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[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]
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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 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.
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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
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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.
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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
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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.
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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]
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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''.
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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. * * *
* * * * *
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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]
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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.
* * * * *
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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.
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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.
* * * * *
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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]
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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. * * *
* * * * *
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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]
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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.
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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
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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.
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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]
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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