Cancer Approval Standards at Stake in Avastin Hearing

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.