Cathy Dombrowski

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 Family Practice 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 Family Practice 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 Family Practice News Digital Network are both owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

This news organization and "The Pink Sheet" are owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

This news organization and "The Pink Sheet" are owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

This news organization and "The Pink Sheet" are owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

Companies seeking accelerated approval for oncology drugs should avoid the temptation of single-arm trials and conduct randomized trials, except for indications with small patient populations or when drug activity is high, a Food and Drug Administration advisory panel concluded Feb. 8.

A single-arm trial, which is easier and faster to conduct, should be reserved for rare circumstances, Dr. Gary Lyman of Duke University, Durham, N.C., noted during an Oncologic Drugs Advisory Committee meeting. For Dr. Silvana Martino of the Angeles Clinic and Research Institute in Santa Monica, Calif., that would be when "patients are few and the activity of the drug is considerable."

Modest effects in a single-arm trial are insufficient to justify approval, agreed Dr. Malcolm Smith of the National Cancer Institute, Rockville, Md.

The committee’s preference for randomized trials confirms the direction in which the FDA is already moving. Dr. Richard Pazdur, director of the FDA’s office of oncology drug products in Silver Spring, Md., noted that the agency is encouraging sponsors to think randomization before conducting a single-arm trial.

Marginal response rates found in single-arm trials in a refractory setting make it difficult to judge whether they are predictive of clinical benefit, he pointed out.

It’s not that a single-arm study will never be acceptable, Dr. Pazdur said, but drugs are often submitted with very small response rates and sometimes the true benefit is not known until a randomized trial assesses survival.

Committee members also supported requiring drug sponsors to conduct two postapproval confirmatory trials instead of one, and they agreed that these trials should be ongoing or at least in the final stages of development at the time of accelerated approval.

The FDA sought support for those requirements to ensure that confirmation of accelerated approval can be provided in a timely fashion. If a single trial fails to show efficacy and then a second trial is conducted, it takes too long to determine whether a drug is, in fact, beneficial, Dr. Pazdur said.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.

Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.

The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.

Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.

The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.

How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.

During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.

Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.

In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.

FDA Cautious on Suicidality

While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.

There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.

Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.

The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.

Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.

Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.

The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.

An issue surrounding obesity drugs is how to limit their use to the appropriate population. Orexigen is taking a proactive approach with plans for a physician education program that includes an algorithm to guide patient selection and decisions on whether to continue therapy. It is based on analyses that found that weight loss in weeks 4-28 is predictive of a 5% or greater weight loss response at week 56 and logistic modeling that predicts those patients at risk of increases in blood pressure or heart rate.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.

Food and Drug Administration review documents for the lupus drug belimumab (Benlysta) highlight a variety of agency concerns that appear to undermine the magnitude of the drug’s effects, leaving it up to a Nov. 16 Arthritis Advisory Committee to decide whether the drug’s benefit/risk ratio can still attain positive territory.

A primary issue is that the two phase III trials conducted by Human Genome Sciences enrolled patients who were on a stable systemic lupus erythematosus (SLE) treatment regimen for at least 30 days. Patients with severe lupus kidney disease or active CNS lupus were excluded since they were considered not to be on a stable regimen. Consequently, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous.

Therefore, the treatment effect was driven by those patients. "Improvement with belimumab shown in the clinical studies was largely due to the effects on these organ systems," the FDA’s review concludes.

Lupus that affects those two systems can be "debilitating in terms of impairing quality of life, but [those cases] are not generally fatal," the agency acknowledges.

With regard to the more deadly forms of the disease, the agency says, "the data are not adequate to demonstrate efficacy in organ involvement associated with poor outcome and mortality, such as kidneys, central nervous system, and blood vessels."

The company is seeking an indication to reduce disease activity in adults with active, autoantibody-positive, SLE who are receiving standard therapy.

Both pivotal phase III studies – 1056 and 1057 – were the subject of special protocol assessments. The former was a 76-week randomized, double-blind, placebo-controlled trial of 819 patients with active seropositive SLE on stable immunosuppressive medications. It was conducted primarily in North America and Europe. Study 1057 was essentially the same, except it was conducted for only 52 weeks in 865 patients primarily in the Asia Pacific and Latin America. Patients received either 1 mg/kg of belimumab, 10 mg/kg of the drug, or placebo.

SLE Responder Index (SRI) was the primary end point, as measured by the proportion of responders at week 52 with a response of at least a 4-point reduction in the SELENA-SLEDAI score compared to baseline; no worsening (an increase of less than 0.3 points from baseline) in physician global assessment; and no new BILAG A organ domain scores or two new BILAG B organ domain scores at 52 weeks compared to baseline.

Patients treated with belimumab 10 mg/kg had a statistically higher rate of response than placebo patients in both studies. The proportion of patients achieving success for each of the subcomponents was numerically higher in the belimumab groups than placebo in each study, although the differences reached statistical significance only in Study 1057.

Belimumab Efficacy May Be Short Lived

The longer-term data from Study 1056 throw into question the robustness of belimumab’s efficacy, the FDA says. In Study 1057, response improved over time and reached statistical significance at week 52. The same pattern occurred in Study 1056, but the statistical significance was lost by week 76 in the longer study.

"A potentially slower onset of benefit and a potential lack of durability need to be considered," since belimumab would be administered as a chronic treatment for SLE, the FDA says.

The agency also found troubling an inconsistent efficacy trend across geographical regions, particularly a numerically smaller difference in efficacy for patients in the United States and Canada, compared to other regions. The SRI for the North American patients in Study 1056 was 32% for placebo and 35% for belimumab 10 mg/kg. In comparison, the SRI for Latin American patients in Study 1057 was 49% in the placebo arm and 61% for the belimumab 10 mg/kg arm.

A post-hoc analysis of racial subgroups found a lack of demonstrated efficacy in patients of African American or African heritage. In Study 1056, 39% of these patients met the SRI, compared to 33% of belimumab 10 mg/kg patients; in Study 1057, those figures were 64% and 46%, respectively.

Sensitivity Analysis Addresses "Medication Failures"

Further complicating interpretation of the efficacy results was the large number of patients in the studies’ placebo arms who switched to protocol-prohibited or restricted background SLE medications. Per protocol, these "medication failures" were considered treatment failures.

Because these treatment failures "may have exaggerated the difference between placebo and belimumab for the primary endpoint analysis," FDA conducted a sensitivity analysis in which the medical team used its judgment to post-hoc assign some of the medical failures to a primary efficacy outcome.

The primary end point for subjects using statins or angiotensin-pathway antihypertensives was designated as a success for placebo subjects and a failure for belimumab recipients.

"Motivation for this imputation scheme was to take a very conservative approach for medication failure subjects who the clinical team did not feel would have unquestionably proceeded to be an efficacy failure had they not received the prohibited medication," the FDA’s briefing document explains.

Based on these assignments the sensitivity analysis found the results for study 1057 to be generally consistent with the primary efficacy analysis.

However, for Study 1056, the difference in treatment effect between the 10 mg/kg belimumab and placebo arms is only marginally statistically significant. This suggests that results of the primary efficacy analyses are "dependent on the disproportional occurrence of medication failures" in the placebo group of that study.

The apparently higher need for rescue medication in the placebo group can be taken as an unofficial signal of efficacy for belimumab, the agency acknowledges. But, the agency concludes, "the clinical importance of taking a prohibited medication relative to the clinical importance of the primary efficacy end point should be evaluated and kept in mind in interpreting the primary efficacy results."

Suicidality an Unexpected Addition to the Safety Issues

In addressing the safety issues that will be presented to the advisory panel, the FDA noted the somewhat unexpected increase in the risk for neuropsychiatric adverse events – suicide in particular. The safety database included 2,133 patients in the two phase III trials plus a randomized, placebo-controlled phase II study (L02).

Two suicides occurred among belimumab patients during the studies, with another in the safety extension of L02. Four cases of suicide attempts or suicidal ideation occurred in belimumab patients. Depression was the most serious adverse event in the psychiatric disorder category. '

Other safety issues to be discussed at the committee are the potential for death – a rate of 0.79 per 100 patient-years for belimumab patients versus 0.43 for those on placebo – as well as malignancies and infections, which have been recognized risks for the drug.

The advisory committee’s review of the efficacy and safety of belimumab comes in the context of Benlysta having the potential to be the first new drug for lupus in 50 years. The prescriber and patient communities are eager for a new therapy.

Elsevier Global Medical News and "The Pink Sheet" are both published by Elsevier.

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration’s evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic’s pivotal data were developed under the agency’s old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company’s prespecified efficacy analyses as well as sensitivity analyses applying the FDA’s new efficacy criteria, according to agency briefing materials released ahead of the agency’s Anti-Infective Drugs Advisory Committee’s Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the “shifting goalposts” created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest’s phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA’s briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance’s early end point of lesion spread cessation at Day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. “These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials,” the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline’s noninferiority. “Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust,” the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor’s justification for the 10% noninferiority margin relied on historical data related to mortality and “even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure],” the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, “but rather a direct measure of patient well-being,” the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless “provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies.”

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators’ recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis “provided supportive evidence for the clinical response end point at TOC,” the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA’s apparent satisfaction with ceftaroline’s demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration's evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic's pivotal data were developed under the agency's old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company's prespecified efficacy analyses as well as sensitivity analyses applying the FDA's new efficacy criteria, according to agency briefing materials released ahead of the agency's Anti-Infective Drugs Advisory Committee's Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the "shifting goalposts" created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest's phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA's briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance's early end point of lesion spread cessation at day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. "These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials," the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline's noninferiority. "Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust," the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor's justification for the 10% noninferiority margin relied on historical data related to mortality and "even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure]," the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, "but rather a direct measure of patient well-being," the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless "provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies."

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators' recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis "provided supportive evidence for the clinical response end point at TOC," the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA's apparent satisfaction with ceftaroline's demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Skin & Allergy News Digital Network and "The Pink Sheet" are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration's evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic's pivotal data were developed under the agency's old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company's prespecified efficacy analyses as well as sensitivity analyses applying the FDA's new efficacy criteria, according to agency briefing materials released ahead of the agency's Anti-Infective Drugs Advisory Committee's Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the "shifting goalposts" created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest's phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA's briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance's early end point of lesion spread cessation at day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. "These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials," the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline's noninferiority. "Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust," the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor's justification for the 10% noninferiority margin relied on historical data related to mortality and "even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure]," the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, "but rather a direct measure of patient well-being," the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless "provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies."

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators' recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis "provided supportive evidence for the clinical response end point at TOC," the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA's apparent satisfaction with ceftaroline's demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Skin & Allergy News Digital Network and "The Pink Sheet" are published by Elsevier.

Sensitivity analyses may help smooth the approval pathway for ceftaroline fosamil under the Food and Drug Administration's evolving efficacy requirements for skin infections and community-acquired bacterial pneumonia, even though the antibiotic's pivotal data were developed under the agency's old standards.

Ceftaroline (Forest Laboratories) was shown to be noninferior to comparator agents pursuant to the company's prespecified efficacy analyses as well as sensitivity analyses applying the FDA's new efficacy criteria, according to agency briefing materials released ahead of the agency's Anti-Infective Drugs Advisory Committee's Sept. 7 review of the beta lactam cephalosporin.

If endorsed by the committee and approved by the FDA, ceftaroline could become a poster child for how to survive the "shifting goalposts" created by the agency’s evolution in antibiotic development standards – the message being if the data are truly robust, sensitivity analyses can get you through the new efficacy hurdles.

Forest acquired ceftaroline through its January 2007 acquisition of Cerexa, which in-licensed rights from Takeda. The phase III trials for complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) began in 2007, prior to FDA-initiated public discussions about use of noninferiority trials for these indications.

New Skin Infections Guidance

In the case of the cSSSIs, the FDA issued new draft guidance on Aug. 26 that proposes changes in the nomenclature, primary efficacy end point, and study population. The draft forgoes the terms cSSSI and uncomplicated SSSI in favor of acute bacterial SSSI and milder skin infections. The document states that noninferiority trials are acceptable for acute bacterial SSSIs, although it does not set a specific margin that should be used.

During a November 2008 meeting on drug development standards for cSSSI, the Anti-Infective Drugs Advisory Committee generally recommended a 10% margin.

The guidance recommends a new primary efficacy end point based on cessation of lesion spread and resolution of fever at 48-72 hours after enrollment. This is a dramatic change from the end point that has generally been used in cSSSI studies: resolution of signs and symptoms at the test-of-cure visit 7-14 days after completion of treatment. The guidance also recommends that patients with wound infections and major cutaneous abscesses be enrolled only if they have coexisting cellulitis.

Forest's phase III studies tested ceftaroline against vancomycin plus aztreonam in adults with cSSSI requiring initial treatment with an intravenous antimicrobial agent in a hospital or urgent care setting. Cellulitis was present in about 35% of patients. Duration of therapy was 5-14 days.

The primary efficacy end point was clinical response rate at the test-of-cure visit, with clinical cure defined as total resolution of all signs and symptoms or improvement such that further antimicrobial therapy was unnecessary.

Ten Percent Noninferiority Margin Draws No Objections

The FDA's briefing documents raise no objections to the prespecified noninferiority margin of 10% in the cSSSI studies, for which the agency had asked Cerexa to provide supporting justification at the end-of-phase II meeting in October 2006.

In both studies, the 10% margin was met for both the modified intent-to-treat and clinically evaluable populations in the test-of-cure visit 8-15 days after the last dose of study drug, as well as at an end-of-therapy visit, a secondary end point.

FDA reviewers conducted a sensitivity analysis using the draft guidance's early end point of lesion spread cessation at day 3 in a study population that includes only patients with cellulitis. As a result, this reanalyzed population represented only about 56-58% of the originally randomized trial populations, reducing the statistical power to demonstrate noninferiority.

Nevertheless, in both studies the responder rate in the ceftaroline group was higher than in the comparator group. "These findings supported the noninferiority of ceftaroline to vancomycin plus aztreonam for a noninferiority margin of less than 4% for both trials," the agency said.

Additional sensitivity analyses that took into account investigator measurements of lesion size and consistency of clinical response at later timepoints also confirmed ceftaroline's noninferiority. "Overall, findings of noninferiority of ceftaroline to vancomycin plus aztreonam based on key sensitivity analyses of Day 3 responder rates in FDA-MITT [modified intention to treat] subjects appeared to be robust," the document stated.

Justifying the Margin in CABP

The noninferiority margin was the issue in the CABP indication. FDA reviewers were concerned about the absence of historical data to justify the noninferiority margin used in the two phase III trials for that indication.

In studies P903-06 and P903-09, ceftaroline was shown to be noninferior to ceftriaxone on the primary end points – clinical cure rate at the test-of-cure visit in the clinically evaluable and in the modified intent-to-treat efficacy populations – with a prespecified noninferiority margin of 10%. Patients received the study drugs for 5-7 days; the test-of-cure visit was 8-15 days after the last drug dose.

The sponsor's justification for the 10% noninferiority margin relied on historical data related to mortality and "even if such a margin was justified, this would not imply that a margin could be extrapolated for clinical response at TOC [test of cure]," the FDA’s briefing documents stated.

There are, however, historical data demonstrating dramatic improvement in patient signs and symptoms after a few days of antibiotic therapy, the agency noted. So FDA reviewers analyzed as an end point the sign and symptom measurements at Day 4 available in case report forms from the two studies, with achievement of a 10% noninferiority margin as the measure of success.

The new end point was not considered a surrogate, "but rather a direct measure of patient well-being," the FDA said.

The FDA analysis was limited to microbiologically confirmed patients. This markedly decreased the size of the study population, the agency said, but the results nevertheless "provided evidence of efficacy as ceftaroline met the 10% noninferiority margin in both studies."

While efficacy was demonstrated, the FDA reviewers noted several problems with their calculations. Investigators' recording of signs and symptoms was not standardized and their evaluation of symptom severity was subjective. Further, no algorithmic combination of the Day 4 signs and symptoms would have precisely corresponded to those discussed in the historical studies, and the measures did not necessarily capture patient feeling, function, or survival. The reviewers also suggested that changes in signs and symptoms could have been influenced by concomitant therapy.

Because the FDA analysis involved several arbitrary choices and cutoffs, the agency conducted sensitivity analyses for several modifications. Their conclusion was that the noninferiority results were relatively robust with regard to end point, timing of assessment, and analysis population, but the 10% noninferiority margin would not have been met in study P903-09 if the assessment had been at Day 3 or end-of-treatment, rather than Day 4.

To further justify a 10% noninferiority margin for a clinical response end point at test-of-cure, reviewers also looked at two recent trials comparing ceftriaxone to daptomycin, with daptomycin considered to be a substitute for a placebo arm. An ad hoc analysis "provided supportive evidence for the clinical response end point at TOC," the FDA concluded.

Much like the cSSSI program, the CABP trials moved along during a time of transition in FDA standards for the indication. The ceftaroline pneumonia clinical trials were initiated prior to discussions at a 2008 FDA/Infectious Diseases Society of America public workshop and Anti-Infective Drugs Advisory Committee meetings in 2008 and 2009 about the use of noninferiority trials for CABP, and a March 2009 draft guidance. The CABP guidance is currently undergoing revisions.

The sensitivity analyses applied by FDA reviewers to view the results in terms of the evolving regulatory requirements for CABP were based largely on discussions at the public forums, the agency said. At the December 2009 anti-infectives advisory committee meeting, members agreed that either all-cause mortality or clinical response could be used as a primary end point.

The FDA's apparent satisfaction with ceftaroline's demonstration of efficacy in skin infections and CABP could mean that the Sept. 7 advisory committee meeting will turn into a referendum on the agency’s current thinking about clinical trial requirements for these two conditions.

Skin & Allergy News Digital Network and "The Pink Sheet" are published by Elsevier.