FDA Asks ODAC to Ponder Shift Away From Single-Arm Studies

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.