
[Federal Register: July 10, 2008 (Volume 73, Number 133)]
[Rules and Regulations]               
[Page 39588-39611]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10jy08-11]                         

=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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, 301-827-6210.

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

[[Page 39589]]

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:

[[Page 39590]]



     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

[[Page 39591]]

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

[[Page 39592]]

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 * * *''.

[[Page 39593]]

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

[[Page 39594]]

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

[[Page 39595]]

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

[[Page 39596]]

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

[[Page 39597]]

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

[[Page 39598]]

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

[[Page 39599]]

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

[[Page 39600]]

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

[[Page 39601]]

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

[[Page 39602]]

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

[[Page 39603]]

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

[[Page 39604]]

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

[[Page 39605]]

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 
constitutes an amendment containing significant data or other 
information.
    We also do not believe that it is necessary to include provisions 
on ``minor'' amendments to ANDAs in Sec.  314.96. The ANDA amendments 
guidance states that, except for those amendments that are classified 
as ``major'' or ``telephone,'' amendments will be designated as 
``minor,'' and the guidance provides examples of minor amendments 
(e.g., deficiencies in a drug master file, problems regarding good 
manufacturing practices). (According to the guidance, an amendment can 
be classified as a ``telephone'' amendment at the agency's discretion 
if the amendment would otherwise be classified as ``minor'' but the 
deficiencies are of a limited number or complexity (e.g., a need for 
clarification of data already submitted, a request for a postapproval 
commitment).) The guidance states that we attempt to review minor 
amendments within 30 to 60 days but notes that we cannot review all of 
these amendments within 60 days. We believe that the comment's proposed 
definition of minor amendment is not appropriate for the reasons we 
stated for not adopting the proposed definition of major amendment. In 
addition, we decline to adopt the specific provisions on minor 
amendments suggested by the comment. The regulations in previous Sec.  
314.94 on amendments to pending ANDAs did not address minor amendments 
and did not parallel the provisions in Sec.  314.60 on NDA amendments. 
Because ANDA amendments often differ in subject matter from NDA 
amendments, we do not believe it is necessary that the provisions on 
the content and timing of ANDA amendments match those for NDA 
amendments. We believe that the ANDA amendments guidance provides 
adequate information to ANDA applicants on minor amendments, and we do 
not find it necessary to codify our policy in the regulations at this 
time.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is not a significant regulatory action under the 
Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because our economic analysis and comments submitted 
in response to the proposed rule show that the provisions of this final 
rule either codify existing practice or bring about changes that impose 
no significant burdens, the agency certifies that the final rule will 
not have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act requires that 
agencies prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

A. Impact of the Final Rule

    As described in sections II and III of this document, the final 
rule makes the following changes: (1) For NDAs and ANDAs, replaces the 
two types of action letters currently used (approvable and not 
approvable letters) with complete response letters; (2) for BLAs, 
incorporates into the regulations an existing policy on complete 
response letters; (3) incorporates into the regulations the terminology 
and procedures used in the user fee performance goals regarding NDA 
resubmissions; and (4) revises regulations governing extension of the 
initial review cycle in response to major amendments to unapproved 
applications, supplements, and resubmissions. For NDAs (with respect to 
resubmissions and amendments) and BLAs, the final rule codifies current 
agency practices. For ANDAs, the final rule revises regulations to be 
consistent with current practice or, where appropriate, with the 
provisions governing NDAs. The most significant impact of the final 
rule is on efficacy supplements to approved NDAs and on

[[Page 39606]]

resubmissions of applications and efficacy supplements. The impact of 
specific provisions of the final rule on NDAs, ANDAs, efficacy 
supplements, manufacturing supplements, and resubmissions is described 
in greater detail in the following paragraphs.
1. Complete Response Letter
    We are amending our regulations to replace approvable and not 
approvable letters with complete response letters. Both approvable and 
not approvable letters indicated that an NDA or ANDA was not approvable 
in its current form, and that changes were necessary or that we 
required additional information. A complete response letter describes 
the deficiencies in an NDA or ANDA and, when possible, recommends 
actions that the applicant might take to place the application in 
condition for approval. In the past, some drug manufacturers expressed 
concern that a not approvable letter sent an unintended message that a 
marketing application would never be approved, which could adversely 
affect a company's ability to raise capital. Thus, in addition to 
allowing us to meet our commitments under the user fee performance 
goals, this regulatory change addresses industry comments by adopting a 
more neutral mechanism to convey that an NDA or ANDA cannot be approved 
in its current form. (We had already adopted a policy of issuing 
complete response letters for BLAs, and the final rule simply codifies 
this policy.) Because this regulatory change is primarily 
administrative in nature and is being made in response to the user fee 
performance goals, it is expected to have little or no economic impact.
2. Resubmissions
    We also are making regulatory changes to implement the user fee 
performance goals and to codify new terminology associated with the 
resubmission of drug marketing applications. A Class 2 resubmission--
incorporating major changes or a significant amount of additional 
data--would start a new 6-month review cycle, whereas a Class 1 
resubmission--incorporating minor changes or a limited amount of 
additional data--would begin a new 2-month review cycle. These changes 
will codify agency practices regarding NDA resubmissions in place since 
1998.
    We are applying the Class 1 and Class 2 provisions to resubmissions 
of efficacy supplements as well. We agreed to make this policy change 
in PDUFA III because efficacy supplements, like original NDAs, contain 
varying amounts of data requiring different review times. We began to 
implement this change in October 2002. The application of the Class 1 
and Class 2 provisions to resubmissions of efficacy supplements 
represents a regulatory change because under PDUFA II, all 
resubmissions of efficacy supplements would start a new 6-month review 
cycle. Under the final rule, a Class 1 resubmission of an efficacy 
supplement will extend the review cycle by only 2 months, rather than 6 
months as occurred under PDUFA II. Review times for Class 2 efficacy 
supplement resubmissions will be largely unaffected by this change. 
Based on data from 1996 to 2000 (the most recent 5-year period for 
which complete data were available), an average of 16 efficacy 
supplements (approximately 40 percent) resubmitted annually would be 
reviewed in 2 months rather than the current 6 months. The final rule 
generally maintains current agency practice with respect to the review 
of other types of NDA supplements, i.e., for chemistry, manufacturing, 
or labeling changes. For ANDA resubmissions, the rule codifies the 
current practice of 6-month review.
3. Amendments to Unapproved Drug Marketing Applications
    We also are revising our regulations on extending the initial 
review cycle following the submission of an amendment to an unapproved 
drug marketing application. The previous regulations stated that, for 
unapproved NDAs and efficacy supplements, submission of a major 
amendment extended the review cycle for the amount of time necessary to 
review the new information but not by more than 180 days. The final 
rule generally extends the review cycle by 3 months if a major 
amendment to an application, efficacy supplement, or resubmission of an 
application or efficacy supplement is submitted within 3 months of the 
end of the initial review cycle. (The final rule states that we may 
defer review until a subsequent review cycle.) If a major amendment is 
submitted more than 3 months before the end of the initial review 
cycle, the review cycle will not be extended (but FDA, in its 
discretion, may review the amendment during the initial review cycle or 
defer it until the subsequent review cycle). These changes codify the 
practice for NDAs that has been in place since 1998. However, we have 
only recently begun to apply this policy to efficacy supplements. 
Before October 2002, under the user fee performance goals, we did not 
extend the review cycle for a major amendment to an efficacy 
supplement. Therefore, as with the change regarding resubmissions of 
efficacy supplements, we believe that it is appropriate to treat the 
change regarding amendments to unapproved efficacy supplements as a 
regulatory change for purposes of this analysis.
    These provisions of the final rule might slightly increase review 
times for efficacy supplements for which at least one major amendment 
was received within 3 months of the end of the initial review cycle. 
Based on data from 1996 to 2000, these regulatory changes could affect 
as many as 11 percent of all efficacy supplements filed, or an average 
of 15 per year. The effect of this change is dependent on the timing of 
future filings and the number of instances in which we exercise our 
review discretion.
    The final rule also codifies our practice of extending the initial 
review cycle for a manufacturing supplement by 2 months when a major 
amendment is submitted within 2 months of the end of the initial review 
cycle. As with major amendments to efficacy supplements, before October 
2002, we did not extend the review cycle for a major amendment for a 
manufacturing supplement, so we are treating this codification as a 
regulatory change.
    This change regarding manufacturing supplements might slightly 
increase review times for these supplements for which at least one 
major amendment was received within 2 months of the end of the initial 
review cycle. Based on data from 1996 to 2000, this regulatory change 
could affect as many as 6 percent of all manufacturing supplements 
filed, or an average of 76 per year. The effect of this change is 
dependent on the timing of future filings and the number of instances 
in which we exercise our review discretion.
    With respect to amendments to ANDAs, the changes to the regulations 
codify our current approach.

B. Summary of Impacts

    Based on the preceding analysis, the changes to provisions 
governing resubmissions could result in reduced review times for up to 
40 percent of efficacy supplements resubmitted annually. However, the 
provisions governing major amendments could slightly increase review 
times for up to 11 percent of efficacy supplements and 6 percent of 
manufacturing supplements (for which at least one major amendment was 
received during the initial review cycle) filed annually. The full 
impact of this rule would be affected by the number of future 
submissions and the extent to which we exercise our discretion to defer 
review until the next cycle. ANDAs will not be

[[Page 39607]]

significantly affected by the changes to regulations.

C. Comments

    We received one comment on the analysis of economic impacts in the 
proposed rule. The comment noted that we did not perform a cost-benefit 
analysis because the proposed rule was not expected to cause 
expenditure of $100 million or more. The comment stated that this would 
be a concern only if the rule brought about negative implications, but 
the comment stated that, if anything, the rule will bring economic 
enhancement. The comment maintained that: (1) More meaningful and 
direct communications will allow companies to market drugs and vaccines 
better; (2) the time to marketing might be shortened; and (3) more 
efficient application procedures will help companies optimize their 
earnings goals.
    We agree with the comment that the rule will not have a negative 
economic impact on applicants seeking approval of drug and biological 
products.

D. Conclusion

    Because this final rule generally amends previous regulations 
governing applications for approval to market new drugs and generic 
drugs to reflect user fee terminology and performance goals that have 
already been incorporated into FDA policies (except with respect to 
complete response letters, as noted above), we certify that the rule 
will not have a significant economic impact on a substantial number of 
small entities. Therefore, no further analysis is required under the 
Regulatory Flexibility Act.

V. Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a 
class of actions that do not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Paperwork Reduction Act of 1995

    This final rule does not contain new information collection 
provisions that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 
U.S.C. 3501-3520). The final rule substitutes complete response letters 
for approvable and not approvable letters (in previous Sec. Sec.  
314.110 and 314.120, respectively) when we take action on marketing 
applications. The final rule retains the provisions requiring the 
recipient of the action letter (a complete response letter under the 
final rule) to amend the application (i.e., resubmit it), withdraw it, 
or ask us to provide an opportunity for a hearing on whether there are 
grounds for denying approval of the application. The final rule also 
revises the regulations (Sec. Sec.  314.60, 314.96, 314.110, and 
314.120) on extending the review cycle due to the submission of 
amendments before we issue an action letter and due to resubmissions, 
but does not change the information required in such amendments and 
resubmissions. OMB already has approved the information collection 
discussed earlier concerning responses to action letters under OMB 
control number 0910-0001, which expires on May 31, 2011.
    The final rule also establishes regulations on the issuance of 
complete response letters to biologics license applicants and 
supplement applicants. The final rule codifies current agency practice 
on the issuance of complete response letters to these applicants and on 
applicant actions in response to these letters (resubmission or 
withdrawal of the application or supplement). OMB has already approved 
the information collection concerning responses to complete response 
letters for BLAs and BLA supplements under OMB control number 0910-
0338, which expires on June 30, 2010.
    We conclude that this final rule contains no new collection of 
information. Therefore, OMB clearance under the PRA is not required.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we have concluded that the 
rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

List of Subjects

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
312, 314, 600, and 601 are amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
1. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 371, 
381, 382, 383, 393; 42 U.S.C. 262.

0
2. Section 312.84 is amended in paragraph (c) by revising the first 
sentence to read as follows:


Sec.  312.84   Risk-benefit analysis in review of marketing 
applications for drugs to treat life-threatening and severely-
debilitating illnesses.

* * * * *
    (c) If FDA concludes that the data presented are not sufficient for 
marketing approval, FDA will issue a complete response letter under 
Sec.  314.110 of this chapter or the biological product licensing 
procedures. * * *
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
3. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 
356b, 356c, 371, 374, 379e.

0
4. Section 314.3 is amended in paragraph (b) by removing the 
definitions for ``Approvable letter'' and ``Not approvable letter'' and 
by adding the following definitions in alphabetical order:


Sec.  314.3   Definitions

* * * * *
    (b) * * *
    Class 1 resubmission means the resubmission of an application or 
efficacy supplement, following receipt of a complete response letter, 
that

[[Page 39608]]

contains one or more of the following: Final printed labeling, draft 
labeling, certain safety updates, stability updates to support 
provisional or final dating periods, commitments to perform 
postmarketing 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.
    Class 2 resubmission means the resubmission of an application or 
efficacy supplement, following receipt of a complete response letter, 
that includes any item not specified in the definition of ``Class 1 
resubmission,'' including any item that would require presentation to 
an advisory committee.
    Complete response letter means a written communication to an 
applicant from FDA 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.
* * * * *
    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:
    (1) Add or modify an indication or claim;
    (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) Provide for, or provide evidence of effectiveness necessary 
for, the traditional approval of a product originally approved under 
subpart H of part 314; or
    (8) Incorporate other information based on at least one adequate 
and well-controlled clinical study.
* * * * *
    Original application means 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.
* * * * *
    Resubmission means submission by the applicant of all materials 
needed to fully address all deficiencies identified in the complete 
response letter. 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.
* * * * *


Sec.  314.50   [Amended]

0
5. Section 314.50 is amended in paragraph (d)(5)(vi)(b) in the fourth 
sentence by removing the phrase ``following receipt of an approvable 
letter'' and by adding in its place the phrase ``in a resubmission 
following receipt of a complete response letter''.

0
6. Section 314.60 is amended as follows:
    a. By revising the section heading;
    b. By revising paragraph (a);
    c. By redesignating paragraphs (b) and (c) as paragraphs (c) and 
(d), respectively;
    d. By adding new paragraph (b); and
    e. By revising newly redesignated paragraphs (c)(1)(iii) and 
(c)(1)(iv), and the first sentence of paragraph (c)(2), to read as 
follows:


Sec.  314.60   Amendments to an unapproved application, supplement, or 
resubmission.

    (a) FDA generally assumes that when an original application, 
supplement to an approved application, or resubmission of an 
application or supplement is submitted to the agency for review, the 
applicant believes that the agency can approve the application, 
supplement, or resubmission as submitted. However, the applicant may 
submit an amendment to an application that has been filed under Sec.  
314.101 but is not yet approved.
    (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 
constitutes an agreement by the applicant under section 505(c) of the 
act to extend the initial review cycle by 3 months. (For references to 
a resubmission of an application or efficacy supplement in paragraph 
(b) of this section, the timeframe for reviewing the resubmission is 
the ``review cycle'' rather than the ``initial review cycle.'') FDA may 
instead defer review of the amendment until the subsequent review 
cycle. If the agency extends the initial review cycle for an original 
application, efficacy supplement, or resubmission under this paragraph, 
the division responsible for reviewing the application, supplement, or 
resubmission will notify the applicant of the extension. 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 submission of a major amendment. FDA may, at its 
discretion, review any subsequent major amendment during the initial 
review cycle (as extended) or defer review until the subsequent review 
cycle.
    (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 will not extend the cycle. FDA may, at its discretion, review 
such an amendment during the initial review cycle or defer review until 
the subsequent review cycle.
    (3) Submission of an amendment to an original application, efficacy 
supplement, or resubmission of an application or efficacy supplement 
that is not a major amendment will not extend the initial review cycle. 
FDA may, at its discretion, review such an amendment during the initial 
review cycle or defer review until the subsequent review cycle.
    (4) 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. FDA may instead defer review of 
the amendment until the subsequent review cycle. If the agency extends 
the initial review cycle for a manufacturing supplement under this 
paragraph, 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. FDA may, at its discretion, review any subsequent 
major amendment during the initial review cycle (as extended) or defer 
review until the subsequent review cycle.
    (5) Submission of an amendment to a supplement other than an 
efficacy or manufacturing supplement will not extend the initial review 
cycle. FDA may, at its discretion, review such an amendment during the 
initial review cycle or defer review until the subsequent review cycle.
    (6) 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.
    (7) 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 
of this part.

[[Page 39609]]

    (c)(1) * * *
    (iii) The applicant has not obtained a right of reference to the 
investigation described in paragraph (c)(1)(ii) of this section; and
    (iv) The report of the investigation described in paragraph 
(c)(1)(ii) of this section would be essential to the approval of the 
unapproved application.
    (2) The submission of an amendment described in paragraph (c)(1) of 
this section will cause the unapproved application to be deemed to be 
withdrawn by the applicant under Sec.  314.65 on the date of receipt by 
FDA of the amendment. * * *
* * * * *

0
7. Section 314.65 is amended by revising the second sentence to read as 
follows:


Sec.  314.65   Withdrawal by the applicant of an unapproved 
application.

    * * * If, by the time it receives such notice, the agency has 
identified any deficiencies in the application, we will list such 
deficiencies in the letter we send the applicant acknowledging the 
withdrawal. * * *


Sec.  314.71   [Amended]

0
8. Section 314.71 is amended in paragraph (c) by adding the phrase 
``except as specified otherwise in this part'' at the end of the 
sentence.

0
9. Section 314.96 is amended by revising paragraph (a)(2) and by 
removing paragraph (a)(3) to read as follows:


Sec.  314.96   Amendments to an unapproved abbreviated application.

    (a) * * *
    (2) 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.
* * * * *

0
10. Section 314.100 is revised to read as follows:


Sec.  314.100   Timeframes for reviewing applications and abbreviated 
applications.

    (a) Except as provided in paragraph (c) of this section, within 180 
days of receipt of an application for a new drug under section 505(b) 
of the act or an abbreviated application for a new drug under section 
505(j) of the act, FDA will review it and send the applicant either an 
approval letter under Sec.  314.105 or a complete response letter under 
Sec.  314.110. This 180-day period is called the ``initial review 
cycle.''
    (b) At any time before approval, an applicant may withdraw an 
application under Sec.  314.65 or an abbreviated application under 
Sec.  314.99 and later submit it again for consideration.
    (c) 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, as the result of a major amendment.

0
11. Section 314.101 is amended by revising paragraph (f)(1)(ii) and by 
revising the last sentence of paragraph (f)(2) to read as follows:


Sec.  314.101   Filing an application and receiving an abbreviated new 
drug application.

* * * * *
    (f)(1) * * *
    (ii) Issue a notice of opportunity for a hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an application 
in response to a complete response letter.
    (2) * * * If FDA disapproves the abbreviated new drug application, 
FDA will issue a notice of opportunity for hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an abbreviated 
new drug application in response to a complete response letter.
* * * * *

0
12. Section 314.102 is amended in the last sentence in paragraph (b) by 
removing the phrase ``an action'' and adding in its place the phrase 
``a complete response'' and by revising paragraph (d) to read as 
follows:


Sec.  314.102   Communications between FDA and applicants.

* * * * *
    (d) End-of-review conference. At the conclusion of FDA's review of 
an NDA as designated by the issuance of a complete response letter, FDA 
will provide the applicant with an opportunity to meet with agency 
reviewing officials. The purpose of the meeting will be to discuss what 
further steps need to be taken by the applicant before the application 
can be approved. Requests for such meetings must be directed to the 
director of the division responsible for reviewing the application.
* * * * *


Sec.  314.103   [Amended]

    13. Section 314.103 is amended in paragraph (c)(1) in the first 
sentence by removing the phrase ``an approvable or not approvable'' and 
adding in its place the phrase ``a complete response'' and by removing 
the phrase ``or Sec.  314.120, respectively''.


Sec.  314.105   [Amended]

0
14. Section 314.105 is amended in paragraph (b) in the first sentence 
by removing the phrase ``(rather than an approvable letter under Sec.  
314.110)''.

0
15. Section 314.107 is amended by adding a new sentence at the 
beginning of paragraph (b)(3)(v) to read as follows:


Sec.  314.107   Effective date of approval of a 505(b)(2) application 
or abbreviated new drug application under section 505(j) of the act.

* * * * *
    (b) * * *
    (3) * * *
    (v) FDA will issue a tentative approval letter when tentative 
approval is appropriate in accordance with paragraph (b)(3) of this 
section. * * *
* * * * *

0
16. Section 314.110 is revised to read as follows:


Sec.  314.110   Complete response letter to the applicant.

    (a) Complete response letter. FDA will send the applicant a 
complete response letter if the agency determines 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.
    (1) Description of specific deficiencies. A complete response 
letter will describe all of the specific deficiencies that the agency 
has identified in an application or abbreviated application, except as 
stated in paragraph (a)(3) of this section.
    (2) Complete review of data. A complete response letter reflects 
FDA's complete review of the data submitted in an original application 
or abbreviated application (or, where appropriate, a resubmission) and 
any amendments that the agency has reviewed. The complete response 
letter will identify any amendments that the agency has not yet 
reviewed.
    (3) Inadequate data. If FDA determines, after an application is 
filed or an abbreviated application is received, that the data 
submitted are inadequate to support approval, the agency might issue a 
complete response letter without first conducting required inspections 
and/or reviewing proposed product labeling.
    (4) Recommendation of actions for approval. When possible, a 
complete response letter will recommend actions that the applicant 
might take to place the application or abbreviated application in 
condition for approval.
    (b) Applicant actions. After receiving a complete response letter, 
the applicant must take one of following actions:

[[Page 39610]]

    (1) Resubmission. Resubmit the application or abbreviated 
application, addressing all deficiencies identified in the complete 
response letter.
    (i) A resubmission of an application or efficacy supplement that 
FDA classifies as a Class 1 resubmission constitutes an agreement by 
the applicant to start a new 2-month review cycle beginning on the date 
FDA receives the resubmission.
    (ii) A resubmission of an application or efficacy supplement that 
FDA classifies as a Class 2 resubmission constitutes an agreement by 
the applicant to start a new 6-month review cycle beginning on the date 
FDA receives the resubmission.
    (iii) 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 of the 
initial supplement), beginning on the date FDA receives the 
resubmission.
    (iv) A major resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new 6-month review cycle 
beginning on the date FDA receives the resubmission.
    (v) A minor resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new review cycle beginning on 
the date FDA receives the resubmission.
    (2) Withdrawal. Withdraw the application or abbreviated 
application. A decision to withdraw an application or abbreviated 
application is without prejudice to a subsequent submission.
    (3) Request opportunity for hearing. Ask the agency to provide the 
applicant an opportunity for a hearing on the question of whether there 
are grounds for denying approval of the application or abbreviated 
application under section 505(d) or (j)(4) of the act, respectively. 
The applicant must submit the request to the Associate Director for 
Policy, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993. 
Within 60 days of the date of the request for an opportunity for a 
hearing, or within a different time period to which FDA and the 
applicant agree, the agency will either approve the application or 
abbreviated application under Sec.  314.105, or refuse to approve the 
application under Sec.  314.125 or abbreviated application under Sec.  
314.127 and give the applicant written notice of an opportunity for a 
hearing under Sec.  314.200 and section 505(c)(1)(B) or (j)(5)(c) of 
the act on the question of whether there are grounds for denying 
approval of the application or abbreviated application under section 
505(d) or (j)(4) of the act, respectively.
    (c) Failure to take action. (1) An applicant agrees to extend the 
review period under section 505(c)(1) or (j)(5)(A) of the act until it 
takes any of the actions listed in paragraph (b) of this section. For 
an application or abbreviated application, FDA may consider an 
applicant's failure to take any of such actions 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. FDA will grant 
any reasonable request for such an extension. FDA 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.
    (2) If FDA considers an applicant's failure to take action in 
accordance with paragraph (c)(1) of this section to be a request to 
withdraw the application, the agency will notify the applicant in 
writing. The applicant will have 30 days from the date of the 
notification to explain why the application should not be withdrawn and 
to request an extension of time in which to resubmit the application. 
FDA will grant any reasonable request for an extension. If the 
applicant does not respond to the notification within 30 days, the 
application will be deemed to be withdrawn.


Sec.  314.120   [Removed and Reserved]

0
17. Section 314.120 is removed and reserved.


Sec.  314.125   [Amended]

    18. Section 314.125 is amended in paragraph (a)(1) by removing the 
phrase ``an approvable or a not approvable'' and adding in its place 
the phrase ``a complete response'', and by removing the phrase ``or 
Sec.  314.120''.


Sec.  314.430   [Amended]

    19. Section 314.430 is amended in paragraph (b) in the first 
sentence by removing the phrase ``approvable letter is sent to the 
applicant under Sec.  314.110'' and adding in its place the phrase 
``approval letter is sent to the applicant under Sec.  314.105 or 
tentative approval letter is sent to the applicant under Sec.  
314.107''; and by removing the last sentence.

0
20. Section 314.440 is amended as follows:
    a. In paragraph (a)(1) by removing the phrase ``Document and 
Records Section'' and by adding in its place the phrase ``Central 
Document Room'';
    b. In paragraph (a)(3) by removing the phrase ``or Sec.  314.120'';
    c. In the introductory text of paragraph (b) by removing the phrase 
``or Sec.  314.120''; and
    d. By revising paragraph (a)(2) to read as follows:


Sec.  314.440   Addresses for applications and abbreviated 
applications.

    (a) * * *
    (2) Except as provided in paragraph (a)(4) of this section, an 
abbreviated application under Sec.  314.94, and amendments, 
supplements, and resubmissions should be directed to the Office of 
Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food 
and Drug Administration, Metro Park North II, 7500 Standish Place, rm. 
150, Rockville, MD 20855. This includes items sent by parcel post or 
overnight courier service. Correspondence not associated with an 
abbreviated application should be addressed specifically to the 
intended office or division and to the person as follows: Office of 
Generic Drugs, Center for Drug Evaluation and Research, Food and Drug 
Administration, Attn: [insert name of person], Metro Park North II, 
HFD-[insert mail code of office or division], 7500 Standish Place, rm. 
150, Rockville, MD 20855. The mail code for the Office of Generic Drugs 
is HFD-600, the mail codes for the Divisions of Chemistry I, II, and 
III are HFD-620, HFD-640, and HFD-630, respectively, and the mail code 
for the Division of Bioequivalence is HFD-650.
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
21. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

0
22. Section 600.3 is amended by adding new paragraphs (ll) and (mm) to 
read as follows:


Sec.  600.3  Definitions.

* * * * *
    (ll) Complete response letter means a written communication to an 
applicant from FDA 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.
    (mm) Resubmission means a submission by the biologics license 
applicant or supplement applicant of all

[[Page 39611]]

materials needed to fully address all deficiencies identified in the 
complete response letter. 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.

PART 601--LICENSING

0
23. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority:  15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).


Sec.  601.3  [Added]

0
24. Section 601.3 is added to subpart A to read as follows:


Sec.  601.3  Complete response letter to the applicant.

    (a) Complete response letter. The Food and Drug Administration will 
send the biologics license applicant or supplement applicant a complete 
response letter if the agency determines that it will not approve the 
biologics license application or supplement in its present form.
    (1) Description of specific deficiencies. A complete response 
letter will describe all of the deficiencies that the agency has 
identified in a biologics license application or supplement, except as 
stated in paragraph (a)(2) of this section.
    (2) Inadequate data. If FDA determines, after a biologics license 
application or supplement is filed, that the data submitted are 
inadequate to support approval, the agency might issue a complete 
response letter without first conducting required inspections, testing 
submitted product lots, and/or reviewing proposed product labeling.
    (3) Recommendation of actions for approval. 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.
    (b) Applicant actions. After receiving a complete response letter, 
the biologics license applicant or supplement applicant must take 
either of the following actions:
    (1) Resubmission. Resubmit the application or supplement, 
addressing all deficiencies identified in the complete response letter.
    (2) Withdrawal. Withdraw the application or supplement. A decision 
to withdraw the application or supplement is without prejudice to a 
subsequent submission.
    (c) Failure to take action. (1) FDA may consider a biologics 
license applicant or 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. FDA will grant any reasonable request for such an 
extension. FDA may consider an applicant's failure to resubmit the 
application or supplement within the extended time period or request an 
additional extension to be a request by the applicant to withdraw the 
application.
    (2) If FDA considers an applicant's failure to take action in 
accordance with paragraph (c)(1) of this section to be a request to 
withdraw the application, the agency will notify the applicant in 
writing. The applicant will have 30 days from the date of the 
notification to explain why the application or supplement should not be 
withdrawn and to request an extension of time in which to resubmit the 
application or supplement. FDA will grant any reasonable request for an 
extension. If the applicant does not respond to the notification within 
30 days, the application or supplement will be deemed to be withdrawn.

    Dated: June 26, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-15608 Filed 7-9-08; 8:45 am]

BILLING CODE 4160-01-S
