, and other non-Hispanic minorities were about 40% less likely than were non-Hispanic whites to seek care for psoriasis.
The number of psoriasis prescriptions obtained was not significantly different among the racial/ethnic groups, the researchers reported.
The study is important because of the lack of data on psoriasis in nonwhite populations, senior author Junko Takeshita, MD, PhD, also of the University of Pennsylvania, said in an interview.
“Based on a few existing studies, we know that psoriasis is less common among minorities, but minorities, particularly blacks, may have more severe disease,” she said. “Also, minorities report poorer quality of life due to psoriasis than whites, independent of psoriasis severity. Furthermore, we previously published a study among Medicare beneficiaries with psoriasis that revealed that blacks are about 70% less likely to receive biologic therapies than whites, independent of socioeconomic status and access to medical care,” she added.
“The take-home message for clinicians is that while psoriasis is less common among minorities than whites, minorities may suffer from a larger burden of disease, yet have fewer visits and are less likely to see a dermatologist for their psoriasis,” Dr. Takeshita said. “This disparity in health care utilization for psoriasis does not seem to be entirely explained by racial/ethnic differences in socioeconomic status and health insurance. It is yet unknown why this disparity exists, and I’m not sure that minority patients being ‘hesitant to pursue care’ is the entire answer, though it may be a contributing factor,” she noted.
The study findings were limited by several factors including the relatively small sample size and the use of self-reports.
Many factors could be contributing to the disparity, including patient, physician/other health care provider, and health care system factors, but “once we identify the major causes of the disparity, we can develop methods to address the causes and reduce the disparity,” said Dr. Takeshita, who is a dermatologist and an epidemiologist. In the meantime, she added, “some things I think that are important to ensure equitable care for psoriasis are making sure that clinicians/dermatologists are comfortable diagnosing and treating psoriasis in nonwhite individuals, and encouraging clinicians to help increase awareness of psoriasis by educating their minority patients that psoriasis is still a common skin disease among nonwhite individuals.”
The study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Takeshita has received a research grant from Pfizer; she and another author, Joel Gelfand, MD, have received payment for psoriasis-related continuing medical education work supported indirectly by Eli Lilly; Dr. Gelfand’s other disclosures included serving as a consultant for, and having received research grants from, several other pharmaceutical companies. Dr. Fischer, a medical student at Johns Hopkins University, Baltimore, at the time of the research, and a fourth author had no financial disclosures.
SOURCE: Fischer AH et al. J Am Acad Dermatol. 2018 Jan;78[1]:200-3. doi: 10.1016/j.jaad.2017.07.052.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point: Black, Asian, and non-Hispanic patients with psoriasis often have more severe disease than do white patients but are significantly less likely to seek care.
Major finding:
Data source: A cohort study of data from the Medical Expenditure Panel Survey on 842 psoriasis patients in the United States.
Disclosures: The study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Two of the four authors had no financial disclosures. One author has received a research grant from Pfizer and payment for psoriasis-related continuing medical education work supported indirectly by Eli Lilly; another author’s disclosures included the latter, as well serving as a consultant for, and having received research grants from, several other pharmaceutical companies.
Source: Fischer AH et al. J Am Acad Dermatol. 2018 Jan;78[1]:200-3. doi: 10.1016/j.jaad.2017.07.05
Caplacizumab improves outcomes in aTTP
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab. 
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.
Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).
Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.
Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.
Patients and treatment
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.
If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.
“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.
“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”
According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).
The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).
The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).
For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).
Safety
“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.
The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).
Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Drug granted breakthrough status as first-line SAA therapy
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA aims to improve review of generic drugs
The US Food and Drug Administration (FDA) has announced that it is taking new steps to facilitate efficient review of generic drugs.
The agency has released 2 documents intended to help streamline and improve the submission and review of generic drug applications, or Abbreviated New Drug Applications (ANDAs).
The first document is a draft guidance for industry, “Good ANDA Submission Practices,” which highlights common, recurring deficiencies the FDA sees in generic drug applications that may lead to a delay in their approval.
The FDA’s goal in releasing this document is to reduce the number of review cycles for ANDAs by helping applicants avoid these deficiencies.
The second document is a Manual of Policies and Procedures (MAPP), “Good ANDA Assessment Practices,” which outlines ANDA assessment practices for FDA staff.
This document formalizes a more streamlined generic review process, including the introduction of new templates designed to make each cycle of the review process more efficient and complete.
Releasing these new documents is part of the FDA’s Drug Competition Action Plan, which has 3 main goals:
- To reduce actions by branded pharmaceutical companies that can delay generic drug entry into the marketplace
- To resolve scientific and regulatory obstacles that can make it difficult to win approval of generic versions of certain complex drugs
- To improve the efficiency and predictability of the FDA’s generic review process to reduce the time it takes to get a generic drug approved and lessen the number of review cycles needed for generic applications.
The new MAPP and draft guidance documents for ANDAs are intended to help the FDA meet the third goal of the Drug Competition Action Plan.
The FDA is hoping to address the second goal of the plan later this year, building upon its initiatives to accelerate review and approval of complex generics.
The agency is also planning to develop guidance documents during the first quarter of 2018 that will address 3 issues related to the first goal of the plan—potential abuses of the citizen petition process, companies that restrict access to testing samples of branded drugs, and abuses of the single, shared system REMS (risk evaluation and mitigation strategy) negotiation process.
The US Food and Drug Administration (FDA) has announced that it is taking new steps to facilitate efficient review of generic drugs.
The agency has released 2 documents intended to help streamline and improve the submission and review of generic drug applications, or Abbreviated New Drug Applications (ANDAs).
The first document is a draft guidance for industry, “Good ANDA Submission Practices,” which highlights common, recurring deficiencies the FDA sees in generic drug applications that may lead to a delay in their approval.
The FDA’s goal in releasing this document is to reduce the number of review cycles for ANDAs by helping applicants avoid these deficiencies.
The second document is a Manual of Policies and Procedures (MAPP), “Good ANDA Assessment Practices,” which outlines ANDA assessment practices for FDA staff.
This document formalizes a more streamlined generic review process, including the introduction of new templates designed to make each cycle of the review process more efficient and complete.
Releasing these new documents is part of the FDA’s Drug Competition Action Plan, which has 3 main goals:
- To reduce actions by branded pharmaceutical companies that can delay generic drug entry into the marketplace
- To resolve scientific and regulatory obstacles that can make it difficult to win approval of generic versions of certain complex drugs
- To improve the efficiency and predictability of the FDA’s generic review process to reduce the time it takes to get a generic drug approved and lessen the number of review cycles needed for generic applications.
The new MAPP and draft guidance documents for ANDAs are intended to help the FDA meet the third goal of the Drug Competition Action Plan.
The FDA is hoping to address the second goal of the plan later this year, building upon its initiatives to accelerate review and approval of complex generics.
The agency is also planning to develop guidance documents during the first quarter of 2018 that will address 3 issues related to the first goal of the plan—potential abuses of the citizen petition process, companies that restrict access to testing samples of branded drugs, and abuses of the single, shared system REMS (risk evaluation and mitigation strategy) negotiation process.
The US Food and Drug Administration (FDA) has announced that it is taking new steps to facilitate efficient review of generic drugs.
The agency has released 2 documents intended to help streamline and improve the submission and review of generic drug applications, or Abbreviated New Drug Applications (ANDAs).
The first document is a draft guidance for industry, “Good ANDA Submission Practices,” which highlights common, recurring deficiencies the FDA sees in generic drug applications that may lead to a delay in their approval.
The FDA’s goal in releasing this document is to reduce the number of review cycles for ANDAs by helping applicants avoid these deficiencies.
The second document is a Manual of Policies and Procedures (MAPP), “Good ANDA Assessment Practices,” which outlines ANDA assessment practices for FDA staff.
This document formalizes a more streamlined generic review process, including the introduction of new templates designed to make each cycle of the review process more efficient and complete.
Releasing these new documents is part of the FDA’s Drug Competition Action Plan, which has 3 main goals:
- To reduce actions by branded pharmaceutical companies that can delay generic drug entry into the marketplace
- To resolve scientific and regulatory obstacles that can make it difficult to win approval of generic versions of certain complex drugs
- To improve the efficiency and predictability of the FDA’s generic review process to reduce the time it takes to get a generic drug approved and lessen the number of review cycles needed for generic applications.
The new MAPP and draft guidance documents for ANDAs are intended to help the FDA meet the third goal of the Drug Competition Action Plan.
The FDA is hoping to address the second goal of the plan later this year, building upon its initiatives to accelerate review and approval of complex generics.
The agency is also planning to develop guidance documents during the first quarter of 2018 that will address 3 issues related to the first goal of the plan—potential abuses of the citizen petition process, companies that restrict access to testing samples of branded drugs, and abuses of the single, shared system REMS (risk evaluation and mitigation strategy) negotiation process.
Stressed for Success
As I write this column, the holiday season has just begun, and its incumbent demands lie ahead. By the time this article reaches you, we will have outlasted the season and its associated stress. But it’s not just the holiday baking, gift-wrapping, and decorating that overwhelms us—we face enormous professional stress during this time of year, with its emphasis on home, family, good health, and harmony.
Stress is simply a part of human nature. And despite its bad rap, not all stress is problematic; it’s what motivates people to prepare or perform. Routine, “normal” stress that is temporary or short-lived can actually be beneficial. When placed in danger, the body prepares to either face the threat or flee to safety. During these times, your pulse quickens, you breathe faster, your muscles tense, your brain uses more oxygen and increases activity—all functions that aid in survival.1
But not every situation we encounter necessitates an increase in endorphin levels and blood pressure. Tell that to our stress levels, which are often persistently elevated! Chronic stress can cause the self-protective responses your body activates when threatened to suppress immune, digestive, sleep, and reproductive systems, leading them to cease normal functioning over time.1 This “bad” stress—or distress—can contribute to health problems such as hypertension, cardiovascular disease, obesity, and diabetes.
Stress can elicit a variety of responses: behavioral, psychologic/emotional, physical, cognitive, and social.2 For many, consumption (of tobacco, alcohol, drugs, sugar, fat, or caffeine) is a coping mechanism. While many people look to food for comfort and stress relief, research suggests it may have undesired effects. Eating a high-fat meal when under stress can slow your metabolism and result in significant weight gain.3 Stress can also influence whether people undereat or overeat and affect neurohormonal activity—which leads to increased production of cortisol, which leads to weight gain (particularly in women).4 Let’s be honest: Gaining weight seldom lowers someone’s stress level.
Everyone has different triggers that cause their stress levels to spike, but the workplace has been found to top the list. Within the “work” category, commonly reported stressors include
- Heavy workload or too much responsibility
- Long hours
- Poor management, unclear expectations, or having no say in decision-making.5
For health care providers, day-to-day stress is a chronic problem; responses to the Clinician Reviews annual job satisfaction survey have demonstrated that.6,7 Many of our readers report ongoing issues related to scheduling, work/life balance, compensation, and working conditions. That tension has a direct negative effect, not only on us, but on our families and our patients as well. A missed soccer game or a holiday on call are obvious stressors—but our inability to help patients achieve optimal health is a source of distress that we may not recognize the ramifications of. How often has a clinician felt caught in what feels like an unattainable quest?
Mitigating this workplace stress is the challenge. Changing jobs is another high-stress event, so up and quitting is probably not the answer. Identifying the problem is the first essential step.
If workload is the issue, focus on setting realistic goals for your day. Goal-setting provides purposeful direction and helps you feel in control. There will undeniably be days in which your plan must be completely abandoned. When this happens, don’t fret—reassess! Decide what must get done and what can wait. If possible, avoid scheduling patient appointments that will put you into overload. Learn to say “no” without feeling as though you are not a team player. And when you feel swamped, put a positive spin on the day by noting what you have accomplished, rather than what you have been unable to achieve.
If you find that your voice is but a whisper in the decision-making process, look for ways to become more involved. How can you provide direction on issues relating to organizational structure and clinical efficiency? Don’t suppress your feelings or concerns about the work environment. Pulling up a chair at the management table is crucial to improving the workplace and reducing stress for everyone (including the management!). Discuss key frustration points. Clear documentation of the issues that impede patient satisfaction (eg, long wait times) will aid in your dialogue.
Literature has identified common professional frustrations related to base pay rates, on-call pay, overtime pay, individual productivity compensation, and general incentive payments, which are further supported by our job satisfaction surveys.6-8 Knowing what’s included in the typical compensation packages in your region can reduce not only your own stress, but your employer’s as well. While this may seem a futile exercise, the investment in evaluating your own value, and the value your employer places on you, is well worth the return.
Previous experience dictates our ability to handle stress. If you have confidence in yourself, your contribution to your patients, and your ability to influence events and persevere through challenges, you are better equipped to handle the stress. If you can put the stressors in perspective by knowing the time frame of the stress, how long it will last, and what to expect, it will be easier to cope with the situation.
While trying to write this column, I was initially so stressed that I could barely compose a sentence! I knew that the stress of meeting my editorial deadline was “good” stress, though, so I kept taking short walks, and (as you can read) I got through it. Whether you turn to exercise or music or (as one friend does!) closet purging—managing your stress is key to maintaining good health.
[polldaddy:9906029]
1. National Institute of Mental Health. 5 things you should know about stress. www.nimh.nih.gov/health/publications/stress/index.shtml. Accessed December 4, 2017.
2. New York State Office of Mental Health. Common stress reactions: a self-assessment. www.omh.ny.gov/omhweb/disaster_resources/pandemic_influenza/doctors_nurses/Common_Stress_Reactions.html. Accessed December 7, 2017.
3. Smith M. Stress, high fat, and your metabolism [video]. WebMD. www.webmd.com/balance/stress-management/video/stress-high-fat-and-your-metabolism. Accessed December 7, 2017.
4. Slachta A. Stressed women more likely to develop obesity. Cardiovascular Business. November 15, 2017. www.cardiovascularbusiness.com/topics/lipid-metabolic/stressed-women-more-likely-develop-obesity-study-finds. Accessed December 7, 2017.
5. WebMD. Causes of stress. www.webmd.com/balance/guide/causes-of-stress#1. Accessed December 7, 2017.
6. Job satisfaction. Clinician Reviews. 2017;27(12):25-30.
7. Beyond salary: are you happy with your work? Clinician Reviews. 2016;26(12):23-26.
8. O’Hare S, Young AF. The advancing role of advanced practice clinicians: compensation, development, & leadership trends (2016). HealthLeaders Media. www.healthleadersmedia.com/whitepaper/advancing-role-advanced-practice-clinicians-compensation-development-leadership-trends. Accessed December 7, 2017.
As I write this column, the holiday season has just begun, and its incumbent demands lie ahead. By the time this article reaches you, we will have outlasted the season and its associated stress. But it’s not just the holiday baking, gift-wrapping, and decorating that overwhelms us—we face enormous professional stress during this time of year, with its emphasis on home, family, good health, and harmony.
Stress is simply a part of human nature. And despite its bad rap, not all stress is problematic; it’s what motivates people to prepare or perform. Routine, “normal” stress that is temporary or short-lived can actually be beneficial. When placed in danger, the body prepares to either face the threat or flee to safety. During these times, your pulse quickens, you breathe faster, your muscles tense, your brain uses more oxygen and increases activity—all functions that aid in survival.1
But not every situation we encounter necessitates an increase in endorphin levels and blood pressure. Tell that to our stress levels, which are often persistently elevated! Chronic stress can cause the self-protective responses your body activates when threatened to suppress immune, digestive, sleep, and reproductive systems, leading them to cease normal functioning over time.1 This “bad” stress—or distress—can contribute to health problems such as hypertension, cardiovascular disease, obesity, and diabetes.
Stress can elicit a variety of responses: behavioral, psychologic/emotional, physical, cognitive, and social.2 For many, consumption (of tobacco, alcohol, drugs, sugar, fat, or caffeine) is a coping mechanism. While many people look to food for comfort and stress relief, research suggests it may have undesired effects. Eating a high-fat meal when under stress can slow your metabolism and result in significant weight gain.3 Stress can also influence whether people undereat or overeat and affect neurohormonal activity—which leads to increased production of cortisol, which leads to weight gain (particularly in women).4 Let’s be honest: Gaining weight seldom lowers someone’s stress level.
Everyone has different triggers that cause their stress levels to spike, but the workplace has been found to top the list. Within the “work” category, commonly reported stressors include
- Heavy workload or too much responsibility
- Long hours
- Poor management, unclear expectations, or having no say in decision-making.5
For health care providers, day-to-day stress is a chronic problem; responses to the Clinician Reviews annual job satisfaction survey have demonstrated that.6,7 Many of our readers report ongoing issues related to scheduling, work/life balance, compensation, and working conditions. That tension has a direct negative effect, not only on us, but on our families and our patients as well. A missed soccer game or a holiday on call are obvious stressors—but our inability to help patients achieve optimal health is a source of distress that we may not recognize the ramifications of. How often has a clinician felt caught in what feels like an unattainable quest?
Mitigating this workplace stress is the challenge. Changing jobs is another high-stress event, so up and quitting is probably not the answer. Identifying the problem is the first essential step.
If workload is the issue, focus on setting realistic goals for your day. Goal-setting provides purposeful direction and helps you feel in control. There will undeniably be days in which your plan must be completely abandoned. When this happens, don’t fret—reassess! Decide what must get done and what can wait. If possible, avoid scheduling patient appointments that will put you into overload. Learn to say “no” without feeling as though you are not a team player. And when you feel swamped, put a positive spin on the day by noting what you have accomplished, rather than what you have been unable to achieve.
If you find that your voice is but a whisper in the decision-making process, look for ways to become more involved. How can you provide direction on issues relating to organizational structure and clinical efficiency? Don’t suppress your feelings or concerns about the work environment. Pulling up a chair at the management table is crucial to improving the workplace and reducing stress for everyone (including the management!). Discuss key frustration points. Clear documentation of the issues that impede patient satisfaction (eg, long wait times) will aid in your dialogue.
Literature has identified common professional frustrations related to base pay rates, on-call pay, overtime pay, individual productivity compensation, and general incentive payments, which are further supported by our job satisfaction surveys.6-8 Knowing what’s included in the typical compensation packages in your region can reduce not only your own stress, but your employer’s as well. While this may seem a futile exercise, the investment in evaluating your own value, and the value your employer places on you, is well worth the return.
Previous experience dictates our ability to handle stress. If you have confidence in yourself, your contribution to your patients, and your ability to influence events and persevere through challenges, you are better equipped to handle the stress. If you can put the stressors in perspective by knowing the time frame of the stress, how long it will last, and what to expect, it will be easier to cope with the situation.
While trying to write this column, I was initially so stressed that I could barely compose a sentence! I knew that the stress of meeting my editorial deadline was “good” stress, though, so I kept taking short walks, and (as you can read) I got through it. Whether you turn to exercise or music or (as one friend does!) closet purging—managing your stress is key to maintaining good health.
[polldaddy:9906029]
As I write this column, the holiday season has just begun, and its incumbent demands lie ahead. By the time this article reaches you, we will have outlasted the season and its associated stress. But it’s not just the holiday baking, gift-wrapping, and decorating that overwhelms us—we face enormous professional stress during this time of year, with its emphasis on home, family, good health, and harmony.
Stress is simply a part of human nature. And despite its bad rap, not all stress is problematic; it’s what motivates people to prepare or perform. Routine, “normal” stress that is temporary or short-lived can actually be beneficial. When placed in danger, the body prepares to either face the threat or flee to safety. During these times, your pulse quickens, you breathe faster, your muscles tense, your brain uses more oxygen and increases activity—all functions that aid in survival.1
But not every situation we encounter necessitates an increase in endorphin levels and blood pressure. Tell that to our stress levels, which are often persistently elevated! Chronic stress can cause the self-protective responses your body activates when threatened to suppress immune, digestive, sleep, and reproductive systems, leading them to cease normal functioning over time.1 This “bad” stress—or distress—can contribute to health problems such as hypertension, cardiovascular disease, obesity, and diabetes.
Stress can elicit a variety of responses: behavioral, psychologic/emotional, physical, cognitive, and social.2 For many, consumption (of tobacco, alcohol, drugs, sugar, fat, or caffeine) is a coping mechanism. While many people look to food for comfort and stress relief, research suggests it may have undesired effects. Eating a high-fat meal when under stress can slow your metabolism and result in significant weight gain.3 Stress can also influence whether people undereat or overeat and affect neurohormonal activity—which leads to increased production of cortisol, which leads to weight gain (particularly in women).4 Let’s be honest: Gaining weight seldom lowers someone’s stress level.
Everyone has different triggers that cause their stress levels to spike, but the workplace has been found to top the list. Within the “work” category, commonly reported stressors include
- Heavy workload or too much responsibility
- Long hours
- Poor management, unclear expectations, or having no say in decision-making.5
For health care providers, day-to-day stress is a chronic problem; responses to the Clinician Reviews annual job satisfaction survey have demonstrated that.6,7 Many of our readers report ongoing issues related to scheduling, work/life balance, compensation, and working conditions. That tension has a direct negative effect, not only on us, but on our families and our patients as well. A missed soccer game or a holiday on call are obvious stressors—but our inability to help patients achieve optimal health is a source of distress that we may not recognize the ramifications of. How often has a clinician felt caught in what feels like an unattainable quest?
Mitigating this workplace stress is the challenge. Changing jobs is another high-stress event, so up and quitting is probably not the answer. Identifying the problem is the first essential step.
If workload is the issue, focus on setting realistic goals for your day. Goal-setting provides purposeful direction and helps you feel in control. There will undeniably be days in which your plan must be completely abandoned. When this happens, don’t fret—reassess! Decide what must get done and what can wait. If possible, avoid scheduling patient appointments that will put you into overload. Learn to say “no” without feeling as though you are not a team player. And when you feel swamped, put a positive spin on the day by noting what you have accomplished, rather than what you have been unable to achieve.
If you find that your voice is but a whisper in the decision-making process, look for ways to become more involved. How can you provide direction on issues relating to organizational structure and clinical efficiency? Don’t suppress your feelings or concerns about the work environment. Pulling up a chair at the management table is crucial to improving the workplace and reducing stress for everyone (including the management!). Discuss key frustration points. Clear documentation of the issues that impede patient satisfaction (eg, long wait times) will aid in your dialogue.
Literature has identified common professional frustrations related to base pay rates, on-call pay, overtime pay, individual productivity compensation, and general incentive payments, which are further supported by our job satisfaction surveys.6-8 Knowing what’s included in the typical compensation packages in your region can reduce not only your own stress, but your employer’s as well. While this may seem a futile exercise, the investment in evaluating your own value, and the value your employer places on you, is well worth the return.
Previous experience dictates our ability to handle stress. If you have confidence in yourself, your contribution to your patients, and your ability to influence events and persevere through challenges, you are better equipped to handle the stress. If you can put the stressors in perspective by knowing the time frame of the stress, how long it will last, and what to expect, it will be easier to cope with the situation.
While trying to write this column, I was initially so stressed that I could barely compose a sentence! I knew that the stress of meeting my editorial deadline was “good” stress, though, so I kept taking short walks, and (as you can read) I got through it. Whether you turn to exercise or music or (as one friend does!) closet purging—managing your stress is key to maintaining good health.
[polldaddy:9906029]
1. National Institute of Mental Health. 5 things you should know about stress. www.nimh.nih.gov/health/publications/stress/index.shtml. Accessed December 4, 2017.
2. New York State Office of Mental Health. Common stress reactions: a self-assessment. www.omh.ny.gov/omhweb/disaster_resources/pandemic_influenza/doctors_nurses/Common_Stress_Reactions.html. Accessed December 7, 2017.
3. Smith M. Stress, high fat, and your metabolism [video]. WebMD. www.webmd.com/balance/stress-management/video/stress-high-fat-and-your-metabolism. Accessed December 7, 2017.
4. Slachta A. Stressed women more likely to develop obesity. Cardiovascular Business. November 15, 2017. www.cardiovascularbusiness.com/topics/lipid-metabolic/stressed-women-more-likely-develop-obesity-study-finds. Accessed December 7, 2017.
5. WebMD. Causes of stress. www.webmd.com/balance/guide/causes-of-stress#1. Accessed December 7, 2017.
6. Job satisfaction. Clinician Reviews. 2017;27(12):25-30.
7. Beyond salary: are you happy with your work? Clinician Reviews. 2016;26(12):23-26.
8. O’Hare S, Young AF. The advancing role of advanced practice clinicians: compensation, development, & leadership trends (2016). HealthLeaders Media. www.healthleadersmedia.com/whitepaper/advancing-role-advanced-practice-clinicians-compensation-development-leadership-trends. Accessed December 7, 2017.
1. National Institute of Mental Health. 5 things you should know about stress. www.nimh.nih.gov/health/publications/stress/index.shtml. Accessed December 4, 2017.
2. New York State Office of Mental Health. Common stress reactions: a self-assessment. www.omh.ny.gov/omhweb/disaster_resources/pandemic_influenza/doctors_nurses/Common_Stress_Reactions.html. Accessed December 7, 2017.
3. Smith M. Stress, high fat, and your metabolism [video]. WebMD. www.webmd.com/balance/stress-management/video/stress-high-fat-and-your-metabolism. Accessed December 7, 2017.
4. Slachta A. Stressed women more likely to develop obesity. Cardiovascular Business. November 15, 2017. www.cardiovascularbusiness.com/topics/lipid-metabolic/stressed-women-more-likely-develop-obesity-study-finds. Accessed December 7, 2017.
5. WebMD. Causes of stress. www.webmd.com/balance/guide/causes-of-stress#1. Accessed December 7, 2017.
6. Job satisfaction. Clinician Reviews. 2017;27(12):25-30.
7. Beyond salary: are you happy with your work? Clinician Reviews. 2016;26(12):23-26.
8. O’Hare S, Young AF. The advancing role of advanced practice clinicians: compensation, development, & leadership trends (2016). HealthLeaders Media. www.healthleadersmedia.com/whitepaper/advancing-role-advanced-practice-clinicians-compensation-development-leadership-trends. Accessed December 7, 2017.
Model validates use of HCV+ livers for transplant
As the evidence supporting the idea of transplanting livers infected with hepatitis C into patients who do not have the disease continues to mount, a multi-institutional team of researchers has developed a mathematical model that shows when hepatitis C–positive-to-negative transplant may improve survival for patients who might otherwise die awaiting a disease-free liver.
In a report published in the journal Hepatology (doi: 10.1002/hep.29723), the researchers noted how direct-acting antivirals (DAAs) have changed the calculus of hepatitis C (HCV) status in liver transplant by reducing the number of HCV-positive patients on the wait list and providing treatment for HCV-negative patients who receive HCV-positive livers. “It is important that further research in this area continues, as we expect that the supply of HCV-positive organs may continue to increase in light of the growing opioid epidemic,” said lead author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital Institute for Technology Assessment in Boston.
Dr. Chhatwal and coauthors claimed their study provides some of the first empirical data for transplanting livers from patients with HCV into patients who do not have the disease.
The researchers performed their analysis using a Markov-based mathematical model known as Simulation of Liver Transplant Candidates (SIM-LT). The model had been validated in previous studies that Dr. Chhatwal and some coauthors had published (Hepatology. 2017;65:777-88; Clin Gastroenterol Hepatol 2018;16:115-22). Dr. Chhatwal and coauthors revised the SIM-LT model to simulate a virtual trial of HCV-negative patients on the liver transplant waiting list to compare outcomes in patients willing to accept any liver to those willing to accept only HCV-negative livers.
The patients willing to receive HCV-positive livers were given 12 weeks of DAA therapy preemptively and had a higher risk of graft failure. The model incorporated data from published studies using the United Network for Organ Sharing (UNOS) and used reported outcomes of the Organ Procurement and Transplantation Network to validate the findings.
The study showed that the clinical benefits of an HCV-negative patient receiving an HCV-positive liver depend on the patient’s Model for End-Stage Liver Disease (MELD) score. Using the measured change in life-years, the researchers found that patients with a MELD score below 20 actually witnessed reduction in life-years when accepting any liver, but that the benefits of accepting any liver started to accrue at MELD score 20. The benefit topped out at MELD 28, with 0.172 life years gained, but even sustained at 0.06 life years gained at MELD 40.
The effectiveness of using HCV-positive livers may also depend on region. UNOS Region 1 – essentially New England minus western Vermont – has the highest rate of HCV-positive organs, and a patient there with MELD 28 would gain 0.36 life-years by accepting any liver regardless of HCV status. However, Region 7 – the Dakotas and upper Midwest plus Illinois – has the lowest HCV-positive organ rate, and a MELD 28 patient there would gain only 0.1 life-year accepting any liver.
“Transplanting HCV-positive livers into HCV-negative patients receiving preemptive DAA therapy could be a viable option for improving patient survival on the LT waiting list, especially in UNOS regions with high HCV-positive donor organ rates,” said Dr. Chhatwal and coauthors. They concluded that their analysis could help direct future clinical trials evaluating the effectiveness of DAA therapy in liver transplant by recognizing patients who could benefit most from accepting HCV-positive donor organs.
The study authors reported having no financial disclosures. The study was supported by grants from the American Cancer Society, Health Resources and Services Administration, National Institutes of Health, National Science Foundation, and Massachusetts General Hospital Research Scholars Program. Coauthor Fasiha Kanwal, MD, received support from the Veterans Administration Health Services, Research & Development Center for Innovations in Quality, Effectiveness and Safety and Public Health Service.
SOURCE: Chhatwal J et al. Hepatology. doi:10.1002/hep.29723.
As the evidence supporting the idea of transplanting livers infected with hepatitis C into patients who do not have the disease continues to mount, a multi-institutional team of researchers has developed a mathematical model that shows when hepatitis C–positive-to-negative transplant may improve survival for patients who might otherwise die awaiting a disease-free liver.
In a report published in the journal Hepatology (doi: 10.1002/hep.29723), the researchers noted how direct-acting antivirals (DAAs) have changed the calculus of hepatitis C (HCV) status in liver transplant by reducing the number of HCV-positive patients on the wait list and providing treatment for HCV-negative patients who receive HCV-positive livers. “It is important that further research in this area continues, as we expect that the supply of HCV-positive organs may continue to increase in light of the growing opioid epidemic,” said lead author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital Institute for Technology Assessment in Boston.
Dr. Chhatwal and coauthors claimed their study provides some of the first empirical data for transplanting livers from patients with HCV into patients who do not have the disease.
The researchers performed their analysis using a Markov-based mathematical model known as Simulation of Liver Transplant Candidates (SIM-LT). The model had been validated in previous studies that Dr. Chhatwal and some coauthors had published (Hepatology. 2017;65:777-88; Clin Gastroenterol Hepatol 2018;16:115-22). Dr. Chhatwal and coauthors revised the SIM-LT model to simulate a virtual trial of HCV-negative patients on the liver transplant waiting list to compare outcomes in patients willing to accept any liver to those willing to accept only HCV-negative livers.
The patients willing to receive HCV-positive livers were given 12 weeks of DAA therapy preemptively and had a higher risk of graft failure. The model incorporated data from published studies using the United Network for Organ Sharing (UNOS) and used reported outcomes of the Organ Procurement and Transplantation Network to validate the findings.
The study showed that the clinical benefits of an HCV-negative patient receiving an HCV-positive liver depend on the patient’s Model for End-Stage Liver Disease (MELD) score. Using the measured change in life-years, the researchers found that patients with a MELD score below 20 actually witnessed reduction in life-years when accepting any liver, but that the benefits of accepting any liver started to accrue at MELD score 20. The benefit topped out at MELD 28, with 0.172 life years gained, but even sustained at 0.06 life years gained at MELD 40.
The effectiveness of using HCV-positive livers may also depend on region. UNOS Region 1 – essentially New England minus western Vermont – has the highest rate of HCV-positive organs, and a patient there with MELD 28 would gain 0.36 life-years by accepting any liver regardless of HCV status. However, Region 7 – the Dakotas and upper Midwest plus Illinois – has the lowest HCV-positive organ rate, and a MELD 28 patient there would gain only 0.1 life-year accepting any liver.
“Transplanting HCV-positive livers into HCV-negative patients receiving preemptive DAA therapy could be a viable option for improving patient survival on the LT waiting list, especially in UNOS regions with high HCV-positive donor organ rates,” said Dr. Chhatwal and coauthors. They concluded that their analysis could help direct future clinical trials evaluating the effectiveness of DAA therapy in liver transplant by recognizing patients who could benefit most from accepting HCV-positive donor organs.
The study authors reported having no financial disclosures. The study was supported by grants from the American Cancer Society, Health Resources and Services Administration, National Institutes of Health, National Science Foundation, and Massachusetts General Hospital Research Scholars Program. Coauthor Fasiha Kanwal, MD, received support from the Veterans Administration Health Services, Research & Development Center for Innovations in Quality, Effectiveness and Safety and Public Health Service.
SOURCE: Chhatwal J et al. Hepatology. doi:10.1002/hep.29723.
As the evidence supporting the idea of transplanting livers infected with hepatitis C into patients who do not have the disease continues to mount, a multi-institutional team of researchers has developed a mathematical model that shows when hepatitis C–positive-to-negative transplant may improve survival for patients who might otherwise die awaiting a disease-free liver.
In a report published in the journal Hepatology (doi: 10.1002/hep.29723), the researchers noted how direct-acting antivirals (DAAs) have changed the calculus of hepatitis C (HCV) status in liver transplant by reducing the number of HCV-positive patients on the wait list and providing treatment for HCV-negative patients who receive HCV-positive livers. “It is important that further research in this area continues, as we expect that the supply of HCV-positive organs may continue to increase in light of the growing opioid epidemic,” said lead author Jagpreet Chhatwal, PhD, of Massachusetts General Hospital Institute for Technology Assessment in Boston.
Dr. Chhatwal and coauthors claimed their study provides some of the first empirical data for transplanting livers from patients with HCV into patients who do not have the disease.
The researchers performed their analysis using a Markov-based mathematical model known as Simulation of Liver Transplant Candidates (SIM-LT). The model had been validated in previous studies that Dr. Chhatwal and some coauthors had published (Hepatology. 2017;65:777-88; Clin Gastroenterol Hepatol 2018;16:115-22). Dr. Chhatwal and coauthors revised the SIM-LT model to simulate a virtual trial of HCV-negative patients on the liver transplant waiting list to compare outcomes in patients willing to accept any liver to those willing to accept only HCV-negative livers.
The patients willing to receive HCV-positive livers were given 12 weeks of DAA therapy preemptively and had a higher risk of graft failure. The model incorporated data from published studies using the United Network for Organ Sharing (UNOS) and used reported outcomes of the Organ Procurement and Transplantation Network to validate the findings.
The study showed that the clinical benefits of an HCV-negative patient receiving an HCV-positive liver depend on the patient’s Model for End-Stage Liver Disease (MELD) score. Using the measured change in life-years, the researchers found that patients with a MELD score below 20 actually witnessed reduction in life-years when accepting any liver, but that the benefits of accepting any liver started to accrue at MELD score 20. The benefit topped out at MELD 28, with 0.172 life years gained, but even sustained at 0.06 life years gained at MELD 40.
The effectiveness of using HCV-positive livers may also depend on region. UNOS Region 1 – essentially New England minus western Vermont – has the highest rate of HCV-positive organs, and a patient there with MELD 28 would gain 0.36 life-years by accepting any liver regardless of HCV status. However, Region 7 – the Dakotas and upper Midwest plus Illinois – has the lowest HCV-positive organ rate, and a MELD 28 patient there would gain only 0.1 life-year accepting any liver.
“Transplanting HCV-positive livers into HCV-negative patients receiving preemptive DAA therapy could be a viable option for improving patient survival on the LT waiting list, especially in UNOS regions with high HCV-positive donor organ rates,” said Dr. Chhatwal and coauthors. They concluded that their analysis could help direct future clinical trials evaluating the effectiveness of DAA therapy in liver transplant by recognizing patients who could benefit most from accepting HCV-positive donor organs.
The study authors reported having no financial disclosures. The study was supported by grants from the American Cancer Society, Health Resources and Services Administration, National Institutes of Health, National Science Foundation, and Massachusetts General Hospital Research Scholars Program. Coauthor Fasiha Kanwal, MD, received support from the Veterans Administration Health Services, Research & Development Center for Innovations in Quality, Effectiveness and Safety and Public Health Service.
SOURCE: Chhatwal J et al. Hepatology. doi:10.1002/hep.29723.
FROM HEPATOLOGY
Key clinical point: Making hepatitis C virus–positive livers available to HCV-negative patients awaiting liver transplant could improve survival of patients on the liver transplant waiting list.
Major finding: Patients with a Model for End-Stage Liver Disease score of 28 willing to receive any liver gained 0.172 life-years.
Data source: Simulated trial using Markov-based mathematical model and data from published studies and the United Network for Organ Sharing.
Disclosures: Dr. Chhatwal and coauthors reported having no financial disclosures. The study was supported by grants from the American Cancer Society, Health Resources and Services Administration, National Institutes of Health, National Science Foundation, and Massachusetts General Hospital Research Scholars Program. Coauthor Fasiha Kanwal, MD, received support from the Veterans Administration Health Services, Research & Development Center for Innovations in Quality, Effectiveness and Safety and Public Health Service.
Source: Chhatwal J et al. Hepatology. doi:10.1002/hep.29723.
Rheumatology News Best of 2017: Top News Highlights
Best of 2017: Top News Highlights is a supplement to Rheumatology News that presents some of the top stories published in the newspaper in 2017.
The ideas and opinions expressed in Best of 2017: Top News Highlights do not necessarily reflect those of the Publisher. Frontline Medical Communications Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.
Best of 2017: Top News Highlights is a supplement to Rheumatology News that presents some of the top stories published in the newspaper in 2017.
The ideas and opinions expressed in Best of 2017: Top News Highlights do not necessarily reflect those of the Publisher. Frontline Medical Communications Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.
Best of 2017: Top News Highlights is a supplement to Rheumatology News that presents some of the top stories published in the newspaper in 2017.
The ideas and opinions expressed in Best of 2017: Top News Highlights do not necessarily reflect those of the Publisher. Frontline Medical Communications Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.
FDA grants breakthrough therapy designation for severe aplastic anemia drug
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).
Eltrombopag already is approved as a second-line therapy in patients with refractory SAA and is approved for adults and children with refractory chronic immune thrombocytopenia (ITP).
“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, head of Novartis Oncology Global Drug Development, said in a statement.
California tops state tobacco prevention spending
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said. 
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said.
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.
California will spend almost as much money on tobacco prevention and smoking cessation as the other states combined in 2018, putting it closest to the spending level recommended for each state by the Centers for Disease Control and Prevention, according to a report on the effects of the 1998 tobacco settlement.
The Golden State has budgeted almost $328 million for tobacco prevention and cessation this year, which amounts to just over 45% of all states’ total spending of $722 million and 94% of the CDC’s recommendation of $348 million. Alaska is the only state close to that in terms of the CDC-recommended level, reaching 93% of its spending target of $10.2 million. In third place for recommended spending is North Dakota, which has budgeted $5.3 million for 2018, or 54% of its CDC target, the report said.
“Broken Promises to Our Children: A State-by-State Look at the 1998 Tobacco Settlement 19 Years Later” was released by the Campaign for Tobacco-Free Kids, American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Robert Wood Johnson Foundation, Americans for Nonsmokers’ Rights, and Truth Initiative.
As for actual spending, Florida is second behind California with almost $69 million – 35% of its CDC-recommended level – budgeted for tobacco prevention and smoking cessation in 2018, and New York is third at just over $39 million, which is 19.4% of the CDC recommendation. Two states – Connecticut and West Virginia – will spend no money on such programs this year, the report noted.
The CDC has said that all states combined should be spending $3.3 billion for the year on prevention and cessation efforts, which is about 4.5 times higher than actual budgeted spending. The report also pointed out that the $722 million the states will spend this year amounts to just 2.6% of the $27.5 billion they will collect from the 1998 tobacco settlement and tobacco taxes. By comparison, the report cited data from the Federal Trade Commission showing that the tobacco companies spent $8.9 billion on marketing in 2015.