FDA Response June 25 2009

From: Berbakos, Elizabeth G [mailto:[email protected]]
Sent: Thursday, June 25, 2009 1:11 PM
To: Aguilar, Brenda; Matsuoka, Karen Y.; Malanoski, Margaret A.
Cc: Lutter, Randall; Boocker, Nancy; Axelrad, Jane A; Presley, Denver; Capezzuto, JonnaLynn
Subject: FW: Antimicrobials

Karen/Brenda, please see the attached response to your questions on the
Antimicrobials Guidance.
Liz

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1) The PRA requires agencies to solicit comment on, among other things, “ways
to enhance the quality, utility, and clarity of the information to be collected.”
FDA Response:
We believe that the comments identified below refer to policy issues rather than
paperwork burdens. None of these comments specifically mentioned the information
collections or paperwork burdens. We also note that none of these comments on the
guidance explicitly questioned the practical utility of the ICR. No comments were
submitted in response to FDA’s 30-day PRA Notice, so we do not believe these
comments identified by OMB were PRA-related.
A -- Wyeth specifically requested clarification on reporting option IV.C. (see page
5).
FDA Response:
Application holders for systemic antibacterial products should have the expertise to
properly meet the requirements for maintaining the susceptibility test interpretive criteria
(breakpoints) in the labeling of their approved products. The type of information that an
application holder might submit will depend upon the scientific basis for why the firm
believes that the standard does not apply to its drug product. FDA expects an application
holder to articulate its scientific rationale for why the standard would not apply and no
labeling change is needed. This type of scientific assessment and reasoning is
commonly provided throughout the New Drug Application process.
In addition, FDA intends to issue a separate guidance document with recommendations
on the scientific issues associated with updating susceptibility test interpretive criteria.
This guidance was intended to address procedural issues of how FDA will comply with
the Congressional mandate in section 1111 of the Food and Drug Administration
Amendments Act (FDAAA). We believe this separate guidance will provide the level of
detail requested by Wyeth.
B -- Wyeth also suggested that the utility of the information collection could be
improved—and burden reduced—if FDA were more clear about why FDA decided
to adopt any particular standard. I quote: “We believe that recognition of a
standard by publishing in the FR does not appropriately communicate revisions
or updates to the standard and places an undue burden on the application holder
to identify and assess each change. Communication of this information is
necessary for the application holder to make a timely and accurate assessment of
the label, determine if a labeling update is needed, provide justification for not
making a label change, or justification to accept an alternate standard.”
“Determine if a labeling update is needed” is burden associated with option IV.C.
“Provide justification for not making a label change” is IV.C.
FDA Response:
We disagree that we are placing an additional burden on application holders. All
application holders are under a continuing obligation to update their labeling “when new

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information becomes available that causes the labeling to become inaccurate, false, or
misleading” (21 CFR 201.56(a)). Thus, application holders should be independently
reviewing their records, published literature, and the actions of nationally and
internationally recognized standard setting organizations, to determine whether the
susceptibility test interpretive criteria for their drug products is up to date. This guidance
provides a less burdensome alternative of relying on an FDA-recognized breakpoint to
update labeling. Without this guidance, the application holder would still have to evaluate
whether its labeling needs updating.
We note that nationally and internationally recognized standard setting organizations
generally have an open process for updating their standards. The information
considered in this process should provide adequate information about the need to
update labeling. In addition, prior to the first FDA recognition of breakpoints, we intend to
request input from an Advisory Committee, which will be a public process.
2) The PRA requires agencies to solicit comment on the “accuracy of FDA’s
estimated burden...”
Hospira indirectly commented on the burden associated with assessing which
reporting option (including the option of not changing the labeling at all). Hospira
does not cite IV.C., but it is clearly implied. The comment reads as follows:
“The process for the evaluation of the published standards would first include an
assessment of the changes to determine whether the published standards should
be accepted (approach IV.B.1) or whether the applicant chooses to maintain the
current standard used in their application or another standard not recognized by
the Agency (Approach IV.B.2). Either scenario would most likely exceed the 60
days suggested by the Agency....”
Again, Hospira does note cite IV.C. but the “or whether the applicant chooses to
maintain the current standard used in their application” is option IV.C. Therefore,
it is relevant to this collection.
FDA Response:
Hospira’s comment does not mention the accuracy of FDA’s estimated paperwork
burden (i.e., it does not take issue with the estimated 16 hours to prepare a submission
explaining why a recognized breakpoint does not require updated labeling). This
comment applies to a policy issue regarding the timing of when an application holder
should submit its updated labeling or its explanation why no update is needed. As the
guidance explains, all application holders are under a continuing obligation to update
their labeling “when new information becomes available that causes the labeling to
become inaccurate, false, or misleading” (21 CFR 201.56(a)). If the labeling is false or
misleading in any particular, a drug can be deemed misbranded. The guidance is merely
a recommendation about how quickly an application holder should update its labeling.
We note that we have revised the guidance to recommend that application holders make
their submission within 90 days of FDA recognizing a standard. We disagree with
Hospira’s argument that it would most likely exceed 60 days suggested by the Agency to
decide whether to update labeling. It is important to remember that FDA recognition of a

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standard will occur after a standard setting organization has adopted and published a
new standard. Generally, this is a lengthy process where the standard setting
organization considers scientific evidence for a new standard at a meeting and then
adopts the standard at a following meeting many months later. During this period an
application holder has more than adequate time to consider whether the scientific
evidence is appropriate for its drug product.
3) The PRA requires agencies to solicit comment on “ways to minimize the burden
of the collection of information on respondents...”
Almost every commenter said that it is burdensome to have to keep searching the
FR to see if FDA published updated standards. Since learning about the FR notice
is the trigger for any of the 3 reporting options—including IV.C—this is a relevant
comment. In fact, Merck specifically identifies this comment as pertaining to
option IV.C: “The Draft Guidance seems to suggest that marketing application
holders will learn about and react to recognized standard when published in the
FR. A described in the Draft Guidance, we believe that is a reversal of the process.
It would be a significant burden to mobilize internal resource to put together and
submit a labeling supplement to meet the 60 [calendar] day deadline form
publication of a recognized standard. We believe a more direct process would be
for the agency to first notify appropriate antibacterial application holders with
sufficient time to respond prior to FR publication.”
These commenters suggested a specific alternative. FDA should address the
alternative.
FDA Response:
As explained in our response to question 2, applications holders currently have an
ongoing obligation to update their labeling and monitor scientific information regarding
their drug products. By issuing an FR Notice recognizing breakpoints, we are helping
these application holders. The FR Notice gives them the option to significantly reduce
the burden of providing scientific information to support their proposed labeling changes.
In addition, they should know about the possible need to update an individual drug
product’s labeling well before FDA issues its FR Notice because they can monitor the
standard-setting process.
We disagree that it is a significant burden to for an application holder to look for
notification in an FR Notice. One purpose of the Federal Register is to provide notice to
interested parties of government regulatory actions. This mechanism developed
generally to avoid the burden on government agencies to notify each potential regulated
entity and the general public of its proposed or final regulatory actions. In addition, FDA’s
website will also make the FR Notice publicly available.
4) Comments regarding the information collection requirements but covered
under different ICRs
These comments should be acknowledged and the response should be something
to the effect that they are covered under different OMB control numbers. To the
extent that the comments suggest that the burden estimates for those ICRs are

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not accurate or the utility of those ICRs could be improved, FDA should state that
FDA will revise the estimates or improve the utility of those ICRs when they next
come up for renewal.
FDA Response:
We will address those comments, to the extent necessary and appropriate, when we
propose 0910-0572 and 0910-0001 to OMB for extension of the approvals.

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