[Federal Register: July 10, 2008 (Volume 73, Number 133)]
[Rules and Regulations]
[Page 39588-39611]
[DOCID:fr10jy08-11]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 312, 314, 600, and 601

[Docket No. FDA-2004-N-0510] (formerly Docket No. 2004N-0267)

Applications for Approval to Market a New Drug; Complete Response
Letter; Amendments to Unapproved Applications

AGENCY:  Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is amending its
regulations on new drug applications (NDAs) and abbreviated new drug
applications (ANDAs) for approval to market new drugs and generic drugs
(drugs for which approval is sought in an ANDA). The final rule
discontinues FDA's use of approvable letters and not approvable letters
when taking action on marketing applications. Instead, we will send
applicants a complete response letter to indicate that the review cycle
for an application is complete and that the application is not ready
for approval. We are also revising the regulations on extending the
review cycle due to the submission of an amendment to an unapproved
application and starting a new review cycle after the resubmission of
an application following receipt of a complete response letter. In
addition, we are adding to the regulations on biologics license
applications (BLAs) provisions on the issuance of complete response
letters to BLA applicants. We are taking these actions to implement the
user fee performance goals referenced in the Prescription Drug User Fee
Amendments of 2002 (PDUFA III) that address procedures and establish
target timeframes for reviewing human drug applications.

DATES:  This rule is effective August 11, 2008.

FOR FURTHER INFORMATION CONTACT:  Brian L. Pendleton, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 6304, Silver Spring, MD 20993, 301-796-
3504; or
    Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. The Proposed Rule
    B. Changes to the Proposed Rule
II. Summary of the Final Rule
    A. Complete Response Letters
    B. Resubmissions
    C. Amendments to Unapproved Applications
III. Comments on the Proposed Rule
    A. General Comments
    B. Definitions (Proposed Sec.  314.3(b))
    C. Timeframes for Review (Proposed Sec.  314.100)
    D. Complete Response Letters (Proposed Sec.  314.110)
    E. Complete Response Letters for BLAs
    F. Miscellaneous Provisions Related to Complete Response Letters
    G. Amendments to NDAs (Proposed Sec.  314.60)
    H. Amendments to ANDAs (Proposed Sec.  314.96)
IV. Analysis of Economic Impacts
    A. Impact of the Final Rule
    B. Summary of Impacts
    C. Comments
    D. Conclusion
V. Environmental Impact
VI. Paperwork Reduction Act of 1995
VII. Federalism

I. Background

    In the Federal Register of July 20, 2004 (69 FR 43351), we
published a proposed rule to replace approvable and not approvable
letters with complete response letters and to make other changes to our
regulations on NDAs, ANDAs, and BLAs. Previous Sec.  314.110 (21 CFR
314.110) set forth provisions on the issuance of and response to
approvable letters; Sec.  314.120 (21 CFR 314.120) addressed the
issuance of and response to not approvable letters. The proposed rule
proposed to replace those provisions with a revised Sec.  314.110
regarding the issuance of complete response letters upon completion of
our review of NDAs and ANDAs.

A. The Proposed Rule

    The preamble to the proposed rule stated that the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics Evaluation
and Research (CBER) agreed to revise their regulations and procedures
to provide for the issuance of complete response letters as part of our
prescription drug

user fee performance goals. We first made the commitment regarding
complete response letters as part of the user fee performance goals
established in conjunction with the enactment of the Food and Drug
Administration Modernization Act of 1997 (Public Law 105-115) (the user
fee provisions of this act are known as ``PDUFA II''). We repeated this
commitment in the performance goals developed in conjunction with the
enactment of the Prescription Drug User Fee Amendments of 2002 (PDUFA
III), set forth in title V, subtitle A, of the Public Health Security
and Bioterrorism Preparedness and Response Act of 2002 (Public Law 107-
188). Section 502 of PDUFA III states that user fees will be dedicated
to expediting the drug development process and the process for review
of human drug applications in accordance with the new performance
goals, which are set forth in an enclosure to letters from Tommy
Thompson, Secretary of Health and Human Services, to the Chairman of
the House Committee on Energy and Commerce and the Ranking Member of
the Senate Committee on Health, Education, Labor, and Pensions (June 4,
2002) (Goals Letter).
    The proposed rule stated that, because there are no provisions on
action letters in the biological product regulations, CBER had only to
change its standard operating procedures to incorporate the issuance of
a complete response letter at the end of a review cycle for a
biological product. We noted that although CBER had already done this,
we proposed to add a regulation (proposed Sec.  601.3) on the issuance
of complete response letters concerning BLAs and BLA supplements.
    As we stated in the proposed rule, our intent in replacing
approvable and not approvable letters with complete response letters is
to adopt a more consistent and neutral mechanism to convey that we
cannot approve an application in its present form. We believe that
issuance of complete response letters will provide a more consistent
approach to informing sponsors of changes that must be made before an
application can be approved, with no implication as to the ultimate
approvability of the application.
    The proposed rule stated our intent to incorporate into the
regulations for NDAs the terminology based on the user fee performance
goals regarding class 1 and class 2 resubmissions to original NDAs and
efficacy supplements. In addition, we proposed to revise our
regulations on amendments to unapproved applications, efficacy
supplements, and resubmissions to be consistent with user fee
performance goals for these amendments.

B. Changes to the Proposed Rule

    We received 11 comments on the proposed rule. Several comments
expressed support for the adoption of complete response letters and for
several of the proposed changes to incorporate user fee goals into the
regulations. However, some comments objected to certain portions of the
proposed rule, including the following:
     The codification of different initial review cycles for
human drug applications and supplements to such applications (proposed
Sec.  314.100);
     The absence of a provision to allow applicants to request
an extension of time in which to submit a resubmission following
receipt of a complete response letter (proposed Sec.  314.110(c));
     The review cycle applicable to a resubmission of a
supplement other than an efficacy supplement (proposed Sec.
314.110(b)(1)(iii));
     FDA's discretion to defer review of an amendment until the
next review cycle (proposed Sec.  314.60(b)).
    We address all of the comments in section III of this document.
    After considering the comments, we have concluded that it is
appropriate to make several revisions to the proposed rule. The final
rule deletes the reference in proposed Sec.  314.100(a)(2) to the
adjustment of the initial review cycle for human drug applications and
supplements to such applications. Adjustment of the initial review
cycle to fewer or greater than 180 days for human drug applications and
supplements, accepted by mutual agreement between industry and FDA
under the agency's user fee performance goals, is provided for under
the adjustment by mutual agreement provision in revised Sec.
314.100(c) (see the response to comment 7 in section III.C.1 of this
document).
    The final rule also revises Sec.  314.110(c) to allow applicants an
extension of time in which to resubmit an application, to avoid having
the applicant's failure to resubmit within 1 year be regarded as a
request to withdraw the application. This revision addresses some
comments' concerns that 1 year might not be enough time in which to
resubmit an application after receipt of a complete response letter.
The final rule also revises Sec.  314.110(b)(1)(iii) to state that
resubmission of an NDA supplement other than an efficacy supplement
constitutes an agreement by the applicant to start a new review cycle,
beginning on the date we receive the resubmission, that is the same
length as the initial review cycle for the supplement (excluding any
extension due to a major amendment of the initial supplement).
    In addition to these revisions, the final rule includes other
changes to the proposed rule in response to comments.
    Several comments objected to the regulations in proposed Sec.
314.60(b) that give FDA the option to defer review of different types
of amendments until the subsequent review cycle. However, we have
determined that we need to have the ability to defer review of
amendments to the next review cycle under appropriate circumstances.
Although our policy, as reflected in guidance, is to try to review most
amendments during the initial review cycle, there are circumstances
under which deferral is necessary and appropriate, as discussed in
section III.G.1 of this document.
    On our own initiative, we also have revised Sec.  314.60(b) to
correct an inadvertent omission of a user fee performance goal
regarding major amendments to manufacturing supplements. Revised Sec.
314.60(b)(4) now specifies that submission of a major amendment to a
manufacturing supplement submitted within 2 months of the end of the
initial review cycle constitutes an agreement to extend the cycle by 2
months.
    Also on our own initiative, we have revised the proposed rule to
clarify the definition of ``efficacy supplement'' in Sec.  314.3(b) (21
CFR 314.3(b)), to state the correct address to which requests for a
hearing on the denial of approval of an NDA or ANDA must be submitted
in Sec.  314.110(b)(3), and to state the correct addresses to which
NDAs and ANDAs must be submitted in Sec.  314.440(a)(1) and (a)(2) (21
CFR 314.440(a)(1) and (a)(2)), respectively.

II. Summary of the Final Rule

A. Complete Response Letters

    We are revising our regulations to substitute complete response
letters for approvable and not approvable letters at the completion of
the review cycle for an NDA or ANDA. Under revised Sec.  314.110, we
will send a complete response letter if we determine that we will not
approve an NDA or ANDA in its present form for one or more reasons. A
complete response letter usually will describe all of the specific
deficiencies that the agency has identified in an application. Table 1
of this document summarizes the changes to our regulations that we are
making related to the adoption of complete response letters:

     Table 1.--Summary of Changes Regarding Substitution of Complete Response Letters for Approvable and Not
                                               Approvable Letters
----------------------------------------------------------------------------------------------------------------
                                                            Revised Regulations  (changes to proposed rule in
                  Previous Regulations                                           italics)
----------------------------------------------------------------------------------------------------------------
Approvable Letter for NDA                                Complete Response Letter
 States that NDA is basically approvable if       States that FDA will not approve NDA or ANDA
 certain issues are resolved.                             in its present form.
 Indicates that NDA substantially meets           Describes all specific deficiencies that FDA
 requirements of part 314 and FDA can approve it if       has identified in the application (except when the
 applicant submits additional information or agrees to    agency determines that data submitted are inadequate
 specific conditions (e.g., labeling changes).            to support approval and issues a complete response
                                                          letter without first conducting required inspection
Approvable Letter for ANDA                                and/or reviewing labeling). Deficiencies could be
 Indicates that ANDA substantially meets          minor (e.g., requiring labeling changes) or major
 requirements of part 314 and is approvable if minor      (e.g., requiring additional clinical trials).
 deficiencies are corrected.                              Reflects complete review of data in NDA or
 Describes deficiencies and states when           ANDA and any amendments FDA has reviewed.
 applicant must respond.                                  When possible, recommends actions applicant
                                                          might take to place application in condition for
Not Approvable Letter for NDA or ANDA                     approval.
 States that NDA cannot be approved for one of
 reasons in Sec.   314.125 or ANDA cannot be approved
 for one of reasons in Sec.   314.127.
 Describes deficiencies in NDA or ANDA.
----------------------------------------------------------------------------------------------------------------

    For products for which approval of a BLA is required for marketing,
we are adopting a new regulation, Sec.  601.3, which states that we
will send an applicant a complete response letter if we determine that
we will not approve a BLA or BLA supplement in its present form.

B. Resubmissions

    We are revising our regulations on the extension of the review
period due to resubmission of an NDA or ANDA after receipt of a
complete response letter. A class 2 resubmission of an NDA following
receipt of a complete response letter starts a new 6-month review
cycle. A class 1 resubmission of an NDA starts a new 2-month review
cycle.
    These provisions on class 1 and class 2 resubmissions also apply to
efficacy supplements to NDAs. For other types of NDA supplements,
resubmission starts a new review cycle the same length as the initial
review cycle of the supplement under Sec.  314.100(a), excluding any
extension due to a major amendment of the initial supplement.
    A ``major'' resubmission of an ANDA following receipt of a complete
response letter starts a new 6-month review cycle. A ``minor''
resubmission of an ANDA starts a new review cycle of an unspecified
length; under current FDA guidance, a minor resubmission usually starts
a new review cycle of between 30 to 60 days.
    The changes to our regulations on applicants' responses to action
letters are summarized in the following Table 2.

       Table 2.--Summary of Changes to Regulations Regarding Applicant's Response to Agency Action Letters
----------------------------------------------------------------------------------------------------------------
                                                            Revised Regulations  (changes to proposed rule in
                  Previous Regulations                                           italics)
----------------------------------------------------------------------------------------------------------------
Applicant's Response to Approvable Letter or Not         NDA or ANDA Applicant's Response to Complete Response
 Approvable Letter for NDA (or NDA Supplement)            Letter
Within 10 days of date of letter, NDA applicant must do  Review period is extended until applicant takes one of
 one of following:                                        following actions:
 Amend application or notify FDA of intent to     Resubmit NDA or ANDA, addressing identified
 file amendment.                                          deficiencies.
 Withdraw application.                           --Class 1 resubmission of NDA or efficacy supplement
 Request opportunity for hearing.                 starts new 2-month review cycle
 Agree to extend review period to decide which   --Class 2 resubmission of NDA or efficacy supplement
 of above actions to take.                                starts new 6-month cycle
                                                         --Resubmission of NDA supplement other than efficacy
Response to Approvable Letter for ANDA (or ANDA           supplement starts new cycle same length as initial
 Supplement)                                              review cycle for supplement (excluding any extension
 Correct deficiencies by specified date or FDA    due to major amendment)
 will refuse to approve ANDA or ANDA supplement.         --Major resubmission of ANDA or ANDA supplement starts
 Request opportunity for hearing within 10        new 6-month cycle
 days.                                                   --Minor resubmission of ANDA or ANDA supplement starts
                                                          new cycle of variable length
Response to Not Approvable Letter for ANDA (or ANDA       Withdraw NDA or ANDA.
 supplement)                                              Request opportunity for hearing.
 Same as for NDAs except that 10-day period      FDA may consider failure to take action within 1 year
 does not apply (with exception of request for            to be request to withdraw, unless applicant has
 opportunity for hearing).                                requested extension of time in which to resubmit.
 FDA may regard failure to respond within 180
 days as request to withdraw.
----------------------------------------------------------------------------------------------------------------

C. Amendments to Unapproved Applications

    We are also revising our regulations in Sec.  314.60 on extending
the review cycle following the submission of an amendment to an
unapproved NDA. Under revised Sec.  314.60(b)(1), submission of a major
amendment within 3 months of the end of the initial review cycle
constitutes an agreement to extend the review cycle by 3 months. Under
Sec.  314.60(b)(2), submission of a major amendment more than 3 months
before the end of the initial review cycle will not extend the cycle;
nor will the initial review cycle for a nonmajor amendment be extended
under Sec.  314.60(b)(3). These provisions apply to

amendments to original applications, efficacy supplements, and
resubmissions of applications and efficacy supplements. Under Sec.
314.60(b)(4), submission of a major amendment to a manufacturing
supplement within 2 months of the end of the initial review cycle
constitutes an agreement to extend the review cycle by 2 months. Under
Sec.  314.60(b)(5), submission of an amendment to a supplement other
than an efficacy or manufacturing supplement will not extend the review
cycle. For all of these amendments, we may, at our discretion, defer
review of the amendment until the subsequent review cycle, rather than
extend the initial cycle or review the amendment during the initial
cycle.
    Table 3 of this document summarizes the changes to our regulations
on amendments submitted before an action letter.

            Table 3.--Summary of Changes to Regulations on Amendments Submitted Before Action Letter
----------------------------------------------------------------------------------------------------------------
                                                            Revised Regulations  (changes to proposed rule in
                  Previous Regulations                                           italics)
----------------------------------------------------------------------------------------------------------------
Amendments to Unapproved NDAs and NDA Supplements        Amendments to Unapproved NDAs, Efficacy Supplements,
 Submission of major amendment constitutes        and Resubmissions of NDAs and Efficacy Supplements
 agreement to extend deadline for FDA decision.           Submission of major amendment within 3 months
 FDA may not extend review period more than 180   of end of initial review cycle may extend cycle by 3
 days.                                                    months; FDA may instead defer review to subsequent
 Submission of nonmajor amendment will not        cycle.
 extend review period.                                    Initial review cycle may be extended only once
                                                          for major amendment.
Amendments to Unapproved ANDAs and ANDA Supplements       Submission of major amendment more than 3
 Submission of amendment containing significant   months before end of initial review cycle will not
 data or information constitutes agreement to extend      extend cycle; FDA may instead defer review.
 review period up to 180 days.                            Submission of nonmajor amendment will not
 Same for amendments to unapproved ANDA           extend review cycle; FDA may instead defer review.
 supplements.                                            .......................................................
                                                         Amendments to Unapproved Manufacturing Supplements
                                                          Submission of major amendment within 2 months
                                                          of end of initial review cycle may extend cycle by 2
                                                          months; FDA may instead defer review.
                                                         .......................................................
                                                         Amendments to Unapproved NDA Supplements Other Than
                                                          Efficacy and Manufacturing Supplements
                                                          Submission of any amendment will not extend
                                                          initial review cycle; FDA may instead defer review.
                                                         .......................................................
                                                         Amendments to Unapproved ANDAs
                                                          Unchanged.
----------------------------------------------------------------------------------------------------------------

III. Comments on the Proposed Rule

    We received written comments from 6 drug manufacturers; 4
associations representing the drug, biologic, and medical device
industries; and an individual (11 comments in all). A summary of the
comments received and our responses follow.

A. General Comments

    (Comment 1) One comment stated that throughout the proposed rule
the word ``response'' is used without identifying whose response. As an
example, the comment cites proposed Sec.  314.101(f)(1)(ii), under
which we would issue a notice of opportunity for hearing if an
applicant asked us to provide it an opportunity for a hearing on an
application ``in response to a complete response letter.'' To clarify
whose response is being referenced in a particular provision, the
comment recommended that the provision always identify the respondent
(e.g., use ``an applicant's response to a complete response letter'' in
the above example).
    (Response) We do not believe that it is necessary to revise Sec.
314.101(f)(1)(ii) as requested because only an applicant (not FDA) can
respond to a complete response letter as defined in Sec.  314.3(b). We
reviewed the other provisions in the proposed rule to ensure that the
language does not suggest that the agency might respond to a complete
response letter and that the use of the term ``response'' is not
otherwise confusing. We conclude that it is unnecessary to revise the
regulations in parts 314, 600, and 601 (21 CFR parts 314, 600, and 601)
to identify who is responding to a complete response letter, as it is
always the applicant who is responding.
    (Comment 2) One comment encouraged us to consider an approval
process whereby once we issue an approval letter, the applicant may
begin marketing upon notification of approval and not have to address
any additional regulatory hurdles, other than perhaps waiting for the
exclusivity period of a previously approved drug to end.
    (Response) The comment is beyond the scope of this rulemaking. With
the exception of Sec.  314.430 on public disclosure of information in
applications, this rule does not address approval or post-approval
regulatory matters.

B. Definitions (Proposed Sec.  314.3(b))

1. Class 1 and Class 2 Resubmissions
    Proposed Sec.  314.3(b) would have defined ``Class 1 resubmission''
as the resubmission of an application, following receipt of a complete
response letter, that contains final printed labeling, draft labeling,
certain safety updates, stability updates to support provisional or
final dating periods, commitments to perform Phase 4 studies (including
proposals for such studies), assay validation data, final release
testing on the last lots used to support approval, minor reanalyses of
previously submitted data, and other comparatively minor information.
    (Comment 3) Two comments stated that the proposed definition of
class 1 resubmission lists items that qualify a resubmission as class 1
and concludes the list with the conjunction ``and,'' implying that a
class 1 resubmission contains all of the listed items. The comments
recommended that a class 1 resubmission be defined as a

resubmission that ``contains one or more of the following'' listed
items.
    (Response) We agree that this change is appropriate and have
revised the definition of class 1 resubmission accordingly. Also, on
our own initiative, but in a similar spirit of clarifying what was
proposed, we are further revising the definition of class 1
resubmission to state that it includes not only the resubmission of an
application but also the resubmission of an efficacy supplement. We are
making a corresponding revision to the definition of ``Class 2
resubmission'' in Sec.  314.3. This makes these definitions consistent
with the provisions on class 1 and class 2 resubmissions of
applications and efficacy supplements in Sec.  314.110(b)(1)(i) and
(b)(1)(ii). In addition, because we now refer to Phase 4 studies as
``postmarketing'' studies (see 21 CFR 314.81(b)(2)(viii)), we are
revising the definition of class 1 resubmission accordingly.
    (Comment 4) One comment asked how we intended to ensure consistency
across review divisions regarding the classification of resubmissions.
    (Response) We believe that the definition of class 1 resubmission
provides adequate information on the types of resubmissions that are
regarded as class 1 resubmissions and, by omission, the types of
resubmissions that are regarded as class 2 resubmissions. For several
years, CDER review divisions have been applying these definitions in
reviewing resubmissions of applications that are subject to user fees.
Nevertheless, CDER will provide training and information to help ensure
that the final rule is applied consistently among the review divisions.
2. Complete Response Letter
    Proposed Sec.  314.3(b) would have defined ``complete response
letter'' as a written communication to an applicant from FDA usually
identifying all of the deficiencies in an application or abbreviated
application that must be satisfactorily addressed before it can be
approved.
    (Comment 5) One comment stated that absent unusual circumstances, a
complete response letter should clearly define the specific
deficiencies in an application to avoid presentation of new issues at a
later date and minimize the potential for cycles of complete response
letters. Two comments stated that specifying that a complete response
letter ``usually'' identifies all of the deficiencies in an application
is contrary to the plain meaning of ``complete response'' because any
response that does not identify all of the deficiencies in an
application is not complete. The comments stated that the use of vague
language makes the regulation impossible to interpret and leaves the
regulatory process open to inconsistencies across divisions. The
comments stated that the user fee goals do not include similarly vague
language but instead reflect FDA's commitment to review and act on
certain percentages of applications within specified timeframes. The
comments noted that the user fee goals state that the term ``review and
act on'' means the issuance of a complete action letter after the
complete review of a filed complete application. The comments
acknowledged that, for drug products, we might issue a complete
response letter without first conducting inspections or reviewing
labeling (under proposed Sec.  314.110(a)(3)), but the comments
requested that we revise the definition of complete response letter to
specify which aspects of a complete review might be postponed while
allowing the agency to issue a complete response letter. One of the
comments suggested that the definition specify that we may issue a
complete response letter ``without first conducting required
inspections and/or reviewing proposed product labeling when FDA
determines that the data submitted are inadequate to support approval
as described in Sec.  314.110(a)(3).''
    (Response) We do not agree that the definition of complete response
letter should be revised as suggested. The statement that a complete
response letter ``usually'' identifies all of the deficiencies in an
application is appropriate because Sec.  314.110(a)(1) states that a
complete response letter will describe all of the deficiencies ``except
as stated in paragraph (a)(3) * * *'' In turn, paragraph (a)(3) states
that if we determine that the data submitted are inadequate to support
approval, we might issue a complete response letter without first
conducting required inspections and/or reviewing proposed product
labeling. Those are the only circumstances under which the complete
response letter would not describe all of the known deficiencies in an
application. We do not believe that it is necessary for the definition
of complete response letter to specify which particular aspects of a
complete review might be postponed.
    However, we believe that it is necessary to revise the definition
of complete response letter to make clear that a complete response
letter is a communication ``usually describing all of the deficiencies
that the agency has identified in an application or abbreviated
application that must be satisfactorily addressed before it can be
approved'' (Sec.  314.3(b)). This addresses the possibility that an
applicant's response to a deficiency that we have identified in an
application might reveal other deficiencies that we had not identified
and which we accordingly had been unable to describe in the complete
response letter. Although we seek to identify all deficiencies during
the initial review period, we sometimes become aware of deficiencies
only during a subsequent review period. It would be inconsistent with
section 505(d) of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 355(d)) and FDA regulations to approve an application
despite an applicant's failure to address deficiencies solely because
those deficiencies were identified only after issuance of a complete
response letter, and we do not intend to allow this result.
    (Comment 6) One comment recommended that we add to the definition
of complete response letter the following statement: ``Where
appropriate, a complete response letter will describe the actions
necessary to place the application in condition for approval.''
    (Response) Because this statement appears in revised Sec.
314.110(a)(4), we do not believe that it is necessary to add this
statement to the definition of complete response letter in Sec.  314.3.
3. Efficacy Supplement
    Proposed Sec.  314.3(b) would have defined ``efficacy supplement''
as a supplement to an approved application proposing to make one or
more of the following changes to product labeling:
    1. Add or modify an indication for use;
    2. Revise the dose or dose regimen;
    3. Provide for a new route of administration;
    4. Make a comparative efficacy claim naming another drug product;
    5. Significantly alter the intended patient population;
    6. Change the marketing status from prescription to over-the-
counter use;
    7. Complete the traditional approval of a product originally
approved under subpart H of this part; or
    8. Incorporate other information based on at least one adequate and
well-controlled clinical study.
    On our own initiative, we are making three changes to the proposed
definition of efficacy supplement. First, we are revising the
definition to state that an efficacy supplement means a supplement to
an approved application proposing ``to make one or more related changes
from among the following changes to product labeling * * *''.

This change makes the definition consistent with our user fee
``bundling'' policy, which allows certain related changes (such as a
change in indication and a related change in dose regimen) to be made
in the same supplement with only one fee (see the FDA guidance for
industry entitled ``Submitting Separate Marketing Applications and
Clinical Data for Purposes of Assessing User Fees'').
    The second change that we are making to the definition of efficacy
supplement is to replace the term ``indication for use'' (in the first
listed change) with the term ``indication or claim.'' The definition of
``human drug application'' in section 735(1) of the act (21 U.S.C.
379g(1)) includes the term ``indication for a use.'' As part of our
user fee assessment policy, we have interpreted the term ``indication
for a use'' more broadly than the term ``indication,'' as the latter
term is commonly used (i.e., to mean a claim that a drug is effective
for a particular use, for purposes of complying with the requirements
on the content and format of labeling for prescription drugs in 21 CFR
201.57(c). This change clarifies that an efficacy supplement can be
submitted to add or modify an indication or claim.
    The third change that we are making to the definition of efficacy
supplement concerns efficacy supplements that involve the traditional
approval of a product that was originally approved under part 314,
subpart H, regarding accelerated approval for drugs for serious or
life-threatening illnesses. It is possible that an efficacy supplement
might be intended to provide evidence of effectiveness for the
traditional approval of a subpart H drug but not actually complete the
traditional approval of the drug. Therefore, we are revising the
definition of efficacy supplement to clarify that such a supplement can
be submitted to provide for the traditional approval of a product
originally approved under subpart H or to provide evidence of
effectiveness necessary for traditional approval of such a product.

C. Timeframes for Review (Proposed Sec.  314.100)

1. Initial Review Cycle
    Proposed Sec.  314.100(a)(1) stated that, except as provided in
Sec.  314.100(a)(2), within 180 days of receipt of an NDA or ANDA, we
will review the application and send the applicant an approval letter
or a complete response letter; this 180-day period is called the
initial review cycle. Proposed Sec.  314.100(a)(2) stated that, for
drug applications that are human drug applications, as defined in
section 735(1)(A) and (B) of the act, or supplements to such
applications, as defined in section 735(2) of the act, the initial
review cycle will be adjusted to be consistent with the agency's user
fee performance goals for reviewing such applications and supplements.
    (Comment 7) One comment objected to proposed Sec.  314.100(a)(2),
stating that although the user fee goals recognize that we typically do
not meet the 180-day statutory review deadline, this should not be
memorialized in a regulation. The comment stated that even though the
statutory review period is regarded mainly as aspirational, it is
important to maintain it within the regulations.
    (Response) We agree with the comment that a specific provision
solely addressing the adjustment of the initial review cycle for human
drug applications and supplements to these applications is not
necessary. Therefore, we have deleted proposed Sec.  314.100(a)(2).
However, we note that, since the enactment of the Prescription Drug
User Fee Act of 1992 (PDUFA) (Public Law 102-571), there has been a
mutual understanding between industry and the agency that the review
cycle for an application or supplement subject to user fees may be
adjusted (either shortened or lengthened) in accordance with the user
fee performance goals. Previous Sec.  314.100(c) provided for an
extension of the review cycle by mutual agreement between FDA and an
applicant (as well as an extension as a result of a major amendment
under Sec. Sec.  314.60 or 314.96). Consistent with the long-standing
approach to applications subject to user fees, we have revised Sec.
314.100(c) to state that the initial review cycle may be adjusted by
mutual agreement between FDA and an applicant or as provided in
Sec. Sec.  314.60 and 314.96.
    Correspondingly, the final rule also deletes proposed Sec.
314.101(f)(2). Current Sec.  314.101(f)(1) states that within 180 days
after the date of filing, plus the period of time the review period was
extended (if any), FDA will either approve the application or issue a
notice of opportunity for hearing. Proposed Sec.  314.101(f)(2) stated
that, for human drug applications and supplements, the 180-day period
after the date of filing would be adjusted to be consistent with the
user fee performance goals. Proposed Sec.  314.101(f)(2) is not needed
because Sec.  314.101(f)(1) encompasses extension of the review period
beyond 180 days as well as circumstances under which FDA might approve
an application in less than 180 days, regardless of whether such
actions are the result of conformance to user fee performance goals.
2. Withdrawal and Later Submission
    Proposed Sec.  314.100(b) stated that at any time before approval,
an applicant may withdraw an application under Sec.  314.65 (21 CFR
314.65) or an abbreviated application under Sec.  314.99 (21 CFR
314.99) and later submit it again for consideration.
    (Comment 8) Two comments stated that Sec.  314.100(b) should be
revised to address the withdrawal of an application after receipt of a
complete response letter. The comments stated that if a complete
response letter is followed by withdrawal of the application, the
subsequent submission of ``the same'' application would also constitute
a ``resubmission.'' The comments suggested adding the following to
Sec.  314.100(b): ``Except when preceded by a complete response letter,
applications withdrawn prior to approval that are submitted again for
the same product are not considered resubmissions as defined in Sec.
314.3(b) of this part.''
    (Response) We do not agree with the comments because we regard an
application that is withdrawn at any time before approval and submitted
again for the same product as an original application, rather than a
resubmission. The final rule defines ``original application'' (in Sec.
314.3(b)) as a pending application for which FDA has never issued a
complete response letter or approval letter, or an application that was
submitted again after FDA had refused to file it or after it was
withdrawn without being approved. Under the proposed rule, a
``resubmission'' was defined (in proposed Sec.  314.110(b)(1)) as
``submission by the applicant of all materials needed to fully address
all deficiencies identified in the complete response letter.''
Consistent with our approach to applications that are withdrawn before
approval and later submitted again, we have added the following
statement to the definition of resubmission: ``An application or
abbreviated application for which FDA issued a complete response
letter, but which was withdrawn before approval and later submitted
again, is not a resubmission.'' For clarity, we are moving the
definition of resubmission to Sec.  314.3 from Sec.  314.110(b)(1).

D. Complete Response Letters (Proposed Sec.  314.110)

1. Content of Complete Response Letters
    Proposed Sec.  314.110(a) would have required us to send an
applicant a

complete response letter if we determined that we will not approve the
application or abbreviated application in its present form for one or
more of the reasons given in Sec.  314.125 or Sec.  314.127,
respectively.
    (Comment 9) One comment stated that it concurred with our view that
the complete response letter should be a neutral mechanism to convey
that an application cannot be approved in its present form. The comment
agreed that use of the complete response letter will ensure consistency
in how sponsors are informed of changes needed for approval, without
implying anything about ultimate approvability. One comment stated that
use of the complete response letter will provide a more efficient
mechanism for application review.
    (Response) As stated in the preamble to the proposed rule, we agree
that the use of complete response letters will provide a more neutral
and consistent mechanism than the use of approvable and not approvable
letters to convey that an application cannot be approved in its present
form.
    a. Specific deficiencies. Under proposed Sec.  314.110(a)(1), a
complete response letter would have described all of the specific
deficiencies in an application or abbreviated application, except as
stated in Sec.  314.110(a)(3).
    (Comment 10) One comment stated that we should clearly identify and
define the specific deficiencies in an application when drafting a
complete response letter, adding that one purpose of the complete
response letter is to minimize paperwork and delays between an
applicant and the agency.
    (Response) We agree with the comment. The intent of Sec.
314.110(a)(1) is that we will identify and describe all of the known
deficiencies (except as provided in Sec.  314.110(a)(3)) to enable
applicants to provide appropriate responses. However, consistent with
our response to comment 5, we have revised Sec.  314.110(a)(1) to state
that a complete response letter will describe all of the specific
deficiencies that we have identified in an application at the time we
issue the complete response letter. This change reflects the
possibility that we might become aware of certain deficiencies only
during a subsequent review period, such as while reviewing an
applicant's response to a previously identified deficiency.
    (Comment 11) One comment asked that we clarify what mechanisms of
communication we will use during the review cycle to convey to sponsors
potential deficiencies that we have discovered to enable sponsors to
address these deficiencies as quickly as possible. The comment stated
that there would be few, if any, applications that would completely
satisfy FDA reviewers in the first review cycle.
    (Response) Because this comment concerns communication before
issuance of the complete response letter, it is beyond the scope of
this rulemaking. Nevertheless, it is worth noting that the user fee
goals include mechanisms to improve communications about potential
deficiencies during the review cycle. For example, the Goals Letter
(2002) states that it is the intention of CDER and CBER to notify a
sponsor of deficiencies in an application when each discipline has
finished its initial review of its section of the pending application.
In addition, the Goals Letter states that the review division and the
safety group assigned to the review of a particular application will
try to communicate their comments on a proposed risk management tool
and plan, as well as on protocols for observational studies, as early
in the review process as possible.
    b. Complete review of data. Proposed Sec.  314.110(a)(2) stated
that a complete response letter reflects our complete review of the
data submitted in an original application or abbreviated application
(or, where appropriate, a resubmission) and any amendments for which
the review cycle was extended. It further stated that the complete
response letter will identify any amendments for which the review cycle
was not extended that we have not yet reviewed.
    (Comment 12) Two comments stated that it was unclear whether
complete review of the data includes review of information submitted in
major amendments submitted more than 3 months before the end of the
initial cycle or nonmajor amendments (which do not trigger extensions
under the user fee goals or the proposed rule). The comments stated
that the regulation should not define the scope of material included in
a complete response letter as ``amendments for which the review cycle
was extended.''
    (Response) We agree that Sec.  314.110(a)(2) should include any
amendments that we have reviewed, whether or not they resulted in an
extension of the review cycle. Therefore, we are revising Sec.
314.110(a)(2) to state that a complete response letter reflects our
complete review of the data submitted in an original application or
abbreviated application (or, where appropriate, a resubmission) and any
amendments that we have reviewed. Correspondingly, we are also revising
Sec.  314.110(a)(2) to state that the complete response letter will
identify any amendments that we have not yet reviewed.
    c. Determination that data are inadequate. Under proposed Sec.
314.110(a)(3), if we determined, after an application is filed or an
abbreviated application is received, that the data submitted are
inadequate to support approval, we might issue a complete response
letter without first conducting required inspections and/or reviewing
proposed product labeling.
    (Comment 13) One comment maintained that stating that we ``might''
issue a complete response letter without conducting required
inspections and/or reviewing labeling adds ambiguity to agency actions.
The comment stated that if we determine that the data are inadequate
during the first half of the review cycle, it might be acceptable for
us to issue a complete response letter without conducting inspections
or reviewing labeling; however, a complete response letter sent toward
the end of the cycle should thoroughly evaluate all components of the
NDA. The comment stated that leaving to the review divisions the
decision on whether we issue a complete response letter before we
conduct inspections and review the labeling would unintentionally
encourage inconsistency. The comment recommended that we revise Sec.
314.110(a)(3) to state that if we determine ``early in the review
cycle'' or ``within the first half of the review cycle'' that the data
are inadequate, we might issue a complete response letter without
conducting inspections or a labeling review.
    (Response) We understand the comment's concern about possible
uncertainty as to the timing of a decision to issue a complete response
letter without conducting an inspection or labeling review. However, it
is possible that we might not determine until later in the review cycle
that the data in the application are inadequate. Therefore, we believe
that it is not appropriate to specify in Sec.  314.110(a)(3) a time
after which we could no longer conclude that the data submitted are
inadequate to support approval.
    (Comment 14) One comment stated no objection to this proposal under
the circumstances described but maintained that the complete response
letter should indicate the status of each review team (labeling,
chemistry and manufacturing, microbiology, bioequivalence, and/or
clinical reviews and inspection status).
    (Response) Rather than having the complete response letter state
the status of each review team, we believe that it is appropriate for
the letter to specify what portions, if any, of the review are

incomplete, as review of a portion of an application may require input
from more than one review team, and it is the status of the portion of
a review, not the status of the review team, that is most relevant.
This is the approach that we currently use in issuing approvable and
not approvable letters.
    (Comment 15) One comment asked us to comment on the future of
CDER's Pre-Approval Inspection Program and how it would be incorporated
into the proposed new review scheme.
    (Response) Inspection of the facilities used in the manufacture of
a proposed drug product is an essential part of the application review
process. The Pre-Approval Inspection Program will not be affected by
this rulemaking.
    d. Actions to place application in condition for approval. Proposed
Sec.  314.110(a)(4) stated, ``Where appropriate,'' a complete response
letter will describe the actions necessary to place the application or
abbreviated application in condition for approval.
    (Comment 16) One comment stated that we should delete ``Where
appropriate'' from Sec.  314.110(a)(4). The comment stated that a
complete response letter should describe the actions and/or specify the
data needed to place the application in condition for approval. One
comment stated that we should specify precisely the amendments or
procedures we will require as an appropriate reply to a complete
response letter so that an applicant does not have to guess what is
necessary to remedy the deficiencies cited in the letter. The comment
stated that this would help applicants address FDA concerns more
effectively.
    (Response) We agree with the comments that the complete response
letter should provide an applicant with information, whenever possible,
on what the applicant could do to obtain approval. However, there may
be times when what the applicant has submitted to the agency simply
does not permit us to specify what the applicant would need to do to
put the application in a position for approval. The intent of Sec.
314.110(a)(4) is for us to provide the applicant with sufficient detail
on what actions might be necessary to resolve the deficiencies cited in
the complete response letter. Providing clear guidance to applicants in
the complete response letter will be helpful both to applicants and the
agency.
    However, at the time of issuance of the complete response letter,
we may not have enough information to be certain about precisely what
actions, including possibly conducting studies and/or submitting data,
may ultimately be necessary to place an application in condition for
approval. For example, we might have determined that there is a problem
with the formulation of a proposed drug product but not be able to tell
the applicant what it could do to resolve the problem, except in a
general sense. Because of such potential circumstances, we have
replaced ``Where appropriate'' with ``When possible'' in Sec.
314.110(a)(4).
    In addition, we recognize that although it is appropriate for us to
recommend actions that an applicant might take to place its application
in condition for approval, we cannot require an applicant to take
specific actions--and only those actions--to obtain approval. There
might be multiple acceptable approaches that an applicant could take to
remedy a deficiency in its application, and we might lack information
that would affect our views on what actions an applicant should take.
Therefore, we have revised Sec.  314.110(a)(4) to state that, when
possible, a complete response letter will, rather than describe the
actions necessary to place an application or abbreviated application in
condition for approval, ``recommend actions that the applicant might
take to place the application or abbreviated application in condition
for approval.''
2. Responses to Complete Response Letters
    Under proposed Sec.  314.110(b)(1) to (b)(3), an applicant was
required to take one of three actions after receiving a complete
response letter: Resubmit the application, withdraw the application, or
request an opportunity for a hearing on whether there are grounds for
denying approval of the application.
    a. Resubmission. Under proposed Sec.  314.110(b)(1), an applicant
could, in response to a complete response letter, resubmit the
application or abbreviated application, addressing all deficiencies
identified in the complete response letter. Proposed Sec.
314.110(b)(1) further stated that, for purposes of Sec.  314.110, a
resubmission would mean submission by the applicant of all materials
needed to fully address all deficiencies identified in the complete
response letter.
    As stated in our response to comment 8, we are relocating the
definition of resubmission to Sec.  314.3 from Sec.  314.110(b)(1) and
adding a sentence clarifying that an application or abbreviated
application for which we issued a complete response letter, but which
was withdrawn before approval and later submitted again, is not a
resubmission.
    i. Resubmission of an NDA supplement other than an efficacy
supplement. Under proposed Sec.  314.110(b)(1)(iii), a resubmission of
an NDA supplement other than an efficacy supplement would constitute an
agreement by the applicant to start a new 6-month review cycle
beginning on the date we receive the resubmission.
    (Comment 17) Three comments objected to the proposed 6-month cycle
for resubmissions of other-than-efficacy supplements. One comment
stated that it seemed unreasonable that a resubmission not requiring
clinical data would require an additional 6 months for review. Two
comments stated that because one of our user fee goals is to act on 90
percent of manufacturing supplements that require prior approval within
4 months, a 6-month review time for a resubmission of such a supplement
would be longer than the review time for the original supplement. The
comments stated that this is inappropriate because many of these
resubmissions need only include data necessary to answer questions from
the initial cycle and do not require as much review time as the initial
supplement. The comments recommended that we revise Sec.
314.110(b)(1)(iii) to state that the length of the review cycle for the
resubmission of an other-than-efficacy supplement will not exceed that
for the original supplement. The comments further recommended that we
establish a ``Type 1/Type 2'' scheme for resubmissions of prior
approval chemistry and manufacturing supplements that would be similar
to the approach for resubmissions of original applications and efficacy
supplements, but with a 2-month review cycle for Type 1 resubmissions
and a 4-month cycle for Type 2 resubmissions.
    (Response) We agree with the comments that the review cycle for the
resubmission of a supplement that is not an efficacy supplement should
be the same as the initial review cycle for the original supplement.
Therefore, we have revised Sec.  314.110(b)(1)(iii) to state that a
resubmission of an NDA supplement other than an efficacy supplement
constitutes an agreement by the applicant to start a new review cycle
the same length as the initial review cycle for the supplement
(excluding any extension due to a major amendment), beginning on the
date FDA receives the resubmission. Under Sec.  314.100(a), the initial
review cycle for a supplement other than an efficacy supplement is 180
days, unless it is adjusted by mutual agreement or as a result of a
major amendment under Sec.  314.100(c). Under revised Sec.
314.110(b)(1)(iii), because the initial review cycle for a
manufacturing supplement requiring prior approval is 4 months under the
user fee goals, the

review cycle for a resubmission of a manufacturing supplement would be
4 months (it would not be increased to reflect any extension of the
initial review cycle for the manufacturing supplement resulting from a
major amendment of the initial supplement). Given this change to Sec.
314.110(b)(1)(iii), we believe that establishing a separate ``Type 1/
Type 2'' classification scheme for resubmissions of prior approval
chemistry and manufacturing supplements is not needed to ensure
appropriate review cycles for these resubmissions and would create
unnecessary administrative burdens.
    ii. Minor resubmission of an ANDA. Proposed Sec.  314.110(b)(1)(v)
stated that a minor resubmission of an ANDA constitutes an agreement by
the applicant to start a new review cycle beginning on the date we
receive the resubmission.
    (Comment 18) One comment opposed this provision, stating that the
failure to specify the length of the new review cycle would seriously
hinder an applicant's ability to predict the approval date for its
application, resulting in substantial commercial disadvantage. The
comment stated that any delay in the onset of launch preparation due to
an unpredictable approval date could harm the manufacturer's ability to
prepare for the initial marketing of their products. The comment
maintained that without a target date for completion of review, an
applicant would be forced to follow up with FDA continually, contrary
to requests by CDER's Office of Generic Drugs that applicants follow up
only at the targeted time. The comment claimed that the statement in
the preamble that the review cycle for a minor resubmission of an ANDA
might last ``from 30 days to a few months'' was contrary to the
guidance on ``Major, Minor and Telephone Amendments to Abbreviated New
Drug Applications'' (ANDA amendments guidance), which purportedly was
revised to produce more minor amendments and fewer major amendments to
move applications through the review process more quickly. The comment
maintained that without a definition of ``a few months,'' performance
standards would be reduced as much as 50 percent or more, and the
distinction between major and minor amendments would blur.
    The comment also disagreed with the statement in the preamble that
the proposed revisions for ANDA resubmissions are ``similar'' to those
for NDA resubmissions. The comment stated that user fee goals
apparently are being implemented at the expense of generic drug
manufacturers by reducing the transparency of the review process and
extending review times for minor resubmissions. The comment asked that
we revise Sec.  314.110(b)(1)(v) to state that minor resubmissions of
ANDAs are reviewed 30 to 60 days from receipt. The comment also stated
that we should assess the issuance and classification of all complete
response letters to uphold the intent to reduce ANDA approval times and
resolve more deficiencies by telephone rather than complete a response
letter.
    (Response) We do not agree that the provision on minor
resubmissions of ANDAs will interfere with generic drug manufacturers'
ability to market their products in a timely manner. Under the ANDA
amendments guidance, which the Office of Generic Drugs applies to major
and minor resubmissions of ANDAs, we attempt to review minor
resubmissions within 30 to 60 days, although not all can be reviewed
within 60 days. In accordance with the ANDA amendments guidance, we
will continue to work closely with ANDA sponsors to provide them with
sufficient information about our review of ANDA resubmissions to enable
sponsors to plan for the marketing of approved products. We agree with
the comment that resolving deficiencies by telephone rather than by
complete response letter benefits both applicants and the agency, and
we will seek to do so where appropriate in accordance with the ANDA
amendments guidance.
    b. Request for a hearing. Under proposed Sec.  314.110(b)(3), after
receiving a complete response letter, an applicant could ask us to
provide it with an opportunity for a hearing on the question of whether
there are grounds for denying approval of the NDA or ANDA.
    On our own initiative, we have revised Sec.  314.110(b)(3) to
update the information on the address to which requests for a hearing
on the denial of approval of an NDA or ANDA must be submitted, as a
result of the recent relocation of certain CDER offices.
    (Comment 19) One comment stated that we should consider having an
independent evaluator within FDA attend the hearings to confirm or
negate grounds for denying approval. The comment also asked whether
these hearings would be open public hearings.
    (Response) With respect to the nature of hearings on the denial of
approval of applications, Sec.  314.201 states that parts 10 through 16
(21 CFR parts 10 through 16) apply to these hearings. These hearings
are not open public hearings; appearance and participation are governed
by Sec.  12.40 through Sec.  12.45.
    We do not believe that an independent evaluator is needed for
hearings on grounds for denial of approval. Section 314.200(f) provides
for separation of functions between CDER and the Commissioner of Food
and Drugs (the Commissioner) upon receipt of a request for a hearing.
CDER prepares an analysis of the request and a proposed order ruling on
the issue and submits them to the Commissioner for review and decision.
When CDER recommends denial of a hearing on all issues, no CDER
representative will participate or advise in the review and decision by
the Commissioner. When CDER recommends that a hearing be granted on one
or more issues, separation of functions terminates as to those issues.
The Commissioner may modify the text of those issues but may not deny a
hearing on those issues. Separation of functions continues with respect
to issues on which CDER has recommended denial of a hearing. The
Commissioner will neither evaluate nor rule on CDER's recommendation on
such issues, and such issues will not be included in the notice of
hearing. Participants in the hearing may make a motion to the presiding
officer for the inclusion of any such issue in the hearing. Under Sec.
12.60, the presiding officer of any hearing will be the Commissioner, a
member of the Commissioner's office to whom responsibility for the
matter has been delegated, or an administrative law judge qualified
under 5 U.S.C. 3105. Separation of functions on all issues resumes upon
issuance of a notice of a hearing. We believe that these provisions
provide an adequate means of ensuring that the Commissioner makes an
independent assessment of the evidence for and against approval of an
application. Therefore, no independent evaluator is needed.
3. Failure to Take Action
    Under proposed Sec.  314.110(c), an applicant would be considered
to agree to extend the review period under section 505(c)(1) of the act
until it takes any of the actions listed in Sec.  314.110(b) (i.e.,
resubmission of the application, withdrawal, or request for a hearing).
Proposed Sec.  314.110(c) further stated that for an NDA, we might
consider an applicant's failure to take any of these actions within 1
year after receiving a complete response letter to be a request by the
applicant to withdraw the NDA (for an ANDA, the specified period was 6
months).
    (Comment 20) Several comments objected to the elimination of the
opportunity, available in previous Sec. Sec.  314.110(a)(5) and
314.120(a)(5), for

an applicant to notify us within 10 days of receipt of an action letter
that it agrees to an extension of the review period so that it can
determine how to respond further. One comment stated that it was not
clear whether any sponsor communication with us regarding an intent to
resubmit or amend an application would cancel or postpone the proposed
1-year timeframe. The comment stated that if an applicant believed that
it must resubmit within 1 year to avoid automatic withdrawal, the
result could be a less-than-complete resubmission. Three comments
stated that the absence of a resubmission within 1 year of receipt of a
complete response letter cannot reasonably be characterized as failure
to take action. Several comments stated that it might take several
months for an applicant to reach agreement with us on what studies are
needed for approval and then more time to conduct the studies and
submit the results.
    The comments suggested several ways to revise the regulations to
allow applicants to request an extension of the review period. One
comment stated that we should expand the first option in Sec.
314.110(b) (resubmission) to permit a sponsor to resubmit its
application addressing all deficiencies or state its intent to do so
(if the sponsor estimates that it will take more than 1 year to address
all deficiencies).
    Several comments recommended revisions to Sec.  314.110(c). One
comment stated that Sec.  314.110(c) should be revised to clarify that
additional time for resubmission will be granted if the applicant is
diligently working to address all deficiencies. The comment stated that
inaction for 1 year should be regarded as a request to withdraw the
application if the applicant has not communicated an intent to resubmit
or submitted evidence of progress being made toward the completion of
work needed to address all deficiencies.
    One comment stated that Sec.  314.110(c) should be revised to allow
an applicant to notify us, within a specified time, of its intent to
resubmit or to agree to a specified extension of time to reflect an
agreed-upon action plan to address deficiencies; absent such
notification, we could consider the application withdrawn if it was not
resubmitted within 1 year. The comment further stated that if an
additional study was required, we should allow an extension beyond the
1-year period.
    Two comments recommended that Sec.  314.110(c) be revised in one of
two ways. One approach would be to add an option for the applicant to
notify us, within a specified time after receipt of a complete response
letter, of an intent to resubmit. If the application is not resubmitted
within 1 year, the applicant would be required to provide annual
confirmation of its intent to resubmit; if the applicant provided no
such notification, we could consider the application withdrawn. The
alternative approach would require us to notify the applicant
requesting a reply within a specified time regarding its intention to
resubmit; failure to respond within the specified time would constitute
a request for withdrawal.
    One comment recommended that applicants be given the option to
state their intention to address deficiencies as well as how and when
this will be done. The comment suggested that we would use the target
date as the closing date for the application. If the applicant later
determined that it could not meet this deadline, it could seek another
extension, which we could grant or deny at our discretion.
    (Response) We agree that proposed Sec.  314.110(c) should be
revised to allow applicants to request an extension of time in which to
submit a resubmission. We acknowledge that in some circumstances it
might take more than 1 year after issuance of a complete response
letter for an applicant to reach agreement with us on what clinical
studies might be needed, to conduct any required studies, and to
provide the results in a resubmission. Therefore, we are revising Sec.
314.110(c) (renumbered as Sec.  314.110(c)(1)) to state that, for an
NDA or ANDA, we may consider an applicant's failure to take any of the
actions in Sec.  314.110(b) within 1 year after issuance of a complete
response letter to be a request by the applicant to withdraw the
application, unless the applicant has requested an extension of time in
which to resubmit the application. Section 314.110(c) further states
that we will grant any reasonable request for such an extension. In
addition, Sec.  314.110(c) states that we may consider an applicant's
failure to resubmit the application within the extended time period or
to request an additional extension to be a request by the applicant to
withdraw the application.
    Although, as stated in the proposed rule, ANDA resubmissions
usually do not involve generation of clinical data, for consistency we
have decided to apply the 1-year period (subject to extension) to ANDA
resubmissions as well as NDA resubmissions. In addition, we have
revised Sec.  314.110(c)(1) to state that the applicant's 1-year
deadline for taking action begins ``after issuance of a complete
response letter'' rather than ``after [the applicant] receiv[es]'' the
complete response letter. This change provides certainty as to the
start of the 1-year period. In addition, on our own initiative we have
revised the first sentence of Sec.  314.110(c)(1) to make clear that
this paragraph addresses extension of the review period (until any of
the actions listed in Sec.  314.110(b) are taken) for an NDA under
section 505(c)(1) of the act or an ANDA under section (j)(5)(A) of the
act (the proposed rule inadvertently referred only to section 505(c)(1)
for NDA applicants).
    (Comment 21) Two comments stated that because deeming an
application withdrawn is optional under proposed Sec.  314.110(c),
differences between and within centers might create an uneven playing
field in which some applications are withdrawn while similarly situated
applications are not. The comments stated that the decision to withdraw
should rest with the applicant.
    (Response) We believe that it is reasonable and within the scope of
our authority to consider an applicant's failure to take any
significant action within a reasonable period of time to be a request
to withdraw the application. Nevertheless, we do not believe that Sec.
314.110(c) should require us to deem an application to be withdrawn
under these circumstances. Although we agree with the comments that
there should not be significant differences across CDER regarding this
matter, decisions on whether to regard an applicant's failure to take
action as a request to withdraw the application will reflect the
circumstances surrounding each particular application.
    (Comment 22) One comment stated that we should notify an applicant
before deeming an application withdrawn within 1 year for failure to
take action under Sec.  314.110(c), and applicants should have
reasonable time to respond.
    (Response) We agree that it is appropriate for us to notify an
applicant that we intend to regard an application as withdrawn for
failure to take action. Therefore, we are adding Sec.  314.110(c)(2),
which states that if we consider an applicant's failure to take action
in accordance with Sec.  314.110(c)(1) to be a request to withdraw the
application, we will notify the applicant in writing. Section
314.110(c)(2) further states that the applicant will have 30 days from
the date of the notification to explain why the application should not
be withdrawn and request an extension of time in which to resubmit the
application. Additionally, Sec.  314.110(c)(2) states that we will
grant any reasonable request for an extension. Finally, Sec.
314.110(c)(2) states that if the

applicant does not respond to the notification within 30 days, the
application will be deemed to be withdrawn.

E. Complete Response Letters for BLAs

    To incorporate the use of complete response letters into the
biologics regulations, the proposed rule added a definition of complete
response letter to Sec.  600.3 and added Sec.  601.3 regarding complete
response letters. We received comments on these proposed regulations as
well as on the lack of regulations on other matters related to BLAs.
1. General
    (Comment 23) One comment stated that although we proposed many
changes to Sec.  314.110 regarding complete response letters for NDAs
and ANDAs, we proposed only select changes for the corresponding
regulations for BLAs in Sec.  601.3. The comment specifically noted the
lack of a definition of resubmission in Sec.  601.3 and the fact that
NDA and ANDA applicants have three options for responding to a complete
response letter under Sec.  314.110(b) while BLA applicants have only
two options under Sec.  601.3(b). The comment recommended that we
revise Sec.  601.3 to include the topics in Sec.  314.110 or explain
the brevity of the biologics regulations. One comment recommended that
we revise the biologics regulations to be consistent with the
procedures and timeframes for review of resubmissions and amendments of
drug applications in part 314.
    (Response) BLAs have long been reviewed under procedures and
timelines that differ from those for NDAs and ANDAs. In addition, the
biologics regulations are less prescriptive and detailed than the NDA
and ANDA regulations, and we have relied on guidance documents to
specify many of the procedures under which we review BLAs. With respect
to the biologics regulations, the proposed rule primarily was intended
to codify CBER's practice of issuing complete response letters for
BLAs. A comprehensive revision of the regulations on the review of BLAs
was not intended, and we do not believe it is necessary. It also should
be noted that although many of the procedures and timeframes in the NDA
regulations reflect user fee goals and resources, many of the
biological products subject to the licensing regulations in part 601
are not subject to user fees. For these reasons, we will not, at this
time, establish more detailed regulations on amendments to BLAs or
resubmissions of BLAs following issuance of a complete response letter.
    With respect to the two examples of inconsistency noted by one
comment, we are adding a definition of resubmission to the biologics
regulations at Sec.  600.3 (see the response to comment 27), and we
have concluded that it is not necessary that Sec.  601.3(b) specify the
right to request a hearing because that right is stated elsewhere in
the biologics regulations (see the response to comment 26).
2. Definitions (Proposed Sec.  600.3)
    Proposed Sec.  600.3(jj) would have defined ``complete response
letter'' as a written communication to an applicant from FDA usually
identifying all of the deficiencies in a BLA or BLA supplement that
must be satisfactorily addressed before it can be approved.
    (Comment 24) Three comments objected to the definition of complete
response letter for essentially the same reasons that two of those
comments provided for objecting to the definition of complete response
letter for NDAs and ANDAs in Sec.  314.3(b). Specifically, the comments
maintained that stating that a complete response letter ``usually''
identifies all of the deficiencies in a BLA that must be satisfactorily
addressed is contrary to the plain meaning of ``complete response,''
makes the regulation too vague and open to varying interpretation
across review divisions, and is inconsistent with statements in the
user fee goals. One comment stated that according to CBER's Standard
Operating Procedures and Policies (SOPP) 8405, ``Complete Review and
Issuance of Action Letters,'' the complete response letter will
summarize all of the deficiencies remaining in a BLA. The comments
stated that there might be circumstances when it would be reasonable
for us to postpone certain aspects of a complete review; these
circumstances, which are set forth in SOPP 8405, are limited to testing
of submitted product lots, pre-licensing inspections, and evaluation of
final printed labeling.
    Two comments recommended that the definition of complete response
letter for BLAs specifically note those aspects of a complete review
that may be postponed while allowing the agency to issue the letter.
One of those comments specifically recommended defining a complete
response letter as ``a written communication to the applicant from FDA
identifying all of the specific deficiencies in a biologics license
application or supplement that must be satisfactorily addressed before
it can be approved. A complete response letter may be issued without
conducting testing of submitted product lots, required inspections, or
evaluation of final printed labeling or suitable alternative.'' One
comment recommended that the definition state that a complete response
letter identifies all deficiencies in a BLA ``except when such
communication is issued without conducting testing of submitted product
lots, required inspections, or evaluation of final printed labeling.''
The comment recommended that the preamble to the final rule state that
``evaluation of final printed labeling'' does not include the
communication of deficiencies pertaining to intended use or product
claims. The comment stated that early communication and resolution of
such items are critical to efficient review, and deficiencies in these
areas might require additional studies.
    (Response) We agree with the comments that, generally, a complete
response letter will identify all of the deficiencies in a BLA.
Consistent with our response to comment 5, we have revised the
definition of complete response letter in Sec.  600.3 to state that a
complete response letter is a communication ``usually describing all of
the deficiencies that the agency has identified in a biologics license
application or supplement that must be satisfactorily addressed before
it can be approved.'' (The definition of complete response letter is
set forth in Sec.  600.3(ll), rather than Sec.  600.3(jj) as proposed,
because two other definitions have been added to Sec.  600.3 since the
issuance of the proposed rule.) We also agree with the comments that
exceptions to this general rule include when the complete response
letter concerns a BLA with respect to which we have not conducted
required inspections, tested product lots, and/or reviewed proposed
product labeling. Therefore, we are revising Sec.  601.3(a) (rather
than the definition of complete response letter in Sec.  600.3) to
state in Sec.  601.3(a)(1) that a complete response letter will
describe all of the deficiencies that the agency has identified in a
BLA or BLA supplement, except as stated in Sec.  601.3(a)(2). Section
601.3(a)(2) states that if we determine, after a BLA or BLA supplement
is filed, that the data are inadequate to support approval, we might
issue a complete response letter without first conducting required
inspections, testing submitted product lots, and/or reviewing proposed
product labeling. The provision refers to proposed product labeling
rather than the suggested final printed labeling because we generally
review the latter only after an applicant has addressed

any major deficiencies in an application.
    (Comment 25) One comment stated that the definition of complete
response letter should include the statement, ``Where appropriate, a
complete response letter will describe the actions necessary to place
the application in condition for approval.''
    (Response) Consistent with Sec.  314.110(a)(4) (see our response to
comment 16), we have added the following statement in Sec.  601.3(a)(3)
(rather than to the definition of complete response letter in Sec.
600.3): ``When possible, a complete response letter will recommend
actions that the applicant might take to place its biologics license
application or supplement in condition for approval.''
3. Complete Response Letter (Proposed Sec.  601.3)
    a. Complete response letter. Proposed Sec.  601.3(a) stated that we
would send the BLA applicant or BLA supplement applicant a complete
response letter if we determined that we would not approve the
application or supplement in its present form. As stated in our
response to comment 24, we have added Sec.  601.3(a)(1) stating that a
complete response letter will describe all of the deficiencies that the
agency has identified in a BLA or BLA supplement, except as stated in
Sec.  601.3(a)(2). As discussed in our response to comment 25, we also
are adding Sec.  601.3(a)(3) stating that, when possible, a complete
response letter will recommend actions that the applicant might take to
place its BLA or BLA supplement in condition for approval.
    b. Applicant actions. i. General. Under proposed Sec.  601.3(b),
after receiving a complete response letter, the biologics license
applicant or supplement applicant was required to either resubmit the
application or supplement or withdraw it.
    (Comment 26) One comment stated that although NDA and ANDA
applicants have three options following receipt of a complete response
letter (resubmit the application, withdraw it, or request a hearing),
BLA applicants have only two options (resubmit or withdraw the
application). The comment recommended that we either revise Sec.  601.3
or explain this omission from the biologics regulations.
    (Response) We do not believe that it is necessary to include, in
Sec.  601.3, a reference to the option to request a hearing. Under
Sec.  601.4(b) (21 CFR 601.4(b)), if we determine that an establishment
or product that is the subject of a BLA does not meet the requirements
for approval, we will deny the BLA and inform the applicant of the
grounds for, and of an opportunity for a hearing on, the decision.
Section 601.4(b) further states that if the applicant requests, we will
issue a notice of opportunity for a hearing on the matter pursuant to
Sec.  12.21(b). Because the right to request a hearing regarding a
denial of approval is set forth in Sec.  601.4(b), we do not believe
that it is necessary to revise Sec.  601.3 as requested.
    ii. Resubmission. Under proposed Sec.  601.3(b)(1), after receiving
a complete response letter, a BLA applicant or supplement applicant
could resubmit the application or supplement, addressing all
deficiencies identified in the complete response letter.
    (Comment 27) Two comments stated that describing a resubmission
without any qualifying language appears to require resubmission of the
original application or supplement (as opposed to a resubmission
limited to responses to the deficiencies listed in the complete
response letter). Three comments recommended that the biologics
regulations include a definition of resubmission.
    (Response) We agree that the regulations should define
``resubmission.'' Therefore, we have added a definition of resubmission
in Sec.  600.3(mm), stating that a resubmission is a submission by the
biologics license applicant or supplement applicant of all materials
needed to fully address all deficiencies identified in the complete
response letter. This parallels the definition of resubmission in Sec.
314.3(b).
    (Comment 28) Two comments stated that the biologics regulations
(like the drug regulations) should clarify that applications withdrawn
prior to approval that are submitted again for the same product are not
considered resubmissions.
    (Response) We agree. Therefore, consistent with the definition of
resubmission in Sec.  314.3(b) for NDAs and ANDAs (see the response to
comment 8), the definition of resubmission in Sec.  600.3(mm) includes
the statement, ``A biologics license application or supplement for
which FDA issued a complete response letter, but which was withdrawn
before approval and later submitted again, is not a resubmission.''
    c. Failure to take action. Under proposed Sec.  601.3(c), we could
consider a BLA applicant or BLA supplement applicant's failure to
either resubmit or withdraw the application or supplement within 1 year
after receiving a complete response letter to be a request by the
applicant to withdraw the application or supplement.
    (Comment 29) As with proposed Sec.  314.110(c) concerning complete
response letters to NDA and ANDA applicants, several comments objected
to the lack of an option in Sec.  601.3(c) to seek an extension of time
in which to resubmit an application or supplement. Two comments stated
that the absence of a resubmission within 1 year of receipt of a
complete response letter cannot reasonably be characterized as failure
to take action. Three comments stated that it might take at least
several months for an applicant to reach agreement with us on what
studies are needed for approval and then more time to conduct the
studies and submit the results. One comment maintained that although
the preamble to the proposed rule stated that Sec.  601.3 is intended
to incorporate current CBER policy, Sec.  601.3(c) does not reflect
current policy and does not afford applicants the opportunity to notify
us of their intent to resubmit an application to prevent us from
considering it withdrawn.
    Four comments suggested revisions to Sec.  601.3(c). One comment
recommended that it be revised to state as follows: ``FDA may consider
a biologics license applicant or supplement applicant's failure to
resubmit, amend the application to request an extension of time to
respond, or withdraw the application or supplement within 1 year after
receiving a complete response letter to be a request by the applicant
to withdraw the application or supplement.'' One comment recommended
that the first option in proposed Sec.  601.3(b) be revised to permit
sponsors to resubmit the BLA or supplement addressing all deficiencies
or state their intention to do so (if they conclude that it will take
more than 1 year to address all deficiencies).
    Two comments recommended that Sec.  601.3(c) be revised in one of
two ways. One approach would be to add an option for the BLA or BLA
supplement applicant to notify us, within a specified time after
receipt of a complete response letter, of an intent to resubmit. If the
resubmission is not submitted within 1 year, the applicant would be
required to provide annual confirmation of its intent to resubmit; if
the applicant provides no such notification, we could consider the
application or supplement withdrawn. The alternative approach would
require us to notify the applicant requesting a reply within a
specified time regarding its intention to resubmit; failure to respond
within the specified time would constitute a request for withdrawal.
    (Response) For the reasons stated in the discussion of Sec.
314.110(c) (see the response to comments 20 and 22), we

agree that Sec.  601.3(c) should be revised to, among other things,
allow applicants to seek an extension of time in which to resubmit an
application (beyond 1 year after issuance of the complete response
letter), and to notify applicants when we decide to consider an
applicant's failure to take action as required under Sec.  601.3 to be
a request to withdraw the application. Therefore, we are revising Sec.
601.3(c) to state, in Sec.  601.3(c)(1), that we may consider a BLA
applicant or BLA supplement applicant's failure to either resubmit or
withdraw the application or supplement within 1 year after issuance of
a complete response letter to be a request by the applicant to withdraw
the application or supplement, unless the applicant has requested an
extension of time in which to resubmit the application or supplement.
Section 601.3(c)(1) further states that we will grant any reasonable
request for such an extension. Finally, Sec.  601.3(c)(1) states that
we may consider an applicant's failure to resubmit the application or
supplement within the extended time period or to request an additional
extension to be a request by the applicant to withdraw the application.
    We also are adding Sec.  601.3(c)(2), which states that if we
consider an applicant's failure to take action in accordance with Sec.
601.3(c)(1) to be a request to withdraw the application, we will notify
the applicant in writing. Section 601.3(c)(2) further states that the
applicant will have 30 days from the date of the notification to
explain why the application or supplement should not be withdrawn and
request an extension of time in which to resubmit the application or
supplement, and we will grant any reasonable request for an extension.
Finally, Sec.  601.3(c)(2) states that if the applicant does not
respond to the notification within 30 days, the application or
supplement will be deemed to be withdrawn.
    As with revised Sec.  314.110(c)(1), we are substituting the phrase
``after issuance of a complete response letter'' for the phrase ``after
receiving a complete response letter'' to provide certainty about the
start of the 1-year period.

F. Miscellaneous Provisions Related to Complete Response Letters

1. Content and Format of Applications (Proposed Sec.  314.50)
    Proposed Sec.  314.50(d)(5)(vi)(b) would have required NDA
applicants to submit safety update reports 4 months after the initial
submission, in a resubmission following receipt of a complete response
letter, and at other times as requested by us. Previous Sec.
314.50(d)(5)(vi)(b) had required the submission of safety updates 4
months after the initial submission, after receiving an approvable
letter, and when otherwise requested by us.
    (Comment 30) One comment stated that in most cases, a sponsor would
receive the complete response letter toward the end of the initial
cycle, normally well after it had submitted the traditional 4-month
safety update. The comment stated that the amount of data needed in a
resubmission could be substantial if there are many ongoing studies.
Therefore, the comment requested that we include in the preamble to the
final rule general guidance on whether there would be any difference in
expectations on the content of the safety update provided in the
resubmission.
    (Response) We will expect applicants to provide the same type of
data and other information in safety updates included in a resubmission
as we did with safety updates included in a resubmission following
receipt of a not approvable letter. Not approvable letters set forth in
detail the information that we expected applicants to include in the
safety update. As the comment suggests, this could include substantial
information regarding any ongoing clinical studies. We will expect
applicants to provide the same level of information in a resubmission
following receipt of a complete response letter.
2. Withdrawal by the Applicant of an Unapproved Application (Proposed
Sec.  314.65)
    Proposed Sec.  314.65 stated in part that if, by the time we
received notice of an applicant's request to withdraw an unapproved
application, we had identified any deficiencies in the application, we
would list such deficiencies in the letter we sent the applicant
acknowledging the withdrawal.
    (Comment 31) One comment stated that all communications before the
issuance of approval or tentative approval should remain confidential.
Therefore, the comment recommended that the following statement be
added to Sec.  314.65: ``This communication, like all communications
prior to approval or tentative approval, will not be publicly
disclosed.''
    (Response) We agree with the comment that the letter to an
applicant acknowledging the withdrawal of its application is a
confidential communication. However, we do not believe that it is
necessary to add to Sec.  314.65 the language suggested by the comment.
The confidential nature of such communications is already addressed in
Sec.  314.430.
3. Public Disclosure of Existence of Applications (Proposed Sec.
314.430)
    Proposed Sec.  314.430(b) stated that we would not publicly
disclose the existence of an application or abbreviated application
before an approval letter was sent to the applicant under Sec.  314.105
or a tentative approval letter was sent to the applicant under Sec.
314.107, unless the existence of the application or abbreviated
application had been previously publicly disclosed or acknowledged.
Previous Sec.  314.430(b) stated that we would not make such a
disclosure before issuance of an approvable letter. In the proposed
rule, we acknowledged that our proposed change might result in later
disclosure than sometimes occurred under the previous regulation with
respect to those applications for which we issued approvable letters.
But we stated that the proposed change was consistent with our
presumption that, before approval, the existence of an application is
confidential commercial information under Sec.  20.61 (21 CFR 20.61).
However, we invited comment on whether it would be appropriate for us
to disclose the existence of an application following issuance of a
complete response letter and, if so, under what conditions.
    (Comment 32) Six comments agreed with the proposal to not disclose
the existence of an NDA or ANDA before we send an approval letter or
tentative approval letter unless the existence of the application has
been previously publicly disclosed or acknowledged. Two comments stated
that it was appropriate to continue our current policy on disclosure;
one comment stated that this was consistent with the presumption that
the existence of an application is confidential commercial information.
One comment specifically opposed the alternative approach we suggested
in the proposed rule, under which we could disclose the existence of an
NDA or ANDA following issuance of a complete response letter unless the
applicant notified us by a specified date that the applicant had not
publicly disclosed or acknowledged the application's existence. The
comment stated that such disclosure could be harmful, particularly in
the generic drug sector, to any competitive advantage that a sponsor
might have in a race to product launch. The comment also agreed with
the statement in the proposed rule that requiring applicants to notify
us to prevent our disclosing the existence of their applications would

create the potential for error and would be burdensome.
    One comment preferred the alternative approach suggested in the
proposed rule. One comment, although opposed to routine disclosure of
the existence of an application following issuance of a complete
response letter, appeared to suggest that we revise the regulation to
state that we could make such a disclosure provided the applicant asked
us to do so within 10 days of receipt of the complete response letter.
The comment stated that this would place the onus on the applicant to
request disclosure and would prevent inadvertent disclosure by the
agency prior to approval.
    (Response) We believe that it is appropriate to not publicly
disclose the existence of an NDA or ANDA (unless the existence has
already been disclosed or acknowledged) until we have issued an
approval letter or tentative approval letter for that application. As
we stated in the preamble to the proposed rule, this is consistent with
our long-standing presumption that before approval or tentative
approval, the existence of an application is confidential commercial
information. In addition, we believe that this approach is preferable
to one that would require applicants to notify us, after issuance of a
complete response letter, that they object to disclosure. As we stated
in the preamble to the proposed rule, such a notification system would
create the potential for inadvertent disclosure and pose administrative
burdens for applicants and the agency. Similarly, we do not believe
that it is appropriate to codify a procedure under which an applicant
could notify us that we may disclose the existence of its application.
An applicant may publicly disclose the existence of its application at
any time.
4. Addresses for Applications and Abbreviated Applications (Proposed
Sec.  314.440)
    The proposed rule would have revised Sec.  314.440(a)(1) to state
that, except as provided in Sec.  314.440(a)(4), an application under
Sec.  314.50 or Sec.  314.54 submitted for filing should be directed to
the Central Document Room, 12229 Wilkins Ave., Rockville, MD 20852-
1833.
    The proposed rule correctly revised the title of the office to
which applications must be submitted under Sec.  314.440(a)(1) from
``Document and Records Section'' to ``Central Document Room,'' but it
inadvertently changed the address for the office. The final rule states
the correct address to which these applications must be submitted as
follows: Central Document Room, 5901-B Ammendale Rd., Beltsville, MD
20705-1266.
    In addition, on our own initiative we are revising Sec.
314.440(a)(2) concerning addresses for ANDAs to specify the current
address for the Office of Generic Drugs and to update related
information.

G. Amendments to NDAs (Proposed Sec.  314.60)

    We proposed several revisions to Sec.  314.60 concerning amendments
to unapproved NDAs. Previous Sec.  314.60 stated in part that
submission of a major amendment ordinarily would extend the
application's review period only for the time necessary to review the
new information, but not more than 180 days; submission of an amendment
that was not a major amendment would not extend the review period. We
proposed to revise Sec.  314.60 to, among other things, specify how
long the review cycle would be extended for several types of
amendments. In addition, proposed Sec.  314.60(b) would allow us to
defer all of these amendments to the next review cycle.
1. General
    (Comment 33) Several comments objected to the proposal to give us
discretion to defer review of these amendments. One comment stated that
unilateral deferrals by FDA are inappropriate and requested that we
explain the conditions under which reviews would be deferred. Two
comments stated that the user fee goals do not suggest that we should
have an unlimited option to unilaterally defer review of amendments.
The comments maintained that the user fee goal concerning extension of
the review cycle for a major amendment submitted within 3 months of the
end of the review cycle was intended to encourage a single, contiguous
review leading to a complete response. These comments recognized,
however, that deferral might sometimes result in more efficient review
and effective use of resources. Therefore, the comments recommended
that the regulations list the specific conditions under which we could
defer review of amendments.
    One comment stated that the regulations should emphasize that we
will ordinarily strive to complete full review of an application,
including amendments, by the user fee goal date. The comment maintained
that deferral of review is only appropriate if an amendment is
submitted so late in the cycle that it cannot be reviewed by the goal
date or contribute to an approval decision because there are other
major deficiencies that cannot be addressed in the initial cycle.
    (Response) We do not agree with the comments concerning our
discretion to defer review of amendments. We believe that it is
necessary for the efficient review of applications for us to have the
ability to defer review of amendments where appropriate. Our current
policy on the review of amendments is set forth in our guidance
document entitled ``Good Review Management Principles and Practices for
PDUFA Products'' (the GRMP guidance). The GRMP guidance states that
during the initial review cycle, we ordinarily review all amendments
that we ask the applicant to make during the review and any amendments
previously agreed upon (e.g., during the pre-NDA/BLA meeting). The
guidance further states that we might review substantial amendments
submitted late in the review cycle during a subsequent cycle,
depending, in part, on other identified deficiencies. As for all other
amendments, the guidance states that we attempt to review them during
the first review cycle but might not be able to do so or might decide
not to do so in some circumstances (e.g., when the content of such an
amendment does not address a known deficiency in the application).
    The GRMP guidance notes that under the user fee goals, submission
of a major amendment during the last 3 months of a review may trigger a
3-month extension of the review clock. The guidance states that we
decide whether to extend the review clock based on consideration of a
variety of factors, including content of the amendment, FDA workload
and resources, and the existence of other known deficiencies possibly
affecting approval that have not been addressed by the amendment. The
guidance states that the underlying principle guiding our decision is
to consider the most efficient path toward completion of a
comprehensive review that addresses the deficiencies in an application
and leads toward a first cycle approval when possible.
    As the GRMP guidance states, although we strive to review
amendments during the initial review cycle for an application, there
are circumstances under which this is not possible or would not be an
efficient use of resources. Although the GRMP guidance specifies some
of the circumstances in which deferral of review of an amendment to the
next review cycle might be appropriate, we do not believe that we can
codify in the regulations all of the circumstances under which we might
defer review of an amendment. Therefore, we conclude that Sec.  314.60
must provide us with the

discretion to defer review of various types of amendments until the
subsequent review cycle, when appropriate.
    (Comment 34) Two comments stated that Sec.  314.60 should require
us to provide written notification to the applicant when we defer an
amendment to the next cycle because deferral is essentially an action
decision. The comments stated that such notification should describe
the deficiencies that preclude approval.
    (Response) We agree with the comments that we should provide
written notification to an applicant when we defer review of an
amendment to the subsequent review cycle. We currently provide such
notice in our approvable and not approvable letters. Therefore, we have
added a new Sec.  314.60(b)(7) stating as follows: ``When FDA defers
review of an amendment until the subsequent review cycle, the agency
will notify the applicant of the deferral in the complete response
letter sent to the applicant under Sec.  314.110.'' We do not believe
that it is necessary to codify in the regulations that we will provide
a reason for the deferral. Usually, the reasons for deferral are
general in nature (e.g., the amendment contains substantial new
information or does not address a known deficiency). We would be
willing to discuss the reasons for deferral after the applicant
receives the complete response letter.
2. Major Amendment Within 3 Months of the End of the Cycle (Proposed
Sec.  314.60(b)(1))
    Under proposed Sec.  314.60(b)(1), submission of a major amendment
to an original application, efficacy supplement, or resubmission of an
application or efficacy supplement within 3 months of the end of the
initial review cycle constituted an agreement by the applicant under
section 505(c) of the act to extend the initial review cycle by 3
months. Proposed Sec.  314.60(b)(1) further stated that we might
instead defer review of the amendment until the subsequent review
cycle. Proposed Sec.  314.60(b)(1) also stated that the initial review
cycle for an original application, efficacy supplement, or resubmission
of an application or efficacy supplement may be extended only once due
to the submission of a major amendment. It further stated that we
might, at our discretion, review any subsequent major amendment during
the initial review cycle (as extended) or defer review to the
subsequent cycle.
    On our own initiative, we are revising Sec.  314.60(b)(1) with
respect to amendments to resubmissions. Unlike applications and
supplements (21 CFR 314.71(c)), resubmissions are not subject to the
``initial review cycle'' provision in Sec.  314.100(a); they just have
a ``review cycle.'' Therefore, we are adding to Sec.  314.60(b)(1) a
statement clarifying that, for references to a resubmission of an
application or efficacy supplement in Sec.  314.60(b), the timeframe
for reviewing the resubmission is the ``review cycle'' rather than the
``initial review cycle.''
    (Comment 35) One comment stated that, for clarity, the regulations
should include a definition of ``major amendment.''
    (Response) We do not believe that it is necessary to include a
definition of major amendment in the regulations. Previous Sec.
314.60(a) did not define a major amendment; it only gave an example of
a major amendment (i.e., ``an amendment that contains significant new
data from a previously unreported study or detailed new analyses of
previously submitted data''). Because we are uncertain that we can
define major amendment in a way that encompasses all types of
amendments that should be treated as major amendments, we decline to
add a definition to the regulations.
    (Comment 36) Two comments recommended not codifying the 3-month
extension for a major amendment submitted within 3 months of the end of
the initial review cycle because, although this is consistent with
current user fee goals, those goals could change as a result of future
negotiations on user fees. The comments stated that the timeframes
agreed upon in the user fee negotiations historically have taken
precedence over existing regulatory timeframes, as was recognized in
proposed Sec.  314.100(a)(2). The comments stated that if we believed
it was necessary to codify user fee goals on extensions, we should
revise Sec.  314.60(b) to state that for human drug applications, any
extension of review due to a major amendment will be consistent with
the user fee goals, similar to proposed Sec.  314.100(a)(2).
    (Response) As stated in the preamble to the proposed rule, we are
revising Sec.  314.60 to state that submission of a major amendment
within 3 months of the end of the review cycle will extend the review
cycle by 3 months because we want to make the regulation consistent
with the current user fee goal on these amendments. At present, we do
not anticipate a change in this goal. If this goal does in fact change
as a result of a future user fee agreement, we could issue a proposed
rule proposing to make the regulation match the user fee goal on this
matter.
    (Comment 37) Four comments specifically addressed the provision in
proposed Sec.  314.60(b)(1) allowing deferral of review of a major
amendment submitted within 3 months of the end of the initial review
cycle. One comment stated that the option to defer review was arbitrary
and inconsistent with the user fee goals. The comment stated that
neither the proposed codified provision nor the preamble gave examples
of when it might be appropriate to defer review. The comment claimed
that because the overwhelming majority of these amendments are
submitted in response to FDA requests, it would be unreasonable to
penalize applicants by deferring review of the amendments. The comment
also stated that early communication of information and data requests
in accordance with GRMP principles will ordinarily result in receipt of
responses early in the initial cycle, giving us more time to complete
our review by the goal date. Therefore, the comment recommended that
Sec.  314.60(b)(1) be revised to state that the agency will make every
effort to complete its review of the full application, including
amendments, by the user fee goal date. The comment maintained that
review of these major amendments should only be deferred when the
amount of new information and the timing of the submission make it
impossible to review the amendment in the initial cycle.
    One comment recommended revising Sec.  314.60(b)(1) to state that
we would not be required to review a major amendment that pertains to
one section of the application if we have previously identified
deficiencies in another section that prevent first-cycle approval. Two
comments recommended revising Sec.  314.60(b)(1) to state that we may
defer review of a major amendment submitted within the last 3 months of
the initial cycle that meets any of the following criteria: (1) It
amends technical sections of an application in which we have identified
deficiencies that prohibit approval during the initial cycle and that
do not contain information needed to put the application in condition
for approval; (2) it amends a technical section other than sections in
which we have identified deficiencies preventing approval, where review
of the amendment will not result in approval during the current cycle;
or (3) it is an amendment for which, under the user fee goals, we could
not extend the review cycle (e.g., a second major amendment submitted
within the last 3 months of the initial cycle).
    (Response) We do not agree with any of the proposed revisions to
Sec.  314.60(b)(1). As stated in the GRMP guidance, we usually seek to
review

amendments, including major amendments, during the initial review
cycle. However, we do not believe that it is necessary to codify this
intent in Sec.  314.60(b)(1) or elsewhere in this section. As stated in
our response to comment 33, we do not believe that we can codify all of
the circumstances under which it might be appropriate to defer review
of major amendments. In addition, we do not agree with the claim that
the overwhelming majority of amendments are submitted in response to
agency requests, and the comment provides no evidence supporting this
statement. For these reasons, we believe that it is appropriate to
include in Sec.  314.60(b)(1) a statement that we can defer review of a
major amendment submitted within 3 months of the end of the initial
review cycle rather than extend the cycle by 3 months.
    (Comment 38) One comment stated that Sec.  314.60(b)(1) also should
specify that we would not be required to review a second major
amendment submitted within 3 months of the goal date with no
accompanying extension of the review clock.
    (Response) We do not agree with the suggested change. Proposed
Sec.  314.60(b)(1) stated that the initial review cycle may be extended
only once due to the submission of a major amendment, and any
subsequent major amendment would either be reviewed during the initial
review cycle or deferred. We believe that it is appropriate that Sec.
314.60(b)(1) include these provisions to make clear that we will not
extend the review cycle for a second major amendment.
3. Major Amendment More Than 3 Months Before the End of the Cycle
(Proposed Sec.  314.60(b)(2))
    Under proposed Sec.  314.60(b)(2), submission of a major amendment
to an original application, efficacy supplement, or resubmission of an
application or efficacy supplement more than 3 months before the end of
the initial review cycle would not have extended the cycle. Proposed
Sec.  314.60(b)(2) further stated that we might, at our discretion,
review such an amendment during the initial review cycle or defer
review until the subsequent review cycle.
    (Comment 39) One comment stated that the deferral provision in
Sec.  314.60(b)(2) would have the unintended effect of widening
differences among review divisions regarding when review of these major
amendments is deferred and would seem to discourage the possibility of
dialogue on the merits of submission of a major amendment. Two comments
stated that, because the user fee goals do not address major amendments
submitted more than 3 months before the end of the review period, the
implication is that review can be accommodated during the initial
cycle. One comment stated that we should not defer the review of major
amendments submitted well in advance of the goal date, so this option
should be deleted from the rule. One comment recommended that Sec.
314.60(b)(2) state that we will ordinarily make every effort to
complete our review of an application or efficacy supplement, including
any amendments submitted more than 3 months before the end of the
initial cycle, by the user fee goal date.
    Several comments stated that the regulation should specify the
criteria under which we could defer review of these major amendments.
Two comments recommended that Sec.  314.60(b)(2) state that we may
defer review of a major amendment submitted more than 3 months before
the end of the initial cycle when we have already identified at least
one major deficiency (such as a failed pivotal trial) that is not
addressed by the amendment and is unlikely to be addressed during the
current cycle due to a need for significant additional research or
development.
    (Response) We do not agree with any of the proposed revisions to
Sec.  314.60(b)(2). For the reasons stated in our response to comment
33, we do not believe that we can codify all of the circumstances under
which it might be appropriate to defer review of these major
amendments. Consequently, we have retained the provision in Sec.
314.60(b)(2) giving us the discretion to defer review of these
amendments to the next review cycle.
4. Nonmajor Amendment (Proposed Sec.  314.60(b)(3))
    Under proposed Sec.  314.60(b)(3), the submission of an amendment
to an original application, efficacy supplement, or resubmission of an
application or efficacy supplement that is not a major amendment would
not have extended the initial review cycle. Proposed Sec.  314.60(b)(3)
further stated that we might, at our discretion, review such an
amendment during the initial review cycle or defer review until the
subsequent review cycle.
    (Comment 40) One comment stated that Sec.  314.60(b)(3) would have
the unintended effect of widening differences in interpretation among
review divisions regarding these nonmajor amendments. The comment added
that Sec.  314.60(b)(3) seemed contrary to Sec.  314.102(b), which
encourages reviewers to communicate promptly to applicants easily
correctable deficiencies so that the deficiencies can be corrected
through amendments before the review period ends. One comment stated
that by their very nature, these amendments are less complex and
require less time to review, which provides even more reason to expect
that they be reviewed in the initial cycle. Therefore, the comment
maintained that Sec.  314.60(b)(3) should state that we will ordinarily
review all nonmajor amendments by the user fee goal date.
    Several comments stated that Sec.  314.60(b)(3) should set forth
the criteria for deferral of review. One comment recommended that Sec.
314.60(b)(3) state that we could defer review of a nonmajor amendment
that is submitted close to the end of the cycle and which could not
contribute to an approval decision because other major deficiencies
cannot be satisfactorily addressed. One comment suggested that the
regulation state that we could defer review if a nonmajor amendment is
submitted late in the review cycle (such as 1 to 2 months before the
end) or if the amendment does not provide information that addresses
easily correctable deficiencies, provided other major deficiencies
prevent approval at the end of the initial cycle. Similarly, two
comments recommended that Sec.  314.60(b)(3) state that we may defer
review of a nonmajor amendment that is received within 1 month of the
end of the initial cycle or that does not contain information adequate
to put the application in condition for approval during the current
cycle. One comment recommended stating that we could defer review of a
nonmajor amendment that is received late in the review cycle (e.g.,
within weeks of the goal date) when review of the amendment is not
expected to impact the outcome of the application review.
    (Response) We do not agree with any of the proposed revisions to
Sec.  314.60(b)(3). For the reasons stated in our response to comment
33, we do not believe that we can codify all of the circumstances under
which it might be appropriate to defer review of these nonmajor
amendments. Consequently, we have retained the provision in Sec.
314.60(b)(3) giving us the discretion to defer review of these
amendments to the next review cycle.
5. Amendment to Supplement Other Than Efficacy Supplement (Proposed
Sec.  314.60(b)(4))
    Under proposed Sec.  314.60(b)(4), submission of an amendment to a
supplement other than an efficacy

supplement would not have extended the initial review cycle. Proposed
Sec.  314.60(b)(4) further stated that we might, at our discretion,
review such an amendment during the initial review cycle or defer
review until the subsequent review cycle.
    On our own initiative, we have revised Sec.  314.60(b)(4) to ensure
that the regulation is consistent with the user fee performance goal
regarding major amendments to manufacturing supplements. In PDUFA III,
industry and the agency agreed that submission of a major amendment to
a manufacturing supplement submitted within 2 months of the goal date
would extend the goal date for acting on the supplement by 2 months,
and that there can be only one such extension per review cycle.
Although industry and the agency have been acting in accordance with
this user fee goal since the enactment of PDUFA III in 2002, we
inadvertently failed to incorporate this practice into the proposed
rule issued in 2004. Consequently, we have revised Sec.  314.60(b)(4)
to state that submission of a major amendment to a manufacturing
supplement within 2 months of the end of the initial review cycle
constitutes an agreement by the applicant under section 505(c) of the
act to extend the initial review cycle by 2 months. Consistent with the
approach to major amendments in Sec.  314.60(b)(2), revised Sec.
314.60(b)(4) further states: FDA may instead defer review of a major
amendment to a manufacturing supplement until the subsequent review
cycle; if we extend the initial review cycle, the division responsible
for reviewing the supplement will notify the applicant of the
extension; the initial review cycle for a manufacturing supplement may
be extended only once due to submission of a major amendment; and we
may, at our discretion, review any subsequent major amendment during
the initial review cycle (as extended) or defer review until the
subsequent review cycle.
    In accordance with the change to Sec.  314.60(b)(4), revised Sec.
314.60(b)(5) states that submission of an amendment to a supplement
other than an efficacy or manufacturing supplement will not extend the
initial review cycle, and we have discretion to review or defer review
of such an amendment. Proposed Sec.  314.60(b)(5) has been renumbered
as Sec.  314.60(b)(6).
    (Comment 41) One comment recommended that we revise proposed Sec.
314.60(b)(4) to state that we might consider deferring review of other-
than-efficacy supplements that are received late in the review cycle
(e.g., within weeks of the goal date) when their review is not expected
to impact the outcome of the application review. Two comments stated
that the regulation should permit us to defer review of any other-than-
efficacy supplement that either is received within 1 month of the end
of the initial cycle or contains information that is inadequate to put
the application in condition for approval during the current cycle.
    (Response) We do not agree with either of the suggested revisions
to proposed Sec.  314.60(b)(4) (now Sec.  314.60(b)(5)). For the
reasons stated in our response to comment 33, we do not believe that we
can codify all of the circumstances under which it might be appropriate
to defer review of amendments to supplements other than efficacy or
manufacturing supplements. Consequently, we have retained the provision
in Sec.  314.60(b)(5) giving us the discretion to defer review of these
amendments to the next review cycle.
6. Contents of Major Amendment (Proposed Sec.  314.60(b)(5))
    Under proposed Sec.  314.60(b)(5) (now Sec.  314.60(b)(6)), a major
amendment could not include data to support an indication for a use
that was not included in the original application, supplement, or
resubmission.
    (Comment 42) One comment stated that it would be unfair in most
cases to expect us to meet the goal date for review of an application
if a major amendment was submitted for a completely new indication in
the middle of the initial review cycle. However, the comment stated
that sometimes we request additional data or safety updates, which can
lead to the expansion or modification of an indication (e.g.,
submission of long-term safety data supporting chronic use). The
comment added that there might be a significant public health reason to
allow the submission of a major amendment to support a new indication.
Therefore, the comment recommended that Sec.  314.60(b)(6) be modified
to allow exceptions when data to support a new or expanded indication
are either requested by us or submitted with our prior concurrence.
    (Response) We agree with the comment that it is appropriate to
allow a major amendment to include data to support a slightly modified
indication (e.g., increasing or decreasing the age range, increasing
the severity of the disease) but not a completely new indication,
regardless of whether the data supporting the new indication were
submitted at the applicant's initiative or at our request. Therefore,
we have revised Sec.  314.60(b)(6) to state as follows: ``A major
amendment may not include data to support an indication or claim that
was not included in the original application, supplement, or
resubmission, but it may include data to support a minor modification
of an indication or claim that was included in the original
application, supplement, or resubmission.'' In addition, for the
reasons stated in section III.B.3 of this document regarding Sec.
314.3, we are substituting the phrase ``indication or claim'' for
``indication for a use.''

H. Amendments to ANDAs (Proposed Sec.  314.96)

    Proposed Sec.  314.96(a)(2) stated that submission of an amendment
containing significant data or information before the end of the
initial review cycle constitutes an agreement between FDA and the
applicant to extend the initial review cycle only for the time
necessary to review the significant data or information and for no more
than 180 days.
    (Comment 43) One comment objected to proposed Sec.  314.96(a)(2)
and recommended several changes. First, the comment stated that it
appeared that the only proposed change to Sec.  314.96 was the removal
of the condition that the cycle will be extended only for the time
necessary to review the data. The comment maintained that this was not
consistent with the intent to reduce ANDA approval times as stated in
the ANDA amendments guidance. Second, the comment stated that Sec.
314.96(a)(2) does not provide a definition of ``significant.'' The
comment recommended that the term ``major amendment'' be substituted
for ``amendment containing significant data or information'' in Sec.
314.96(a)(2). Third, the comment stated that Sec.  314.96 lacks a
provision regarding the submission of an amendment that contains data
or information not considered significant. Finally, the comment stated
that, in contrast to the provisions on major and nonmajor amendments to
NDAs in Sec.  314.60, it appeared that any amendment of an ANDA
submitted at any time during the initial cycle constitutes an agreement
to extend the review cycle by 6 months. The comment maintained that the
provisions on NDA amendments that take into consideration the timing
and content of amendments were fair and appropriate and recommended
that a similar approach be taken with ANDA amendments. To address all
of these concerns, the comment recommended that Sec.  314.96 be revised
to state as follows: ``The submission of a major amendment to an
original ANDA at any time within the initial review cycle constitutes
an agreement between the

FDA and the applicant to extend the cycle only by the time necessary to
review the data, and for no more than 180 days. A major amendment is
defined as any new or revised information or data that, if it were to
be submitted post-approval, would be categorized as a Prior Approval
Supplement as defined in 314.70(b). The submission of a minor amendment
to an original ANDA within 3 months of the end of the initial review
cycle constitutes an agreement between the FDA and the applicant to
extend the cycle by 30 to 60 days. The submission of a minor amendment
more than 3 months before the close of the initial review cycle would
not extend the review cycle. A minor amendment is defined as any new or
revised information that, if it were to be submitted post-approval,
would be categorized as a Changes Being Effected or Changes Being
Effected in 30 Days supplement as defined in 314.70(c).''
    (Response) Contrary to the comment, revised Sec.  314.96(a)(2)
retains the provision in previous Sec.  314.96(a)(2) that the
submission of an amendment to an ANDA containing significant data or
information before the end of the review cycle constitutes an agreement
to extend the review cycle ``only for the time necessary to review the
significant data or information and for no more than 180 days.''
    We do not agree with the comment's recommended changes to Sec.
314.96. We do not believe that it is necessary to add a definition of
major amendment in Sec.  314.96. The ANDA amendments guidance does not
provide a definition of major amendment but provides a listing of types
of amendments that we regard as major amendments. These include, but
are not limited to, amendments relating to the manufacture of a new
batch of drug product, a new bioequivalence study that is unrelated to
the manufacture of a new batch of the drug product, and new analytical
methods and validation data. We believe that the guidance provides
adequate information to applicants about the types of amendments that
we regard as ``containing significant data or information'' under Sec.
314.96(a)(2). We do not agree with the comment's suggested definition
of major amendment because the matters that are the subject of
supplements submitted under Sec.  314.70 do not necessarily correlate
with matters that are the subject of amendments submitted under Sec.
314.96, and the regulatory environment in which we review supplements
differs from that in which we review amendments (e.g., we have much
more information about a drug product after approval than we do before
approval). For these reasons, we conclude that it is appropriate to
retain the flexibility provided in Sec.  314.96(a)(2) concerning what