Sue Sutter

Recent data on late-stage clinical success rates confirm that cancer drug development is a risky proposition for pharmaceutical and biotech companies, even before the Food and Drug Administration gets tougher on accelerated approval requirements.

A new study by BIO (Biotechnology Industry Organization) and the institutional research service firm BioMedTracker shows that oncology had the lowest phase III success rate among seven therapeutic areas, with only 34% of candidates succeeding at this stage over a 7-year period. The cardiovascular area had the next lowest phase III success rate (46%), and the autoimmune area had the highest success rate (63%).

Cancer also had the second lowest phase II success rate (29%), trailing only the cardiovascular sector by 1 percentage point.

The study examined the clinical phase status from year-end 2003 to year-end 2010 of more than 4,200 drugs and 7,300 indications in BioMedTracker’s database. The study encompasses all companies – from big pharma to small biotech, both publicly and privately held – that are conducting development on therapeutics for approval in the United States.

A summary of the study findings was presented during a panel discussion on clinical trial success rates at the BIO CEO & Investor Conference in New York on Feb. 15. BIO said the full study would be published at a later date.

The overall success rate for all drugs and biologics from phase I to FDA approval was approximately 9%, with lead indications faring far better than secondary indications (14.5% vs. 3.2%, respectively).

Success rates in oncology tracked behind the overall numbers. Cancer therapeutics had an 11% overall success rate by lead indication, second worst only to the cardiovascular category. Only 2% of secondary indications for cancer therapeutics made it from phase I to approval, tying with the endocrine and respiratory therapeutic areas for the worst rate on this metric.

Infectious disease had the best overall success rate by lead indication (15%), whereas secondary indications had the best chance of success in the autoimmune sector (7%).

In a deeper look at the overall rates for oncology, treatments for head and neck cancer were most likely to succeed (19%), followed by renal cell carcinoma (15%). Treatments for non–small cell lung cancer had the worst clinical success rate, a dismal 2%.

"Strikingly, oncology drugs have the toughest time making their way through the clinic, despite [cancer’s] being the most closely studied area in drug development," BioMedTracker senior biotechnology analyst Michael Hay said in a press release announcing the study results.

The study’s findings come at a time when the FDA is contemplating tougher accelerated approval requirements for cancer treatments.

On Feb. 8, the agency’s Oncologic Drugs Advisory Committee endorsed several FDA proposals for tightening the accelerated approval standards, recommending that sponsors generally be required to conduct randomized trials rather than single-arm studies, and that there be more extensive postmarketing studies to confirm clinical benefit.

The unattractive success rates in the therapeutic area, coupled with tougher regulatory hurdles, could give big pharma companies, biotech firms, and venture capitalists pause before they commit resources to those cancer indications with the highest failure rates.

Among the study limitations highlighted at the BIO meeting was its time frame; clinical programs that did not advance during the 7-year period and are still ongoing in a particular phase were not counted toward the success rate. The study also did not look at the reasons for failure, such as economic conditions vs. bad data.

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

Recent data on late-stage clinical success rates confirm that cancer drug development is a risky proposition for pharmaceutical and biotech companies, even before the Food and Drug Administration gets tougher on accelerated approval requirements.

A new study by BIO (Biotechnology Industry Organization) and the institutional research service firm BioMedTracker shows that oncology had the lowest phase III success rate among seven therapeutic areas, with only 34% of candidates succeeding at this stage over a 7-year period. The cardiovascular area had the next lowest phase III success rate (46%), and the autoimmune area had the highest success rate (63%).

Cancer also had the second lowest phase II success rate (29%), trailing only the cardiovascular sector by 1 percentage point.

The study examined the clinical phase status from year-end 2003 to year-end 2010 of more than 4,200 drugs and 7,300 indications in BioMedTracker’s database. The study encompasses all companies – from big pharma to small biotech, both publicly and privately held – that are conducting development on therapeutics for approval in the United States.

A summary of the study findings was presented during a panel discussion on clinical trial success rates at the BIO CEO & Investor Conference in New York on Feb. 15. BIO said the full study would be published at a later date.

The overall success rate for all drugs and biologics from phase I to FDA approval was approximately 9%, with lead indications faring far better than secondary indications (14.5% vs. 3.2%, respectively).

Success rates in oncology tracked behind the overall numbers. Cancer therapeutics had an 11% overall success rate by lead indication, second worst only to the cardiovascular category. Only 2% of secondary indications for cancer therapeutics made it from phase I to approval, tying with the endocrine and respiratory therapeutic areas for the worst rate on this metric.

Infectious disease had the best overall success rate by lead indication (15%), whereas secondary indications had the best chance of success in the autoimmune sector (7%).

In a deeper look at the overall rates for oncology, treatments for head and neck cancer were most likely to succeed (19%), followed by renal cell carcinoma (15%). Treatments for non–small cell lung cancer had the worst clinical success rate, a dismal 2%.

"Strikingly, oncology drugs have the toughest time making their way through the clinic, despite [cancer’s] being the most closely studied area in drug development," BioMedTracker senior biotechnology analyst Michael Hay said in a press release announcing the study results.

The study’s findings come at a time when the FDA is contemplating tougher accelerated approval requirements for cancer treatments.

On Feb. 8, the agency’s Oncologic Drugs Advisory Committee endorsed several FDA proposals for tightening the accelerated approval standards, recommending that sponsors generally be required to conduct randomized trials rather than single-arm studies, and that there be more extensive postmarketing studies to confirm clinical benefit.

The unattractive success rates in the therapeutic area, coupled with tougher regulatory hurdles, could give big pharma companies, biotech firms, and venture capitalists pause before they commit resources to those cancer indications with the highest failure rates.

Among the study limitations highlighted at the BIO meeting was its time frame; clinical programs that did not advance during the 7-year period and are still ongoing in a particular phase were not counted toward the success rate. The study also did not look at the reasons for failure, such as economic conditions vs. bad data.

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

Recent data on late-stage clinical success rates confirm that cancer drug development is a risky proposition for pharmaceutical and biotech companies, even before the Food and Drug Administration gets tougher on accelerated approval requirements.

A new study by BIO (Biotechnology Industry Organization) and the institutional research service firm BioMedTracker shows that oncology had the lowest phase III success rate among seven therapeutic areas, with only 34% of candidates succeeding at this stage over a 7-year period. The cardiovascular area had the next lowest phase III success rate (46%), and the autoimmune area had the highest success rate (63%).

Cancer also had the second lowest phase II success rate (29%), trailing only the cardiovascular sector by 1 percentage point.

The study examined the clinical phase status from year-end 2003 to year-end 2010 of more than 4,200 drugs and 7,300 indications in BioMedTracker’s database. The study encompasses all companies – from big pharma to small biotech, both publicly and privately held – that are conducting development on therapeutics for approval in the United States.

A summary of the study findings was presented during a panel discussion on clinical trial success rates at the BIO CEO & Investor Conference in New York on Feb. 15. BIO said the full study would be published at a later date.

The overall success rate for all drugs and biologics from phase I to FDA approval was approximately 9%, with lead indications faring far better than secondary indications (14.5% vs. 3.2%, respectively).

Success rates in oncology tracked behind the overall numbers. Cancer therapeutics had an 11% overall success rate by lead indication, second worst only to the cardiovascular category. Only 2% of secondary indications for cancer therapeutics made it from phase I to approval, tying with the endocrine and respiratory therapeutic areas for the worst rate on this metric.

Infectious disease had the best overall success rate by lead indication (15%), whereas secondary indications had the best chance of success in the autoimmune sector (7%).

In a deeper look at the overall rates for oncology, treatments for head and neck cancer were most likely to succeed (19%), followed by renal cell carcinoma (15%). Treatments for non–small cell lung cancer had the worst clinical success rate, a dismal 2%.

"Strikingly, oncology drugs have the toughest time making their way through the clinic, despite [cancer’s] being the most closely studied area in drug development," BioMedTracker senior biotechnology analyst Michael Hay said in a press release announcing the study results.

The study’s findings come at a time when the FDA is contemplating tougher accelerated approval requirements for cancer treatments.

On Feb. 8, the agency’s Oncologic Drugs Advisory Committee endorsed several FDA proposals for tightening the accelerated approval standards, recommending that sponsors generally be required to conduct randomized trials rather than single-arm studies, and that there be more extensive postmarketing studies to confirm clinical benefit.

The unattractive success rates in the therapeutic area, coupled with tougher regulatory hurdles, could give big pharma companies, biotech firms, and venture capitalists pause before they commit resources to those cancer indications with the highest failure rates.

Among the study limitations highlighted at the BIO meeting was its time frame; clinical programs that did not advance during the 7-year period and are still ongoing in a particular phase were not counted toward the success rate. The study also did not look at the reasons for failure, such as economic conditions vs. bad data.

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’s Oncologic Drugs Advisory Committee will consider whether and when randomized studies, rather than single-arm trials, should be required for accelerated approval during the panel’s Feb. 8 meeting to discuss difficulties associated with completing confirmatory postmarketing studies.

In one of four nonvoting questions posed to the committee, the FDA asks whether there are scenarios in which a randomized study should be required to secure accelerated approval and, alternatively, to discuss situations where single-arm trials may be appropriate. The draft questions were released in conjunction with other ODAC briefing documents (pdf) on Feb. 4.

The FDA also poses three questions on postmarketing studies to confirm clinical benefit. These relate to the number of confirmatory trials that should be required, whether accelerated approval should be delayed until confirmatory trials are underway, and whether data from cooperative group studies should be supplemented with an additional confirmatory trial conducted under the sponsor’s direct supervision.

ODAC’s views on the issues could embolden the FDA to shift its regulatory stance on accelerated approval of cancer drugs. The agency could require more extensive clinical work both up front and after approval in an attempt to reduce the risk that confirmatory studies will drag out too long or not produce useful information. For sponsors, such changes would mean greater expense and risk of failure up front, and higher costs post approval.

In the Firestorm of Avastin

The meeting comes in the midst of the FDA’s efforts to rescind accelerated approval of the breast cancer indication for Genentech’s Avastin after postapproval trials failed to confirm the progression-free survival benefit seen in an earlier study. Genentech has requested a hearing on the FDA’s proposal to revoke the indication and is proposing to conduct a new confirmatory study.

During a July 20 meeting in which ODAC voted 12-1 in favor of revoking the breast cancer indication, the FDA’s Office of Oncology Drug Products Director Richard Pazdur said the committee would meet in 2011 to generally discuss sponsors’ due diligence in completing confirmatory studies.

At the upcoming meeting, ODAC will hear presentations on the status of postmarketing studies for six accelerated-approval drugs: Lilly’s Erbitux (cetuximab) for metastatic colorectal cancer; GlaxoSmithKline’s Bexxar (tositumomab) for non-Hodgkin’s lymphoma; Genzyme’s Clolar (clofarabine) for pediatric acute lymphoblastic leukemia; GSK’s Arranon for leukemia and lymphoma; Amgen’s Vectibix (panitumumab) for metastatic colorectal cancer; and Novartis’s Gleevec (imatinib) for gastrointestinal stromal tumors.

The product-specific updates will serve as a springboard for discussion on the broader issues of improving the planning and conduct of postmarketing confirmatory trials.

Addressing Registration Data First

However, before the FDA seeks ODAC’s views on confirmatory trial issues, it wants to know whether more extensive data should be required to win accelerated approval.

The agency notes that single-arm studies have formed the basis for 29 of the 49 oncology drug accelerated approvals to date.

"Single-arm trials for accelerated approval have usually been performed in refractory populations where no available therapy exists. As a greater number of drugs are approved, identification and documentation of a refractory population is increasingly problematic. In addition, marginal response rates observed in single-arm trials in a refractory setting make it difficult to determine whether the findings are ‘reasonably likely’ to predict clinical benefit," the FDA says.

Potential alternatives to single-arm trials include randomized trials in less refractory patients against an active control using a surrogate end point analyzed at an earlier time point, or randomized trials in refractory populations comparing the investigational agent to best supportive care or investigator-chosen therapies, the FDA says.

The agency has previously suggested that cancer drug sponsors need to move away from the single-arm study model in pursuing accelerated approval.

The issue of single-arm versus randomized trials arose during ODAC’s May 2009 review of GSK’s Arzerra (ofatumumab) for chronic lymphocytic leukemia. In a follow-up to that meeting, Dr. Pazdur said conducting randomized trials in less heavily pretreated patients would provide a clearer picture of efficacy than single-arm studies in multirefractory patients.

Number and Timing of Confirmatory Studies

The agency also seeks advice on the number and timing of confirmatory studies.

The time between either successful completion of a required postmarketing study or withdrawal of the indication can be prolonged, the FDA notes. For oncology drugs, the agency has frequently granted approval on the basis of a single well-conducted trial and usually receives proposals for a single confirmatory trial to be conducted post approval.

"However, in the setting of accelerated approval, when only one confirmatory postmarketing trial is conducted, there is the increased risk that clinical benefit will not be demonstrated in a timely manner if that single trial fails to confirm a benefit or does not accrue patients as rapidly as planned. This may lead to either withdrawal of the indication or the need to conduct a second trial, resulting in substantial delays."

The agency asks ODAC whether sponsors should be required to conduct at least two trials post approval to verify clinical benefit.

Although the FDA appears to be suggesting that doing two confirmatory studies is a better path forward, following such a policy provides a sponsor with no guarantees. Such was the case with Avastin, where Genentech’s AVADO and RIBBON1 trials showed a significant improvement on progression-free survival but failed to verify the magnitude of benefit seen in the E2100 study.

The FDA also asks whether accelerated approval should be delayed until confirmatory trials are ongoing.

"Once a drug gains accelerated approval in a refractory disease stage, accrual to a confirmatory trial in the same setting is difficult," the agency says. "Pursuing a confirmatory clinical trial in a less refractory setting can potentially circumvent this problem. However, changes in science, accrual challenges, and other hurdles may lead to delays. The FDA believes that more timely completion of accelerated-approval confirmatory trials can be enhanced if accelerated approval is granted when the confirmatory trial is ongoing."

Examining the Role of Cooperative Groups

The fourth question posed focuses on the use of cooperative study groups to conduct confirmatory trials. Even when a postmarketing study is being conducted by a cooperative group, the ultimate responsibility for completing the trial with due diligence rests with the drug sponsor. This responsibility holds added importance since the FDA Amendments Act of 2007 allows for imposition of civil money penalties if sponsors fail to complete trials on a timely basis, the agency notes.

The FDA asks whether, in those cases where a cooperative group is used, an additional trial conducted under the sponsor’s direct supervision should be required to ensure timely satisfaction of postmarketing obligations.

The complexities encountered in using cooperative groups are exemplified in Novartis’s briefing materials for Gleevec. Three of the company’s postmarketing commitments for imatinib’s accelerated approval in the adjuvant treatment of GIST are encompassed in an ongoing study sponsored by the American College of Surgeons Oncology Group (ACOSOG) and the National Cancer Institute under a Cooperative Research and Development Agreement.

There was no specific provision in the original CRADA granting Novartis access to data from the primary analysis for regulatory purposes, thereby necessitating a contractual amendment. Four-year follow-up data on recurrence-free survival were due in November, but this submission has been delayed pending receipt of data from ACOSOG.

"For industry sponsors, collaborations with cooperative groups can add challenges to a study very different to those encountered with industry-sponsored studies requiring close collaboration between all parties involved," Novartis said. "Often, as is the case with ACOSOG Z9001, the conduct of the study is within the control of the cooperative group."

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

The Food and Drug Administration’s Oncologic Drugs Advisory Committee will consider whether and when randomized studies, rather than single-arm trials, should be required for accelerated approval during the panel’s Feb. 8 meeting to discuss difficulties associated with completing confirmatory postmarketing studies.

In one of four nonvoting questions posed to the committee, the FDA asks whether there are scenarios in which a randomized study should be required to secure accelerated approval and, alternatively, to discuss situations where single-arm trials may be appropriate. The draft questions were released in conjunction with other ODAC briefing documents (pdf) on Feb. 4.

The FDA also poses three questions on postmarketing studies to confirm clinical benefit. These relate to the number of confirmatory trials that should be required, whether accelerated approval should be delayed until confirmatory trials are underway, and whether data from cooperative group studies should be supplemented with an additional confirmatory trial conducted under the sponsor’s direct supervision.

ODAC’s views on the issues could embolden the FDA to shift its regulatory stance on accelerated approval of cancer drugs. The agency could require more extensive clinical work both up front and after approval in an attempt to reduce the risk that confirmatory studies will drag out too long or not produce useful information. For sponsors, such changes would mean greater expense and risk of failure up front, and higher costs post approval.

In the Firestorm of Avastin

The meeting comes in the midst of the FDA’s efforts to rescind accelerated approval of the breast cancer indication for Genentech’s Avastin after postapproval trials failed to confirm the progression-free survival benefit seen in an earlier study. Genentech has requested a hearing on the FDA’s proposal to revoke the indication and is proposing to conduct a new confirmatory study.

During a July 20 meeting in which ODAC voted 12-1 in favor of revoking the breast cancer indication, the FDA’s Office of Oncology Drug Products Director Richard Pazdur said the committee would meet in 2011 to generally discuss sponsors’ due diligence in completing confirmatory studies.

At the upcoming meeting, ODAC will hear presentations on the status of postmarketing studies for six accelerated-approval drugs: Lilly’s Erbitux (cetuximab) for metastatic colorectal cancer; GlaxoSmithKline’s Bexxar (tositumomab) for non-Hodgkin’s lymphoma; Genzyme’s Clolar (clofarabine) for pediatric acute lymphoblastic leukemia; GSK’s Arranon for leukemia and lymphoma; Amgen’s Vectibix (panitumumab) for metastatic colorectal cancer; and Novartis’s Gleevec (imatinib) for gastrointestinal stromal tumors.

The product-specific updates will serve as a springboard for discussion on the broader issues of improving the planning and conduct of postmarketing confirmatory trials.

Addressing Registration Data First

However, before the FDA seeks ODAC’s views on confirmatory trial issues, it wants to know whether more extensive data should be required to win accelerated approval.

The agency notes that single-arm studies have formed the basis for 29 of the 49 oncology drug accelerated approvals to date.

"Single-arm trials for accelerated approval have usually been performed in refractory populations where no available therapy exists. As a greater number of drugs are approved, identification and documentation of a refractory population is increasingly problematic. In addition, marginal response rates observed in single-arm trials in a refractory setting make it difficult to determine whether the findings are ‘reasonably likely’ to predict clinical benefit," the FDA says.

Potential alternatives to single-arm trials include randomized trials in less refractory patients against an active control using a surrogate end point analyzed at an earlier time point, or randomized trials in refractory populations comparing the investigational agent to best supportive care or investigator-chosen therapies, the FDA says.

The agency has previously suggested that cancer drug sponsors need to move away from the single-arm study model in pursuing accelerated approval.

The issue of single-arm versus randomized trials arose during ODAC’s May 2009 review of GSK’s Arzerra (ofatumumab) for chronic lymphocytic leukemia. In a follow-up to that meeting, Dr. Pazdur said conducting randomized trials in less heavily pretreated patients would provide a clearer picture of efficacy than single-arm studies in multirefractory patients.

Number and Timing of Confirmatory Studies

The agency also seeks advice on the number and timing of confirmatory studies.

The time between either successful completion of a required postmarketing study or withdrawal of the indication can be prolonged, the FDA notes. For oncology drugs, the agency has frequently granted approval on the basis of a single well-conducted trial and usually receives proposals for a single confirmatory trial to be conducted post approval.

"However, in the setting of accelerated approval, when only one confirmatory postmarketing trial is conducted, there is the increased risk that clinical benefit will not be demonstrated in a timely manner if that single trial fails to confirm a benefit or does not accrue patients as rapidly as planned. This may lead to either withdrawal of the indication or the need to conduct a second trial, resulting in substantial delays."

The agency asks ODAC whether sponsors should be required to conduct at least two trials post approval to verify clinical benefit.

Although the FDA appears to be suggesting that doing two confirmatory studies is a better path forward, following such a policy provides a sponsor with no guarantees. Such was the case with Avastin, where Genentech’s AVADO and RIBBON1 trials showed a significant improvement on progression-free survival but failed to verify the magnitude of benefit seen in the E2100 study.

The FDA also asks whether accelerated approval should be delayed until confirmatory trials are ongoing.

"Once a drug gains accelerated approval in a refractory disease stage, accrual to a confirmatory trial in the same setting is difficult," the agency says. "Pursuing a confirmatory clinical trial in a less refractory setting can potentially circumvent this problem. However, changes in science, accrual challenges, and other hurdles may lead to delays. The FDA believes that more timely completion of accelerated-approval confirmatory trials can be enhanced if accelerated approval is granted when the confirmatory trial is ongoing."

Examining the Role of Cooperative Groups

The fourth question posed focuses on the use of cooperative study groups to conduct confirmatory trials. Even when a postmarketing study is being conducted by a cooperative group, the ultimate responsibility for completing the trial with due diligence rests with the drug sponsor. This responsibility holds added importance since the FDA Amendments Act of 2007 allows for imposition of civil money penalties if sponsors fail to complete trials on a timely basis, the agency notes.

The FDA asks whether, in those cases where a cooperative group is used, an additional trial conducted under the sponsor’s direct supervision should be required to ensure timely satisfaction of postmarketing obligations.

The complexities encountered in using cooperative groups are exemplified in Novartis’s briefing materials for Gleevec. Three of the company’s postmarketing commitments for imatinib’s accelerated approval in the adjuvant treatment of GIST are encompassed in an ongoing study sponsored by the American College of Surgeons Oncology Group (ACOSOG) and the National Cancer Institute under a Cooperative Research and Development Agreement.

There was no specific provision in the original CRADA granting Novartis access to data from the primary analysis for regulatory purposes, thereby necessitating a contractual amendment. Four-year follow-up data on recurrence-free survival were due in November, but this submission has been delayed pending receipt of data from ACOSOG.

"For industry sponsors, collaborations with cooperative groups can add challenges to a study very different to those encountered with industry-sponsored studies requiring close collaboration between all parties involved," Novartis said. "Often, as is the case with ACOSOG Z9001, the conduct of the study is within the control of the cooperative group."

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

The Food and Drug Administration’s Oncologic Drugs Advisory Committee will consider whether and when randomized studies, rather than single-arm trials, should be required for accelerated approval during the panel’s Feb. 8 meeting to discuss difficulties associated with completing confirmatory postmarketing studies.

In one of four nonvoting questions posed to the committee, the FDA asks whether there are scenarios in which a randomized study should be required to secure accelerated approval and, alternatively, to discuss situations where single-arm trials may be appropriate. The draft questions were released in conjunction with other ODAC briefing documents (pdf) on Feb. 4.

The FDA also poses three questions on postmarketing studies to confirm clinical benefit. These relate to the number of confirmatory trials that should be required, whether accelerated approval should be delayed until confirmatory trials are underway, and whether data from cooperative group studies should be supplemented with an additional confirmatory trial conducted under the sponsor’s direct supervision.

ODAC’s views on the issues could embolden the FDA to shift its regulatory stance on accelerated approval of cancer drugs. The agency could require more extensive clinical work both up front and after approval in an attempt to reduce the risk that confirmatory studies will drag out too long or not produce useful information. For sponsors, such changes would mean greater expense and risk of failure up front, and higher costs post approval.

In the Firestorm of Avastin

The meeting comes in the midst of the FDA’s efforts to rescind accelerated approval of the breast cancer indication for Genentech’s Avastin after postapproval trials failed to confirm the progression-free survival benefit seen in an earlier study. Genentech has requested a hearing on the FDA’s proposal to revoke the indication and is proposing to conduct a new confirmatory study.

During a July 20 meeting in which ODAC voted 12-1 in favor of revoking the breast cancer indication, the FDA’s Office of Oncology Drug Products Director Richard Pazdur said the committee would meet in 2011 to generally discuss sponsors’ due diligence in completing confirmatory studies.

At the upcoming meeting, ODAC will hear presentations on the status of postmarketing studies for six accelerated-approval drugs: Lilly’s Erbitux (cetuximab) for metastatic colorectal cancer; GlaxoSmithKline’s Bexxar (tositumomab) for non-Hodgkin’s lymphoma; Genzyme’s Clolar (clofarabine) for pediatric acute lymphoblastic leukemia; GSK’s Arranon for leukemia and lymphoma; Amgen’s Vectibix (panitumumab) for metastatic colorectal cancer; and Novartis’s Gleevec (imatinib) for gastrointestinal stromal tumors.

The product-specific updates will serve as a springboard for discussion on the broader issues of improving the planning and conduct of postmarketing confirmatory trials.

Addressing Registration Data First

However, before the FDA seeks ODAC’s views on confirmatory trial issues, it wants to know whether more extensive data should be required to win accelerated approval.

The agency notes that single-arm studies have formed the basis for 29 of the 49 oncology drug accelerated approvals to date.

"Single-arm trials for accelerated approval have usually been performed in refractory populations where no available therapy exists. As a greater number of drugs are approved, identification and documentation of a refractory population is increasingly problematic. In addition, marginal response rates observed in single-arm trials in a refractory setting make it difficult to determine whether the findings are ‘reasonably likely’ to predict clinical benefit," the FDA says.

Potential alternatives to single-arm trials include randomized trials in less refractory patients against an active control using a surrogate end point analyzed at an earlier time point, or randomized trials in refractory populations comparing the investigational agent to best supportive care or investigator-chosen therapies, the FDA says.

The agency has previously suggested that cancer drug sponsors need to move away from the single-arm study model in pursuing accelerated approval.

The issue of single-arm versus randomized trials arose during ODAC’s May 2009 review of GSK’s Arzerra (ofatumumab) for chronic lymphocytic leukemia. In a follow-up to that meeting, Dr. Pazdur said conducting randomized trials in less heavily pretreated patients would provide a clearer picture of efficacy than single-arm studies in multirefractory patients.

Number and Timing of Confirmatory Studies

The agency also seeks advice on the number and timing of confirmatory studies.

The time between either successful completion of a required postmarketing study or withdrawal of the indication can be prolonged, the FDA notes. For oncology drugs, the agency has frequently granted approval on the basis of a single well-conducted trial and usually receives proposals for a single confirmatory trial to be conducted post approval.

"However, in the setting of accelerated approval, when only one confirmatory postmarketing trial is conducted, there is the increased risk that clinical benefit will not be demonstrated in a timely manner if that single trial fails to confirm a benefit or does not accrue patients as rapidly as planned. This may lead to either withdrawal of the indication or the need to conduct a second trial, resulting in substantial delays."

The agency asks ODAC whether sponsors should be required to conduct at least two trials post approval to verify clinical benefit.

Although the FDA appears to be suggesting that doing two confirmatory studies is a better path forward, following such a policy provides a sponsor with no guarantees. Such was the case with Avastin, where Genentech’s AVADO and RIBBON1 trials showed a significant improvement on progression-free survival but failed to verify the magnitude of benefit seen in the E2100 study.

The FDA also asks whether accelerated approval should be delayed until confirmatory trials are ongoing.

"Once a drug gains accelerated approval in a refractory disease stage, accrual to a confirmatory trial in the same setting is difficult," the agency says. "Pursuing a confirmatory clinical trial in a less refractory setting can potentially circumvent this problem. However, changes in science, accrual challenges, and other hurdles may lead to delays. The FDA believes that more timely completion of accelerated-approval confirmatory trials can be enhanced if accelerated approval is granted when the confirmatory trial is ongoing."

Examining the Role of Cooperative Groups

The fourth question posed focuses on the use of cooperative study groups to conduct confirmatory trials. Even when a postmarketing study is being conducted by a cooperative group, the ultimate responsibility for completing the trial with due diligence rests with the drug sponsor. This responsibility holds added importance since the FDA Amendments Act of 2007 allows for imposition of civil money penalties if sponsors fail to complete trials on a timely basis, the agency notes.

The FDA asks whether, in those cases where a cooperative group is used, an additional trial conducted under the sponsor’s direct supervision should be required to ensure timely satisfaction of postmarketing obligations.

The complexities encountered in using cooperative groups are exemplified in Novartis’s briefing materials for Gleevec. Three of the company’s postmarketing commitments for imatinib’s accelerated approval in the adjuvant treatment of GIST are encompassed in an ongoing study sponsored by the American College of Surgeons Oncology Group (ACOSOG) and the National Cancer Institute under a Cooperative Research and Development Agreement.

There was no specific provision in the original CRADA granting Novartis access to data from the primary analysis for regulatory purposes, thereby necessitating a contractual amendment. Four-year follow-up data on recurrence-free survival were due in November, but this submission has been delayed pending receipt of data from ACOSOG.

"For industry sponsors, collaborations with cooperative groups can add challenges to a study very different to those encountered with industry-sponsored studies requiring close collaboration between all parties involved," Novartis said. "Often, as is the case with ACOSOG Z9001, the conduct of the study is within the control of the cooperative group."

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

The Food and Drug Administration plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

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 plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

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 plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

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

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Photo credit: Jan Christian @ www.ambrotosphotography.com

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Photo credit: Jan Christian @ www.ambrotosphotography.com

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

A clinical reviewer for the Food and Drug Administration Center for Biologics Evaluation and Research sees no problem with using an anal dysplasia end point, or extrapolating male data to females, to support approval of Merck’s human papillomavirus vaccine Gardasil for prevention of anal cancer.

Photo credit: Jan Christian @ www.ambrotosphotography.com

Nevertheless, the agency is asking an advisory committee for input on these very issues at a Nov. 17 meeting, and a later review by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices panel may be key for utilization and reimbursement.

In his clinical review, medical officer Dr. Jeffrey Roberts of the Center for Biologics Evaluation and Research (CBER) said available data support approval of Gardasil for males and females aged 9-26 years, to prevent anal intraepithelial neoplasia (AIN) and anal cancer caused by human papillomavirus types 6, 11, 16, and 18, according to a briefing document for the meeting, which was posted by the FDA more than 2 weeks earlier than usual.

The session will mark the third time the FDA’s vaccines advisory committee has reviewed Merck’s quadrivalent HPV vaccine. To date, each meeting has amounted to a slam dunk for the company, and the FDA’s briefing documents on the anal cancer indication suggest Gardasil’s third trip before the committee is unlikely to be much different.

While a Gardasil anal cancer indication appears headed for a committee endorsement and FDA approval, a less certain question is whether the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) will find the data persuasive enough to recommend routine vaccination of males. ACIP’s deliberations are important to Merck for purposes of securing widespread use and reimbursement of Gardasil in boys and men.

FDA Cautious on HPV Vaccines

In May 2006, the FDA’s vaccines committee unanimously supported Gardasil’s safety and efficacy for its initial indication: the prevention of cervical cancer and precancerous lesions in girls and women.

In September 2009, seven of eight committee members said the vaccine was efficacious and safe for preventing genital warts in males 9-26 years old.

However, panelists raised concerns about several issues, including evidence on the duration of the vaccine’s effect, clarity about its effect in situations of preinfection with HPV types 6 and 11, and the need for data on a larger group of men.

The FDA’s decision to hold three advisory committee meetings on Gardasil could be viewed as a desire for outside input due to the politically sensitive issues involved in vaccinating adolescents and teenagers to prevent sexually transmitted conditions. The agency also sought advisory panel review for licensing of GlaxoSmithKline PLC’s bivalent HPV vaccine Cervarix, although much of the committee’s focus was on the formulation’s novel adjuvant.

Gardasil is currently approved for prevention of cervical, vulvar, and vaginal cancers and associated precancerous lesions in girls and women aged 9-26 years, as well as for the prevention of genital warts in males and females aged 9-26 years.

Notably, the FDA has not sought advisory committee review of Merck’s bid to expand the vaccine’s use to women aged 27-45 years. The company has received two "complete response" letters for this population, and is waiting to hear back from the FDA after submitting 48-month, end-of-trial data from the FUTURE III study in 3,817 older women.

Males-Only Substudy Equals No Female Data

Merck’s supplemental biologics license application for the AIN/anal cancer indication was submitted in February, and the company expects a regulatory decision by the end of 2010.

The pivotal data come from a 602-patient substudy of men who have sex with men (MSM) and were part of the 4,065-subject trial that supported approval of the genital warts indication for males. The MSM population was targeted because of high rates of anal HPV infection and disease that result from behavior-associated risk factors in this group, Merck said in its briefing material for the committee.

Gardasil was 78% efficacious in preventing the primary composite end point – HPV 6/11/16/18-related AIN of any grade and anal cancer. Efficacy fell to 75% in preventing advanced dysplasia involving cases of AIN grade 2 or higher.

CBER is convening the Vaccines and Related Biological Products Advisory Committee "to discuss the efficacy data, particularly use of the AIN end point to assess efficacy in the prevention of anal cancer," Dr. Roberts said in his review. "In addition, because the applicant is requesting that the AIN and AC [anal cancer] indication be extended to females based on clinical data in males only, CBER is seeking input on this approach to the female indication."

The agency takes issue with Merck’s inclusion of cases of condyloma acuminatum under the grouping of AIN 1 in the primary end point. These low-grade lesions are simply warts and unlikely to progress to advanced dysplasia, Dr. Roberts said. Consequently, their inclusion in an anal neoplasia/anal cancer end point is of questionable value, and the agency’s review instead emphasizes the AIN 2+ end point.

Dr. Roberts concludes that data linking anal high-risk HPV infection to AIN and subsequent anal cancer are persuasive. "AIN (particularly AIN 2+) is a reasonable correlate end point for evaluating an intervention for the prevention of anal cancer."

A key issue is the extent to which there are differences in the natural history of anal HPV infection in males and females, such as the progression of AIN.

"CBER reviewers are not aware of data to suggest that there are fundamental differences between males and females, in terms of anal anatomy, histology, or physiology. There are not, therefore, reasons to presume, a priori, that there are fundamental differences in the pathophysiology of anal HPV infections," Dr. Roberts writes.

Data show that specific behavioral and immune variables are strongly correlated with the risk of HPV acquisition and progression of HPV-associated neoplasia. "However, gender, in and of itself, does not appear to be one of the factors that modulate these risks to any substantial degree," Dr. Roberts said, adding that the percentage of anal cancers linked to HPV is approximately 90% in both men and women.

Consequently, it is reasonable to extrapolate efficacy data in males to support the AIN/anal cancer indication for females based on available epidemiological, histological, and pathophysiological data, he concludes.

CBER has not altered its overall assessment of the safety data, and no changes in the vaccine’s current postmarketing program are recommended. "Gardasil continues to have an acceptable safety profile. No new safety signals were identified," Dr. Roberts said.

Eyeing ACIP’s February 2011 Meeting

FDA approval of the AIN/anal cancer indication later this year would likely spur ACIP to revisit, at its Feb. 23-24, 2011, meeting, an earlier decision not to recommend routine administration of Gardasil to males.

ACIP currently recommends routine vaccination of females aged 11-12 years with either Gardasil or Cervarix. Vaccination is also recommended for females aged 13-26 years who have not been previously inoculated.

However, ACIP does not recommend routine use of Gardasil, the only HPV vaccine approved for both genders, in males.

ACIP met in October 2009, shortly after the FDA approved the male genital warts indication, to consider a recommendation on routine use in boys and men.

A Morbidity and Mortality Weekly Report (MMWR) article reflecting ACIP’s October 2009 deliberations cites mathematical modeling suggesting that adding male vaccination is not a cost-effective strategy for reducing the overall burden of HPV-associated conditions when vaccination coverage of females is high. Instead, improving coverage in 11- and 12-year-old girls could be a more effective and cost-efficient strategy.

ACIP nevertheless provided guidance that Gardasil may be given to males who are 9-26 years old to reduce their likelihood of acquiring genital warts. The MMWR article notes that Gardasil appeared to have high efficacy for prevention of AIN in the MSM population, but this information was not available before the committee’s October 2009 meeting and had not yet been reviewed by the FDA.

At its most recent meeting on Oct. 28, 2010, one day before the FDA’s Gardasil briefing documents were released, ACIP heard a presentation from Merck on the AIN/anal cancer data. The committee also heard presentations on provider attitudes and practices regarding HPV vaccine use in males, cost-effectiveness of male vaccination, and other considerations for vaccination recommendations in males.

Dr. Lauri Markowitz, a CDC epidemiologist who serves as the agency’s lead on the ACIP HPV working group, said in an interview that the committee requested additional data on modeling, epidemiology, and HPV infection, among other issues. She said the committee could ultimately decide to vote on routine administration to males or on a strong recommendation targeting use in the MSM population.

Internal Medicine News and "The Pink Sheet" are published by Elsevier.

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

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

The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.

During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:

• continued marketing with no label changes;

• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;

• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or

• market withdrawal.

First Up: Assessing the Level of Risk

Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.

The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.

SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.

The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.

In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.

After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.

Study Population Was High-Risk

Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.

In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.

Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.

In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.

A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.

Assessing Risk by Subgroup

There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.

In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.

However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.

“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.

Three-Month Decision Point

Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.

Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.

The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.

Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.

Elsevier Global Medical News and “The Pink Sheet” are both owned 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.

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.