[Federal Register Volume 76, Number 91 (Wednesday, May 11, 2011)]
[Notices]
[Pages 27332-27335]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-11539]


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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; Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of hearing.

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SUMMARY: The Food and Drug Administration (FDA) is granting a hearing 
to Genentech, Inc. (Genentech), on the Center for Drug Evaluation and 
Research's (CDER's) proposal to withdraw approval of the breast cancer 
indication for bevacizumab (Avastin). Genentech is the sponsor for 
Avastin. Genentech and CDER are the parties to the hearing. The issues 
to be discussed and resolved at the hearing relate directly to the 
statutory and regulatory standard for FDA to withdraw accelerated 
approval of the metastatic

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breast cancer (MBC or breast cancer) indication for Avastin.

DATES:  Date and Time: The hearing will be held on June 28 and 29, 
2011, from 8 a.m. to 5 p.m.

ADDRESSES: The hearing will be held at FDA's White Oak Campus, 10903 
New Hampshire Ave., Bldg 31, Rm. 1503 (Great Room), Silver Spring, MD 
20993.

FOR FURTHER INFORMATION CONTACT: Talisha Williams, Office of the 
Ombudsman, Office of the Commissioner, Food and Drug Administration, 
10903 New Hampshire Ave., Silver Spring, MD 20993, 301-796-8530, e-
mail: Talisha.Williams@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: Registration and Requests to Make Oral 
Presentations: On June 28, 2011, up to 2 hours of the hearing have been 
reserved for oral presentations by persons other than the parties.
    If you wish to make an oral presentation during the hearing, you 
must register by submitting an electronic or written request by May 27, 
2011, to Talisha Williams (see FOR FURTHER INFORMATION CONTACT). 
Depending on the number of requests, FDA may not be able to honor all 
such requests. You must provide your name, title, business affiliation 
(if applicable), address, telephone and fax numbers, e-mail address, 
and (if applicable) type of organization you represent (e.g., industry, 
consumer organization). You also should submit a brief summary of the 
presentation, including the discussion topic(s) that will be addressed 
and the approximate time requested for your presentation. We encourage 
individuals and organizations with common interests to consolidate or 
coordinate their presentations to allow adequate time for each request 
for presentation. If there are many requests to present during the 2-
hour period, the amount of time that can be allotted to each presenter 
may be limited to provide an opportunity to as many persons wishing to 
present as possible. Persons registered to make an oral presentation 
should check in with Talisha Williams before the hearing. Participants 
should submit a copy of each presentation to Talisha Williams.
    We will file the hearing schedule, indicating the order of 
presentation and the time allotted to each person, with the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852 and it will be posted on 
http://www.regulations.gov. We will mail, e-mail, or telephone the 
schedule to each participant before the hearing. In anticipation of the 
hearing presentations moving ahead of schedule, participants are 
encouraged to arrive early to ensure their designated order of 
presentation. Participants who are not present when called risk 
forfeiting their scheduled time.
    If you need special accommodations due to a disability, please 
contact Talisha Williams at least 7 days in advance.
    Registration and Requests to Attend the Hearing: The public hearing 
is free, but all persons wishing to attend the hearing, who have not 
registered to make an oral presentation, must register with FDA in 
advance of the hearing. By May 20, 2011, FDA will post further details 
regarding the registration process for attendees to its Web site at 
http://www.fda.gov. Beginning May 27, 2011, you will be able to 
register to attend the hearing via FDA's Web site at http://www.fda.gov. Space in the Great Room, where the hearing is to be held, 
will be limited to 300 persons from the general public, and thus 
registration will be first-come, first-served.
    Web cast: The hearing will also be available to be viewed online 
via a Web cast. Availability of the Web cast to the public will also be 
limited to a certain number of persons, and registration will be 
required to access the Web cast. By May 20, 2011, FDA will post further 
details regarding the Web cast and the registration process for the Web 
cast to the Agency's Web site at http://www.fda.gov. Beginning May 27, 
2011, you will be able to register to access the Web cast via FDA's Web 
site at http://www.fda.gov.
    Comments: Regardless of participation in the public hearing, 
interested persons may submit electronic or written comments on CDER's 
proposal to withdraw approval of the MBC indication. Submit electronic 
comments to http://www.regulations.gov. Submit written comments to the 
Division of Dockets Management (see Registration and Requests to Make 
Oral Presentations). Comments must be submitted by July 14, 2011. It is 
only necessary to send one set of comments. It is no longer necessary 
to send two copies of mailed comments. Identify comments with the 
docket number found in brackets in the heading of this document. 
Submission of comments prior to the meeting is strongly encouraged.
    All documents filed or posted in this matter are available for 
public review under Docket No. FDA-2010-N-0621 in the Division of 
Dockets Management (see Registration and Requests to Make Oral 
Presentations) between 9 a.m. and 4 p.m., Monday through Friday. 
Persons with access to the Internet may obtain documents at http://www.regulations.gov.

I. Background

    Section 506 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
(21 U.S.C. 356), which was added to the statute with the passage of the 
Food and Drug Modernization Act of 1997, provides for the accelerated, 
or fast track, approval of a drug product when FDA determines that the 
``* * * product has an effect on a clinical endpoint or on a surrogate 
endpoint that is reasonably likely to predict clinical benefit'' 
(section 506(b)(1)). Section 506 of the FDC&C Act also provides 
explicit authority for FDA to use expedited procedures to withdraw 
accelerated approval of a product under certain circumstances.
    FDA's regulations regarding the accelerated approval of biological 
products (Sec. Sec.  601.40 through 601.46; part 601, subpart E) (21 
CFR 601.40 through 601.46; 21 CFR part 601, subpart E)) set forth the 
procedures that FDA uses to withdraw accelerated approval for a 
biological product. Under Sec.  601.43(b), FDA notifies the sponsor of 
the biological product of an opportunity for a hearing on a proposal to 
withdraw approval of the product. FDA conducts such hearings in 
accordance with the procedures set forth in part 15 (21 CFR part 15), 
with some specific modifications, including the presence of an advisory 
committee duly constituted under 21 CFR part 14, which provides advice 
and recommendations to the Agency (Sec.  601.43(e)).
    On February 22, 2008, under section 506 of the FD&C Act and FDA's 
implementing regulations for accelerated approval of biological 
products, CDER approved supplemental biological license application 
125085/91 (the sBLA), which was submitted by Genentech. The sBLA sought 
approval of Avastin for use in combination with the chemotherapy drug 
paclitaxel for the treatment of patients who have not received 
chemotherapy for metastatic HER2 negative breast cancer. Consistent 
with the regulations requiring postmarket studies for accelerated 
approval (see CFR 601.41 and 601.43), CDER's approval of the MBC 
indication for Avastin was subject to the requirement that the product 
be studied further to verify and describe clinical benefit. The two 
specific ongoing clinical trials identified to verify and describe 
clinical benefit were: Trial BO17708 (AVADO) (NCT 00333775) and Trial 
AVF 3694g (RIBBON1) (NCT 00262067). On November 16, 2009, Genentech 
submitted the results of the AVADO and RIBBON1 trials to CDER.

[[Page 27334]]

    On December 16, 2010, CDER issued a notice for opportunity for a 
hearing (NOOH) on a proposal to withdraw approval of the MBC indication 
for Avastin. The NOOH stated CDER's conclusions that AVADO and RIBBON1 
failed to verify clinical benefit with respect to the MBC indication 
for Avastin and that, because of that failure, the risk/benefit 
assessment that supported the initial approval of the MBC indication 
had changed significantly such that Avastin no longer met the safety 
and effectiveness requirements for continued marketing for that 
indication. On January 16, 2011, Genentech requested a hearing and 
submitted the data and information on which it intends to rely at the 
hearing.
    By letter dated February 23, 2011, Karen Midthun (the Presiding 
Officer), advised the parties that FDA was granting the hearing request 
and that the Commissioner of Food and Drugs (the Commissioner) had 
appointed her as presiding officer. The letter stated that, although 
not required by FDA's regulations (see Sec.  601.43(d)), the Agency 
would be observing separation of functions for purposes of the hearing. 
The letter further communicated FDA's conclusion that FDA's regulations 
require that the Agency's Oncologic Drugs Advisory Committee (ODAC) 
serve as the advisory committee for the hearing and to provide advice 
and recommendations to the Commissioner under Sec.  601.43(e)(1). 
Finally, the Presiding Officer directed Genentech and CDER to submit a 
joint statement of undisputed facts and disputed issues.
    On April 7, 2011, Genentech and CDER submitted a ``Joint Statement 
of Undisputed Facts and Select Issues in Dispute'' (Joint Statement). 
On April 8, 2011, Genentech and CDER submitted separate statements of 
questions to be presented at the hearing.

II. Hearing Issues and Process

    FDA hereby grants Genentech's request for a hearing under Sec.  
601.43 and part 15 on CDER's proposal to withdraw approval of the MBC 
indication for Avastin.

A. Issues

    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 Sec.  601.43. This regulation was 
finalized in 1992 (57 FR 58942, 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 
Sec.  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 Sec.  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

[[Page 27335]]

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 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.

B. Process

    As further specified previously in this document, the hearing will 
be held in the Agency's White Oak Conference Center on June 28 and 29, 
2011. Although no statute or regulation requires that separation of 
functions be applied to this proceeding, the Agency is observing 
separation of functions as a matter of policy in this matter. As the 
Center responsible for the proposed action, CDER, like Genentech, will 
be a party to the hearing and will be responsible for presenting its 
position at the hearing in accordance with Sec.  601.43 and part 15.
    In accordance with Sec.  601.43(e)(2), no person other than the 
Presiding Officer, the three designated representatives for each party, 
and the members of the advisory committee may question witnesses 
present at the hearing.
    Because this is a public hearing, it is subject to our regulations 
concerning the policy and procedures for electronic media coverage of 
public agency administrative proceedings (Sec. Sec.  10.200 through 
10.206 (21 CFR 10.200 through 10.206)). These procedures are primarily 
intended to expedite media access to our public proceedings. 
Representatives of the electronic media may be permitted, subject to 
certain limitations, to videotape, film, or otherwise record our public 
administrative proceedings, including the testimony of witnesses in the 
proceedings. Accordingly, the parties and nonparty participants to this 
hearing, and all other interested persons, are directed to Sec. Sec.  
10.200 through 10.206, for a more complete explanation of those 
regulations' effect on this hearing.

III. Transcripts

    Please be advised that, as soon as a transcript is available, it 
will be accessible at http://www.regulations.gov. It may be viewed at 
the Division of Dockets Management (see Registration and Requests to 
Make Oral Presentation). A transcript will also be available in either 
hardcopy or on CD-ROM, after submission of a Freedom of Information 
request. Written requests are to be sent to the Division of Freedom of 
Information (HFI-35), Office of Management Programs, Food and Drug 
Administration, 5600 Fishers Lane, Rm. 6-30, Rockville, MD 20857.

    Dated: May 6, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-11539 Filed 5-6-11; 4:15 pm]
BILLING CODE 4160-01-P