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FDA Ponders Vaccines From Human Tumor Cell Lines
A Food and Drug Administration advisory panel will meet Sept. 19 to discuss the use of cell lines derived from human tumors to manufacture vaccines.
The Vaccines and Related Biological Products Advisory Committee meeting comes as several therapeutic cancer vaccines derived from tumor cell lines are in phase III trials. As applications come in, the agency must determine how to address issues such as genetic stability and product characterization.
NovaRx Corp. reported June 20 that it has completed enrollment in its phase III clinical trial of belagenpumatucel-L (Lucanix), a whole-tumor cell vaccine for non–small cell lung cancer.The first interim analysis of overall survival will occur in the third quarter of 2012. If the independent data-monitoring committee finds that the trial meets statistical significance for the prespecified end points, the company anticipates filing a Biologics License Application (BLA) based on those results.
The allogeneic vaccine is composed of human tumor cells modified to block production of transforming growth factor–beta (TGF-beta). Tumors use TGF-beta to hide from the immune system, so blocking production allows the initiation of strong immune responses to the tumor, according to the company.
Another whole-tumor cell vaccine, algenpantucel-L (HyperAcute Pancreas) from NewLink Genetics Corp., is in phase III trials with stages I and II surgically resected pancreatic cancer patients. Those trials reached the midpoint of enrollment in the second quarter, the company said on June 19.The first interim analysis of data is expected in early 2013.
Algenpantucel- L contains two allogeneic pancreatic cancer tumor cell lines that were modified to express alpha-gal. Each cell line provides a broad range of pancreatic cancer antigens to the vaccine, which is administered by intradermal injection. Phase III patients receive a series of up to 18 treatments over a period of about 6 months, followed by monthly maintenance treatments for 6 months. The primary end point of the trial is overall survival.
The modified cell lines are grown in large cultures, then harvested, irradiated, and packaged, with about 150 million cells of each delivered with each treatment.
An advantage to the whole-tumor cell vaccines is that they are off the shelf, facilitating manufacturing to fit demand and lowering production costs.
This contrasts with autologous vaccines that are customized for each patient. Dendreon Corp. has faced slow sales for its prostate cancer vaccine sipuleucel-T (Provenge), the first therapeutic cancer vaccine to gain FDA approval, largely because of cost and manufacturing complexity.
Encouraged by sipuleucel-T’s approval and undaunted by its slow sales, several autologous vaccines featuring different technologies were on view at the American Society of Clinical Oncology annual meeting in June.
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.
A Food and Drug Administration advisory panel will meet Sept. 19 to discuss the use of cell lines derived from human tumors to manufacture vaccines.
The Vaccines and Related Biological Products Advisory Committee meeting comes as several therapeutic cancer vaccines derived from tumor cell lines are in phase III trials. As applications come in, the agency must determine how to address issues such as genetic stability and product characterization.
NovaRx Corp. reported June 20 that it has completed enrollment in its phase III clinical trial of belagenpumatucel-L (Lucanix), a whole-tumor cell vaccine for non–small cell lung cancer.The first interim analysis of overall survival will occur in the third quarter of 2012. If the independent data-monitoring committee finds that the trial meets statistical significance for the prespecified end points, the company anticipates filing a Biologics License Application (BLA) based on those results.
The allogeneic vaccine is composed of human tumor cells modified to block production of transforming growth factor–beta (TGF-beta). Tumors use TGF-beta to hide from the immune system, so blocking production allows the initiation of strong immune responses to the tumor, according to the company.
Another whole-tumor cell vaccine, algenpantucel-L (HyperAcute Pancreas) from NewLink Genetics Corp., is in phase III trials with stages I and II surgically resected pancreatic cancer patients. Those trials reached the midpoint of enrollment in the second quarter, the company said on June 19.The first interim analysis of data is expected in early 2013.
Algenpantucel- L contains two allogeneic pancreatic cancer tumor cell lines that were modified to express alpha-gal. Each cell line provides a broad range of pancreatic cancer antigens to the vaccine, which is administered by intradermal injection. Phase III patients receive a series of up to 18 treatments over a period of about 6 months, followed by monthly maintenance treatments for 6 months. The primary end point of the trial is overall survival.
The modified cell lines are grown in large cultures, then harvested, irradiated, and packaged, with about 150 million cells of each delivered with each treatment.
An advantage to the whole-tumor cell vaccines is that they are off the shelf, facilitating manufacturing to fit demand and lowering production costs.
This contrasts with autologous vaccines that are customized for each patient. Dendreon Corp. has faced slow sales for its prostate cancer vaccine sipuleucel-T (Provenge), the first therapeutic cancer vaccine to gain FDA approval, largely because of cost and manufacturing complexity.
Encouraged by sipuleucel-T’s approval and undaunted by its slow sales, several autologous vaccines featuring different technologies were on view at the American Society of Clinical Oncology annual meeting in June.
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.
A Food and Drug Administration advisory panel will meet Sept. 19 to discuss the use of cell lines derived from human tumors to manufacture vaccines.
The Vaccines and Related Biological Products Advisory Committee meeting comes as several therapeutic cancer vaccines derived from tumor cell lines are in phase III trials. As applications come in, the agency must determine how to address issues such as genetic stability and product characterization.
NovaRx Corp. reported June 20 that it has completed enrollment in its phase III clinical trial of belagenpumatucel-L (Lucanix), a whole-tumor cell vaccine for non–small cell lung cancer.The first interim analysis of overall survival will occur in the third quarter of 2012. If the independent data-monitoring committee finds that the trial meets statistical significance for the prespecified end points, the company anticipates filing a Biologics License Application (BLA) based on those results.
The allogeneic vaccine is composed of human tumor cells modified to block production of transforming growth factor–beta (TGF-beta). Tumors use TGF-beta to hide from the immune system, so blocking production allows the initiation of strong immune responses to the tumor, according to the company.
Another whole-tumor cell vaccine, algenpantucel-L (HyperAcute Pancreas) from NewLink Genetics Corp., is in phase III trials with stages I and II surgically resected pancreatic cancer patients. Those trials reached the midpoint of enrollment in the second quarter, the company said on June 19.The first interim analysis of data is expected in early 2013.
Algenpantucel- L contains two allogeneic pancreatic cancer tumor cell lines that were modified to express alpha-gal. Each cell line provides a broad range of pancreatic cancer antigens to the vaccine, which is administered by intradermal injection. Phase III patients receive a series of up to 18 treatments over a period of about 6 months, followed by monthly maintenance treatments for 6 months. The primary end point of the trial is overall survival.
The modified cell lines are grown in large cultures, then harvested, irradiated, and packaged, with about 150 million cells of each delivered with each treatment.
An advantage to the whole-tumor cell vaccines is that they are off the shelf, facilitating manufacturing to fit demand and lowering production costs.
This contrasts with autologous vaccines that are customized for each patient. Dendreon Corp. has faced slow sales for its prostate cancer vaccine sipuleucel-T (Provenge), the first therapeutic cancer vaccine to gain FDA approval, largely because of cost and manufacturing complexity.
Encouraged by sipuleucel-T’s approval and undaunted by its slow sales, several autologous vaccines featuring different technologies were on view at the American Society of Clinical Oncology annual meeting in June.
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.
Obesity Drugs' CV Risk Assessment Needs Hard End Points
An end point that involves objectively determinable events is the best way to assess cardiovascular outcomes for obesity drugs, committee members of the Endocrinologic and Metabolic Drugs Advisory Committee agreed at the panel’s March 29 meeting.
But if a cardiovascular outcomes trial (CVOT) has two analysis time points – one prior to approval and one after approval – an end point that includes more subjectively determined events could be used in the early assessment, the two statisticians on the panel agreed.
The assessment of a suitable end point came during a full day of discussion about when and how CV outcome trials should be conducted for weight-loss drugs.
On the previous day, the panel heard presentations from the Food and Drug Administration and a series of guest speakers on the disease, current therapies, past trials, and agency guidance for assessing the CV safety of diabetes drugs. The diabetes guidance calls for a meta-analysis of phase II and III results to look at CV risk, with an outcomes trial required before approval, after approval, or not at all, depending on what the meta-analysis finds.
On the lone voting question the FDA put to the panel, members agreed 17-6 that sponsors should conduct a meta-analysis or CVOT for drugs that do not have a theoretic risk or signal for CV harm. In explaining their yes votes, 13 members said that a two-stage assessment process would be acceptable. This would involve one assessment before approval and the second post approval.
FDA officials had already assured panel members that outcomes trials must be conducted pre-approval for obesity drugs that do have a CV signal. The issue of the appropriate end point arose in the context of design parameters for those studies.
The panel was asked whether the primary end point should be major adverse cardiovascular events (MACE) – identified as CV death, nonfatal myocardial infarction, and nonfatal stroke – or MACE-Plus, which includes those events and others, such as hospitalized unstable angina and emergency coronary revascularization.
Noise a Problem With More Subjective CV Events
Expanding the MACE composite end point could result in more CV events, facilitating the detection of a safety signal. Panel members, however, were concerned about the statistical "noise" created by including events that are determined by a physician’s judgment and are not objectively measured.
Gaining the additional events may not be worth it, Dr. William O. Cooper of Vanderbilt University in Nashville, Tenn., pointed out. Hospitalization for angina could depend on whether the patient is very vocal about his or her condition or has access to health care or who the treating physician is. The additional events "are much more subjective, and I think we’d have difficulty both in terms of adjudication and what they might mean," he said.
Enrichment of a study to find a signal is desirable, noted Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, but "minimizing or reducing bias is equally desirable, if not more so. And if you add end points that are somewhat subjective ... you’re adding noise and thereby biasing the results toward the null, which will drive you to a false sense of reassurance about ruling out cardiovascular risk."
Limiting the end point to MACE, whose ascertainment and adjudication is less subjective, "is the way to go," he said. If more events are desired, he suggested using objective end points that can be standardized and adjudicated and are less prone to bias, such as ischemia-driven revascularization.
"If there are other end points that might be impacted by the test drug, it might make sense to assess them in an additional analysis, but not as part of an expanded MACE," said Dr. John H. Alexander of Duke University in Durham, N.C. "As a general rule, I would stick to MACE as our main end point."
Two-Step Analysis Can Use Two End Points
The panel previously discussed the two-stage assessment process for drugs with a CV signal. Dr. Allison B. Goldfine of the Joslin Diabetes Center in Boston suggested that if this option were used, the end point could be different in the preapproval and postapproval analyses.
"When you’re setting up your preapproval [study], you really want the larger safety net and the larger number of observations of events to actually help inform about potential risk," she said. "Within the preapproval window, I would be more inclined to allow documented ischemia or ischemia-driven revascularization" as part of a MACE-Plus end point.
Expanding MACE to include events along the same pathophysiological pathways would facilitate acquiring the number of events needed to assess safety, Dr. Goldfine noted. There would be the potential for noise, but investigators would still have a good idea of the safety signal. The analysis after approval would use "only the harder MACE," she suggested, asking the panel’s statisticians for input.
"That makes perfect sense to me. I’ll go along with that," said Dr. Michael A. Proschan of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. That "sounds like a reasonable idea," Erica Brittain, Ph.D., also of NIAID, agreed.
Cathy Dombrowski is with "The Pink Sheet." Both this news organization and "The Pink Sheet" are owned by Elsevier.
cardiovascular outcomes trial, CVOT, diabetes, major adverse cardiovascular events, nonfatal myocardial infarction, nonfatal stroke
An end point that involves objectively determinable events is the best way to assess cardiovascular outcomes for obesity drugs, committee members of the Endocrinologic and Metabolic Drugs Advisory Committee agreed at the panel’s March 29 meeting.
But if a cardiovascular outcomes trial (CVOT) has two analysis time points – one prior to approval and one after approval – an end point that includes more subjectively determined events could be used in the early assessment, the two statisticians on the panel agreed.
The assessment of a suitable end point came during a full day of discussion about when and how CV outcome trials should be conducted for weight-loss drugs.
On the previous day, the panel heard presentations from the Food and Drug Administration and a series of guest speakers on the disease, current therapies, past trials, and agency guidance for assessing the CV safety of diabetes drugs. The diabetes guidance calls for a meta-analysis of phase II and III results to look at CV risk, with an outcomes trial required before approval, after approval, or not at all, depending on what the meta-analysis finds.
On the lone voting question the FDA put to the panel, members agreed 17-6 that sponsors should conduct a meta-analysis or CVOT for drugs that do not have a theoretic risk or signal for CV harm. In explaining their yes votes, 13 members said that a two-stage assessment process would be acceptable. This would involve one assessment before approval and the second post approval.
FDA officials had already assured panel members that outcomes trials must be conducted pre-approval for obesity drugs that do have a CV signal. The issue of the appropriate end point arose in the context of design parameters for those studies.
The panel was asked whether the primary end point should be major adverse cardiovascular events (MACE) – identified as CV death, nonfatal myocardial infarction, and nonfatal stroke – or MACE-Plus, which includes those events and others, such as hospitalized unstable angina and emergency coronary revascularization.
Noise a Problem With More Subjective CV Events
Expanding the MACE composite end point could result in more CV events, facilitating the detection of a safety signal. Panel members, however, were concerned about the statistical "noise" created by including events that are determined by a physician’s judgment and are not objectively measured.
Gaining the additional events may not be worth it, Dr. William O. Cooper of Vanderbilt University in Nashville, Tenn., pointed out. Hospitalization for angina could depend on whether the patient is very vocal about his or her condition or has access to health care or who the treating physician is. The additional events "are much more subjective, and I think we’d have difficulty both in terms of adjudication and what they might mean," he said.
Enrichment of a study to find a signal is desirable, noted Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, but "minimizing or reducing bias is equally desirable, if not more so. And if you add end points that are somewhat subjective ... you’re adding noise and thereby biasing the results toward the null, which will drive you to a false sense of reassurance about ruling out cardiovascular risk."
Limiting the end point to MACE, whose ascertainment and adjudication is less subjective, "is the way to go," he said. If more events are desired, he suggested using objective end points that can be standardized and adjudicated and are less prone to bias, such as ischemia-driven revascularization.
"If there are other end points that might be impacted by the test drug, it might make sense to assess them in an additional analysis, but not as part of an expanded MACE," said Dr. John H. Alexander of Duke University in Durham, N.C. "As a general rule, I would stick to MACE as our main end point."
Two-Step Analysis Can Use Two End Points
The panel previously discussed the two-stage assessment process for drugs with a CV signal. Dr. Allison B. Goldfine of the Joslin Diabetes Center in Boston suggested that if this option were used, the end point could be different in the preapproval and postapproval analyses.
"When you’re setting up your preapproval [study], you really want the larger safety net and the larger number of observations of events to actually help inform about potential risk," she said. "Within the preapproval window, I would be more inclined to allow documented ischemia or ischemia-driven revascularization" as part of a MACE-Plus end point.
Expanding MACE to include events along the same pathophysiological pathways would facilitate acquiring the number of events needed to assess safety, Dr. Goldfine noted. There would be the potential for noise, but investigators would still have a good idea of the safety signal. The analysis after approval would use "only the harder MACE," she suggested, asking the panel’s statisticians for input.
"That makes perfect sense to me. I’ll go along with that," said Dr. Michael A. Proschan of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. That "sounds like a reasonable idea," Erica Brittain, Ph.D., also of NIAID, agreed.
Cathy Dombrowski is with "The Pink Sheet." Both this news organization and "The Pink Sheet" are owned by Elsevier.
An end point that involves objectively determinable events is the best way to assess cardiovascular outcomes for obesity drugs, committee members of the Endocrinologic and Metabolic Drugs Advisory Committee agreed at the panel’s March 29 meeting.
But if a cardiovascular outcomes trial (CVOT) has two analysis time points – one prior to approval and one after approval – an end point that includes more subjectively determined events could be used in the early assessment, the two statisticians on the panel agreed.
The assessment of a suitable end point came during a full day of discussion about when and how CV outcome trials should be conducted for weight-loss drugs.
On the previous day, the panel heard presentations from the Food and Drug Administration and a series of guest speakers on the disease, current therapies, past trials, and agency guidance for assessing the CV safety of diabetes drugs. The diabetes guidance calls for a meta-analysis of phase II and III results to look at CV risk, with an outcomes trial required before approval, after approval, or not at all, depending on what the meta-analysis finds.
On the lone voting question the FDA put to the panel, members agreed 17-6 that sponsors should conduct a meta-analysis or CVOT for drugs that do not have a theoretic risk or signal for CV harm. In explaining their yes votes, 13 members said that a two-stage assessment process would be acceptable. This would involve one assessment before approval and the second post approval.
FDA officials had already assured panel members that outcomes trials must be conducted pre-approval for obesity drugs that do have a CV signal. The issue of the appropriate end point arose in the context of design parameters for those studies.
The panel was asked whether the primary end point should be major adverse cardiovascular events (MACE) – identified as CV death, nonfatal myocardial infarction, and nonfatal stroke – or MACE-Plus, which includes those events and others, such as hospitalized unstable angina and emergency coronary revascularization.
Noise a Problem With More Subjective CV Events
Expanding the MACE composite end point could result in more CV events, facilitating the detection of a safety signal. Panel members, however, were concerned about the statistical "noise" created by including events that are determined by a physician’s judgment and are not objectively measured.
Gaining the additional events may not be worth it, Dr. William O. Cooper of Vanderbilt University in Nashville, Tenn., pointed out. Hospitalization for angina could depend on whether the patient is very vocal about his or her condition or has access to health care or who the treating physician is. The additional events "are much more subjective, and I think we’d have difficulty both in terms of adjudication and what they might mean," he said.
Enrichment of a study to find a signal is desirable, noted Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, but "minimizing or reducing bias is equally desirable, if not more so. And if you add end points that are somewhat subjective ... you’re adding noise and thereby biasing the results toward the null, which will drive you to a false sense of reassurance about ruling out cardiovascular risk."
Limiting the end point to MACE, whose ascertainment and adjudication is less subjective, "is the way to go," he said. If more events are desired, he suggested using objective end points that can be standardized and adjudicated and are less prone to bias, such as ischemia-driven revascularization.
"If there are other end points that might be impacted by the test drug, it might make sense to assess them in an additional analysis, but not as part of an expanded MACE," said Dr. John H. Alexander of Duke University in Durham, N.C. "As a general rule, I would stick to MACE as our main end point."
Two-Step Analysis Can Use Two End Points
The panel previously discussed the two-stage assessment process for drugs with a CV signal. Dr. Allison B. Goldfine of the Joslin Diabetes Center in Boston suggested that if this option were used, the end point could be different in the preapproval and postapproval analyses.
"When you’re setting up your preapproval [study], you really want the larger safety net and the larger number of observations of events to actually help inform about potential risk," she said. "Within the preapproval window, I would be more inclined to allow documented ischemia or ischemia-driven revascularization" as part of a MACE-Plus end point.
Expanding MACE to include events along the same pathophysiological pathways would facilitate acquiring the number of events needed to assess safety, Dr. Goldfine noted. There would be the potential for noise, but investigators would still have a good idea of the safety signal. The analysis after approval would use "only the harder MACE," she suggested, asking the panel’s statisticians for input.
"That makes perfect sense to me. I’ll go along with that," said Dr. Michael A. Proschan of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. That "sounds like a reasonable idea," Erica Brittain, Ph.D., also of NIAID, agreed.
Cathy Dombrowski is with "The Pink Sheet." Both this news organization and "The Pink Sheet" are owned by Elsevier.
cardiovascular outcomes trial, CVOT, diabetes, major adverse cardiovascular events, nonfatal myocardial infarction, nonfatal stroke
cardiovascular outcomes trial, CVOT, diabetes, major adverse cardiovascular events, nonfatal myocardial infarction, nonfatal stroke
FROM A MEETING OF THE FDA'S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE
FDA Says Weight Loss Drug Needs CV Outcome Trial
The Food and Drug Administration has concluded that a long-term cardiovascular outcome study is necessary to determine the cardiovascular safety of weight loss drug Qnexa (phentermine/topiramate) – and the agency is asking the Endocrinologic and Metabolic Drugs Advisory Committee Feb. 22 for input on whether the study should be conducted before or after approval.
Studies of the drug to date have involved mostly overweight and obese patients with low to moderate baseline cardiovascular (CV) risk, the agency explained in briefing documents for the meeting. As a result, the agency concluded, "it is unknown what the clinical significance of [phentermine/topiramate’s] cardiovascular effects and metabolic effects will be in a higher-risk cardiovascular population with chronic treatment."
Because of that, the agency concluded that "only a long-term, cardiovascular outcome trial can define the effect of [phentermine/topiramate’s] treatment on risk for major adverse cardiovascular events in an obese at-risk population."
When such a trial should be conducted is a discussion question for the panel.
Uncertainty about the cardiovascular safety of Vivus’s Qnexa contributed to a 10-6 vote against approval of the drug when it last went before the advisory committee in 2010.
Twelve of the 16 voting members from that panel will consider Qnexa this time around as well, according to the draft roster for the meeting. Six of the returnees voted in favor of approval in 2010 and six voted no. They will be joined by 10 new voting members.
Contrave CV Study Could Be a Clue
Even if the panel indicates that a postapproval cardiovascular study would be acceptable, that does not guarantee that the FDA will go along.
The agency directed Orexigen Therapeutics to study CV risk in Contrave, a combination of naltrexone and bupropion, in a preapproval trial, although an advisory panel voted 13-7 in favor of approving the drug. The committee voted 11-8, with 1 abstention, that a postmarketing CV trial would be acceptable.
After first announcing it would discontinue development of Contrave, Orexigen reached an agreement with the agency to move forward with an outcomes trial, under a special protocol assessment.
The study, as outlined by Orexigen, provides a glimpse into FDA thinking on what it currently is willing to accept in terms of CV safety in weight loss drugs. The Contrave trial is to enroll 10,000 patients overall, with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events. An interim analysis can be conducted when 87 major adverse CV events occur and serve as the basis for re-filing the Contrave new drug application. The company expects that to come within 2 years and after an enrollment of 7,000.
As for the acceptable risk threshold, the agreement on the Contrave trial is that the upper bound of the 95% confidence interval should exclude those with a risk of 2.0 at the interim and 1.4 at the final analysis. Any patient who does not achieve a predefined weight loss goal after 16 weeks of treatment will discontinue Contrave therapy.
Guidance for diabetes drugs calls on sponsors to exclude an 80% or higher increased risk of CV events before approval. Postapproval CV outcomes trials may be necessary if the risk ratio from a meta-analysis of phase II and phase III studies is between 1.3 and 1.8, but may not be required if the risk ratio is below 1.3.
Some members of the panel that reviewed Abbott Laboratories’ Meridia (sibutramine) in 2010 suggested that sponsors be required to rule out an unacceptable level of CV risk for investigational weight loss drugs similar to that for the diabetes treatments.
Advisory committee members pushed for obesity CV guidance throughout their 2010 reviews of four weight loss drugs, which also included Arena Pharmaceuticals’ Lorqess (lorcaserin).
A March 28-29 advisory committee on CV risk in obesity drugs will give panel members an opportunity to weigh in on an acceptable risk and should provide an indication of whether the FDA leans toward the risk level set out in the Contrave trial protocol or in the diabetes guidance.
One of the factors that prompted Orexigen to proceed with its study was the FDA’s agreement that any changes in its expectations with regard to CV safety for weight loss drugs would not affect how the agency will assess results from the Contrave study.
REMS for Teratogenicity Up for Debate
The potential teratogenicity of the topiramate component of Contrave was another factor in the "complete response" letter for the drug, but this issue seems more resolved than the cardiovascular safety issue. The company initially resubmitted for an indication excluding women of childbearing potential, but the FDA said a contraindication against women who are pregnant is sufficient.
Teratogenicity will be discussed at the committee review. The briefing materials note that preliminary results from three studies conducted since the previous advisory committee meeting "were consistent in demonstrating a lack of association between topiramate exposure and risk of major congenital malformations."
However, the agency points out that "depending on the analysis, topiramate monotherapy exposure in pregnancy is likely to be associated with a two- to fivefold increased prevalence of oral clefts."
The FDA is asking the committee to consider the risk of oral clefts in babies born to women taking topiramate and a proposed Qnexa risk evaluation and mitigation strategy (REMS).
The agency has proposed and the company has agreed to a REMS that includes certification of pharmacies that dispense the drug and voluntary training of health care providers to support their risk/benefit discussions with women of childbearing potential.
Certified pharmacies would be required to remind women of childbearing potential to use contraception and to test for pregnancy. The drug could be shipped directly to the patients or to a nearby pharmacy for pickup.
The FDA’s division of risk management suggested that restricted distribution of Qnexa with mandatory pregnancy testing would have limited impact because the same restrictions are not required when topiramate is used for seizures or migraine prophylaxis. Doctors also could bypass the REMS by prescribing the topiramate and phentermine individually, the division noted.
The impact on other topiramate prescriptions was a factor for the agency. To impose the same restrictions on topiramate used for epilepsy and migraine would impose an undue burden for patients with those conditions, the division said.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
The Food and Drug Administration has concluded that a long-term cardiovascular outcome study is necessary to determine the cardiovascular safety of weight loss drug Qnexa (phentermine/topiramate) – and the agency is asking the Endocrinologic and Metabolic Drugs Advisory Committee Feb. 22 for input on whether the study should be conducted before or after approval.
Studies of the drug to date have involved mostly overweight and obese patients with low to moderate baseline cardiovascular (CV) risk, the agency explained in briefing documents for the meeting. As a result, the agency concluded, "it is unknown what the clinical significance of [phentermine/topiramate’s] cardiovascular effects and metabolic effects will be in a higher-risk cardiovascular population with chronic treatment."
Because of that, the agency concluded that "only a long-term, cardiovascular outcome trial can define the effect of [phentermine/topiramate’s] treatment on risk for major adverse cardiovascular events in an obese at-risk population."
When such a trial should be conducted is a discussion question for the panel.
Uncertainty about the cardiovascular safety of Vivus’s Qnexa contributed to a 10-6 vote against approval of the drug when it last went before the advisory committee in 2010.
Twelve of the 16 voting members from that panel will consider Qnexa this time around as well, according to the draft roster for the meeting. Six of the returnees voted in favor of approval in 2010 and six voted no. They will be joined by 10 new voting members.
Contrave CV Study Could Be a Clue
Even if the panel indicates that a postapproval cardiovascular study would be acceptable, that does not guarantee that the FDA will go along.
The agency directed Orexigen Therapeutics to study CV risk in Contrave, a combination of naltrexone and bupropion, in a preapproval trial, although an advisory panel voted 13-7 in favor of approving the drug. The committee voted 11-8, with 1 abstention, that a postmarketing CV trial would be acceptable.
After first announcing it would discontinue development of Contrave, Orexigen reached an agreement with the agency to move forward with an outcomes trial, under a special protocol assessment.
The study, as outlined by Orexigen, provides a glimpse into FDA thinking on what it currently is willing to accept in terms of CV safety in weight loss drugs. The Contrave trial is to enroll 10,000 patients overall, with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events. An interim analysis can be conducted when 87 major adverse CV events occur and serve as the basis for re-filing the Contrave new drug application. The company expects that to come within 2 years and after an enrollment of 7,000.
As for the acceptable risk threshold, the agreement on the Contrave trial is that the upper bound of the 95% confidence interval should exclude those with a risk of 2.0 at the interim and 1.4 at the final analysis. Any patient who does not achieve a predefined weight loss goal after 16 weeks of treatment will discontinue Contrave therapy.
Guidance for diabetes drugs calls on sponsors to exclude an 80% or higher increased risk of CV events before approval. Postapproval CV outcomes trials may be necessary if the risk ratio from a meta-analysis of phase II and phase III studies is between 1.3 and 1.8, but may not be required if the risk ratio is below 1.3.
Some members of the panel that reviewed Abbott Laboratories’ Meridia (sibutramine) in 2010 suggested that sponsors be required to rule out an unacceptable level of CV risk for investigational weight loss drugs similar to that for the diabetes treatments.
Advisory committee members pushed for obesity CV guidance throughout their 2010 reviews of four weight loss drugs, which also included Arena Pharmaceuticals’ Lorqess (lorcaserin).
A March 28-29 advisory committee on CV risk in obesity drugs will give panel members an opportunity to weigh in on an acceptable risk and should provide an indication of whether the FDA leans toward the risk level set out in the Contrave trial protocol or in the diabetes guidance.
One of the factors that prompted Orexigen to proceed with its study was the FDA’s agreement that any changes in its expectations with regard to CV safety for weight loss drugs would not affect how the agency will assess results from the Contrave study.
REMS for Teratogenicity Up for Debate
The potential teratogenicity of the topiramate component of Contrave was another factor in the "complete response" letter for the drug, but this issue seems more resolved than the cardiovascular safety issue. The company initially resubmitted for an indication excluding women of childbearing potential, but the FDA said a contraindication against women who are pregnant is sufficient.
Teratogenicity will be discussed at the committee review. The briefing materials note that preliminary results from three studies conducted since the previous advisory committee meeting "were consistent in demonstrating a lack of association between topiramate exposure and risk of major congenital malformations."
However, the agency points out that "depending on the analysis, topiramate monotherapy exposure in pregnancy is likely to be associated with a two- to fivefold increased prevalence of oral clefts."
The FDA is asking the committee to consider the risk of oral clefts in babies born to women taking topiramate and a proposed Qnexa risk evaluation and mitigation strategy (REMS).
The agency has proposed and the company has agreed to a REMS that includes certification of pharmacies that dispense the drug and voluntary training of health care providers to support their risk/benefit discussions with women of childbearing potential.
Certified pharmacies would be required to remind women of childbearing potential to use contraception and to test for pregnancy. The drug could be shipped directly to the patients or to a nearby pharmacy for pickup.
The FDA’s division of risk management suggested that restricted distribution of Qnexa with mandatory pregnancy testing would have limited impact because the same restrictions are not required when topiramate is used for seizures or migraine prophylaxis. Doctors also could bypass the REMS by prescribing the topiramate and phentermine individually, the division noted.
The impact on other topiramate prescriptions was a factor for the agency. To impose the same restrictions on topiramate used for epilepsy and migraine would impose an undue burden for patients with those conditions, the division said.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
The Food and Drug Administration has concluded that a long-term cardiovascular outcome study is necessary to determine the cardiovascular safety of weight loss drug Qnexa (phentermine/topiramate) – and the agency is asking the Endocrinologic and Metabolic Drugs Advisory Committee Feb. 22 for input on whether the study should be conducted before or after approval.
Studies of the drug to date have involved mostly overweight and obese patients with low to moderate baseline cardiovascular (CV) risk, the agency explained in briefing documents for the meeting. As a result, the agency concluded, "it is unknown what the clinical significance of [phentermine/topiramate’s] cardiovascular effects and metabolic effects will be in a higher-risk cardiovascular population with chronic treatment."
Because of that, the agency concluded that "only a long-term, cardiovascular outcome trial can define the effect of [phentermine/topiramate’s] treatment on risk for major adverse cardiovascular events in an obese at-risk population."
When such a trial should be conducted is a discussion question for the panel.
Uncertainty about the cardiovascular safety of Vivus’s Qnexa contributed to a 10-6 vote against approval of the drug when it last went before the advisory committee in 2010.
Twelve of the 16 voting members from that panel will consider Qnexa this time around as well, according to the draft roster for the meeting. Six of the returnees voted in favor of approval in 2010 and six voted no. They will be joined by 10 new voting members.
Contrave CV Study Could Be a Clue
Even if the panel indicates that a postapproval cardiovascular study would be acceptable, that does not guarantee that the FDA will go along.
The agency directed Orexigen Therapeutics to study CV risk in Contrave, a combination of naltrexone and bupropion, in a preapproval trial, although an advisory panel voted 13-7 in favor of approving the drug. The committee voted 11-8, with 1 abstention, that a postmarketing CV trial would be acceptable.
After first announcing it would discontinue development of Contrave, Orexigen reached an agreement with the agency to move forward with an outcomes trial, under a special protocol assessment.
The study, as outlined by Orexigen, provides a glimpse into FDA thinking on what it currently is willing to accept in terms of CV safety in weight loss drugs. The Contrave trial is to enroll 10,000 patients overall, with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events. An interim analysis can be conducted when 87 major adverse CV events occur and serve as the basis for re-filing the Contrave new drug application. The company expects that to come within 2 years and after an enrollment of 7,000.
As for the acceptable risk threshold, the agreement on the Contrave trial is that the upper bound of the 95% confidence interval should exclude those with a risk of 2.0 at the interim and 1.4 at the final analysis. Any patient who does not achieve a predefined weight loss goal after 16 weeks of treatment will discontinue Contrave therapy.
Guidance for diabetes drugs calls on sponsors to exclude an 80% or higher increased risk of CV events before approval. Postapproval CV outcomes trials may be necessary if the risk ratio from a meta-analysis of phase II and phase III studies is between 1.3 and 1.8, but may not be required if the risk ratio is below 1.3.
Some members of the panel that reviewed Abbott Laboratories’ Meridia (sibutramine) in 2010 suggested that sponsors be required to rule out an unacceptable level of CV risk for investigational weight loss drugs similar to that for the diabetes treatments.
Advisory committee members pushed for obesity CV guidance throughout their 2010 reviews of four weight loss drugs, which also included Arena Pharmaceuticals’ Lorqess (lorcaserin).
A March 28-29 advisory committee on CV risk in obesity drugs will give panel members an opportunity to weigh in on an acceptable risk and should provide an indication of whether the FDA leans toward the risk level set out in the Contrave trial protocol or in the diabetes guidance.
One of the factors that prompted Orexigen to proceed with its study was the FDA’s agreement that any changes in its expectations with regard to CV safety for weight loss drugs would not affect how the agency will assess results from the Contrave study.
REMS for Teratogenicity Up for Debate
The potential teratogenicity of the topiramate component of Contrave was another factor in the "complete response" letter for the drug, but this issue seems more resolved than the cardiovascular safety issue. The company initially resubmitted for an indication excluding women of childbearing potential, but the FDA said a contraindication against women who are pregnant is sufficient.
Teratogenicity will be discussed at the committee review. The briefing materials note that preliminary results from three studies conducted since the previous advisory committee meeting "were consistent in demonstrating a lack of association between topiramate exposure and risk of major congenital malformations."
However, the agency points out that "depending on the analysis, topiramate monotherapy exposure in pregnancy is likely to be associated with a two- to fivefold increased prevalence of oral clefts."
The FDA is asking the committee to consider the risk of oral clefts in babies born to women taking topiramate and a proposed Qnexa risk evaluation and mitigation strategy (REMS).
The agency has proposed and the company has agreed to a REMS that includes certification of pharmacies that dispense the drug and voluntary training of health care providers to support their risk/benefit discussions with women of childbearing potential.
Certified pharmacies would be required to remind women of childbearing potential to use contraception and to test for pregnancy. The drug could be shipped directly to the patients or to a nearby pharmacy for pickup.
The FDA’s division of risk management suggested that restricted distribution of Qnexa with mandatory pregnancy testing would have limited impact because the same restrictions are not required when topiramate is used for seizures or migraine prophylaxis. Doctors also could bypass the REMS by prescribing the topiramate and phentermine individually, the division noted.
The impact on other topiramate prescriptions was a factor for the agency. To impose the same restrictions on topiramate used for epilepsy and migraine would impose an undue burden for patients with those conditions, the division said.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
FDA Questions Earlier Denosumab Use in Prostate Cancer
The Food and Drug Administration questions whether an additional indication for denosumab to delay bone metastases in men with castrate-resistant prostate cancer who are at high risk for such metastases would provide benefit beyond that seen with the current use of denosumab to prevent skeletal-related events in solid tumors metastatic to bone.
The pivotal trial (20050147) for the castrate-resistant prostate cancer (CRPC) indication was not designed to demonstrate that administering "denosumab prior to the development of osseous metastases would add to the clinical benefit already established for denosumab" in preventing skeletal-related events (SREs) in metastatic disease, the FDA says in briefing materials for a Feb. 8 Oncologic Drugs Advisory Committee meeting.
The indication for the drug (marketed as Xgeva by Amgen Inc.) to be discussed by the panel is "for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases. Xgeva prolongs bone metastasis–free survival by reducing the risk of developing bone metastases." The FDA approved Xgeva for the prevention of SREs in late 2010.
To find clinically meaningful benefit for the new indication, a study would have to compare the clinical benefits of continuous denosumab treatment of the CRPC target population with the benefits of treatment only after bone metastasis occurs, the FDA suggests.
In such a trial, the agency notes, an appropriate end point would be designed to assess a meaningful clinical benefit, such as prevention of SREs.
"If denosumab administered to patients with CRPC (at high risk for bone metastases) does not add to the benefit observed in patients who have metastatic disease, then patients will only be exposed to the increased risks of the drug," the agency points out.
In its briefing materials, Amgen says the benefit of the bone metastasis–free survival (BMFS) indication "is complementary to and consistent" with the benefit of preventing SREs in metastatic CRPC. It "allows physicians the opportunity to intervene earlier in the prostate cancer treatment continuum to prevent the significant morbidity associated with bone metastases," the company contends.
More Risk With Longer Exposure
The FDA expressed concern that treatment to delay bone metastasis would extend patient exposure to denosumab and increase the risk for osteonecrosis of the jaw (ONJ), a major safety concern with the biologic.
As confirmed by an adjudication committee, ONJ occurred in 33 (or 4.6%) of the denosumab-treated patients and in none of the placebo patients during the primary analysis phase of study 20050147. In the follow-up of patients through the extended blinded treatment phase, overall incidence of ONJ was 5.4% in the denosumab-treated patients.
These figures are higher than those in study 20050103, a prostate cancer trial that supported Xgeva’s indication for SRE prevention. Median duration of exposure in the two trials was 19.3 months in 20050147 vs. 11.9 months in 20050103.
The 20050147 results "suggest the possibility that the risk of ONJ increases with increasing exposure to denosumab as Xgeva, and that continued long-term exposure may increase the ONJ rate to a level that off-sets the risk/benefit profile for the SRE indication in patients with prostate cancer," the FDA points out.
A 120-day safety update reported another six patients with ONJ events among the 100 patients in the denosumab arm of the open-label extension phase of study 20050147.
What’s An Appropriate Surrogate for Benefit?
Use of bone metastasis–free survival as the basis for drug approval or a labeling claim would set a precedent, and the FDA will ask the panel to weigh in on whether the end point is either a surrogate for clinical benefit or a direct clinical benefit.
The agency’s opinion is that "available data with denosumab do not support a conclusion that BMFS is a surrogate [end point] for OS [overall survival]".
The two prostate cancer trials did not show a treatment effect for denosumab on overall survival or on progression-free survival, and there was no improvement in PSA over time vs. placebo in the pivotal trial for BMFS, the FDA says.
"Ultimately, an application with BMFS as a primary end point would be strengthened by findings that also demonstrate an improvement in the time to SREs or a substantial improvement in quality of life (especially related to clinically relevant pain scores)," the FDA says.
Is Magnitude of Effect Large Enough?
Even if BMSF were considered a meaningful benefit, the FDA will ask the panel to consider whether the magnitude of BMFS seen in study 20050147 is sufficient to conclude that Xgeva has a favorable risk/benefit profile in CRPC patients who are at high risk for bone metastases.
In the trial, patients receiving Xgeva had a median time to bone metastases of 29.5 months, compared to 25.2 months for placebo patients. This 4.2-month improvement in median BMFS was statistically significant, and resulted in a hazard ratio of 0.85 (95% confidence interval, 0.73-0.98). Overall survival was similar between treatment arms; the effect on PFS was not statistically significant.
Study 20050147 was a randomized, double-blind, placebo-controlled multicenter study in men who had either a PSA level of at least 8 ng/mL or a PSA doubling time no greater than 10 months. Xgeva patients received 120 mg subcutaneously every 4 weeks. The primary end point was BMFS (defined as time to first occurrence of bone metastasis) or death from any cause. Secondary end points, tested sequentially if the previous end point was statistically significant, were time to first bone metastasis (symptomatic or asymptomatic) and overall survival. Metastases were monitored by imaging.
The rate of improvement is smaller than that proposed as sufficient evidence of benefit for a drug in nonmetastatic CRPC by some ODAC members at a September 2011 meeting, the FDA points out. During that panel session (which was a general discussion of prostate cancer treatments), Brent Logan, Ph.D., of the Medical College of Wisconsin, Milwaukee, suggested that benefit from a delay in bone metastasis depends on the length of the delay and a therapy’s toxicity.
Although the FDA voiced several concerns about the CPRC indication for Xgeva, the only voting question to ODAC is whether the biologic has "a favorable risk/benefit evaluation for the treatment of castrate-resistant prostate cancer at high risk for metastasis."
"The primary issue of this ODAC is whether BMFS of this magnitude represents clinical benefit, especially in context with the toxicities of therapy and the benefit already observed in patients diagnosed with bone metastases," the briefing materials note.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration questions whether an additional indication for denosumab to delay bone metastases in men with castrate-resistant prostate cancer who are at high risk for such metastases would provide benefit beyond that seen with the current use of denosumab to prevent skeletal-related events in solid tumors metastatic to bone.
The pivotal trial (20050147) for the castrate-resistant prostate cancer (CRPC) indication was not designed to demonstrate that administering "denosumab prior to the development of osseous metastases would add to the clinical benefit already established for denosumab" in preventing skeletal-related events (SREs) in metastatic disease, the FDA says in briefing materials for a Feb. 8 Oncologic Drugs Advisory Committee meeting.
The indication for the drug (marketed as Xgeva by Amgen Inc.) to be discussed by the panel is "for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases. Xgeva prolongs bone metastasis–free survival by reducing the risk of developing bone metastases." The FDA approved Xgeva for the prevention of SREs in late 2010.
To find clinically meaningful benefit for the new indication, a study would have to compare the clinical benefits of continuous denosumab treatment of the CRPC target population with the benefits of treatment only after bone metastasis occurs, the FDA suggests.
In such a trial, the agency notes, an appropriate end point would be designed to assess a meaningful clinical benefit, such as prevention of SREs.
"If denosumab administered to patients with CRPC (at high risk for bone metastases) does not add to the benefit observed in patients who have metastatic disease, then patients will only be exposed to the increased risks of the drug," the agency points out.
In its briefing materials, Amgen says the benefit of the bone metastasis–free survival (BMFS) indication "is complementary to and consistent" with the benefit of preventing SREs in metastatic CRPC. It "allows physicians the opportunity to intervene earlier in the prostate cancer treatment continuum to prevent the significant morbidity associated with bone metastases," the company contends.
More Risk With Longer Exposure
The FDA expressed concern that treatment to delay bone metastasis would extend patient exposure to denosumab and increase the risk for osteonecrosis of the jaw (ONJ), a major safety concern with the biologic.
As confirmed by an adjudication committee, ONJ occurred in 33 (or 4.6%) of the denosumab-treated patients and in none of the placebo patients during the primary analysis phase of study 20050147. In the follow-up of patients through the extended blinded treatment phase, overall incidence of ONJ was 5.4% in the denosumab-treated patients.
These figures are higher than those in study 20050103, a prostate cancer trial that supported Xgeva’s indication for SRE prevention. Median duration of exposure in the two trials was 19.3 months in 20050147 vs. 11.9 months in 20050103.
The 20050147 results "suggest the possibility that the risk of ONJ increases with increasing exposure to denosumab as Xgeva, and that continued long-term exposure may increase the ONJ rate to a level that off-sets the risk/benefit profile for the SRE indication in patients with prostate cancer," the FDA points out.
A 120-day safety update reported another six patients with ONJ events among the 100 patients in the denosumab arm of the open-label extension phase of study 20050147.
What’s An Appropriate Surrogate for Benefit?
Use of bone metastasis–free survival as the basis for drug approval or a labeling claim would set a precedent, and the FDA will ask the panel to weigh in on whether the end point is either a surrogate for clinical benefit or a direct clinical benefit.
The agency’s opinion is that "available data with denosumab do not support a conclusion that BMFS is a surrogate [end point] for OS [overall survival]".
The two prostate cancer trials did not show a treatment effect for denosumab on overall survival or on progression-free survival, and there was no improvement in PSA over time vs. placebo in the pivotal trial for BMFS, the FDA says.
"Ultimately, an application with BMFS as a primary end point would be strengthened by findings that also demonstrate an improvement in the time to SREs or a substantial improvement in quality of life (especially related to clinically relevant pain scores)," the FDA says.
Is Magnitude of Effect Large Enough?
Even if BMSF were considered a meaningful benefit, the FDA will ask the panel to consider whether the magnitude of BMFS seen in study 20050147 is sufficient to conclude that Xgeva has a favorable risk/benefit profile in CRPC patients who are at high risk for bone metastases.
In the trial, patients receiving Xgeva had a median time to bone metastases of 29.5 months, compared to 25.2 months for placebo patients. This 4.2-month improvement in median BMFS was statistically significant, and resulted in a hazard ratio of 0.85 (95% confidence interval, 0.73-0.98). Overall survival was similar between treatment arms; the effect on PFS was not statistically significant.
Study 20050147 was a randomized, double-blind, placebo-controlled multicenter study in men who had either a PSA level of at least 8 ng/mL or a PSA doubling time no greater than 10 months. Xgeva patients received 120 mg subcutaneously every 4 weeks. The primary end point was BMFS (defined as time to first occurrence of bone metastasis) or death from any cause. Secondary end points, tested sequentially if the previous end point was statistically significant, were time to first bone metastasis (symptomatic or asymptomatic) and overall survival. Metastases were monitored by imaging.
The rate of improvement is smaller than that proposed as sufficient evidence of benefit for a drug in nonmetastatic CRPC by some ODAC members at a September 2011 meeting, the FDA points out. During that panel session (which was a general discussion of prostate cancer treatments), Brent Logan, Ph.D., of the Medical College of Wisconsin, Milwaukee, suggested that benefit from a delay in bone metastasis depends on the length of the delay and a therapy’s toxicity.
Although the FDA voiced several concerns about the CPRC indication for Xgeva, the only voting question to ODAC is whether the biologic has "a favorable risk/benefit evaluation for the treatment of castrate-resistant prostate cancer at high risk for metastasis."
"The primary issue of this ODAC is whether BMFS of this magnitude represents clinical benefit, especially in context with the toxicities of therapy and the benefit already observed in patients diagnosed with bone metastases," the briefing materials note.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration questions whether an additional indication for denosumab to delay bone metastases in men with castrate-resistant prostate cancer who are at high risk for such metastases would provide benefit beyond that seen with the current use of denosumab to prevent skeletal-related events in solid tumors metastatic to bone.
The pivotal trial (20050147) for the castrate-resistant prostate cancer (CRPC) indication was not designed to demonstrate that administering "denosumab prior to the development of osseous metastases would add to the clinical benefit already established for denosumab" in preventing skeletal-related events (SREs) in metastatic disease, the FDA says in briefing materials for a Feb. 8 Oncologic Drugs Advisory Committee meeting.
The indication for the drug (marketed as Xgeva by Amgen Inc.) to be discussed by the panel is "for the treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases. Xgeva prolongs bone metastasis–free survival by reducing the risk of developing bone metastases." The FDA approved Xgeva for the prevention of SREs in late 2010.
To find clinically meaningful benefit for the new indication, a study would have to compare the clinical benefits of continuous denosumab treatment of the CRPC target population with the benefits of treatment only after bone metastasis occurs, the FDA suggests.
In such a trial, the agency notes, an appropriate end point would be designed to assess a meaningful clinical benefit, such as prevention of SREs.
"If denosumab administered to patients with CRPC (at high risk for bone metastases) does not add to the benefit observed in patients who have metastatic disease, then patients will only be exposed to the increased risks of the drug," the agency points out.
In its briefing materials, Amgen says the benefit of the bone metastasis–free survival (BMFS) indication "is complementary to and consistent" with the benefit of preventing SREs in metastatic CRPC. It "allows physicians the opportunity to intervene earlier in the prostate cancer treatment continuum to prevent the significant morbidity associated with bone metastases," the company contends.
More Risk With Longer Exposure
The FDA expressed concern that treatment to delay bone metastasis would extend patient exposure to denosumab and increase the risk for osteonecrosis of the jaw (ONJ), a major safety concern with the biologic.
As confirmed by an adjudication committee, ONJ occurred in 33 (or 4.6%) of the denosumab-treated patients and in none of the placebo patients during the primary analysis phase of study 20050147. In the follow-up of patients through the extended blinded treatment phase, overall incidence of ONJ was 5.4% in the denosumab-treated patients.
These figures are higher than those in study 20050103, a prostate cancer trial that supported Xgeva’s indication for SRE prevention. Median duration of exposure in the two trials was 19.3 months in 20050147 vs. 11.9 months in 20050103.
The 20050147 results "suggest the possibility that the risk of ONJ increases with increasing exposure to denosumab as Xgeva, and that continued long-term exposure may increase the ONJ rate to a level that off-sets the risk/benefit profile for the SRE indication in patients with prostate cancer," the FDA points out.
A 120-day safety update reported another six patients with ONJ events among the 100 patients in the denosumab arm of the open-label extension phase of study 20050147.
What’s An Appropriate Surrogate for Benefit?
Use of bone metastasis–free survival as the basis for drug approval or a labeling claim would set a precedent, and the FDA will ask the panel to weigh in on whether the end point is either a surrogate for clinical benefit or a direct clinical benefit.
The agency’s opinion is that "available data with denosumab do not support a conclusion that BMFS is a surrogate [end point] for OS [overall survival]".
The two prostate cancer trials did not show a treatment effect for denosumab on overall survival or on progression-free survival, and there was no improvement in PSA over time vs. placebo in the pivotal trial for BMFS, the FDA says.
"Ultimately, an application with BMFS as a primary end point would be strengthened by findings that also demonstrate an improvement in the time to SREs or a substantial improvement in quality of life (especially related to clinically relevant pain scores)," the FDA says.
Is Magnitude of Effect Large Enough?
Even if BMSF were considered a meaningful benefit, the FDA will ask the panel to consider whether the magnitude of BMFS seen in study 20050147 is sufficient to conclude that Xgeva has a favorable risk/benefit profile in CRPC patients who are at high risk for bone metastases.
In the trial, patients receiving Xgeva had a median time to bone metastases of 29.5 months, compared to 25.2 months for placebo patients. This 4.2-month improvement in median BMFS was statistically significant, and resulted in a hazard ratio of 0.85 (95% confidence interval, 0.73-0.98). Overall survival was similar between treatment arms; the effect on PFS was not statistically significant.
Study 20050147 was a randomized, double-blind, placebo-controlled multicenter study in men who had either a PSA level of at least 8 ng/mL or a PSA doubling time no greater than 10 months. Xgeva patients received 120 mg subcutaneously every 4 weeks. The primary end point was BMFS (defined as time to first occurrence of bone metastasis) or death from any cause. Secondary end points, tested sequentially if the previous end point was statistically significant, were time to first bone metastasis (symptomatic or asymptomatic) and overall survival. Metastases were monitored by imaging.
The rate of improvement is smaller than that proposed as sufficient evidence of benefit for a drug in nonmetastatic CRPC by some ODAC members at a September 2011 meeting, the FDA points out. During that panel session (which was a general discussion of prostate cancer treatments), Brent Logan, Ph.D., of the Medical College of Wisconsin, Milwaukee, suggested that benefit from a delay in bone metastasis depends on the length of the delay and a therapy’s toxicity.
Although the FDA voiced several concerns about the CPRC indication for Xgeva, the only voting question to ODAC is whether the biologic has "a favorable risk/benefit evaluation for the treatment of castrate-resistant prostate cancer at high risk for metastasis."
"The primary issue of this ODAC is whether BMFS of this magnitude represents clinical benefit, especially in context with the toxicities of therapy and the benefit already observed in patients diagnosed with bone metastases," the briefing materials note.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
FDA Panel to Assess Azilect Trial Design
The Food and Drug Administration will ask its Peripheral and Central Nervous System Drugs Advisory Committee to weigh in Oct. 17 on whether a clinical trial with a randomized-start design, if appropriately designed and conducted, can detect a drug’s disease-modifying effect in patients with Parkinson’s disease.
Teva employed a randomized-start design in the Azilect (rasagiline mesylate) ADAGIO trial, its basis for seeking an indication as therapy to delay clinical disease progression in patients with Parkinson’s. The drug was approved in 2006 to treat the signs and symptoms of the disease.
FDA reviewers are skeptical that the trial demonstrated the efficacy of Azilect for the new indication, according to agency briefing documents.
But advisory committee support for the trial design could reassure industry and patient advocates that there is a way to demonstrate a medicine’s ability to delay disease progression, for which there currently is no biological marker.
Ralph D’Agostino, Ph.D., Boston University, noted that the design has "great promise" in a Sept. 24, 2009, editorial that accompanied the ADAGIO publication in the New England Journal of Medicine. Dr. D’Agostino is one of four biostatisticians FDA has appointed as a temporary voting member on the advisory committee to help address the statistical issues raised by agency reviewers.
The Trial Design
The randomized-start design is conducted in two steps. Patients are randomized to treatment or placebo for an appropriate duration, and then patients receiving placebo are switched to the active drug and those on the active drug continue treatment.
The interpretive principle is that a drug has a disease-modification effect if those in the treatment arm during the first phase continue to show greater treatment benefit than those who only initiate treatment in the second phase. The basis for this is that "early (longer) treatment provides a persistent benefit that cannot be achieved if treatment is delayed, presumably due to an effect on the underlying pathology that cannot be ‘re-captured,’" the FDA explains.
The briefing documents note that dropouts between the first and second phase of the trial can introduce complexity into analyses and interpretation of the data. Also, those entering the second phase "will no longer be randomized groups, making statistical comparisons treacherous."
ADAGIO was a multicenter, double-blind study in patients with early Parkinson’s. The treatment arms received either 1 mg/day or 2 mg/day of Azilect. There were two placebo arms in the first phase. In the second, the placebo arms were switched to either the 1-mg or the 2-mg dose. Both phases lasted 36 weeks.
Effects were measured based on changes in Unified Parkinson’s Disease Rating Scale scores. Analyses were conducted to determine: superiority of treatment compared with placebo at the end of 36 weeks; superiority at the end of 72 weeks for early start therapy compared with delayed start treatment; and noninferiority of early start to delayed start in the rate of change in the UPDRS score between weeks 48 and 72.
The last measurement was to ensure that there continued to be an "absolute" difference between the two groups at the end of the study and the levels of their improvement were not converging.
Per protocol, the analyses were to be based on all data from all groups combined. Teva, however, calculated the change from baseline to week 72 for each dose contrast, using data only from that dose.
These analyses found that patients who received 2 mg/day in the first phase received no statistically significantly greater benefit compared to those who initiated therapy in the second phase.
The company’s analysis found statistically significant differences in benefit between the two groups receiving 1 mg/day of Azilect. Analysis per protocol produces a P value of .0506, which, the agency points out, would not be considered significant.
Even if the company’s analysis were accepted for the 1-mg dose, the FDA says, there is no obvious biological explanation for why the 2-mg dose also was not beneficial at week 72. That finding "calls into question any ostensibly positive findings that might be the basis for a disease modifying claim for rasagiline."
Agency Issues With Analyses and Results
FDA reviewers identified a number of issues of concern with the analyses and results from ADAGIO and TEMPO, and will ask the panel to discuss them. TEMPO was the trial used to support Azilect’s original approval and is being offered as supporting evidence for the current supplemental application.
These issues are: sponsor-conducted analyses that differed from those specified in the protocol; a differential response in men and women and the baseline differences in early and delayed women starters in ADAGIO; potentially significant baseline differences in UPDRS scores between early-start and delayed-start patients in datasets used for analyses at 72 weeks, and potential biases introduced because these include nonrandomized groups; the nonlinearity of slopes that presumably are related to varying early effects of treatment; and re-analyses of slopes without early data suggest parallel slopes in the first phase for drug and placebo.
The FDA is asking the advisory committee to vote on whether ADAGIO provides "compelling" evidence that the 1-mg dose met the protocol-specified criteria for success, whether the 2-mg group failed to meet those criteria and whether there is substantial evidence of effectiveness for Azilect as therapy to delay clinical progression of Parkinson’s disease.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration will ask its Peripheral and Central Nervous System Drugs Advisory Committee to weigh in Oct. 17 on whether a clinical trial with a randomized-start design, if appropriately designed and conducted, can detect a drug’s disease-modifying effect in patients with Parkinson’s disease.
Teva employed a randomized-start design in the Azilect (rasagiline mesylate) ADAGIO trial, its basis for seeking an indication as therapy to delay clinical disease progression in patients with Parkinson’s. The drug was approved in 2006 to treat the signs and symptoms of the disease.
FDA reviewers are skeptical that the trial demonstrated the efficacy of Azilect for the new indication, according to agency briefing documents.
But advisory committee support for the trial design could reassure industry and patient advocates that there is a way to demonstrate a medicine’s ability to delay disease progression, for which there currently is no biological marker.
Ralph D’Agostino, Ph.D., Boston University, noted that the design has "great promise" in a Sept. 24, 2009, editorial that accompanied the ADAGIO publication in the New England Journal of Medicine. Dr. D’Agostino is one of four biostatisticians FDA has appointed as a temporary voting member on the advisory committee to help address the statistical issues raised by agency reviewers.
The Trial Design
The randomized-start design is conducted in two steps. Patients are randomized to treatment or placebo for an appropriate duration, and then patients receiving placebo are switched to the active drug and those on the active drug continue treatment.
The interpretive principle is that a drug has a disease-modification effect if those in the treatment arm during the first phase continue to show greater treatment benefit than those who only initiate treatment in the second phase. The basis for this is that "early (longer) treatment provides a persistent benefit that cannot be achieved if treatment is delayed, presumably due to an effect on the underlying pathology that cannot be ‘re-captured,’" the FDA explains.
The briefing documents note that dropouts between the first and second phase of the trial can introduce complexity into analyses and interpretation of the data. Also, those entering the second phase "will no longer be randomized groups, making statistical comparisons treacherous."
ADAGIO was a multicenter, double-blind study in patients with early Parkinson’s. The treatment arms received either 1 mg/day or 2 mg/day of Azilect. There were two placebo arms in the first phase. In the second, the placebo arms were switched to either the 1-mg or the 2-mg dose. Both phases lasted 36 weeks.
Effects were measured based on changes in Unified Parkinson’s Disease Rating Scale scores. Analyses were conducted to determine: superiority of treatment compared with placebo at the end of 36 weeks; superiority at the end of 72 weeks for early start therapy compared with delayed start treatment; and noninferiority of early start to delayed start in the rate of change in the UPDRS score between weeks 48 and 72.
The last measurement was to ensure that there continued to be an "absolute" difference between the two groups at the end of the study and the levels of their improvement were not converging.
Per protocol, the analyses were to be based on all data from all groups combined. Teva, however, calculated the change from baseline to week 72 for each dose contrast, using data only from that dose.
These analyses found that patients who received 2 mg/day in the first phase received no statistically significantly greater benefit compared to those who initiated therapy in the second phase.
The company’s analysis found statistically significant differences in benefit between the two groups receiving 1 mg/day of Azilect. Analysis per protocol produces a P value of .0506, which, the agency points out, would not be considered significant.
Even if the company’s analysis were accepted for the 1-mg dose, the FDA says, there is no obvious biological explanation for why the 2-mg dose also was not beneficial at week 72. That finding "calls into question any ostensibly positive findings that might be the basis for a disease modifying claim for rasagiline."
Agency Issues With Analyses and Results
FDA reviewers identified a number of issues of concern with the analyses and results from ADAGIO and TEMPO, and will ask the panel to discuss them. TEMPO was the trial used to support Azilect’s original approval and is being offered as supporting evidence for the current supplemental application.
These issues are: sponsor-conducted analyses that differed from those specified in the protocol; a differential response in men and women and the baseline differences in early and delayed women starters in ADAGIO; potentially significant baseline differences in UPDRS scores between early-start and delayed-start patients in datasets used for analyses at 72 weeks, and potential biases introduced because these include nonrandomized groups; the nonlinearity of slopes that presumably are related to varying early effects of treatment; and re-analyses of slopes without early data suggest parallel slopes in the first phase for drug and placebo.
The FDA is asking the advisory committee to vote on whether ADAGIO provides "compelling" evidence that the 1-mg dose met the protocol-specified criteria for success, whether the 2-mg group failed to meet those criteria and whether there is substantial evidence of effectiveness for Azilect as therapy to delay clinical progression of Parkinson’s disease.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration will ask its Peripheral and Central Nervous System Drugs Advisory Committee to weigh in Oct. 17 on whether a clinical trial with a randomized-start design, if appropriately designed and conducted, can detect a drug’s disease-modifying effect in patients with Parkinson’s disease.
Teva employed a randomized-start design in the Azilect (rasagiline mesylate) ADAGIO trial, its basis for seeking an indication as therapy to delay clinical disease progression in patients with Parkinson’s. The drug was approved in 2006 to treat the signs and symptoms of the disease.
FDA reviewers are skeptical that the trial demonstrated the efficacy of Azilect for the new indication, according to agency briefing documents.
But advisory committee support for the trial design could reassure industry and patient advocates that there is a way to demonstrate a medicine’s ability to delay disease progression, for which there currently is no biological marker.
Ralph D’Agostino, Ph.D., Boston University, noted that the design has "great promise" in a Sept. 24, 2009, editorial that accompanied the ADAGIO publication in the New England Journal of Medicine. Dr. D’Agostino is one of four biostatisticians FDA has appointed as a temporary voting member on the advisory committee to help address the statistical issues raised by agency reviewers.
The Trial Design
The randomized-start design is conducted in two steps. Patients are randomized to treatment or placebo for an appropriate duration, and then patients receiving placebo are switched to the active drug and those on the active drug continue treatment.
The interpretive principle is that a drug has a disease-modification effect if those in the treatment arm during the first phase continue to show greater treatment benefit than those who only initiate treatment in the second phase. The basis for this is that "early (longer) treatment provides a persistent benefit that cannot be achieved if treatment is delayed, presumably due to an effect on the underlying pathology that cannot be ‘re-captured,’" the FDA explains.
The briefing documents note that dropouts between the first and second phase of the trial can introduce complexity into analyses and interpretation of the data. Also, those entering the second phase "will no longer be randomized groups, making statistical comparisons treacherous."
ADAGIO was a multicenter, double-blind study in patients with early Parkinson’s. The treatment arms received either 1 mg/day or 2 mg/day of Azilect. There were two placebo arms in the first phase. In the second, the placebo arms were switched to either the 1-mg or the 2-mg dose. Both phases lasted 36 weeks.
Effects were measured based on changes in Unified Parkinson’s Disease Rating Scale scores. Analyses were conducted to determine: superiority of treatment compared with placebo at the end of 36 weeks; superiority at the end of 72 weeks for early start therapy compared with delayed start treatment; and noninferiority of early start to delayed start in the rate of change in the UPDRS score between weeks 48 and 72.
The last measurement was to ensure that there continued to be an "absolute" difference between the two groups at the end of the study and the levels of their improvement were not converging.
Per protocol, the analyses were to be based on all data from all groups combined. Teva, however, calculated the change from baseline to week 72 for each dose contrast, using data only from that dose.
These analyses found that patients who received 2 mg/day in the first phase received no statistically significantly greater benefit compared to those who initiated therapy in the second phase.
The company’s analysis found statistically significant differences in benefit between the two groups receiving 1 mg/day of Azilect. Analysis per protocol produces a P value of .0506, which, the agency points out, would not be considered significant.
Even if the company’s analysis were accepted for the 1-mg dose, the FDA says, there is no obvious biological explanation for why the 2-mg dose also was not beneficial at week 72. That finding "calls into question any ostensibly positive findings that might be the basis for a disease modifying claim for rasagiline."
Agency Issues With Analyses and Results
FDA reviewers identified a number of issues of concern with the analyses and results from ADAGIO and TEMPO, and will ask the panel to discuss them. TEMPO was the trial used to support Azilect’s original approval and is being offered as supporting evidence for the current supplemental application.
These issues are: sponsor-conducted analyses that differed from those specified in the protocol; a differential response in men and women and the baseline differences in early and delayed women starters in ADAGIO; potentially significant baseline differences in UPDRS scores between early-start and delayed-start patients in datasets used for analyses at 72 weeks, and potential biases introduced because these include nonrandomized groups; the nonlinearity of slopes that presumably are related to varying early effects of treatment; and re-analyses of slopes without early data suggest parallel slopes in the first phase for drug and placebo.
The FDA is asking the advisory committee to vote on whether ADAGIO provides "compelling" evidence that the 1-mg dose met the protocol-specified criteria for success, whether the 2-mg group failed to meet those criteria and whether there is substantial evidence of effectiveness for Azilect as therapy to delay clinical progression of Parkinson’s disease.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
FDA Considers Infliximab for Pediatric Ulcerative Colitis Maintenance
The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.
"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.
Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."
The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.
The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.
The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.
Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.
Insufficient Long-Term Data
The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.
A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."
The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.
For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.
As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.
Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.
Questions about Maintenance Dosing
Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.
However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."
The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.
No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).
HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.
In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.
"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.
Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."
The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.
The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.
The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.
Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.
Insufficient Long-Term Data
The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.
A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."
The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.
For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.
As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.
Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.
Questions about Maintenance Dosing
Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.
However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."
The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.
No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).
HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.
In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.
"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.
Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."
The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.
The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.
The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.
Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.
Insufficient Long-Term Data
The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.
A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."
The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.
For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.
As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.
Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.
Questions about Maintenance Dosing
Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.
However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."
The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.
No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).
HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.
In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
FDA Panel to Review Adcetris for Lymphoma Indications
The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.
Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.
The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.
Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.
During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.
In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.
The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.
That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.
FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.
However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.
"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.
Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.
For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.
The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."
But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."
For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."
The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.
If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.
In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.
In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.
Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.
The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.
The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.
The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.
The Adcetris Prescription Drug User Fee Act date is Aug. 30.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.
Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.
The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.
Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.
During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.
In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.
The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.
That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.
FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.
However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.
"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.
Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.
For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.
The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."
But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."
For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."
The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.
If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.
In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.
In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.
Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.
The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.
The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.
The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.
The Adcetris Prescription Drug User Fee Act date is Aug. 30.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.
Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.
The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.
Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.
During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.
In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.
The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.
That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.
FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.
However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.
"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.
Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.
For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.
The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."
But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."
For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."
The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.
If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.
In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.
In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.
Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.
The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.
The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.
The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.
The Adcetris Prescription Drug User Fee Act date is Aug. 30.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
FDA Advisory Panel Supports Hereditary Angioedema Drug
A Food and Drug Administration advisory panel has backed the approval of the hereditary angioedema drug icatibant, to be marketed as Firazyr.
Firazyr’s manufacturer, Shire, will enter discussions with the FDA on labeling for the drug, with backing from the panel for a claim to allow patients to self-administer the product, which is delivered through subcutaneous injection.
The Pulmonary-Allergy Drugs Advisory Committee voted 11-1, with one abstention, on June 23 that data for the bradykinin B2 receptor antagonist support self-injection of the drug, which is proposed to treat acute attacks of HAE in adults at a dose of 30 mg.
The panel supported approval of Firazyr by a vote of 12-1, following votes of 12-1 that data provide substantial and convincing evidence that it has a clinically meaningful benefit in acute HAE attacks, and 11-1, with one abstention, that its safety has been adequately addressed.
The "real benefit of this medication that I see will be self-medication," said Dr. Thomas Alexander Platts-Mills of the University of Virginia, Charlottesville.
It will put patients in control, enabling them to get therapy more quickly and to reduce the anxiety of seeking treatment from an emergency department that may or may not be equipped to treat the disease, he noted.
Fully half of hospitals do not have on hand a treatment for HAE acute attacks, and most will not administer a drug brought in by a patient, said Dr. Jay Portnoy of Children’s Mercy Hospitals and Clinics in Kansas City, Mo., so patients with HAE should be equipped to treat themselves, much as epinephrine can be self-administered. Firazyr will probably be used off label for self-administration anyway, he added.
The company is "very gratified" by the committee’s comments in support of self-administration, Suzanne Bruhn, Ph.D., senior vice president for strategic planning and program management for Shire Human Genetic Therapies, told reporters following the meeting.
The self-administration claim would distinguish Firazyr from competitors that are already in the U.S. market for acute HAE attacks. For example, Dyax Corp.’s Kalbitor (ecallantide) is delivered subcutaneously, but because of the potential for anaphylaxis, it must be administered by a health care professional. CSL Behring’s Berinert, which is used only for attacks affecting the face and abdominal area, is delivered intravenously.
Firazyr already is approved for self-administration in Europe and Australia.
Shire HGT would launch the drug within a few weeks of approval, using the experience and infrastructure built up to market its other orphan products, Dr. Bruhn said. Firazyr has an Aug. 25 Prescription Drug User Fee Act date.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
A Food and Drug Administration advisory panel has backed the approval of the hereditary angioedema drug icatibant, to be marketed as Firazyr.
Firazyr’s manufacturer, Shire, will enter discussions with the FDA on labeling for the drug, with backing from the panel for a claim to allow patients to self-administer the product, which is delivered through subcutaneous injection.
The Pulmonary-Allergy Drugs Advisory Committee voted 11-1, with one abstention, on June 23 that data for the bradykinin B2 receptor antagonist support self-injection of the drug, which is proposed to treat acute attacks of HAE in adults at a dose of 30 mg.
The panel supported approval of Firazyr by a vote of 12-1, following votes of 12-1 that data provide substantial and convincing evidence that it has a clinically meaningful benefit in acute HAE attacks, and 11-1, with one abstention, that its safety has been adequately addressed.
The "real benefit of this medication that I see will be self-medication," said Dr. Thomas Alexander Platts-Mills of the University of Virginia, Charlottesville.
It will put patients in control, enabling them to get therapy more quickly and to reduce the anxiety of seeking treatment from an emergency department that may or may not be equipped to treat the disease, he noted.
Fully half of hospitals do not have on hand a treatment for HAE acute attacks, and most will not administer a drug brought in by a patient, said Dr. Jay Portnoy of Children’s Mercy Hospitals and Clinics in Kansas City, Mo., so patients with HAE should be equipped to treat themselves, much as epinephrine can be self-administered. Firazyr will probably be used off label for self-administration anyway, he added.
The company is "very gratified" by the committee’s comments in support of self-administration, Suzanne Bruhn, Ph.D., senior vice president for strategic planning and program management for Shire Human Genetic Therapies, told reporters following the meeting.
The self-administration claim would distinguish Firazyr from competitors that are already in the U.S. market for acute HAE attacks. For example, Dyax Corp.’s Kalbitor (ecallantide) is delivered subcutaneously, but because of the potential for anaphylaxis, it must be administered by a health care professional. CSL Behring’s Berinert, which is used only for attacks affecting the face and abdominal area, is delivered intravenously.
Firazyr already is approved for self-administration in Europe and Australia.
Shire HGT would launch the drug within a few weeks of approval, using the experience and infrastructure built up to market its other orphan products, Dr. Bruhn said. Firazyr has an Aug. 25 Prescription Drug User Fee Act date.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
A Food and Drug Administration advisory panel has backed the approval of the hereditary angioedema drug icatibant, to be marketed as Firazyr.
Firazyr’s manufacturer, Shire, will enter discussions with the FDA on labeling for the drug, with backing from the panel for a claim to allow patients to self-administer the product, which is delivered through subcutaneous injection.
The Pulmonary-Allergy Drugs Advisory Committee voted 11-1, with one abstention, on June 23 that data for the bradykinin B2 receptor antagonist support self-injection of the drug, which is proposed to treat acute attacks of HAE in adults at a dose of 30 mg.
The panel supported approval of Firazyr by a vote of 12-1, following votes of 12-1 that data provide substantial and convincing evidence that it has a clinically meaningful benefit in acute HAE attacks, and 11-1, with one abstention, that its safety has been adequately addressed.
The "real benefit of this medication that I see will be self-medication," said Dr. Thomas Alexander Platts-Mills of the University of Virginia, Charlottesville.
It will put patients in control, enabling them to get therapy more quickly and to reduce the anxiety of seeking treatment from an emergency department that may or may not be equipped to treat the disease, he noted.
Fully half of hospitals do not have on hand a treatment for HAE acute attacks, and most will not administer a drug brought in by a patient, said Dr. Jay Portnoy of Children’s Mercy Hospitals and Clinics in Kansas City, Mo., so patients with HAE should be equipped to treat themselves, much as epinephrine can be self-administered. Firazyr will probably be used off label for self-administration anyway, he added.
The company is "very gratified" by the committee’s comments in support of self-administration, Suzanne Bruhn, Ph.D., senior vice president for strategic planning and program management for Shire Human Genetic Therapies, told reporters following the meeting.
The self-administration claim would distinguish Firazyr from competitors that are already in the U.S. market for acute HAE attacks. For example, Dyax Corp.’s Kalbitor (ecallantide) is delivered subcutaneously, but because of the potential for anaphylaxis, it must be administered by a health care professional. CSL Behring’s Berinert, which is used only for attacks affecting the face and abdominal area, is delivered intravenously.
Firazyr already is approved for self-administration in Europe and Australia.
Shire HGT would launch the drug within a few weeks of approval, using the experience and infrastructure built up to market its other orphan products, Dr. Bruhn said. Firazyr has an Aug. 25 Prescription Drug User Fee Act date.
This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.
FDA Wants Advice on Infection Recurrence with Fidaxomicin
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Hospitalist News Digital Network are both owned by Elsevier.
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Hospitalist News Digital Network are both owned by Elsevier.
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Hospitalist News Digital Network are both owned by Elsevier.
FDA Wants Advice on Infection Recurrence with Fidaxomicin
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.
The Food and Drug Administration accepts findings by Optimer Pharmaceuticals Inc. that the firm’s Dificid (fidaxomicin) is superior to vancomycin in curing Clostridium difficile–associated diarrhea and preventing its return, but the agency will ask an advisory panel on April 5 whether the lower recurrence is clinically significant and should be discussed in labeling.
The company is seeking an indication for the first-in-class macrolide antibacterial for treating C. difficile–associated diarrhea or C. difficile infection, and for reducing the risk of recurrence when it’s used for treatment of initial C. difficile infection.
Failure of the Anti-Infective Drugs Advisory Committee to support language about fidaxomicin’s impact on recurrence could undercut Optimer’s plans to position the antibiotic as first-line treatment for patients who are considered to be at risk for recurrence. Currently, vancomycin and metronidazole are the most common therapies for C. difficile infection, although only the former is approved for that use. But about 20%-30% of those who respond to the two drugs have a recurrence of the infection within 2 months post therapy, Optimer pointed out when it outlined its vision for the drug.
Fidaxomicin has a better profile with regard to preventing recurrence, the firm says in briefing documents for the meeting. Based on two phase III studies that looked at global cure – a composite of cure at the end of treatment and no recurrence by the poststudy visit – Optimer reported superiority for its drug.
In the modified intent-to-treat population, the global cure in Study 003 was 74.4% for fidaxomicin patients and 64.2% for vancomycin recipients (P less than .007); in Study 004, it was 76.7% in the fidaxomicin arm and 63.3% in the vancomycin arm (P less than .001).
The FDA agreed with that assessment following three sensitivity analyses, which changed the numbers but not the conclusion.
The agency also accepted that the antibiotic is noninferior to vancomycin with regard to clinical cure rates at the end-of-treatment visit – the primary end point – with rates of 88% and 87% in the two studies, compared with 84% and 85% for vancomycin.
The FDA analysis of Optimer’s noninferiority margin concluded that the "the historical evidence supports the applicant’s proposed margin of 10% while still preserving over 60% of the treatment effect based on clinical judgment."
If the agency approves fidaxomicin, which has a PDUFA (Prescription Drug User Fee Act) date of May 30, the drug would follow Forest Laboratory Inc.’s Teflaro (ceftaroline) as the second antibiotic to be approved in the last 6 months.
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.