Here are the issues of the hearing as described by the government in its docket. FAMEDS has highlighted the questions at issue to make them easier to find. The FDA and the Avastin's manufacturer, Genentech, look at the same data and draw different conclusions. What this hearing comes down to are a series of decisions that will actually be no more than opinions. Due to the failure of the FDA to specify clear pass/fail criteria for Avastin, there is now mass confusion over this drug. Given the uncertainty, FAMEDS believes that the jury should acquit and keep Avastin on label. To do otherwise, is to render a grave, irreversible injustice upon current patients.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2010-N-0621]
Proposal to Withdraw Approval for the Breast Cancer Indication for Bevacizumab (Avastin); Hearing
The issues to be decided at the hearing relate directly to the statutory and regulatory standard for FDA to withdraw accelerated approval of the MBC indication for Avastin. On April 7, 2011, in response to direction from the Presiding Officer to consult with each other and submit an agreed statement of the issues in dispute in this hearing, counsel for Genentech and CDER reported that they were unable to reach agreement on how to frame the issues to be resolved. The issues for decision will thus be stated in accordance with the statute and regulations.
The applicable regulation is § 601.43. This regulation was finalized in 1992 (57 FR58942, December 11, 1992). In 1997, Congress enacted section 506 of the FD&C Act, which sets out criteria for expedited approval and withdrawal of approval of "fast-track products." It is FDA's position that section 506(b) of the FD&C Act, while enacted after the finalization of the regulation, essentially codifies in the statute FDA's accelerated approval regulations. Section 506(b)(3) of the FD&C Act sets out four bases for expedited withdrawal of approval of a product approved under the accelerated procedures. Section 601.43(a) sets out six bases. In this matter, there appears to be agreement that two of the bases will be at issue in this hearing. These two bases appear in both the regulations and the statute.
One basis for withdrawal of approval of a product approved under the accelerated procedures, set out in nearly identical language in § 601.43(a)(1) and section 506(b)(3)(B) of the FD&C Act, is that FDA may withdraw approval if, in the words of the regulation: "A postmarketing clinical study fails to verify clinical benefit", or, in the words of the statute, if: "[A] post-approval study of the fast track product fails to verify clinical benefit of the product." In this case, the parties agree that "During CDER's review of [the sBLA], Genentech proposed and CDER agreed that the AVADO and RIBBON1 trials could serve as the required trial(s) to verify and describe the clinical benefit" (Joint Statement, paragraph 31). Thus, one ultimate issue in this hearing is:
Issue 1. Do the AVADO and RIBBON1 trials fail to verify the clinical benefit of Avastin for the breast cancer indication for which it was approved?
If, after the hearing, the Commissioner concludes that these studies fail to verify the clinical benefit of Avastin for that indication, FDA may withdraw the approval.
CDER also seeks to base the withdrawal of approval on an alternative ground. This ground is set forth in the regulation and in the statute. Section 601.43(a)(6) states that FDA may withdraw approval if: "Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use."
Section 506(b)(3)(C) of the FD&C Act states that withdrawal is authorized if: "[O]ther evidence demonstrates that the fast track product is not safe or effective under the conditions of use."
In this case, the parties have agreed that the FDA-approved prescribing information for Avastin "is a fair and accurate description of the safety profile of Avastin," and that "[t]he safety data observed in the E2100, AVADO, and RIBBON1 studies were consistent with the safety profile of Avastin described in its approved prescribing information" (Joint Statement, paragraphs 22 and 23). In light of this agreement, the dispute with respect to this issue centers on the effectiveness information for the breast cancer indication, and on the appropriate risk benefit analysis to be made in light of that information as compared to the agreed risk of the product. Thus, FDA does not anticipate that the hearing will involve any dispute about the safety information in the clinical studies.
The safety profile of Avastin described in its approved prescribing information includes a black box warning concerning gastrointestinal perforation, surgery and wound healing complications, and severe or fatal hemorrhage. Genentech does not state that the use of this drug in the treatment of breast cancer is safe in the abstract. Instead, it states that the drug should be found to be safe because its use provides benefits to patients that outweigh its risks. Applying the standard in the regulation and statute to the facts presented, therefore, the issue for resolution will be:
Issue 2.A. Does the available evidence on Avastin demonstrate that the drug has not been shown to be effective for the breast cancer indication for which it was approved?
Issue 2.B. Does the available evidence on Avastin demonstrate that the drug has not been shown to be safe for the breast cancer indication for which it was approved, in that Avastin has not been shown to present a clinical benefit that justifies the risks associated with use of the product for this indication?
A third issue is presented by the fact that both section 506(b)(3) of the FD&C Act and § 601.43(a) do not by their terms require the withdrawal of an accelerated approval even if the bases for withdrawal they describe are present. Instead, in each case, the statute and regulation state that FDA "may" withdraw approval in those circumstances. This standard reflects the fact that decisions on withdrawals of approval of products necessarily reflect judgment on FDA's part as to what actions are appropriate to protect the public with respect to approved products, and what uses of those products should be stated on the labels of those products.
Genentech has stated that the "core issue presented in this proceeding [is] whether FDA should maintain or withdraw the accelerated approval of Avastin for [the MBC indication], subject to Genentech's conduct of a new confirmatory study of Avastin with paclitaxel" (Letter from Michael Labson to the Presiding Officer, April 8, 2011, page 1). CDER has stated the issue, "Whether CDER has appropriately exercised its authority by proposing to withdraw approval of the MBC indication, rather than allowing the indication to remain on the label while the sponsor designs and conducts additional studies intended to verify the drug's clinical benefit" (CDER's Statement of Questions Presented, page 3). Ultimately, while stated differently, the parties seem to agree that there is an issue of the propriety of CDER's proposed withdrawal of this indication now as opposed to the alternative of continuing the approval of the breast cancer indication while Genentech performs new clinical studies of Avastin with paclitaxel to verify the clinical benefit of the MBC indication. This statement of the issue raises the question of why, to confirm an indication for combination use with paclitaxel, Genentech proposed, and CDER agreed, that Genentech could rely on studies of Avastin in combination with chemotherapeutic agents other than paclitaxel. It appears that the explanation is that these studies were already ongoing at the time of the initial approval and both CDER and Genentech believed, at that time, that the results of these studies could provide evidence to verify the claim that Avastin, combined with paclitaxel, would have the effect indicated in the approved labeling.
FDA is addressing the issue of whether to maintain the accelerated approval while additional studies are conducted as the third issue for this hearing as follows:
Issue 3. If the Commissioner agrees with the grounds for withdrawal set out in issue 1, issue 2.A, or issue 2.B, should FDA nevertheless continue the approval of the breast cancer indication while the sponsor designs and conducts additional studies intended to verify the drug's clinical benefit?
While the parties would state the issues differently, the three issues stated in this notice will be those upon which the Commissioner expects to decide this matter. If Genentech prevails on issues 1, 2.A, and 2.B, the approval will be continued. If CDER prevails on issue 1, 2.A, or 2.B, the question of withdrawal will depend on issue 3.
In addition to the issues 1, 2.A, 2.B, and 3, Genentech has proposed to raise issues concerning the consistency of CDER's position here with CDER's decisions with respect to other products for the treatment of MBC or of other products approved under the accelerated approval program. Issues with respect to FDA action on other products are not relevant to this proceeding. Each decision to withdraw or not to withdraw the approval of a product must be made on its own merits. If the decision with respect to another product is in error, that would not justify continuing that error with respect to the MBC indication for Avastin. Moreover, as a practical matter, it would not be possible to evaluate the different circumstances associated with decisions with respect to other products in the context of this or any hearing. FDA has 11 consistently rejected attempts to bring evidence with respect to decisions on other products into hearings on approval or withdrawal of approval of products and will not deviate from that position here.