CDER: Avastin Breast Cancer Claim Undermines Approval Process

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.