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Clues help detect, manage autism in older patients
SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.
About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.
Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.
He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.
This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.
All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.
But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.
Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”
Dr. Amanullah disclosed no funding sources or relevant financial conflicts.
SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.
About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.
Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.
He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.
This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.
All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.
But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.
Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”
Dr. Amanullah disclosed no funding sources or relevant financial conflicts.
SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.
About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.
Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.
He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.
This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.
All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.
But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.
Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”
Dr. Amanullah disclosed no funding sources or relevant financial conflicts.
AT IPA 2016
FDA approves biosimilar adalimumab
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
Research yields fresh insights into ketamine for depression
VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?
Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.
Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).
“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.
“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.
Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.
Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).
“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.
He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.
VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?
Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.
Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).
“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.
“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.
Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.
Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).
“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.
He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.
VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?
Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.
Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).
“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.
“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.
Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.
Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).
“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.
He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Early intensive prophylaxis provides better QoL in hemophilia
ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.
An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.
“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.
In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.
To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.
Patients in the studies were grouped into one of five categories:
• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)
• Gradual initiation with intensive prophylaxis (Canada, France)
• Late initiation with limited prophylaxis (Brazil, China)
• On-demand with good access to factor (Canada and European nations)
• On-demand with variable or limited access to factor (Brazil and China).
Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.
Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.
The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)
The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.
“Despite this limitation, important differences were observed between groups,” they wrote.
The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.
ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.
An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.
“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.
In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.
To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.
Patients in the studies were grouped into one of five categories:
• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)
• Gradual initiation with intensive prophylaxis (Canada, France)
• Late initiation with limited prophylaxis (Brazil, China)
• On-demand with good access to factor (Canada and European nations)
• On-demand with variable or limited access to factor (Brazil and China).
Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.
Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.
The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)
The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.
“Despite this limitation, important differences were observed between groups,” they wrote.
The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.
ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.
An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.
“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.
In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.
To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.
Patients in the studies were grouped into one of five categories:
• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)
• Gradual initiation with intensive prophylaxis (Canada, France)
• Late initiation with limited prophylaxis (Brazil, China)
• On-demand with good access to factor (Canada and European nations)
• On-demand with variable or limited access to factor (Brazil and China).
Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.
Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.
The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)
The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.
“Despite this limitation, important differences were observed between groups,” they wrote.
The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.
AT WFH 2016 WORLD CONGRESS
Key clinical point: Early initiation of intensive bleeding prophylaxis was associated with significantly better health-related quality of life (HRQoL).
Major finding: Boys with severe hemophilia started early on intensive prophylaxis had HRQoL comparable to that of boys with mild hemophilia with good access to factor.
Data source: Pooled analysis of six studies comprising 254 boys with severe hemophilia.
Disclosures: The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.
ASPIRE trial: carfilzomib boosts quality of life in relapsed MM
Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.
In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).
At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.
The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.
Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.
Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.
In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).
At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.
The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.
Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.
Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.
In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).
At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.
The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.
Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Relapsed multiple myeloma patients treated with KRd experienced improved health-related quality of life, compared with those receiving lenalidomide and dexamethasone in the phase III ASPIRE trial.
Major finding: At cycle 12, 25.5% of patients given KRd and 17.4% of patients taking Rd had at least a 5-point improvement on a global health/quality of life measure.
Data source: The phase III ASPIRE study of 792 patients with relapsed multiple myeloma.
Disclosures: Dr. Stewart reported consulting or advisory roles with various drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.
Has mystery of exercise-intolerant chronic thromboembolic disease been solved?
The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.
This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).
“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”
The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:
• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).
• Low pulmonary vascular compliance (2.8 mL/mm Hg).
• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).
• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).
After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.
After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).
Dr. van Kan and coauthors had no financial relationships to disclose.
By studying subjects with symptomatic chronic thromboembolic disease and normal pulmonary pressures, Dr. van Kan and colleagues “cleverly opted to study an interesting group,” Robert B. Cameron, MD, of the University of California, Los Angeles, said in his invited commentary.
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Dr. Robert B. Cameron |
“Logically, this patient group, representing potentially early pathophysiologic CTED, could reveal more pathophysiologic information about mechanisms active during the development of chronic thromboembolic pulmonary hypertension than would be seen in patients with more end-stage disease,” Dr. Cameron said (J Thorac Cardiovasc Surg. 2016;152[3]:771-2).
The early physiologic changes in patients with CTED that Dr. van Kan and colleagues reported on may make it possible to detect chronic thromboembolic pulmonary hypertension and intervene before advance disease sets in, Dr. Cameron said. “Surgical mortality may decrease to very-low levels simply from early surgical intervention,” he said.
Although the retrospective design is a limitation of the study, “these data improve our understanding of CTED and motivate all surgeons to promote prospective trials evaluating these findings and early intervention in a disease that is notoriously difficult to understand and treat,” Dr. Cameron said.
Dr. Cameron had no financial relationships to disclose.
By studying subjects with symptomatic chronic thromboembolic disease and normal pulmonary pressures, Dr. van Kan and colleagues “cleverly opted to study an interesting group,” Robert B. Cameron, MD, of the University of California, Los Angeles, said in his invited commentary.
|
|
Dr. Robert B. Cameron |
“Logically, this patient group, representing potentially early pathophysiologic CTED, could reveal more pathophysiologic information about mechanisms active during the development of chronic thromboembolic pulmonary hypertension than would be seen in patients with more end-stage disease,” Dr. Cameron said (J Thorac Cardiovasc Surg. 2016;152[3]:771-2).
The early physiologic changes in patients with CTED that Dr. van Kan and colleagues reported on may make it possible to detect chronic thromboembolic pulmonary hypertension and intervene before advance disease sets in, Dr. Cameron said. “Surgical mortality may decrease to very-low levels simply from early surgical intervention,” he said.
Although the retrospective design is a limitation of the study, “these data improve our understanding of CTED and motivate all surgeons to promote prospective trials evaluating these findings and early intervention in a disease that is notoriously difficult to understand and treat,” Dr. Cameron said.
Dr. Cameron had no financial relationships to disclose.
By studying subjects with symptomatic chronic thromboembolic disease and normal pulmonary pressures, Dr. van Kan and colleagues “cleverly opted to study an interesting group,” Robert B. Cameron, MD, of the University of California, Los Angeles, said in his invited commentary.
|
|
Dr. Robert B. Cameron |
“Logically, this patient group, representing potentially early pathophysiologic CTED, could reveal more pathophysiologic information about mechanisms active during the development of chronic thromboembolic pulmonary hypertension than would be seen in patients with more end-stage disease,” Dr. Cameron said (J Thorac Cardiovasc Surg. 2016;152[3]:771-2).
The early physiologic changes in patients with CTED that Dr. van Kan and colleagues reported on may make it possible to detect chronic thromboembolic pulmonary hypertension and intervene before advance disease sets in, Dr. Cameron said. “Surgical mortality may decrease to very-low levels simply from early surgical intervention,” he said.
Although the retrospective design is a limitation of the study, “these data improve our understanding of CTED and motivate all surgeons to promote prospective trials evaluating these findings and early intervention in a disease that is notoriously difficult to understand and treat,” Dr. Cameron said.
Dr. Cameron had no financial relationships to disclose.
The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.
This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).
“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”
The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:
• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).
• Low pulmonary vascular compliance (2.8 mL/mm Hg).
• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).
• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).
After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.
After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).
Dr. van Kan and coauthors had no financial relationships to disclose.
The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.
This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).
“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”
The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:
• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).
• Low pulmonary vascular compliance (2.8 mL/mm Hg).
• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).
• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).
After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.
After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).
Dr. van Kan and coauthors had no financial relationships to disclose.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: This study identifies key clinical features of the pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) as well and the mechanisms of responses to treatment that have not been well understood .
Major finding: Exercise intolerance may result from an abnormal pulmonary vascular response and decreased ventilatory efficiency, while pulmonary endarterectomy restores right ventricle stroke volume response and ventilatory efficiency.
Data source: Fourteen subjects with exercise-intolerant CTED but normal pulmonary pressure underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and noninvasive CPET 1 year later.
Disclosures: Dr. van Kan and coauthors had no financial relationships to disclose.
Survival shorter in extended-criteria lung recipients
The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.
“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.
The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.
The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.
Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.
Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.
The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.
These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.
The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.
Dr. Mulligan and his coauthors had no relationships to disclose.
This study provides “greater clarity to the definition and significance of using lungs from an extended-criteria donor,” Benjamin Wei, MD, of the University of Alabama at Birmingham said in his invited commentary (J Thorac Cardiovasc Surg. 2016;152:899-900). “Now, we have more data about what constitutes an ECD for lung transplantation.”
The study also brought clarity on components of donor factors that do not affect survival – namely radiologic, bronchoscope, or laboratory criteria – Dr. Wei said. At the same time, the study raises questions about how transplant surgeons should use the findings. “Do we shy away from using donors with these high risk factors in low-risk recipients, high-risk recipients, neither, or both?” Dr. Wei asks. The study did not compare ECD lungs vs. no transplant, and becoming more selective in donors could cause more patients to die on the waiting list, he said.
A host of other questions also remain unanswered, Dr. Wei said, such as how a single standard-donor lung transplant compares with bilateral ECD transplants, or a single ECD lung vs. bilateral ECD lungs, and if use of ECD lungs by the criteria Dr. Mulligan and his coauthors outlined influences allograft patient survival.
“Of note, this study also did not include recipients receiving donor after cardiac death lungs or extracorporeal membrane oxygenation, both increasingly common situations,” he said. Nonetheless, the findings provide more information that transplant surgeons can base their decision-making on.
Dr. Wei had no financial relationships to disclose.
This study provides “greater clarity to the definition and significance of using lungs from an extended-criteria donor,” Benjamin Wei, MD, of the University of Alabama at Birmingham said in his invited commentary (J Thorac Cardiovasc Surg. 2016;152:899-900). “Now, we have more data about what constitutes an ECD for lung transplantation.”
The study also brought clarity on components of donor factors that do not affect survival – namely radiologic, bronchoscope, or laboratory criteria – Dr. Wei said. At the same time, the study raises questions about how transplant surgeons should use the findings. “Do we shy away from using donors with these high risk factors in low-risk recipients, high-risk recipients, neither, or both?” Dr. Wei asks. The study did not compare ECD lungs vs. no transplant, and becoming more selective in donors could cause more patients to die on the waiting list, he said.
A host of other questions also remain unanswered, Dr. Wei said, such as how a single standard-donor lung transplant compares with bilateral ECD transplants, or a single ECD lung vs. bilateral ECD lungs, and if use of ECD lungs by the criteria Dr. Mulligan and his coauthors outlined influences allograft patient survival.
“Of note, this study also did not include recipients receiving donor after cardiac death lungs or extracorporeal membrane oxygenation, both increasingly common situations,” he said. Nonetheless, the findings provide more information that transplant surgeons can base their decision-making on.
Dr. Wei had no financial relationships to disclose.
This study provides “greater clarity to the definition and significance of using lungs from an extended-criteria donor,” Benjamin Wei, MD, of the University of Alabama at Birmingham said in his invited commentary (J Thorac Cardiovasc Surg. 2016;152:899-900). “Now, we have more data about what constitutes an ECD for lung transplantation.”
The study also brought clarity on components of donor factors that do not affect survival – namely radiologic, bronchoscope, or laboratory criteria – Dr. Wei said. At the same time, the study raises questions about how transplant surgeons should use the findings. “Do we shy away from using donors with these high risk factors in low-risk recipients, high-risk recipients, neither, or both?” Dr. Wei asks. The study did not compare ECD lungs vs. no transplant, and becoming more selective in donors could cause more patients to die on the waiting list, he said.
A host of other questions also remain unanswered, Dr. Wei said, such as how a single standard-donor lung transplant compares with bilateral ECD transplants, or a single ECD lung vs. bilateral ECD lungs, and if use of ECD lungs by the criteria Dr. Mulligan and his coauthors outlined influences allograft patient survival.
“Of note, this study also did not include recipients receiving donor after cardiac death lungs or extracorporeal membrane oxygenation, both increasingly common situations,” he said. Nonetheless, the findings provide more information that transplant surgeons can base their decision-making on.
Dr. Wei had no financial relationships to disclose.
The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.
“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.
The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.
The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.
Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.
Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.
The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.
These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.
The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.
Dr. Mulligan and his coauthors had no relationships to disclose.
The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.
“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.
The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.
The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.
Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.
Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.
The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.
These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.
The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.
Dr. Mulligan and his coauthors had no relationships to disclose.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: Lung transplant recipients who received extended-criteria donor (ECD) lungs have lower rates of 1-year survival than recipients of standard donor lungs.
Major finding: Recipients of ECD lungs had a 41% higher risk of death than recipients of standard lungs, and those who had more severe lung disease had lower rates of 1-year survival after receiving ECD lungs, compared with standard donor lungs.
Data source: Retrospective analysis of 10,995 lung recipients, from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, 3,792 of whom who received extended-criteria donor organs over 7.5 years.
Disclosures: Dr. Mulligan and his coauthors had no financial relationships to disclose.
FDA approves ustekinumab (Stelara) for adult Crohn’s disease
The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.
Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.
The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.
“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.
The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.
Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.
The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.
“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.
The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.
Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.
The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.
“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.
Feds require more transparent reporting of clinical trial results
New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.
The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:
• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.
• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.
• Expands adverse-event reporting.
• Adds potential penalties for noncompliance.
Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.
Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).
“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”
The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.
“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”
“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”
The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.
New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.
The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:
• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.
• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.
• Expands adverse-event reporting.
• Adds potential penalties for noncompliance.
Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.
Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).
“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”
The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.
“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”
“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”
The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.
New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.
The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:
• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.
• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.
• Expands adverse-event reporting.
• Adds potential penalties for noncompliance.
Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.
Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).
“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”
The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.
“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”
“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”
The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.
Therapy granted orphan designation to prevent GVHD
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.” 
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.”
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.”