Applications for Approval to Market a New Drug; Complete Response Letter; Amendments to Unapproved Applications, 39588-39611 [E8-15608]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 73, Number 133 (Thursday, July 10, 2008)]
[Rules and Regulations]
[Pages 39588-39611]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-15608]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 312, 314, 600, and 601

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


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

AGENCY:  Food and Drug Administration, HHS.

ACTION: Final rule.

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

DATES:  This rule is effective August 11, 2008.

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