Elizabeth Mechcatie

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERBURG, MD. – Despite problems with the quality of the safety data in the pivotal trial, the majority of a Food and Drug Administration advisory panel supported approval of the HeartWare left ventricular assist device as a bridge-to-transplant in people with end-stage heart failure at an April 25 meeting of the FDA’s Circulatory System Devices Panel.

At the meeting, the panel voted 9-2 that the benefits of the HeartWare Ventricular Assist System (VAS) outweighed its risks for use as a bridge to cardiac transplantation in patients at risk of death from refractory end-stage heart failure, the indication proposed for approval by the manufacturer, HeartWare.

The HeartWare VAS is a small, lightweight, continuous-flow pump that is implanted entirely in the pericardial space via a median sternotomy; it is the first magnetically levitated left ventricular assist device (LVAD) pump, providing flows of up to 10 L/min; it is connected to an external controller via a 4.2 diameter percutaneous driveline. It is intended for use inside and outside of the hospital and is contraindicated in patients with a body surface area (BSA) of less than 1.2 m², in patients who cannot tolerate anticoagulation therapy, and in pregnant women.

If approved, it would be the first LVAD that does not require an abdominal incision and creation of an abdominal pump pocket.

The panel voted unanimously that based on the available data, there was "reasonable assurance" that the device was effective for this group of patients, and voted 8-3 that there was "reasonable assurance" that it was safe.

The panelists raised issues about the quality of the safety data, which were described as a "mess" and having "more holes ... than Swiss cheese."

But the majority agreed the data supported its effectiveness, particularly when considering the alternatives for this group of patients with end-stage heart failure. The panel chair, Dr. Richard Page, chair of the department of medicine at the University of Wisconsin, Madison, said that despite the safety issues, the bar for efficacy had been met and that the device "represents a real advance in technology" that will make a difference for many patients. Panelist Dr. David Slotwiner, of Long Island Jewish Medical Center, New Hyde Park, N.Y., said that despite flaws in the safety data, he described it as "a novel device for a desperate population."

In the pivotal trial, the ADVANCE (Evaluation of the HeartWare LVAD System for the Treatment of Advanced Heart Failure) trial, a U.S. prospective, multicenter, nonrandomized study, 140 patients with New York Heart Association class IV heart failure, who were on a list for a transplant, received the HeartWare VAS as a bridge to transplant. Their outcomes were compared with 499 patients in a National Institute of Health–sponsored U.S. registry tracking outcomes in recipients of commercially available LVADs, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). More than 90% of those in INTERMACS have received Thoratec’s HeartMate II LVAD. This was the first LVAD study where data from INTERMACS have been used as a contemporaneous control.

The study met the primary end point, which was a success rate at 180 days (defined as remaining on the original device, transplanted, or explanted for recovery) at 180 days among the HeartWare VAD recipients (90.7%) that was noninferior to the success rate in the INTERMACs control group (90.1%).

Safety data from INTERMACS were not available for the safety analysis, so safety data on LVADs from the literature were used for comparison.

Although the trial met the prespecified primary end point, FDA reviewers raised concerns about the comparability of the two groups, and the thrombosis rates, the need to exchange devices, and ischemic strokes in recipients of the HeartWare VAS. Within 180 days, the observed ischemic stroke rate was 8% (11 patients), and the observed hemorrhagic stroke rate was 3% (4 patients). Of the ischemic stroke patients, 27% died or were considered ineligible for transplant because of the stroke; all of the hemorrhagic stroke patients died or became ineligible for transplant.

The panel agreed that while the strokes are a concern, the rates seen in the study did not appear to be substantially different than the rates reported in the literature, although they all agreed that better safety data were needed.

Within 180 days of implantation, seven HVAD pumps were exchanged in seven patients, all of which were associated with signs and symptoms of intraventricular/pump thrombosis, according to the FDA’s analysis. Panelists said that while these cases raised some concerns, it was difficult to make any conclusions without a control group, and one panelist said that in his view, the risks of pump thrombosis were outweighed by the potential benefits.

If approved, the manufacturer’s postmarketing plans include a study that will continue to evaluate patients in the ADVANCE trial. The HeartWare VAS was approved in the European Union in 2009. It is also being studied as destination therapy, comparing it to the HeartMate II.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

Treatment with an antihypertensive that contains aliskiren plus an angiotension-converting enzyme inhibitor or angiotensin receptor blocker is newly contraindicated in patients with diabetes, the Food and Drug Administration announced on April 20.

The contraindication is based on an increased risk of renal impairment, hypotension, and hyperkalemia, as seen in preliminary data from the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) trial, according to the FDA statement. It is being added to the labels for all drugs containing aliskiren (Tekturna), a renin inhibitor.

A warning against the use of aliskiren-containing products in patients with moderate renal impairment who are also taking an ACE inhibitor or angiotensin receptor blocker (ARB) is also being added to these drug labels. Moderate renal impairment is defined as a glomerular filtration rate (GFR) less than 60 mL/min for this purpose.

The ALTITUDE trial is a randomized, double-blind, placebo-controlled study of more than 8,500 people with type 2 diabetes and a high risk for cardiovascular and renal events. It evaluated whether aliskiren plus conventional treatment reduced cardiovascular and renal morbidity and mortality.

All patients were on an ARB or ACE inhibitor. The study was terminated early, after a median of about 27 months, because of a lack of efficacy and because the risks of renal impairment, hypotension, and hyperkalemia were increased in patients on aliskiren, compared with those on placebo. Nearly 37% of those in the aliskiren arm had hyperkalemia and almost 19% had hypotension, compared with 27% and almost 15% of those on placebo, respectively. For both side effects, serious adverse events were also higher in the aliskiren arm.

In addition, about 12% of patients on aliskiren had a renal adverse event, compared with about 10% of those on placebo.

The risk of stroke was higher among those on aliskiren, compared with those on placebo (2.7% vs. 2%), as was the risk of death (6.9% vs. 6.4%), but the FDA statement said that, at this time, "the significance of these findings is unknown" and that the agency has not reached a conclusion about a link between aliskiren and these events.

The single-ingredient formulation of aliskiren was approved in March 2007. Other products that contain aliskiren include:

• aliskiren, amlodipine besylate, and hydrochlorothiazide (Amturnide).

• aliskiren and hydrochlorothiazide (Tekturna HCT).

• aliskiren and amlodipine (Tekamlo).

Aliskiren is also available in combination with valsartan, an ARB marketed as Valturna, but after July 2012 this product will no longer be marketed, according to the FDA. Novartis is keeping it available until that time to give health care professionals time to transition patients to other therapy, according to a Dear Healthcare Professional letter from Novartis.

About 2.4 million prescriptions for aliskiren-containing products were dispensed to 451,000 patients from U.S. outpatient retail pharmacies in 2011, the FDA said. About 22% of patients on aliskiren-containing products were also taking an ACE inhibitor or ARB and diabetes medications – and almost 31% of patients on Valturna also were taking diabetes medications.

More information is available from aliskiren manufacturer Novartis at 888-997-5385 or www.pharma.us.novartis.com.

Adverse events associated with the use of aliskiren products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/MedWatch/report.htm.

Treatment with an antihypertensive that contains aliskiren plus an angiotension-converting enzyme inhibitor or angiotensin receptor blocker is newly contraindicated in patients with diabetes, the Food and Drug Administration announced on April 20.

The contraindication is based on an increased risk of renal impairment, hypotension, and hyperkalemia, as seen in preliminary data from the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) trial, according to the FDA statement. It is being added to the labels for all drugs containing aliskiren (Tekturna), a renin inhibitor.

A warning against the use of aliskiren-containing products in patients with moderate renal impairment who are also taking an ACE inhibitor or angiotensin receptor blocker (ARB) is also being added to these drug labels. Moderate renal impairment is defined as a glomerular filtration rate (GFR) less than 60 mL/min for this purpose.

The ALTITUDE trial is a randomized, double-blind, placebo-controlled study of more than 8,500 people with type 2 diabetes and a high risk for cardiovascular and renal events. It evaluated whether aliskiren plus conventional treatment reduced cardiovascular and renal morbidity and mortality.

All patients were on an ARB or ACE inhibitor. The study was terminated early, after a median of about 27 months, because of a lack of efficacy and because the risks of renal impairment, hypotension, and hyperkalemia were increased in patients on aliskiren, compared with those on placebo. Nearly 37% of those in the aliskiren arm had hyperkalemia and almost 19% had hypotension, compared with 27% and almost 15% of those on placebo, respectively. For both side effects, serious adverse events were also higher in the aliskiren arm.

In addition, about 12% of patients on aliskiren had a renal adverse event, compared with about 10% of those on placebo.

The risk of stroke was higher among those on aliskiren, compared with those on placebo (2.7% vs. 2%), as was the risk of death (6.9% vs. 6.4%), but the FDA statement said that, at this time, "the significance of these findings is unknown" and that the agency has not reached a conclusion about a link between aliskiren and these events.

The single-ingredient formulation of aliskiren was approved in March 2007. Other products that contain aliskiren include:

• aliskiren, amlodipine besylate, and hydrochlorothiazide (Amturnide).

• aliskiren and hydrochlorothiazide (Tekturna HCT).

• aliskiren and amlodipine (Tekamlo).

Aliskiren is also available in combination with valsartan, an ARB marketed as Valturna, but after July 2012 this product will no longer be marketed, according to the FDA. Novartis is keeping it available until that time to give health care professionals time to transition patients to other therapy, according to a Dear Healthcare Professional letter from Novartis.

About 2.4 million prescriptions for aliskiren-containing products were dispensed to 451,000 patients from U.S. outpatient retail pharmacies in 2011, the FDA said. About 22% of patients on aliskiren-containing products were also taking an ACE inhibitor or ARB and diabetes medications – and almost 31% of patients on Valturna also were taking diabetes medications.

More information is available from aliskiren manufacturer Novartis at 888-997-5385 or www.pharma.us.novartis.com.

Adverse events associated with the use of aliskiren products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/MedWatch/report.htm.

Treatment with an antihypertensive that contains aliskiren plus an angiotension-converting enzyme inhibitor or angiotensin receptor blocker is newly contraindicated in patients with diabetes, the Food and Drug Administration announced on April 20.

The contraindication is based on an increased risk of renal impairment, hypotension, and hyperkalemia, as seen in preliminary data from the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) trial, according to the FDA statement. It is being added to the labels for all drugs containing aliskiren (Tekturna), a renin inhibitor.

A warning against the use of aliskiren-containing products in patients with moderate renal impairment who are also taking an ACE inhibitor or angiotensin receptor blocker (ARB) is also being added to these drug labels. Moderate renal impairment is defined as a glomerular filtration rate (GFR) less than 60 mL/min for this purpose.

The ALTITUDE trial is a randomized, double-blind, placebo-controlled study of more than 8,500 people with type 2 diabetes and a high risk for cardiovascular and renal events. It evaluated whether aliskiren plus conventional treatment reduced cardiovascular and renal morbidity and mortality.

All patients were on an ARB or ACE inhibitor. The study was terminated early, after a median of about 27 months, because of a lack of efficacy and because the risks of renal impairment, hypotension, and hyperkalemia were increased in patients on aliskiren, compared with those on placebo. Nearly 37% of those in the aliskiren arm had hyperkalemia and almost 19% had hypotension, compared with 27% and almost 15% of those on placebo, respectively. For both side effects, serious adverse events were also higher in the aliskiren arm.

In addition, about 12% of patients on aliskiren had a renal adverse event, compared with about 10% of those on placebo.

The risk of stroke was higher among those on aliskiren, compared with those on placebo (2.7% vs. 2%), as was the risk of death (6.9% vs. 6.4%), but the FDA statement said that, at this time, "the significance of these findings is unknown" and that the agency has not reached a conclusion about a link between aliskiren and these events.

The single-ingredient formulation of aliskiren was approved in March 2007. Other products that contain aliskiren include:

• aliskiren, amlodipine besylate, and hydrochlorothiazide (Amturnide).

• aliskiren and hydrochlorothiazide (Tekturna HCT).

• aliskiren and amlodipine (Tekamlo).

Aliskiren is also available in combination with valsartan, an ARB marketed as Valturna, but after July 2012 this product will no longer be marketed, according to the FDA. Novartis is keeping it available until that time to give health care professionals time to transition patients to other therapy, according to a Dear Healthcare Professional letter from Novartis.

About 2.4 million prescriptions for aliskiren-containing products were dispensed to 451,000 patients from U.S. outpatient retail pharmacies in 2011, the FDA said. About 22% of patients on aliskiren-containing products were also taking an ACE inhibitor or ARB and diabetes medications – and almost 31% of patients on Valturna also were taking diabetes medications.

More information is available from aliskiren manufacturer Novartis at 888-997-5385 or www.pharma.us.novartis.com.

Adverse events associated with the use of aliskiren products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/MedWatch/report.htm.

ARLINGTON, VA.– A 10-week psychoeducational workshop aimed at increasing resilience in Iraq and Afghanistan war veterans had a significant effect among those who completed the workshop, including those with lower resilience scores at baseline.

However, those with lower baseline resilience scores were also more likely to drop out of the workshop. This finding highlights the potential utility of measuring baseline resilience in veterans as a way to improve retention in time-limited, effective psychotherapeutic intervention programs, especially for participants who are less resilient and have the most to gain from such a program, according to Dr. Matig Mavissakalian of the Cleveland Veterans Affairs Medical Center and Case Western Reserve University, Cleveland.

Characteristics of resilience – a trait that has been associated with optimal coping skills and helping prevent the development and promote recovery of posttraumatic stress disorder (PTSD) –include commitment, dynamism, patience, optimism, faith, altruism, and the ability to show humor when faced with adversity, Dr. Mavissakalian said at the annual conference of the Anxiety and Depression Association of America (ADAA).

The 10-week psychoeducational program, provided at the Cleveland VAMC, is designed specifically for returning soldiers, to promote the use of resources and increase resilience, with an emphasis on understanding and normalizing stress responses, building on strengths, learning new cognitive skills, and improving family relationships, with some family member involvement and individual counseling.

To evaluate the impact of the workshop, the Connor-Davidson Resilience Scale (CD-RISC), a 25-item self-rating measure of resilience, was administered to 65 mostly male veterans with at least one deployment, participating in the workshop over a 4-year period. Their median age was almost 30 years; about 34% had sustained an injury while deployed. Almost 80% were diagnosed with PTSD, 88% were diagnosed with depression/anxiety, and 92% had nightmares; other issues included alcohol and substance abuse in 35%; and family and marital problems in 48%. Over 10 weeks, the use of medications included "any" psychotropics in 69%, which included antidepressants in 61%.

The CD-RISC was re-administered to the 46 veterans who completed the workshop, indicating significant improvements in resilience scores, with a "fairly decent moderate effect size" of about 15%, Dr. Mavissakalian said. There were no differences in baseline resilience scores between those who dropped out and those who had completed the workshop.

But among those who completed the program, there was a trend toward a greater degree of improvement among those with lower resilience scores at baseline than those with higher scores at baseline who completed the program, suggesting a differential effect of initial resilience level on outcome, he added.

The VA has been successful in recruiting veterans for such programs, "but special efforts to increase retention should also be made," he said, noting that a veteran’s resilience score could be an important measure to help identify those individuals who need special efforts to keep them treatment.

An incidental finding was that the cohort of 34 veterans enrolled earlier in the study period, from 2005 to about 2007, had higher baseline resilience scores than those enrolled later in the 4 year period, he said. "So as the war went on, there was less resilience in the soldiers," but because this was a small sample, more data are needed to explain this finding and to see if it persists in a larger study.

He had no disclosures. Until recently, the ADAA was called the Anxiety Disorders Association of America.

ARLINGTON, VA.– A 10-week psychoeducational workshop aimed at increasing resilience in Iraq and Afghanistan war veterans had a significant effect among those who completed the workshop, including those with lower resilience scores at baseline.

However, those with lower baseline resilience scores were also more likely to drop out of the workshop. This finding highlights the potential utility of measuring baseline resilience in veterans as a way to improve retention in time-limited, effective psychotherapeutic intervention programs, especially for participants who are less resilient and have the most to gain from such a program, according to Dr. Matig Mavissakalian of the Cleveland Veterans Affairs Medical Center and Case Western Reserve University, Cleveland.

Characteristics of resilience – a trait that has been associated with optimal coping skills and helping prevent the development and promote recovery of posttraumatic stress disorder (PTSD) –include commitment, dynamism, patience, optimism, faith, altruism, and the ability to show humor when faced with adversity, Dr. Mavissakalian said at the annual conference of the Anxiety and Depression Association of America (ADAA).

The 10-week psychoeducational program, provided at the Cleveland VAMC, is designed specifically for returning soldiers, to promote the use of resources and increase resilience, with an emphasis on understanding and normalizing stress responses, building on strengths, learning new cognitive skills, and improving family relationships, with some family member involvement and individual counseling.

To evaluate the impact of the workshop, the Connor-Davidson Resilience Scale (CD-RISC), a 25-item self-rating measure of resilience, was administered to 65 mostly male veterans with at least one deployment, participating in the workshop over a 4-year period. Their median age was almost 30 years; about 34% had sustained an injury while deployed. Almost 80% were diagnosed with PTSD, 88% were diagnosed with depression/anxiety, and 92% had nightmares; other issues included alcohol and substance abuse in 35%; and family and marital problems in 48%. Over 10 weeks, the use of medications included "any" psychotropics in 69%, which included antidepressants in 61%.

The CD-RISC was re-administered to the 46 veterans who completed the workshop, indicating significant improvements in resilience scores, with a "fairly decent moderate effect size" of about 15%, Dr. Mavissakalian said. There were no differences in baseline resilience scores between those who dropped out and those who had completed the workshop.

But among those who completed the program, there was a trend toward a greater degree of improvement among those with lower resilience scores at baseline than those with higher scores at baseline who completed the program, suggesting a differential effect of initial resilience level on outcome, he added.

The VA has been successful in recruiting veterans for such programs, "but special efforts to increase retention should also be made," he said, noting that a veteran’s resilience score could be an important measure to help identify those individuals who need special efforts to keep them treatment.

An incidental finding was that the cohort of 34 veterans enrolled earlier in the study period, from 2005 to about 2007, had higher baseline resilience scores than those enrolled later in the 4 year period, he said. "So as the war went on, there was less resilience in the soldiers," but because this was a small sample, more data are needed to explain this finding and to see if it persists in a larger study.

He had no disclosures. Until recently, the ADAA was called the Anxiety Disorders Association of America.

ARLINGTON, VA.– A 10-week psychoeducational workshop aimed at increasing resilience in Iraq and Afghanistan war veterans had a significant effect among those who completed the workshop, including those with lower resilience scores at baseline.

However, those with lower baseline resilience scores were also more likely to drop out of the workshop. This finding highlights the potential utility of measuring baseline resilience in veterans as a way to improve retention in time-limited, effective psychotherapeutic intervention programs, especially for participants who are less resilient and have the most to gain from such a program, according to Dr. Matig Mavissakalian of the Cleveland Veterans Affairs Medical Center and Case Western Reserve University, Cleveland.

Characteristics of resilience – a trait that has been associated with optimal coping skills and helping prevent the development and promote recovery of posttraumatic stress disorder (PTSD) –include commitment, dynamism, patience, optimism, faith, altruism, and the ability to show humor when faced with adversity, Dr. Mavissakalian said at the annual conference of the Anxiety and Depression Association of America (ADAA).

The 10-week psychoeducational program, provided at the Cleveland VAMC, is designed specifically for returning soldiers, to promote the use of resources and increase resilience, with an emphasis on understanding and normalizing stress responses, building on strengths, learning new cognitive skills, and improving family relationships, with some family member involvement and individual counseling.

To evaluate the impact of the workshop, the Connor-Davidson Resilience Scale (CD-RISC), a 25-item self-rating measure of resilience, was administered to 65 mostly male veterans with at least one deployment, participating in the workshop over a 4-year period. Their median age was almost 30 years; about 34% had sustained an injury while deployed. Almost 80% were diagnosed with PTSD, 88% were diagnosed with depression/anxiety, and 92% had nightmares; other issues included alcohol and substance abuse in 35%; and family and marital problems in 48%. Over 10 weeks, the use of medications included "any" psychotropics in 69%, which included antidepressants in 61%.

The CD-RISC was re-administered to the 46 veterans who completed the workshop, indicating significant improvements in resilience scores, with a "fairly decent moderate effect size" of about 15%, Dr. Mavissakalian said. There were no differences in baseline resilience scores between those who dropped out and those who had completed the workshop.

But among those who completed the program, there was a trend toward a greater degree of improvement among those with lower resilience scores at baseline than those with higher scores at baseline who completed the program, suggesting a differential effect of initial resilience level on outcome, he added.

The VA has been successful in recruiting veterans for such programs, "but special efforts to increase retention should also be made," he said, noting that a veteran’s resilience score could be an important measure to help identify those individuals who need special efforts to keep them treatment.

An incidental finding was that the cohort of 34 veterans enrolled earlier in the study period, from 2005 to about 2007, had higher baseline resilience scores than those enrolled later in the 4 year period, he said. "So as the war went on, there was less resilience in the soldiers," but because this was a small sample, more data are needed to explain this finding and to see if it persists in a larger study.

He had no disclosures. Until recently, the ADAA was called the Anxiety Disorders Association of America.

The Food and Drug Administration on April 11 addressed antimicrobial resistance resulting from the use of antibiotics in food-producing animals by recommending that the farming industry phase out the use of "medically important" antibiotics and phase in their use only for therapeutic purposes under veterinary supervision.

The guidance for industry, titled "The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals," is a voluntary initiative under which "certain antibiotics would not be used for so-called ‘production’ purposes, such as to enhance growth or improve feed efficiency in an animal," while keeping the drugs available for preventing, controlling, or treating illnesses in these animals under the supervision of a veterinarian, according to the FDA statement.

A major shift is that farmers will now have to consult with a veterinarian regarding the use of these drugs in food-producing animals for targeted therapeutic purposes, for a specific duration of time, which includes preventive uses, Michael Tucker, the FDA’s deputy commissioner for foods, said during a press briefing. He said he expects that the changes will take about 3 years to be phased in.

The FDA also issued two draft documents, which are open for public comment: One is aimed at helping manufacturers remove production uses of their antibiotics from the FDA-approved product labels – voluntarily – and will add, "where appropriate, scientifically supported disease prevention, control, and treatment uses." The second document is a proposed regulation that "outlines ways that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient," according to the statement.

Mr. Tucker acknowledged that the voluntary nature of the program could be considered a possible limitation, but added that an outright ban would require a formal process that would include evidentiary hearings and would be an "intensive lawyer-driven process" that could take decades to complete, and that the voluntary program would achieve the goals of the program faster and more efficiently.

The Infectious Diseases Society of America is among the medical associations that have addressed the problems of inappropriate use of antibiotics in agriculture and animals used for food. IDSA has recommended "ending the use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in food animals; requiring prescriptions and veterinary oversight of all antibiotics given to animals; and ensuring that antibiotic use in all animals, similar to human medicine, is carried out under the supervision of a veterinarian," according to a statement on its Web site.

"The relationship between antibiotic-resistant infections in humans and antibiotic use in agriculture is complex, but well-documented," the statement says, referring to "a large and compelling body of scientific evidence" which demonstrates "that antibiotic use in agriculture contributes to the emergence of resistant bacteria and their spread to humans."

A statement issued by the Alliance for the Prudent Use of Antibiotics (APUA) applauded the release of the guidelines, which it said address "mounting scientific evidence of transfer of resistant genes in the environment to dangerous pathogens in humans and the role that food animal production plays in that process." The guidelines put the food animal industry "on a level playing field" with the human medical community in terms of requiring responsible use of antibiotics, the statement said, referring to the "long-standing irony" that antibiotic use in human medicine requires prescriptions, unlike in the animal industry. The guidelines also promote responsible food production practices already codified in many European countries, Kathy Young, APUA’s executive director, said in the statement. In the statement, Dr. Stuart Levy, APUA’s president and director of the Center for Adaptation Genetics and Drug Resistance, Tufts University, Boston, said that the organization will be involved in carefully monitoring compliance with the program, since it is voluntary.

A statement issued by the Center for Science in the Public Interest, however, described the program as "tragically flawed," and said that it relied "too heavily on the drug industry and animal producers to act voluntarily in the best interest of consumers."

The final guidance and draft documents are being published in the federal register and are available online.

The Food and Drug Administration on April 11 addressed antimicrobial resistance resulting from the use of antibiotics in food-producing animals by recommending that the farming industry phase out the use of "medically important" antibiotics and phase in their use only for therapeutic purposes under veterinary supervision.

The guidance for industry, titled "The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals," is a voluntary initiative under which "certain antibiotics would not be used for so-called ‘production’ purposes, such as to enhance growth or improve feed efficiency in an animal," while keeping the drugs available for preventing, controlling, or treating illnesses in these animals under the supervision of a veterinarian, according to the FDA statement.

A major shift is that farmers will now have to consult with a veterinarian regarding the use of these drugs in food-producing animals for targeted therapeutic purposes, for a specific duration of time, which includes preventive uses, Michael Tucker, the FDA’s deputy commissioner for foods, said during a press briefing. He said he expects that the changes will take about 3 years to be phased in.

The FDA also issued two draft documents, which are open for public comment: One is aimed at helping manufacturers remove production uses of their antibiotics from the FDA-approved product labels – voluntarily – and will add, "where appropriate, scientifically supported disease prevention, control, and treatment uses." The second document is a proposed regulation that "outlines ways that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient," according to the statement.

Mr. Tucker acknowledged that the voluntary nature of the program could be considered a possible limitation, but added that an outright ban would require a formal process that would include evidentiary hearings and would be an "intensive lawyer-driven process" that could take decades to complete, and that the voluntary program would achieve the goals of the program faster and more efficiently.

The Infectious Diseases Society of America is among the medical associations that have addressed the problems of inappropriate use of antibiotics in agriculture and animals used for food. IDSA has recommended "ending the use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in food animals; requiring prescriptions and veterinary oversight of all antibiotics given to animals; and ensuring that antibiotic use in all animals, similar to human medicine, is carried out under the supervision of a veterinarian," according to a statement on its Web site.

"The relationship between antibiotic-resistant infections in humans and antibiotic use in agriculture is complex, but well-documented," the statement says, referring to "a large and compelling body of scientific evidence" which demonstrates "that antibiotic use in agriculture contributes to the emergence of resistant bacteria and their spread to humans."

A statement issued by the Alliance for the Prudent Use of Antibiotics (APUA) applauded the release of the guidelines, which it said address "mounting scientific evidence of transfer of resistant genes in the environment to dangerous pathogens in humans and the role that food animal production plays in that process." The guidelines put the food animal industry "on a level playing field" with the human medical community in terms of requiring responsible use of antibiotics, the statement said, referring to the "long-standing irony" that antibiotic use in human medicine requires prescriptions, unlike in the animal industry. The guidelines also promote responsible food production practices already codified in many European countries, Kathy Young, APUA’s executive director, said in the statement. In the statement, Dr. Stuart Levy, APUA’s president and director of the Center for Adaptation Genetics and Drug Resistance, Tufts University, Boston, said that the organization will be involved in carefully monitoring compliance with the program, since it is voluntary.

A statement issued by the Center for Science in the Public Interest, however, described the program as "tragically flawed," and said that it relied "too heavily on the drug industry and animal producers to act voluntarily in the best interest of consumers."

The final guidance and draft documents are being published in the federal register and are available online.

The Food and Drug Administration on April 11 addressed antimicrobial resistance resulting from the use of antibiotics in food-producing animals by recommending that the farming industry phase out the use of "medically important" antibiotics and phase in their use only for therapeutic purposes under veterinary supervision.

The guidance for industry, titled "The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals," is a voluntary initiative under which "certain antibiotics would not be used for so-called ‘production’ purposes, such as to enhance growth or improve feed efficiency in an animal," while keeping the drugs available for preventing, controlling, or treating illnesses in these animals under the supervision of a veterinarian, according to the FDA statement.

A major shift is that farmers will now have to consult with a veterinarian regarding the use of these drugs in food-producing animals for targeted therapeutic purposes, for a specific duration of time, which includes preventive uses, Michael Tucker, the FDA’s deputy commissioner for foods, said during a press briefing. He said he expects that the changes will take about 3 years to be phased in.

The FDA also issued two draft documents, which are open for public comment: One is aimed at helping manufacturers remove production uses of their antibiotics from the FDA-approved product labels – voluntarily – and will add, "where appropriate, scientifically supported disease prevention, control, and treatment uses." The second document is a proposed regulation that "outlines ways that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient," according to the statement.

Mr. Tucker acknowledged that the voluntary nature of the program could be considered a possible limitation, but added that an outright ban would require a formal process that would include evidentiary hearings and would be an "intensive lawyer-driven process" that could take decades to complete, and that the voluntary program would achieve the goals of the program faster and more efficiently.

The Infectious Diseases Society of America is among the medical associations that have addressed the problems of inappropriate use of antibiotics in agriculture and animals used for food. IDSA has recommended "ending the use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in food animals; requiring prescriptions and veterinary oversight of all antibiotics given to animals; and ensuring that antibiotic use in all animals, similar to human medicine, is carried out under the supervision of a veterinarian," according to a statement on its Web site.

"The relationship between antibiotic-resistant infections in humans and antibiotic use in agriculture is complex, but well-documented," the statement says, referring to "a large and compelling body of scientific evidence" which demonstrates "that antibiotic use in agriculture contributes to the emergence of resistant bacteria and their spread to humans."

A statement issued by the Alliance for the Prudent Use of Antibiotics (APUA) applauded the release of the guidelines, which it said address "mounting scientific evidence of transfer of resistant genes in the environment to dangerous pathogens in humans and the role that food animal production plays in that process." The guidelines put the food animal industry "on a level playing field" with the human medical community in terms of requiring responsible use of antibiotics, the statement said, referring to the "long-standing irony" that antibiotic use in human medicine requires prescriptions, unlike in the animal industry. The guidelines also promote responsible food production practices already codified in many European countries, Kathy Young, APUA’s executive director, said in the statement. In the statement, Dr. Stuart Levy, APUA’s president and director of the Center for Adaptation Genetics and Drug Resistance, Tufts University, Boston, said that the organization will be involved in carefully monitoring compliance with the program, since it is voluntary.

A statement issued by the Center for Science in the Public Interest, however, described the program as "tragically flawed," and said that it relied "too heavily on the drug industry and animal producers to act voluntarily in the best interest of consumers."

The final guidance and draft documents are being published in the federal register and are available online.

GAITHERSBURG, MD. – The majority of a Food and Drug Administration advisory panel agreed at a meeting in March that the data on the Wingspan intracranial stent no longer supported the criteria for its approval as a humanitarian device to treat patients with intracranial arterial stenosis.

At the meeting, which was held to discuss the future of the device, all but 1 of the 15 members of the FDA’s Neurological Devices Panel agreed that the available safety and effectiveness data on the Wingspan stent – which include a randomized controlled study that was terminated early because of a higher stroke rate in the stent arm – did not support the "probable benefit to health" for humanitarian device’s approval as a treatment for intracranial stenosis. About two-thirds of the panel also agreed that there were not sufficient data to indicate that the probable benefit of the stent outweighed its risk in any subpopulation of patients, although several panelists supported keeping the stent available for the very small group of patients with no other options.

The panel was not asked to vote officially on these questions, but panelists clearly stated their opinions.

"I have seen nothing today that shows me that the benefits outweigh the risks that caused a study to be prematurely terminated," said Dr. Christopher Loftus, professor and chairman of the department of neurosurgery, Temple University Hospital, Philadelphia.

Dr. Karen Johnston, chair of neurology at the University of Virginia, Charlottesville, pointed out that making the stent available as an investigational device was an option. "Then we could actually take these patients and offer them this treatment in an organized clinical trial ... and learn something in a standardized way," she said.

In 2004, the Wingspan Stent System with Gateway PTA Balloon Catheter was designated as a humanitarian use device, and in August 2005, the FDA approved the Wingspan system under a humanitarian device exemption (HDE) for use in improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with at least 50% stenosis "that are accessible to the system." The approval was based on a prospective, single-arm study of 45 people outside the United States, with at least 50% stenosis, who had recurrent strokes and were refractory to treatment with warfarin and/or aspirin.

The agency’s criteria for HDE approval is based on safety and "probable benefit" from use of a device, which "outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment." A standard device approval is based on safety and a reasonable assurance of effectiveness.

After the HDE approval, investigators independent of the stent’s manufacturer, Stryker Neurovascular (formerly Boston Scientific Neurovascular), launched the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial. The National Institute of Neurological Disorders and Stroke sponsored the randomized trial, which compared angioplasty and stenting with the Wingspan system combined with aggressive medical therapy (with aspirin and clopidogrel) against aggressive medical therapy alone in high-risk patients with 70%-99% intracranial arterial stenosis (the median was almost 80%). Stryker provided the device for the study. Enrollment was stopped prematurely in April 2011, after it was determined that 14.7% of the patients in the stent arm died or had a stroke within 30 days of enrollment, compared with 5.8% of those in the medical management arm, a significant difference (N. Engl. J. Med. 2011;365:993-1003).

Since these interim results were published in September 2011, four Institutional Review Boards have withdrawn approval of the HDE, according to the FDA. And in December, a citizen’s petition to withdraw the HDE approval was filed by Public Citizen’s Health Research Group, stating that the device was ineffective and there was no reasonable assurance that it was safe under the conditions of use prescribed, recommended, or suggested in the labeling.

At the meeting, Stryker Neurovascular said that the Wingspan system should remain available as a humanitarian device for the small group of patients described in the approved indication. Among the points made by the company was that only about 8% of the patients in the SAMMPRIS study met the inclusion criteria for the HDE study, and that many of the patient subtypes who were treated with the stent in the HDE study were underrepresented in the SAMMPRIS study.

The company said that there was a population of patients for whom the probable benefit of treatment with the device outweighed the risk of injury or illness from its use, such as a patient who has failed treatment with aggressive medical management, or for whom this treatment is inappropriate and have failed another medical therapy regimen.

Fewer than 4,000 people per year are eligible for treatment with the Wingspan stent system, which has been used for an extremely small patient population, according to the company. In each year since the HDE was approved in August 2005, an average of fewer than 2,000 patients have received a Wingspan stent, according to Stryker.

At the meeting, the lead investigator of SAMMPRIS, Dr. Marc Chimowitz, medical professor of neurosciences at the Medical University of South Carolina, Charleston, said based on the data available in April 2011, one has to conclude that medical treatment is superior, but added that the final answer is not available, because longer-term data will be reviewed next year. (Dr. Chimowitz presented the results of SAMMPRIS at the meeting; he was not there on behalf of Stryker.)

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, and at this meeting, three panelists were given waivers because their places of employment were SAMMPRIS study sites.

GAITHERSBURG, MD. – The majority of a Food and Drug Administration advisory panel agreed at a meeting in March that the data on the Wingspan intracranial stent no longer supported the criteria for its approval as a humanitarian device to treat patients with intracranial arterial stenosis.

At the meeting, which was held to discuss the future of the device, all but 1 of the 15 members of the FDA’s Neurological Devices Panel agreed that the available safety and effectiveness data on the Wingspan stent – which include a randomized controlled study that was terminated early because of a higher stroke rate in the stent arm – did not support the "probable benefit to health" for humanitarian device’s approval as a treatment for intracranial stenosis. About two-thirds of the panel also agreed that there were not sufficient data to indicate that the probable benefit of the stent outweighed its risk in any subpopulation of patients, although several panelists supported keeping the stent available for the very small group of patients with no other options.

The panel was not asked to vote officially on these questions, but panelists clearly stated their opinions.

"I have seen nothing today that shows me that the benefits outweigh the risks that caused a study to be prematurely terminated," said Dr. Christopher Loftus, professor and chairman of the department of neurosurgery, Temple University Hospital, Philadelphia.

Dr. Karen Johnston, chair of neurology at the University of Virginia, Charlottesville, pointed out that making the stent available as an investigational device was an option. "Then we could actually take these patients and offer them this treatment in an organized clinical trial ... and learn something in a standardized way," she said.

In 2004, the Wingspan Stent System with Gateway PTA Balloon Catheter was designated as a humanitarian use device, and in August 2005, the FDA approved the Wingspan system under a humanitarian device exemption (HDE) for use in improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with at least 50% stenosis "that are accessible to the system." The approval was based on a prospective, single-arm study of 45 people outside the United States, with at least 50% stenosis, who had recurrent strokes and were refractory to treatment with warfarin and/or aspirin.

The agency’s criteria for HDE approval is based on safety and "probable benefit" from use of a device, which "outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment." A standard device approval is based on safety and a reasonable assurance of effectiveness.

After the HDE approval, investigators independent of the stent’s manufacturer, Stryker Neurovascular (formerly Boston Scientific Neurovascular), launched the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial. The National Institute of Neurological Disorders and Stroke sponsored the randomized trial, which compared angioplasty and stenting with the Wingspan system combined with aggressive medical therapy (with aspirin and clopidogrel) against aggressive medical therapy alone in high-risk patients with 70%-99% intracranial arterial stenosis (the median was almost 80%). Stryker provided the device for the study. Enrollment was stopped prematurely in April 2011, after it was determined that 14.7% of the patients in the stent arm died or had a stroke within 30 days of enrollment, compared with 5.8% of those in the medical management arm, a significant difference (N. Engl. J. Med. 2011;365:993-1003).

Since these interim results were published in September 2011, four Institutional Review Boards have withdrawn approval of the HDE, according to the FDA. And in December, a citizen’s petition to withdraw the HDE approval was filed by Public Citizen’s Health Research Group, stating that the device was ineffective and there was no reasonable assurance that it was safe under the conditions of use prescribed, recommended, or suggested in the labeling.

At the meeting, Stryker Neurovascular said that the Wingspan system should remain available as a humanitarian device for the small group of patients described in the approved indication. Among the points made by the company was that only about 8% of the patients in the SAMMPRIS study met the inclusion criteria for the HDE study, and that many of the patient subtypes who were treated with the stent in the HDE study were underrepresented in the SAMMPRIS study.

The company said that there was a population of patients for whom the probable benefit of treatment with the device outweighed the risk of injury or illness from its use, such as a patient who has failed treatment with aggressive medical management, or for whom this treatment is inappropriate and have failed another medical therapy regimen.

Fewer than 4,000 people per year are eligible for treatment with the Wingspan stent system, which has been used for an extremely small patient population, according to the company. In each year since the HDE was approved in August 2005, an average of fewer than 2,000 patients have received a Wingspan stent, according to Stryker.

At the meeting, the lead investigator of SAMMPRIS, Dr. Marc Chimowitz, medical professor of neurosciences at the Medical University of South Carolina, Charleston, said based on the data available in April 2011, one has to conclude that medical treatment is superior, but added that the final answer is not available, because longer-term data will be reviewed next year. (Dr. Chimowitz presented the results of SAMMPRIS at the meeting; he was not there on behalf of Stryker.)

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, and at this meeting, three panelists were given waivers because their places of employment were SAMMPRIS study sites.

GAITHERSBURG, MD. – The majority of a Food and Drug Administration advisory panel agreed at a meeting in March that the data on the Wingspan intracranial stent no longer supported the criteria for its approval as a humanitarian device to treat patients with intracranial arterial stenosis.

At the meeting, which was held to discuss the future of the device, all but 1 of the 15 members of the FDA’s Neurological Devices Panel agreed that the available safety and effectiveness data on the Wingspan stent – which include a randomized controlled study that was terminated early because of a higher stroke rate in the stent arm – did not support the "probable benefit to health" for humanitarian device’s approval as a treatment for intracranial stenosis. About two-thirds of the panel also agreed that there were not sufficient data to indicate that the probable benefit of the stent outweighed its risk in any subpopulation of patients, although several panelists supported keeping the stent available for the very small group of patients with no other options.

The panel was not asked to vote officially on these questions, but panelists clearly stated their opinions.

"I have seen nothing today that shows me that the benefits outweigh the risks that caused a study to be prematurely terminated," said Dr. Christopher Loftus, professor and chairman of the department of neurosurgery, Temple University Hospital, Philadelphia.

Dr. Karen Johnston, chair of neurology at the University of Virginia, Charlottesville, pointed out that making the stent available as an investigational device was an option. "Then we could actually take these patients and offer them this treatment in an organized clinical trial ... and learn something in a standardized way," she said.

In 2004, the Wingspan Stent System with Gateway PTA Balloon Catheter was designated as a humanitarian use device, and in August 2005, the FDA approved the Wingspan system under a humanitarian device exemption (HDE) for use in improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with at least 50% stenosis "that are accessible to the system." The approval was based on a prospective, single-arm study of 45 people outside the United States, with at least 50% stenosis, who had recurrent strokes and were refractory to treatment with warfarin and/or aspirin.

The agency’s criteria for HDE approval is based on safety and "probable benefit" from use of a device, which "outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment." A standard device approval is based on safety and a reasonable assurance of effectiveness.

After the HDE approval, investigators independent of the stent’s manufacturer, Stryker Neurovascular (formerly Boston Scientific Neurovascular), launched the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial. The National Institute of Neurological Disorders and Stroke sponsored the randomized trial, which compared angioplasty and stenting with the Wingspan system combined with aggressive medical therapy (with aspirin and clopidogrel) against aggressive medical therapy alone in high-risk patients with 70%-99% intracranial arterial stenosis (the median was almost 80%). Stryker provided the device for the study. Enrollment was stopped prematurely in April 2011, after it was determined that 14.7% of the patients in the stent arm died or had a stroke within 30 days of enrollment, compared with 5.8% of those in the medical management arm, a significant difference (N. Engl. J. Med. 2011;365:993-1003).

Since these interim results were published in September 2011, four Institutional Review Boards have withdrawn approval of the HDE, according to the FDA. And in December, a citizen’s petition to withdraw the HDE approval was filed by Public Citizen’s Health Research Group, stating that the device was ineffective and there was no reasonable assurance that it was safe under the conditions of use prescribed, recommended, or suggested in the labeling.

At the meeting, Stryker Neurovascular said that the Wingspan system should remain available as a humanitarian device for the small group of patients described in the approved indication. Among the points made by the company was that only about 8% of the patients in the SAMMPRIS study met the inclusion criteria for the HDE study, and that many of the patient subtypes who were treated with the stent in the HDE study were underrepresented in the SAMMPRIS study.

The company said that there was a population of patients for whom the probable benefit of treatment with the device outweighed the risk of injury or illness from its use, such as a patient who has failed treatment with aggressive medical management, or for whom this treatment is inappropriate and have failed another medical therapy regimen.

Fewer than 4,000 people per year are eligible for treatment with the Wingspan stent system, which has been used for an extremely small patient population, according to the company. In each year since the HDE was approved in August 2005, an average of fewer than 2,000 patients have received a Wingspan stent, according to Stryker.

At the meeting, the lead investigator of SAMMPRIS, Dr. Marc Chimowitz, medical professor of neurosciences at the Medical University of South Carolina, Charleston, said based on the data available in April 2011, one has to conclude that medical treatment is superior, but added that the final answer is not available, because longer-term data will be reviewed next year. (Dr. Chimowitz presented the results of SAMMPRIS at the meeting; he was not there on behalf of Stryker.)

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, and at this meeting, three panelists were given waivers because their places of employment were SAMMPRIS study sites.

Yasmin and other drospirenone-containing oral contraceptives "may be associated" with an increased risk of blood clots, compared with oral contraceptives that contain other progestins, the Food and Drug Administration has concluded.

In a statement issued on April 10, the agency announced that the conclusion is based on its review of epidemiologic studies of the risk of venous thromboembolic events (VTEs) associated with combined oral contraceptives (COCs) that contain drospirenone, a synthetic form of progesterone, and that this information is being added to the labels of these products. The COCs that contain drospirenone as the progestin component are Yasmin (0.03 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2001, the first COC that contained drospirenone; Yaz (0.02 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2006; and Safyral and Beyaz, folate-containing versions of Yasmin and Yaz, respectively, which were approved in 2010. Some generic formulations also are available.

The conflicting results of numerous epidemiologic studies evaluating the VTE risk associated with these COCs were reviewed at a meeting of the FDA’s Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee in December 2011. The panels voted 15-11 that the benefits of these products for preventing pregnancy outweighed their risks, and voted 21-5 that the labels for these products did not adequately reflect available information about their risk-benefit profile.

The labels will state that some of the studies found a threefold increased risk in VTEs associated with drospirenone-containing OCs, compared with those containing levonorgestrel or another progestin, while others found no increased risk, according to the FDA statement.

For example, the Yasmin label now includes the statement that based on the currently available information, "DRSP [drospirenone]-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a threefold increase. Before initiating use of Yasmin in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE."

The new information appears in the warnings and precautions section of the labels, not in the boxed warning.

The FDA statement adds that the risk of blood clots "is higher when using any birth control pills than not using them, but still remains lower than the risk of developing blood clots in pregnancy and in the postpartum period."

Serious adverse events associated with drospirenone-containing COCs should be reported online to the FDA’s MedWatch program or by phone at 800-332-1088.

Yasmin and other drospirenone-containing oral contraceptives "may be associated" with an increased risk of blood clots, compared with oral contraceptives that contain other progestins, the Food and Drug Administration has concluded.

In a statement issued on April 10, the agency announced that the conclusion is based on its review of epidemiologic studies of the risk of venous thromboembolic events (VTEs) associated with combined oral contraceptives (COCs) that contain drospirenone, a synthetic form of progesterone, and that this information is being added to the labels of these products. The COCs that contain drospirenone as the progestin component are Yasmin (0.03 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2001, the first COC that contained drospirenone; Yaz (0.02 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2006; and Safyral and Beyaz, folate-containing versions of Yasmin and Yaz, respectively, which were approved in 2010. Some generic formulations also are available.

The conflicting results of numerous epidemiologic studies evaluating the VTE risk associated with these COCs were reviewed at a meeting of the FDA’s Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee in December 2011. The panels voted 15-11 that the benefits of these products for preventing pregnancy outweighed their risks, and voted 21-5 that the labels for these products did not adequately reflect available information about their risk-benefit profile.

The labels will state that some of the studies found a threefold increased risk in VTEs associated with drospirenone-containing OCs, compared with those containing levonorgestrel or another progestin, while others found no increased risk, according to the FDA statement.

For example, the Yasmin label now includes the statement that based on the currently available information, "DRSP [drospirenone]-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a threefold increase. Before initiating use of Yasmin in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE."

The new information appears in the warnings and precautions section of the labels, not in the boxed warning.

The FDA statement adds that the risk of blood clots "is higher when using any birth control pills than not using them, but still remains lower than the risk of developing blood clots in pregnancy and in the postpartum period."

Serious adverse events associated with drospirenone-containing COCs should be reported online to the FDA’s MedWatch program or by phone at 800-332-1088.

Yasmin and other drospirenone-containing oral contraceptives "may be associated" with an increased risk of blood clots, compared with oral contraceptives that contain other progestins, the Food and Drug Administration has concluded.

In a statement issued on April 10, the agency announced that the conclusion is based on its review of epidemiologic studies of the risk of venous thromboembolic events (VTEs) associated with combined oral contraceptives (COCs) that contain drospirenone, a synthetic form of progesterone, and that this information is being added to the labels of these products. The COCs that contain drospirenone as the progestin component are Yasmin (0.03 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2001, the first COC that contained drospirenone; Yaz (0.02 mg of ethinyl estradiol with 3 mg of drospirenone), approved in 2006; and Safyral and Beyaz, folate-containing versions of Yasmin and Yaz, respectively, which were approved in 2010. Some generic formulations also are available.

The conflicting results of numerous epidemiologic studies evaluating the VTE risk associated with these COCs were reviewed at a meeting of the FDA’s Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee in December 2011. The panels voted 15-11 that the benefits of these products for preventing pregnancy outweighed their risks, and voted 21-5 that the labels for these products did not adequately reflect available information about their risk-benefit profile.

The labels will state that some of the studies found a threefold increased risk in VTEs associated with drospirenone-containing OCs, compared with those containing levonorgestrel or another progestin, while others found no increased risk, according to the FDA statement.

For example, the Yasmin label now includes the statement that based on the currently available information, "DRSP [drospirenone]-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a threefold increase. Before initiating use of Yasmin in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE."

The new information appears in the warnings and precautions section of the labels, not in the boxed warning.

The FDA statement adds that the risk of blood clots "is higher when using any birth control pills than not using them, but still remains lower than the risk of developing blood clots in pregnancy and in the postpartum period."

Serious adverse events associated with drospirenone-containing COCs should be reported online to the FDA’s MedWatch program or by phone at 800-332-1088.

The estimated prevalence of autism spectrum disorders at sites across the country that are tracking prevalence rates among 8-year-old children increased by 23% between 2006 and 2008, according to a report published March 29 by the Centers for Disease Control and Prevention.

An estimated 1 of every 88 children had an ASD in 2008 at the 14 sites, which are part of the Autism and Developmental Disabilities Monitoring (ADDM) Network, an active surveillance system established by the CDC in 2000 to collect data on ASDs and other developmental disabilities in the United States. That represents a 23% increase from 2006, when 1 in 110 children had an ASD, and almost an 80% increase from 2002.

In 2008, prevalence was five times more common in boys, with 1 of every 54 boys affected by an ASD, compared with 1 of every 252 girls, another finding of the study that is included in the report, published in the March 30 issue of Morbidity and Mortality Weekly Report (MMWR 2012;61:1-19).

The study evaluated data from 14 sites in the United States in 2008, and compared the results with those of previous years. Cases are based on the presence of ASD symptoms at any time from birth through the end of the year a child turns 8 (as described in a child’s education and health records, not from parent or professional reports), that meet DSM-IV-TR diagnostic criteria for autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism), or Asperger’s disorder.

"Some of the increase is due to the way children are identified, diagnosed, and served in our local communities, although how much is due to these factors is not known," Coleen A. Boyle, Ph.D., director of the CDC’s National Center on Birth Defects and Developmental Disabilities, said during a telebriefing held to announce the report’s results. She said that research on the risk factors and causes of autism needs to be continued, and pointed out that tracking the prevalence also helps identify potential risk factors and helps guide research on the potential causes of autism.

The median age at diagnosis was 4 years among those tracked in 2008, compared with 4.5 years in 2006, she said. The number of children diagnosed by age 3 years increased from 12% of those born in 1994, to 18% of those born in 2000, according to the report.

During the briefing, Dr. Susan L. Hyman, chairperson of the Autism Subcommittee of the American Academy of Pediatrics (AAP), said that although the age of diagnosis for the children in 2008 was younger than in previous reports, "it’s not early enough." She referred to the AAP recommendation that all children be screened for autism at 18 and 24 months, so that children with autism can be identified and referred for appropriate treatment and services sooner.

"While there are a number of potential reasons for this increase, the nature of the sites where the data have been collected support that the notion that these trends are not just explained by the broadened definition of autism in the change from the DSM-III-R to the DSM-IV in 1994, or to ascertainment," Dr. Robert L. Hendren, director of child and adolescent psychiatry at the University of California, San Francisco, said in an interview. What continues to be frightening about the increase is that it is unexplained, he said, adding "we see increases in obesity and diabetes, and we have good theories about why. We don’t for autism."

Dr. Hendren, professor and vice chair of the department of psychiatry at UCSF, said more research that looks at the gene-environment interaction etiology of autism is needed. "And we need stronger, broadly available targeted treatments for autism that are accessed early and broadly. We also need to help the growing adolescent and adult population with these disorders to live as fulfilling a life as possible."

Dr. Paul H. Lipkin, associate professor of pediatrics at Johns Hopkins University, Baltimore, said, "The rise is likely related in part to improved recognition to the signs and symptoms of [autism spectrum disorder] by professionals, parents, and the general public over the past decade.

"It remains unclear whether there are unrecognized biological or environmental factors affecting early childhood development and adding to this increased prevalence," he said in an interview.

"By looking at 8-year-old children, the CDC is assuring that the identified children are those with ongoing special health care and educational needs, rather than a group whose symptoms may remit," said Dr. Lipkin, who also is the director of the Center for Development and Learning at the Kennedy Krieger Institute in Baltimore.*

In addition to sex differences, the report found wide variations in prevalence estimates by sites, and by racial and ethnic groups. For example, the prevalence of ASDs ranged from 1 of every 210 children in Alabama to 1 of every 47 children in Utah. And at all the sites, the estimated prevalence in non-Hispanic white children was significantly higher than the prevalence in non-Hispanic black children and Hispanic children overall, with one exception: In Florida, the prevalence was significantly higher in Hispanic children than in non-Hispanic white or non-Hispanic black children.

The estimated prevalence of ASD was also significantly higher at sites where there was access to education sources, compared with the sites that only had health sources to help identify cases.

In 2008, the 14 sites covered an area that included a total of about 337,000 children aged 8 years, representing about 8% of the 8-year-olds in the United States. Although the report notes that the ADDM sites are not nationally representative and the results should not be generalized to the United States overall, Dr. Boyle said these trends are comparable to the prevalence estimates in other national surveys.

The ADDM sites are in Alabama, Arizona, Arkansas, Colorado, Florida, Maryland, Missouri, New Jersey, North Carolina, Pennsylvania, South Carolina, Utah, West Virginia, and Wisconsin.

No conflicts of interest were reported.

More information about autism, including a link to the report, is available from the CDC.

* Updated: Additional information added April 4, 2012

The estimated prevalence of autism spectrum disorders at sites across the country that are tracking prevalence rates among 8-year-old children increased by 23% between 2006 and 2008, according to a report published March 29 by the Centers for Disease Control and Prevention.

An estimated 1 of every 88 children had an ASD in 2008 at the 14 sites, which are part of the Autism and Developmental Disabilities Monitoring (ADDM) Network, an active surveillance system established by the CDC in 2000 to collect data on ASDs and other developmental disabilities in the United States. That represents a 23% increase from 2006, when 1 in 110 children had an ASD, and almost an 80% increase from 2002.

In 2008, prevalence was five times more common in boys, with 1 of every 54 boys affected by an ASD, compared with 1 of every 252 girls, another finding of the study that is included in the report, published in the March 30 issue of Morbidity and Mortality Weekly Report (MMWR 2012;61:1-19).

The study evaluated data from 14 sites in the United States in 2008, and compared the results with those of previous years. Cases are based on the presence of ASD symptoms at any time from birth through the end of the year a child turns 8 (as described in a child’s education and health records, not from parent or professional reports), that meet DSM-IV-TR diagnostic criteria for autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism), or Asperger’s disorder.

"Some of the increase is due to the way children are identified, diagnosed, and served in our local communities, although how much is due to these factors is not known," Coleen A. Boyle, Ph.D., director of the CDC’s National Center on Birth Defects and Developmental Disabilities, said during a telebriefing held to announce the report’s results. She said that research on the risk factors and causes of autism needs to be continued, and pointed out that tracking the prevalence also helps identify potential risk factors and helps guide research on the potential causes of autism.

The median age at diagnosis was 4 years among those tracked in 2008, compared with 4.5 years in 2006, she said. The number of children diagnosed by age 3 years increased from 12% of those born in 1994, to 18% of those born in 2000, according to the report.

During the briefing, Dr. Susan L. Hyman, chairperson of the Autism Subcommittee of the American Academy of Pediatrics (AAP), said that although the age of diagnosis for the children in 2008 was younger than in previous reports, "it’s not early enough." She referred to the AAP recommendation that all children be screened for autism at 18 and 24 months, so that children with autism can be identified and referred for appropriate treatment and services sooner.

"While there are a number of potential reasons for this increase, the nature of the sites where the data have been collected support that the notion that these trends are not just explained by the broadened definition of autism in the change from the DSM-III-R to the DSM-IV in 1994, or to ascertainment," Dr. Robert L. Hendren, director of child and adolescent psychiatry at the University of California, San Francisco, said in an interview. What continues to be frightening about the increase is that it is unexplained, he said, adding "we see increases in obesity and diabetes, and we have good theories about why. We don’t for autism."

Dr. Hendren, professor and vice chair of the department of psychiatry at UCSF, said more research that looks at the gene-environment interaction etiology of autism is needed. "And we need stronger, broadly available targeted treatments for autism that are accessed early and broadly. We also need to help the growing adolescent and adult population with these disorders to live as fulfilling a life as possible."

Dr. Paul H. Lipkin, associate professor of pediatrics at Johns Hopkins University, Baltimore, said, "The rise is likely related in part to improved recognition to the signs and symptoms of [autism spectrum disorder] by professionals, parents, and the general public over the past decade.

"It remains unclear whether there are unrecognized biological or environmental factors affecting early childhood development and adding to this increased prevalence," he said in an interview.

"By looking at 8-year-old children, the CDC is assuring that the identified children are those with ongoing special health care and educational needs, rather than a group whose symptoms may remit," said Dr. Lipkin, who also is the director of the Center for Development and Learning at the Kennedy Krieger Institute in Baltimore.*

In addition to sex differences, the report found wide variations in prevalence estimates by sites, and by racial and ethnic groups. For example, the prevalence of ASDs ranged from 1 of every 210 children in Alabama to 1 of every 47 children in Utah. And at all the sites, the estimated prevalence in non-Hispanic white children was significantly higher than the prevalence in non-Hispanic black children and Hispanic children overall, with one exception: In Florida, the prevalence was significantly higher in Hispanic children than in non-Hispanic white or non-Hispanic black children.

The estimated prevalence of ASD was also significantly higher at sites where there was access to education sources, compared with the sites that only had health sources to help identify cases.

In 2008, the 14 sites covered an area that included a total of about 337,000 children aged 8 years, representing about 8% of the 8-year-olds in the United States. Although the report notes that the ADDM sites are not nationally representative and the results should not be generalized to the United States overall, Dr. Boyle said these trends are comparable to the prevalence estimates in other national surveys.

The ADDM sites are in Alabama, Arizona, Arkansas, Colorado, Florida, Maryland, Missouri, New Jersey, North Carolina, Pennsylvania, South Carolina, Utah, West Virginia, and Wisconsin.

No conflicts of interest were reported.

More information about autism, including a link to the report, is available from the CDC.

* Updated: Additional information added April 4, 2012

The estimated prevalence of autism spectrum disorders at sites across the country that are tracking prevalence rates among 8-year-old children increased by 23% between 2006 and 2008, according to a report published March 29 by the Centers for Disease Control and Prevention.

An estimated 1 of every 88 children had an ASD in 2008 at the 14 sites, which are part of the Autism and Developmental Disabilities Monitoring (ADDM) Network, an active surveillance system established by the CDC in 2000 to collect data on ASDs and other developmental disabilities in the United States. That represents a 23% increase from 2006, when 1 in 110 children had an ASD, and almost an 80% increase from 2002.

In 2008, prevalence was five times more common in boys, with 1 of every 54 boys affected by an ASD, compared with 1 of every 252 girls, another finding of the study that is included in the report, published in the March 30 issue of Morbidity and Mortality Weekly Report (MMWR 2012;61:1-19).

The study evaluated data from 14 sites in the United States in 2008, and compared the results with those of previous years. Cases are based on the presence of ASD symptoms at any time from birth through the end of the year a child turns 8 (as described in a child’s education and health records, not from parent or professional reports), that meet DSM-IV-TR diagnostic criteria for autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism), or Asperger’s disorder.

"Some of the increase is due to the way children are identified, diagnosed, and served in our local communities, although how much is due to these factors is not known," Coleen A. Boyle, Ph.D., director of the CDC’s National Center on Birth Defects and Developmental Disabilities, said during a telebriefing held to announce the report’s results. She said that research on the risk factors and causes of autism needs to be continued, and pointed out that tracking the prevalence also helps identify potential risk factors and helps guide research on the potential causes of autism.

The median age at diagnosis was 4 years among those tracked in 2008, compared with 4.5 years in 2006, she said. The number of children diagnosed by age 3 years increased from 12% of those born in 1994, to 18% of those born in 2000, according to the report.

During the briefing, Dr. Susan L. Hyman, chairperson of the Autism Subcommittee of the American Academy of Pediatrics (AAP), said that although the age of diagnosis for the children in 2008 was younger than in previous reports, "it’s not early enough." She referred to the AAP recommendation that all children be screened for autism at 18 and 24 months, so that children with autism can be identified and referred for appropriate treatment and services sooner.

"While there are a number of potential reasons for this increase, the nature of the sites where the data have been collected support that the notion that these trends are not just explained by the broadened definition of autism in the change from the DSM-III-R to the DSM-IV in 1994, or to ascertainment," Dr. Robert L. Hendren, director of child and adolescent psychiatry at the University of California, San Francisco, said in an interview. What continues to be frightening about the increase is that it is unexplained, he said, adding "we see increases in obesity and diabetes, and we have good theories about why. We don’t for autism."

Dr. Hendren, professor and vice chair of the department of psychiatry at UCSF, said more research that looks at the gene-environment interaction etiology of autism is needed. "And we need stronger, broadly available targeted treatments for autism that are accessed early and broadly. We also need to help the growing adolescent and adult population with these disorders to live as fulfilling a life as possible."

Dr. Paul H. Lipkin, associate professor of pediatrics at Johns Hopkins University, Baltimore, said, "The rise is likely related in part to improved recognition to the signs and symptoms of [autism spectrum disorder] by professionals, parents, and the general public over the past decade.

"It remains unclear whether there are unrecognized biological or environmental factors affecting early childhood development and adding to this increased prevalence," he said in an interview.

"By looking at 8-year-old children, the CDC is assuring that the identified children are those with ongoing special health care and educational needs, rather than a group whose symptoms may remit," said Dr. Lipkin, who also is the director of the Center for Development and Learning at the Kennedy Krieger Institute in Baltimore.*

In addition to sex differences, the report found wide variations in prevalence estimates by sites, and by racial and ethnic groups. For example, the prevalence of ASDs ranged from 1 of every 210 children in Alabama to 1 of every 47 children in Utah. And at all the sites, the estimated prevalence in non-Hispanic white children was significantly higher than the prevalence in non-Hispanic black children and Hispanic children overall, with one exception: In Florida, the prevalence was significantly higher in Hispanic children than in non-Hispanic white or non-Hispanic black children.

The estimated prevalence of ASD was also significantly higher at sites where there was access to education sources, compared with the sites that only had health sources to help identify cases.

In 2008, the 14 sites covered an area that included a total of about 337,000 children aged 8 years, representing about 8% of the 8-year-olds in the United States. Although the report notes that the ADDM sites are not nationally representative and the results should not be generalized to the United States overall, Dr. Boyle said these trends are comparable to the prevalence estimates in other national surveys.

The ADDM sites are in Alabama, Arizona, Arkansas, Colorado, Florida, Maryland, Missouri, New Jersey, North Carolina, Pennsylvania, South Carolina, Utah, West Virginia, and Wisconsin.

No conflicts of interest were reported.

More information about autism, including a link to the report, is available from the CDC.

* Updated: Additional information added April 4, 2012

The Food and Drug Administration has clarified its warning and dosing recommendations regarding the potential risk of QT prolongation with the antidepressant citalopram, the agency announced March 28.

In a MedWatch alert issued in August 2011, the agency recommended that citalopram should no longer be used at doses greater than 40 mg a day because of the potential for prolongation of the QT interval, which can lead to torsades de pointes, a potentially fatal cardiac arrhythmia. The 2011 warning also stated that citalopram should not be used in patients with congenital long QT syndrome, and that patients who have congestive heart failure or bradyarrhythmias, or are predisposed to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing the arrhythmia.

There have been postmarketing reports of torsades de pointes associated with citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for treating depression in 1998 and marketed as Celexa by Forest Laboratories. It also is available in generic formulations.

In the March 28 statement posted on the MedWatch site, the FDA said the citalopram label is being revised to include information on the lower doses that should be used in people over age 60 years. In addition, while the use of citalopram "at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation," the statement adds, "because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients."

The FDA’s revised recommendations are as follows:

• Citalopram is not recommended at doses greater than 40 mg per day "because such doses cause too large an effect on the QT interval and confer no additional benefit."

• Citalopram is not recommended for patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. 

• Citalopram is not recommended for patients treated with other drugs that prolong the QT interval.

• The maximum recommended dose of citalopram is 20 mg per day for patients who have hepatic impairment, are older than age 60, are CYP 2C19 poor metabolizers, or are taking cimetidine (Tagamet) or another CYP2C19 inhibitor. These factors result in increased blood levels of citalopram, and increase the risk of QT prolongation and torsades de pointes.

Serious adverse events associated with citalopram should be reported to the FDA’s MedWatch program at 800-332-1088.

The Food and Drug Administration has clarified its warning and dosing recommendations regarding the potential risk of QT prolongation with the antidepressant citalopram, the agency announced March 28.

In a MedWatch alert issued in August 2011, the agency recommended that citalopram should no longer be used at doses greater than 40 mg a day because of the potential for prolongation of the QT interval, which can lead to torsades de pointes, a potentially fatal cardiac arrhythmia. The 2011 warning also stated that citalopram should not be used in patients with congenital long QT syndrome, and that patients who have congestive heart failure or bradyarrhythmias, or are predisposed to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing the arrhythmia.

There have been postmarketing reports of torsades de pointes associated with citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for treating depression in 1998 and marketed as Celexa by Forest Laboratories. It also is available in generic formulations.

In the March 28 statement posted on the MedWatch site, the FDA said the citalopram label is being revised to include information on the lower doses that should be used in people over age 60 years. In addition, while the use of citalopram "at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation," the statement adds, "because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients."

The FDA’s revised recommendations are as follows:

• Citalopram is not recommended at doses greater than 40 mg per day "because such doses cause too large an effect on the QT interval and confer no additional benefit."

• Citalopram is not recommended for patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. 

• Citalopram is not recommended for patients treated with other drugs that prolong the QT interval.

• The maximum recommended dose of citalopram is 20 mg per day for patients who have hepatic impairment, are older than age 60, are CYP 2C19 poor metabolizers, or are taking cimetidine (Tagamet) or another CYP2C19 inhibitor. These factors result in increased blood levels of citalopram, and increase the risk of QT prolongation and torsades de pointes.

Serious adverse events associated with citalopram should be reported to the FDA’s MedWatch program at 800-332-1088.

The Food and Drug Administration has clarified its warning and dosing recommendations regarding the potential risk of QT prolongation with the antidepressant citalopram, the agency announced March 28.

In a MedWatch alert issued in August 2011, the agency recommended that citalopram should no longer be used at doses greater than 40 mg a day because of the potential for prolongation of the QT interval, which can lead to torsades de pointes, a potentially fatal cardiac arrhythmia. The 2011 warning also stated that citalopram should not be used in patients with congenital long QT syndrome, and that patients who have congestive heart failure or bradyarrhythmias, or are predisposed to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing the arrhythmia.

There have been postmarketing reports of torsades de pointes associated with citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for treating depression in 1998 and marketed as Celexa by Forest Laboratories. It also is available in generic formulations.

In the March 28 statement posted on the MedWatch site, the FDA said the citalopram label is being revised to include information on the lower doses that should be used in people over age 60 years. In addition, while the use of citalopram "at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation," the statement adds, "because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients."

The FDA’s revised recommendations are as follows:

• Citalopram is not recommended at doses greater than 40 mg per day "because such doses cause too large an effect on the QT interval and confer no additional benefit."

• Citalopram is not recommended for patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. 

• Citalopram is not recommended for patients treated with other drugs that prolong the QT interval.

• The maximum recommended dose of citalopram is 20 mg per day for patients who have hepatic impairment, are older than age 60, are CYP 2C19 poor metabolizers, or are taking cimetidine (Tagamet) or another CYP2C19 inhibitor. These factors result in increased blood levels of citalopram, and increase the risk of QT prolongation and torsades de pointes.

Serious adverse events associated with citalopram should be reported to the FDA’s MedWatch program at 800-332-1088.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 13-1 that the investigational agent ridaforolimus did not have a favorable risk-benefit profile when used as maintenance therapy in patients with metastatic soft-tissue or bone sarcomas that had stabilized with chemotherapy.

Members of the FDA’s Oncologic Drugs Advisory Committee cited the marginal effect on progression-free survival and the toxicity profile associated with the drug in a phase III clinical trial reviewed at a meeting on March 20.

While several panelists noted the need for such a treatment, ODAC’s chair, Dr. Wyndham H. Wilson, pointed out that patients are exposed for a longer period of time when a drug is approved as maintenance therapy. Therefore, the data showing benefit have to be more robust than do the data supporting use in a treatment setting, and the drug should be "reasonably well tolerated," said Dr. Wilson, chief of the lymphoma therapeutics section at the National Cancer Institute, Bethesda, Md.

Manufacturer Merck Sharp & Dohme Corp. has proposed that ridaforolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), be approved as a maintenance treatment at a dose of 40 mg daily for 5 days of the week.

The study involved 711 patients with metastatic soft-tissue sarcoma (STS) or bone sarcoma that had not progressed after at least four cycles of chemotherapy. Their median age was 53 years; 12 patients were aged 12-17 years. Most (90%) had soft-tissue sarcomas; the rest had bone sarcomas. About two-thirds of the tumors were high grade. About half the patients were in the United States.

Median progression-free survival, the primary end point, reached 17.7 weeks among those on ridaforolimus, compared with 14.6 weeks among those on placebo – a statistically significant difference that represented a reduced risk of 28% of disease progression or death, according to Merck’s analysis.

Overall survival was 91 weeks with ridaforolimus vs. 85 weeks with placebo. This was not significantly different, but the study was not powered to evaluate overall survival.

The safety profile was similar to the safety profile with other mTOR inhibitors, and there were more grade 3/4 adverse events among patients on ridaforolimus (64% vs. 25% on placebo). In all, 14% of those on ridaforolimus discontinued treatment, compared with 2% of those on placebo.

Grade 3/4 stomatitis (12% vs. 1%) and hyperglycemia (13% vs. 2%) were more common with ridaforolimus. There were also more cases of interstitial pneumonitis and renal failure.

Among the main issues raised by the FDA reviewers were that the clinical importance of the statistically significant improvement in progression-free survival was unclear, maintenance treatment did not lead to longer overall survival, and adverse events were a concern for a maintenance treatment in patients with stable disease. The panel agreed with the FDA reviewers.

To date, the FDA has approved three agents as maintenance therapy in patients with cancer: pemetrexed (Alimta) in nonsquamous non–small cell lung cancer (NSCLC), erlotinib (Tarceva) for NSCLC, and rituximab (Rituxan), for non-Hodgkin’s lymphoma. No drug has been approved for maintenance therapy in patients with sarcoma.

If approved, Merck plans to market ridaforolimus as Taltorvic; it is also being studied for various types of solid-tissue cancers, including lung, breast, endometrial, and ovarian cancer, according to the company.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in this meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.