[Federal Register: July 20, 2004 (Volume 69, Number 138)]
[Proposed Rules]
[Page 43351-43366]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20jy04-17]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 312, 314, 600, and 601
[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: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
our regulations on new drug applications (NDAs) and abbreviated new
drug applications (ANDAs) for approval to market new drugs and generic
drugs. We propose to discontinue the use of approvable letters and not
approvable letters when taking action on marketing applications.
Instead, we intend to use complete response letters to indicate that
the review cycle is complete and that the application is not ready for
approval. We also are proposing to revise the regulations on extending
the review cycle due to the submission of an amendment to an unapproved
application and starting a new cycle after a resubmission following
receipt of a complete response letter. In addition, we are proposing to
add to the regulations on biologics license applications (BLAs) a
provision 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 that address procedures and establish target
timeframes for reviewing human drug applications.
DATES: Submit written or electronic comments by October 18, 2004. See
section VIII of this document for the proposed effective date of a
final rule based on this document.
ADDRESSES: You may submit comments, identified by [Docket No. 2004N-
0267], by any of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web Site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
E-mail: fdadockets@oc.fda.gov. Include [Docket No. 2004N-
0267] in the subject line of your e-mail message.
Fax: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name
and [Docket No. 2004N-0267] for this rulemaking. All comments received
will be posted without change to http://www.fda.gov/dockets/ecomments,
including any personal information provided. For detailed instructions
on submitting comments and additional information on the rulemaking
process, see the ``Request for Comments'' heading in the SUPPLEMENTARY
INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/dockets/ecomments and/or
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
The Office of Management and Budget (OMB) is still experiencing
significant delays in the regular mail, including first class and
express mail, and messenger deliveries are not being accepted. To
ensure that comments on the information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB, Attn: Fumie Yokota, Desk Officer for FDA,
FAX: 202-395-6974.
FOR FURTHER INFORMATION CONTACT: Brian L. Pendleton, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-443-5523.
SUPPLEMENTARY INFORMATION:
I. Background
A. User Fee Performance Goals and Complete Response Letters
In conjunction with the Prescription Drug User Fee Act of 1992
(PDUFA) (Public Law 102-571), we committed to meet certain goals for
reviewing and acting on human drug applications, as defined in section
735(1) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
379g(1)). For example, we promised that by September 30, 1997, we would
review and act on at least 90 percent of standard NDAs within 12 months
after the submission date (H. Rep. No. 895, 102d Cong., 2d. sess. 32
(1992) (letter from David A. Kessler, M.D., Commissioner of Food and
Drugs, to Representatives John Dingell and Norman Lent, House Committee
on Energy and Commerce (September 14, 1992))).
FDA's drug application review performance goals were revised 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''). The goals were further revised 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 the 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).
Under the user fee performance goals, the term ``review and act
on'' is defined as the issuance of a complete action letter after the
complete review of a complete application that we have accepted for
filing (Goals Letter at 15). An action letter, if not an approval,
states the specific deficiencies of the application, and where
appropriate, the actions necessary to place the application in
condition for approval (id.).
As part of the user fee performance goals (first in PDUFA II and
again in PDUFA III), FDA's Center for Drug Evaluation and Research
(CDER) and
[[Page 43352]]
Center for Biologics Evaluation and Research (CBER) agreed to revise
their regulations and procedures to provide for the issuance of either
an approval or a ``complete response'' action letter at the completion
of the review cycle for an application (Goals Letter at 15). We are now
proposing to revise our regulations on human drugs in part 314 (21 CFR
part 314) to replace two types of action letters currently used,
approvable letters (Sec. 314.110) and not approvable letters (Sec.
314.120), with complete response letters. Because there are no
provisions on action letters in the biological product regulations in
parts 600 through 680 (21 CFR parts 600 through 680), CBER had only to
change their standard operating procedures to incorporate the use of a
complete response letter at the end of a review cycle for a biological
product. Although CBER has already done this, we are now proposing to
add a regulation (proposed Sec. 601.3) on the issuance of complete
response letters concerning BLAs and BLA supplements.
In replacing approvable and not approvable letters with complete
response letters, our intent is to adopt a consistent and more neutral
mechanism to convey that we cannot approve a drug marketing application
in its current form. Historically, FDA issued a not approvable letter
when deficiencies were major (e.g., no adequate and well-controlled
studies, failure to demonstrate effectiveness, and a major safety
concern). However, the distinction between approvable and not
approvable letters became somewhat blurred. For example, in some cases,
the absence of a second study supporting the effectiveness of a
proposed drug product for a particular indication might have led to a
not approvable letter; in other cases, FDA might have issued an
approvable letter stating the need for additional evidence. Thus,
issuance of an approvable letter might mean that an application needed
only minor changes, such as a revision of labeling, or much more
substantial changes. In addition, we subsequently approved many
applications for which we had first issued a not approvable letter.
Issuance of complete response letters will ensure a consistent approach
to informing sponsors of needed changes before we can approve an
application, with no implication as to the ultimate approvability of
the application.
We also intend to incorporate into the regulations for NDAs the
terminology based on the user fee performance goals regarding Class 1
and Class 2 resubmissions. A ``Class 1 resubmission'' is defined for
performance goal purposes as an application resubmitted after receipt
of an approvable or not approvable letter that includes only certain
items such as draft or final printed labeling, safety or stability
updates, or other minor clarifying information. A ``Class 2
resubmission'' is one that addresses any other items, including any
item that would require presentation to an advisory committee. A Class
1 resubmission has a performance goal of 2 months and a Class 2
resubmission has a performance goal of 6 months. In accordance with the
user fee goals, we are proposing to apply this terminology to original
NDAs as well as to efficacy supplements (supplements to approved
applications to make certain significant changes to product labeling).
As a result, efficacy supplements would be treated like original NDAs
with regard to resubmissions. We are proposing to apply different rules
to resubmissions of other types of NDA supplements.
B. ANDAs
Although the user fee performance goals do not apply to ANDAs, the
current regulations regarding approvable and not approvable letters in
Sec. Sec. 314.110 and 314.120 apply to both NDAs and ANDAs (with a few
exceptions). As a result, any proposed change to the regulations for
NDAs must take into account the impact on ANDAs. Because we intend to
change the regulations for NDAs and we believe that these changes make
sense for other applications, we have decided to propose similar
changes for ANDAs.
C. Amendments to Unapproved Applications
The PDUFA performance goals also state that a major amendment to an
unapproved application submitted within 3 months of the goal date
(i.e., the end of the initial review cycle) extends the goal date by 3
months. We are proposing to incorporate this provision into our
regulations by revising Sec. 314.60 on amendments to unapproved
applications. In accordance with the user fee goals, we are proposing
to apply this provision to efficacy supplements and resubmissions of
applications and efficacy supplements as well, but not to ANDAs.
II. Highlights of the Proposed Rule
A. Complete Response Letters
In accordance with the PDUFA performance goals and in response to
the concerns previously discussed, we are proposing to substitute
complete response letters for approvable and not approvable letters at
the completion of the review cycle for an NDA or ANDA. Under proposed
Sec. 314.110, we will send a complete response letter if we determine
that we will not approve an application or abbreviated application in
its present form. The complete response letter usually would describe
all of the specific deficiencies in the application or abbreviated
application. If we determine, 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.
Table 1 of this document summarizes the changes that we propose to
make in substituting complete response letters for approvable and not
approvable letters:
Table 1.--Summary of Proposed Changes Regarding Substitution of Complete
Response Letter for Approvable and Not Approvable Letters
------------------------------------------------------------------------
Current Regulations Proposed Regulations
------------------------------------------------------------------------
Approvable Letter for NDA Complete Response Letter
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States that NDA is States that FDA will not
basically approvable if certain approve NDA or ANDA in its present
issues are resolved. form.
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Indicates that NDA Describes all specific
substantially meets requirements deficiencies, except when issued
of part 314 (21 CFR part 314) and without conducting required
FDA can approve it if applicant inspections or labeling review
submits additional information or because data found to be
agrees to specific conditions inadequate to support approval.
(e.g., labeling changes).
------------------------------------------------------------------------
Approvable Letter for ANDA ...................................
------------------------------------------------------------------------
[[Page 43353]]
Indicates that ANDA Reflects complete review
substantially meets requirements of data in NDA or ANDA as well as
of part 314 and is approvable if amendments for which review cycle
minor deficiencies are corrected. was extended.
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Describes deficiencies and Where appropriate,
states when applicant must describes actions necessary to
respond. place NDA or ANDA in condition for
approval.
------------------------------------------------------------------------
Not Approvable Letter for NDA or ...................................
ANDA
------------------------------------------------------------------------
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 proposing to adopt a new regulation, Sec. 601.3, stating that
FDA will send a BLA a complete response letter if we determine that we
will not approve the BLA or BLA supplement in its present form.
B. Resubmissions
We also propose to revise the current provisions in Sec. Sec.
314.110 and 314.120 on extension of the review period due to
resubmission of an NDA or ANDA after receipt of an approvable or not
approvable letter (to be replaced by a complete response letter). We
propose that a Class 2 resubmission of an NDA following receipt of a
complete response letter would start a new 6-month review cycle, as is
the case with an ``amendment'' following receipt of a not approvable
letter under current Sec. 314.120(a)(1). A Class 1 resubmission of an
NDA following receipt of a complete response letter would start a new
2-month review cycle.
The proposed rules on Class 1 and Class 2 resubmissions would also
apply to efficacy supplements to NDAs, in accordance with the user fee
performance goals. We believe that this is appropriate because efficacy
supplements, like original applications, contain varying amounts of
data. Where extensive data requiring significant agency resources for
review are provided, the current 6-month review cycle should apply. But
as with some NDA resubmissions, it would be appropriate to consider
some smaller resubmissions of efficacy supplements as Class 1
resubmissions. We propose to apply different rules and terminology to
other types of NDA supplements, including supplements dealing with
chemistry, manufacturing, and controls (CMC) and labeling supplements
for which no clinical data are needed. For NDA supplements other than
efficacy supplements, a resubmission would start a new 6-month review
cycle.
A ``major'' resubmission of an ANDA following receipt of a complete
response letter would start a new 6-month review cycle, as is the case
with an ``amendment'' following receipt of a not approvable letter
under current Sec. 314.120(a)(1). A ``minor'' resubmission of an ANDA
would start a new review cycle of an unspecified length; the period
might last from 30 days to a few months, depending on the issues
involved. Under the relevant current CDER guidance document, entitled
``Major, Minor, and Telephone Amendments to Abbreviated New Drug
Applications'' (December 2001), a minor resubmission usually would
start a new review cycle of between 30 to 60 days.
The proposed changes to our regulations on applicants' responses to
action letters are summarized in the following table 2.
Table 2.--Summary of Proposed Changes to Regulations Regarding
Applicant's Response to Agency Action Letter (Resubmissions)
------------------------------------------------------------------------
Current Regulations Proposed Regulations
------------------------------------------------------------------------
Applicant's Response to Approvable NDA or ANDA Applicant's Response to
Letter or Not Approvable Letter Complete Response Letter
for NDA (or NDA Supplement)
------------------------------------------------------------------------
Within 10 days of date of letter, Review period is extended until
NDA applicant must do one of applicant takes one of following
following: actions:
------------------------------------------------------------------------
Amend application or Resubmit NDA or ANDA,
notify FDA of intent to file addressing identified
amendment. deficiencies.
------------------------------------------------------------------------
Withdraw application. --Class 1 resubmission of NDA or
efficacy supplement starts new, 2-
month cycle
------------------------------------------------------------------------
Request opportunity for --Class 2 resubmission of NDA or
hearing. efficacy supplement starts new, 6-
month cycle
------------------------------------------------------------------------
Agree to extend review --Resubmission of NDA supplement
period to decide which of above other than efficacy supplement
actions to take. starts new, 6-month cycle
------------------------------------------------------------------------
Response to Approvable Letter for ...................................
ANDA (or ANDA Supplement)
------------------------------------------------------------------------
Correct deficiencies by --Major resubmission of ANDA or
specified date or FDA will refuse ANDA supplement starts new, 6-
to approve ANDA or ANDA month cycle
supplement.
------------------------------------------------------------------------
[[Page 43354]]
Request opportunity for --Minor resubmission of ANDA or
hearing within 10 days. ANDA supplement starts new cycle
of variable length
------------------------------------------------------------------------
Response to Not Approvable Letter ...................................
for ANDA (or ANDA Supplement)
------------------------------------------------------------------------
Same as for NDAs except Withdraw NDA or ANDA.
that 10-day period does not apply
(with exception of request for
opportunity for hearing).
------------------------------------------------------------------------
FDA may regard failure to Request opportunity for
respond within 180 days as request hearing.
to withdraw.
------------------------------------------------------------------------
These proposed changes with respect to NDAs are consistent with our
user fee performance goals for resubmissions of human drug applications
following receipt of an action letter. The proposed provisions for
ANDAs are similar, although not identical, to those for NDAs.
C. Amendments to Unapproved Applications
In accordance with our user fee goals, we are proposing to revise
our regulations on extending the review cycle following the submission
of an amendment to an unapproved NDA. Under current Sec. 314.60, the
submission of a major amendment to an unapproved NDA (such as one that
contains significant new data from a previously unreported study or
detailed new analyses of earlier data) may extend the review period by
up to 180 days. Under the user fee goals, a major amendment to an
original NDA submitted within 3 months of the goal date extends the
goal date by 3 months (Goals Letter at 15). Therefore, we propose to
revise Sec. 314.60 to state that submission of a major amendment to an
original NDA within 3 months of the end of the initial review cycle
constitutes an agreement to extend the review cycle by 3 months. The
proposed regulation states that FDA may instead defer review of such an
amendment until the subsequent review cycle.
Under the proposal, the submission of a major amendment to an NDA
more than 3 months before the close of the initial review cycle, or the
submission of a minor amendment during the initial review cycle, would
not extend the review cycle. FDA might, at its discretion, review such
an amendment during the initial review cycle or defer review until the
subsequent review cycle. This proposed change to Sec. 314.60 would
codify for all NDAs our current policy on extending the review cycle
for amendments to unapproved NDAs that are subject to user fees.
Also in accordance with the user fee goals, we are proposing to
revise the regulations to provide that submission of a major amendment
to an efficacy supplement to an approved application within 3 months of
the end of the initial review cycle constitutes an agreement to extend
the review cycle for the supplement by 3 months (although we could
defer review to the subsequent cycle). It is appropriate to treat major
amendments to efficacy supplements the same way as major amendments to
original applications because their review requires significant agency
resources. Amendments to other types of NDA supplements, however, will
not extend the review cycle.
An additional change that is consistent with the user fee goals
would provide that the submission of a major amendment to a
resubmission of an application or efficacy supplement within 3 months
of the end of the initial review cycle constitutes an agreement to
extend the review cycle by 3 months (again, we could elect to defer
review). Because major amendments to these resubmissions generally
require the review of substantial data, it is appropriate to treat them
the same way as major amendments to original applications or efficacy
supplements.
We propose to make only minor revisions to the regulations on
submitting amendments to unapproved ANDAs in Sec. 314.96. The proposed
rule would clarify that an amendment to an ANDA submitted before the
end of the initial review cycle that contains significant data or
information could extend the initial review cycle by as many as 180
days.
Table 3 of this document summarizes the proposed changes to our
regulations on amendments submitted before an action letter:
Table 3.--Summary of Proposed Changes to Regulations on Amendments
Submitted Prior to Action Letter
------------------------------------------------------------------------
Current Regulations Proposed Regulations
------------------------------------------------------------------------
Amendments to Unapproved NDAs and Amendments to Unapproved NDAs and
NDA Supplements Efficacy Supplements
------------------------------------------------------------------------
Submission of major Submission of major
amendment constitutes agreement to amendment within 3 months of end
extend deadline for FDA decision. of initial review cycle
constitutes agreement to extend
cycle by 3 months; FDA may instead
defer review to subsequent cycle.
------------------------------------------------------------------------
FDA may not extend review Initial review cycle may
period more than 180 days. be extended only once for major
amendment.
------------------------------------------------------------------------
Submission of nonmajor Submission of major
amendment will not extend review amendment more than 3 months
period. before end of initial review cycle
will not extend cycle.
------------------------------------------------------------------------
Amendments to Unapproved ANDAs and Submission of minor
ANDA Supplements amendment will not extend review
cycle.
------------------------------------------------------------------------
Submission of amendment ...................................
containing significant data or
information constitutes agreement
to extend review period up to 180
days.
------------------------------------------------------------------------
[[Page 43355]]
Same for amendments to ...................................
unapproved ANDA supplements.
------------------------------------------------------------------------
Amendments to Unapproved NDA
Supplements Other Than Efficacy
Supplements
------------------------------------------------------------------------
Submission of any
amendment will not extend the
initial review cycle.
------------------------------------------------------------------------
Amendments to Resubmissions of
Applications and Efficacy
Supplements
------------------------------------------------------------------------
Submission of major
amendment within 3 months of end
of initial review cycle
constitutes agreement to extend
cycle by 3 months; FDA may instead
defer review to subsequent cycle.
------------------------------------------------------------------------
Amendments to Unapproved ANDAs and
ANDA Supplements
------------------------------------------------------------------------
Unchanged
------------------------------------------------------------------------
III. Description of the Proposed Rule
The proposed rule would make the following five types of revisions
and additions to the regulations: (1) Revisions to remove the use of
approvable and not approvable letters for NDAs and ANDAs and to
incorporate the use of complete response letters and use of the term
``review cycle'', (2) addition of provisions on the issuance of
complete response letters concerning BLAs and BLA supplements, (3)
revisions related to resubmissions of NDAs and ANDAs after receipt of
complete response letters, (4) miscellaneous technical revisions
related to the use of complete response letters for NDAs and ANDAs, and
(5) revisions related to amendments to unapproved NDAs and ANDAs.
A. The Complete Response Letter and the Review Cycle for NDAs and ANDAs
1. Definitions (Proposed Sec. 314.3)
Current Sec. 314.3(b) defines ``approvable letter'' and ``not
approvable letter.'' We propose to revise Sec. 314.3(b) by removing
these definitions and adding a definition of ``complete response
letter.'' A complete response letter would be defined 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. (Under current
Sec. 314.3, ``application'' refers to an NDA and ``abbreviated
application'' refers to an ANDA.)
We also propose to revise Sec. 314.3(b) by adding a definition of
``original application.'' An original application would be defined as a
pending application for which we have never issued a complete response
letter or approval letter or an application that was submitted again
after we had refused to file it or after it was withdrawn without being
approved.
We also propose to add definitions of ``Class 1 resubmission'' and
``Class 2 resubmission'' for resubmissions of NDAs. A ``Class 1
resubmission'' would be defined as the resubmission of an application
(i.e., an NDA), 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.\1\ A ``Class
2 resubmission'' would be defined as the resubmission of an
application, 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. These definitions of Class 1 and Class 2
resubmissions of NDAs reflect those stated in the Goals Letter and will
not be applied to ANDAs.
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\1\ This definition of Class 1 resubmission matches the
definition stated in the user fee Goals Letter, except that the
latter refers to ``other minor clarifying information'' and states
that ``[o]ther specific items may be added later as the Agency gains
experience with the scheme and will be communicated via guidance
documents to industry'' (Goals Letter at 16). The proposed
definition would allow resubmissions that contain unspecified
information of a comparatively minor nature to be treated as Class 1
resubmissions. FDA might address specific types of such
resubmissions in agency guidance.
---------------------------------------------------------------------------
In addition, we propose to revise Sec. 314.3(b) to add a
definition of ``efficacy supplement.'' An ``efficacy supplement'' would
be defined as a supplement to an approved NDA 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 part 314, or (8)
incorporate other information based on at least one adequate and well-
controlled clinical study.
2. Timeframes for Review (Proposed Sec. 314.100)
Current Sec. 314.100 addresses the timeframes for reviewing
applications and abbreviated applications. Section 314.100(a) states
that within 180 days of receipt of an application for a new drug under
section 505(b) of the act (21 U.S.C. 355(b)) or of 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, an approvable letter under Sec. 314.110, or a not approvable
letter under Sec. 314.120. This 180-day period is called the review
clock.
We propose to revise Sec. 314.100(a) by creating two separate
provisions reflecting different review cycles for applications that are
subject to user fees and those that are not subject to such fees.
Proposed Sec. 314.100(a)(1) states that, except as provided in
[[Page 43356]]
Sec. 314.100(a)(2), within 180 days of receipt of an application for a
new drug under section 505(b) of the act or of 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. We propose
to rename this 180-day period the ``initial review cycle'' to be
consistent with the term we currently use.
Proposed Sec. 314.100(a)(2) states that, for applications that are
human drug applications, as defined in section 735(1)(A) and (B) of the
act (NDAs), 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 our user fee performance goals for reviewing such
applications and supplements. We are making this change to reflect
that, under the user fee performance goals, we are not expected to
review and act on all applications that are subject to user fees within
180 days of receipt of such applications. Rather, we have committed to
take action on certain percentages of applications within different
time periods, depending on the type of application (e.g., standard,
priority, supplement, resubmission) and the relevant fiscal year (see
Goals Letter at 1, 2, and 3). In some cases, such as CMC supplements
that require prior approval, we have committed to taking action in less
than 180 days. Consequently, proposed Sec. 314.100(a)(2) reflects that
the initial review cycle for human drug applications and supplements to
such applications may in some cases be shorter or longer than 180 days.
Current Sec. 314.100(b) states that, during the review period, an
applicant may withdraw an application under Sec. 314.65 or an
abbreviated application under Sec. 314.99 and later resubmit it. We
will treat the subsequent submission as a new original application or
abbreviated application. Current Sec. 314.100(b) uses the term
``review period'' rather than ``review clock'' because it is intended
to address withdrawals made at any time while an application or
abbreviated application is pending before the agency (i.e., filed but
not yet approved), not simply withdrawals made while the review clock
is running. (Although not defined in the regulations, the ``review
period'' means the period from filing of an NDA or receipt of an ANDA
to the ultimate disposition of the application, either by approval,
refusal to approve the NDA under Sec. 314.125 or the ANDA under Sec.
314.127, or withdrawal of the application.) Rather than use the term
``review period'' or ``review clock,'' we propose to clarify Sec.
314.100(b) by stating that, 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. We propose to substitute the phrase ``submit it again''
for ``resubmit it'' because we want to limit the terms ``resubmit'' and
``resubmission'' in part 314 to resubmissions after receipt of a
complete response letter.
Current Sec. 314.100(c) states that the review clock may be
extended by mutual agreement between FDA and an applicant or as
provided in Sec. Sec. 314.60 or 314.96, as the result of a major
amendment. To be consistent with proposed Sec. 314.100(a)(1), we
propose to revise this provision by substituting ``initial review
cycle'' for ``review clock.''
3. Filing an NDA and Receiving an ANDA (Proposed Sec. 314.101)
Current Sec. 314.101(f)(1) states that within 180 days after the
date of filing of an NDA, 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 if the applicant asked FDA to provide
it an opportunity for a hearing on an application in response to an
approvable letter or a not approvable letter.
Consistent with our proposed revision of Sec. 314.100(a), we are
proposing to add a new Sec. 314.101(f)(2) (redesignating current Sec.
314.101(f)(2) and (f)(3) as Sec. 314.101(f)(3) and (f)(4),
respectively). The new section states that for applications that are
human drug applications, as defined in section 735(1)(A) and (B) of the
act, and supplements to such applications, as defined in section 735(2)
of the act, the 180-day period specified in Sec. 314.101(f)(1) will be
adjusted to be consistent with the agency's user fee performance goals
for reviewing such applications and supplements. We also propose to
replace references in current Sec. 314.101(f) to approvable and/or not
approvable letters with references to complete response letters.
4. Approvable and Not Approvable Letters (Proposed Sec. Sec. 314.110
and 314.120)
Current Sec. 314.110 sets forth provisions on the issuance of and
response to approvable letters. Section 314.110(a) states that it may
be appropriate for FDA to issue an approvable letter at the end of a
review period to inform an applicant that its application or
abbreviated application is basically approvable if the applicant
resolves certain issues. It also states that an approvable letter
signifies that we believe that we can approve the application or
abbreviated application if the applicant submits specific additional
information or material or agrees to specific conditions (e.g., changes
in labeling). Section 314.110(a) further states that as a practical
matter, an approvable letter in most instances serves as a mechanism
for resolving outstanding issues on drugs that are about to be approved
and marketed.
Current Sec. 314.120 addresses the agency's issuance of not
approvable letters to applicants and applicants' responses to such
letters. Section 314.120(a) states that we will send an applicant a not
approvable letter if we believe that the application may not be
approved for one of the reasons given in Sec. 314.125, or that an
abbreviated application may not be approved for one of the reasons
given in Sec. 314.127.
We propose to revise Sec. 314.110 (and to remove and reserve Sec.
314.120) by replacing references to approvable letters and not
approvable letters with references to complete response letters.
a. Issuance of complete response letters. Proposed Sec. 314.110 is
entitled ``Complete response letter to the applicant.'' Proposed Sec.
314.110(a) states that we will send the applicant a complete response
letter if we determine 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.
Proposed Sec. 314.110(a)(1) states that a complete response letter
will describe all of the specific deficiencies in the application or
abbreviated application, except as stated in proposed Sec.
314.110(a)(3). (Under current procedures, we might also notify the
applicant of deficiencies in certain parts of the application or
abbreviated application before issuance of a complete response letter.)
Following issuance of a complete response letter, we would not
expect to identify any additional deficiencies in an NDA or ANDA.
However, it is possible that we might find additional deficiencies in
an application following review of: (1) Data submitted in an amendment
not reviewed before issuance of the complete response letter, (2) a
resubmission containing new data or analyses, or (3) additional safety
data obtained from any source. These additional deficiencies might be
based wholly on the newly submitted data or might reflect new analyses
of previous data prompted by the new data. Finally, it is also possible
that we might find
[[Page 43357]]
additional deficiencies in previously reviewed data on the basis of
advice from an advisory committee.
Proposed Sec. 314.110(a)(2) states that the 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 for which the review cycle was
extended. It adds that the complete response letter will identify any
amendments for which the review cycle was not extended that we have not
yet reviewed.
Proposed Sec. 314.110(a)(3) states that if we determine, 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.
Proposed Sec. 314.110(a)(4) states that, where appropriate, a
complete response letter will describe the actions necessary to place
the application or abbreviated application in condition for approval.
b. Responses to complete response letters. Current Sec. 314.110(a)
states that within 10 days after the date of an approvable letter, the
sponsor of an NDA must respond in one of the following several ways:
(1) Amend the application (or notify us of an intent to do so), (2)
withdraw the application (failure to respond within 10 days to an
approvable letter is regarded as a request to withdraw the
application), (3) ask us to provide the applicant with an opportunity
for a hearing on whether there are grounds for denying the approval of
the application under section 505(d) of the act, or (4) notify us that
the applicant agrees to extend the review period under section 505(c)
of the act so that the applicant can determine whether to take one of
the previously listed actions.
Current Sec. 314.110(b) addresses the issuance of approvable
letters to ANDA applicants. Under Sec. 314.110(b), we will send an
ANDA applicant an approvable letter only if the abbreviated application
substantially meets the requirements of part 314 and we believe that we
can approve it if minor deficiencies (e.g., regarding labeling) are
corrected. The approvable letter describes the deficiencies in the ANDA
and states a date by which the applicant must respond. Unless the
applicant corrects the deficiencies within the specified period, FDA
will refuse to approve the ANDA. Within 10 days of the date of the
approvable letter, the applicant may request an opportunity for a
hearing.
In proposed Sec. 314.110(b), we direct both NDA and ANDA
applicants to take one of three actions following receipt of a complete
response letter, eliminating (except with respect to resubmissions) the
separate provisions for ANDAs in current Sec. 314.110(b). We also
propose to delete the requirement that NDA applicants take action
within 10 days.
The first option for the recipient of a complete response letter,
stated in proposed Sec. 314.110(b)(1), is to resubmit the application
or abbreviated application, addressing all deficiencies identified in
the letter. For purposes of Sec. 314.110, a resubmission would mean
the submission by an applicant of all materials needed to fully address
all deficiencies identified in the complete response letter.
Under proposed Sec. 314.110(b)(1)(i), a resubmission of an NDA or
an efficacy supplement that we classify as a Class 1 resubmission would
constitute an agreement by the applicant to start a new 2-month review
cycle beginning on the date we receive the resubmission. Under proposed
Sec. 314.110(b)(1)(ii), a resubmission of an NDA or an efficacy
supplement that we classify as a Class 2 resubmission would constitute
an agreement by the applicant to start a new 6-month review cycle
beginning on the date we receive the resubmission.
For NDA supplements other than efficacy supplements, such as a
supplement for a change in CMC or a labeling supplement that does not
require clinical data, we propose to retain the current practice of not
applying the Class 1 and Class 2 terminology and review cycle lengths.
Thus, 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.
For resubmissions of ANDAs, we propose to continue the current
practice of categorizing them as ``major'' or ``minor.'' Under proposed
Sec. 314.110(b)(1)(iv), a major resubmission of an ANDA would
constitute an agreement by the applicant to start a new 6-month review
cycle beginning on the date we receive the resubmission. Under proposed
Sec. 314.110(b)(1)(v), a minor resubmission of an ANDA would
constitute an agreement to start a new review cycle (length
unspecified) beginning on the date we receive the resubmission. The
actual length of the cycle would depend on the contents of the
resubmission. As noted in section II.C of this document, CDER's
guidance on ``Major, Minor, and Telephone Amendments to Abbreviated New
Drug Applications'' provides guidance on how the agency handles these
resubmissions. The guidance states that CDER attempts to review most
minor amendments within 30 to 60 days, and we intend to apply this to
minor resubmissions of ANDAs. Under the proposed rule, resubmissions of
supplements to approved ANDAs would continue to be treated the same as
ANDA resubmissions in accordance with Sec. 314.97.
The second option for the recipient of a complete response letter,
stated in proposed Sec. 314.110(b)(2), is to withdraw the application
or abbreviated application. A decision to withdraw an application or
abbreviated application would be without prejudice to a subsequent
submission.
The third option for the recipient of a complete response letter,
stated in proposed Sec. 314.110(b)(3), is to ask us 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.
Within 60 days of the date of a request for an opportunity for a
hearing, or within a different time period to which we and the
applicant agree, we would take either of the following actions: (1)
Approve the application or abbreviated application under Sec. 314.105
or (2) refuse to approve the NDA under Sec. 314.125 or the ANDA 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.
Under proposed Sec. 314.110(c), an applicant agrees to extend the
review period under section 505(c)(1) of the act until it takes any of
the actions listed in proposed Sec. 314.110(b). Section 505(c)(1) of
the act directs FDA, within 180 days after the filing of an application
under section 505(b) of the act or an additional period agreed upon by
the applicant and the agency, to either approve the application (if we
find that none of the grounds for denying approval stated in section
505(d) of the act applies) or give the applicant an opportunity for a
hearing under section 505(d) on the question of whether such
application is approvable. Thus, the addition of the provision on
agreement to extend the review period in proposed Sec. 314.110(c)
would ensure that, if we do not approve an application, the applicant
is provided a notice of opportunity for a hearing within the time
specified by section 505(c)(1) of the act.
[[Page 43358]]
Proposed Sec. 314.110(c) further states that we may consider an
NDA applicant's failure to take any of the actions listed in Sec.
314.110(b) within 1 year after receiving a complete response letter to
be a request by the applicant to withdraw the application. However,
regarding ANDAs, proposed Sec. 314.110(c) states that we may consider
an applicant's failure to take any of the listed actions within 6
months after receiving a complete response letter to be a request by
the applicant to withdraw the abbreviated application. We believe that
the shorter time period for ANDAs is appropriate because an ANDA
resubmission is not likely to involve generation of clinical data and
deficiencies normally could be addressed within 6 months.
Because we propose to revise current Sec. 314.110 to state the
provisions on complete response letters, we propose to delete current
Sec. 314.120 on not approvable letters and to reserve this section for
future use.
B. Complete Response Letter for BLAs
To incorporate into the biologics regulations the use of complete
response letters for BLAs, we are proposing to add a definition of
``complete response letter'' to Sec. 600.3 and to add Sec. 601.3 on
complete response letters.
1. Definition (Proposed Sec. 600.3)
We propose to add to current Sec. 600.3, paragraph (jj) to define
a complete response letter. Under proposed Sec. 600.3(jj), a complete
response letter would be defined as a written communication to an
applicant from FDA usually identifying all of the deficiencies in a
biologics license application or supplement that must be satisfactorily
addressed before it can be approved. (Current Sec. 600.3(gg) defines a
``supplement'' as a request to the Director, Center for Biologics
Evaluation and Research, to approve a change in an approved license
application.)
2. Complete Response Letter to the Applicant (Proposed Sec. 601.3)
To incorporate current CBER policy into the regulations, we are
proposing to establish a new Sec. 601.3 on complete response letters.
Under proposed Sec. 601.3(a), FDA will send the biologics license
applicant or supplement applicant a complete response letter if we
determine that we will not approve the biologics license application or
supplement in its present form.
Under proposed Sec. 601.3(b), a biologics license applicant or
supplement applicant must take one of two actions after receiving a
complete response letter. Under proposed Sec. 601.3(b)(1), the license
or supplement applicant may resubmit the application or supplement,
addressing all deficiencies identified in the complete response letter.
Under proposed Sec. 601.3(b)(2), the license or supplement applicant
may withdraw the application or supplement; a decision to withdraw
would be without prejudice to a subsequent submission.
Finally, under proposed Sec. 601.3(c), 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
receiving a complete response letter to be a request by the applicant
to withdraw the application or supplement.
C. Miscellaneous Revisions Related to Adoption of Complete Response
Letters for NDAs and ANDAs
To reflect FDA's use of complete response letters for NDAs and
ANDAs, the agency proposes to make the following additional revisions
to its regulations:
1. Content and Format of Applications (Proposed Sec. 314.50)
Current Sec. 314.50 specifies the content and format of NDAs.
Section 314.50(d) describes the technical sections required in each
application. Section 314.50(d)(5)(vi)(b) states that an applicant
periodically must update its pending application with new safety
information that might affect the statement of contraindications,
warnings, precautions, and adverse reactions in the draft labeling. The
applicant must file these safety update reports 4 months after the
initial submission, after receiving an approvable letter, and when
otherwise requested by FDA.
We propose to revise Sec. 314.50(d)(5)(vi)(b) by replacing the
requirement to submit a safety update report following receipt of an
approvable letter with a requirement to submit a safety update report
in a resubmission following receipt of a complete response letter. This
would ensure that we have more extensive safety information than was
available at the time of the original submission. In addition, we
could, if appropriate, require submission of a safety update report
immediately before issuing an approval letter under the current
provision that allows us to require submission of a report ``at other
times as requested by FDA.''
2. Withdrawal by the Applicant of an Unapproved Application (Proposed
Sec. 314.65)
Current Sec. 314.65 states that an applicant may at any time
withdraw an application that is not yet approved by notifying us in
writing. It further states that we will consider an applicant's failure
to respond within 10 days to an approvable letter under Sec. 314.110
or a not approvable letter under Sec. 314.120 to be a request by the
applicant to withdraw the application.
We propose to revise Sec. 314.65 to delete the reference to
responding within 10 days to an approvable or not approvable letter,
consistent with proposed Sec. 314.110. In addition, we propose to add
a statement that if, by the time we receive a notice of withdrawal, we
have identified any deficiencies in the application, we will list those
deficiencies in the letter we send the applicant acknowledging the
withdrawal.
3. Communications Between FDA and Applicants (Proposed Sec. 314.102)
Current Sec. 314.102 addresses communications between FDA and
applicants. Section 314.102(b) states that FDA reviewers shall make
every reasonable effort to communicate promptly to applicants easily
correctable deficiencies found in an application or an abbreviated
application when those deficiencies are discovered, particularly
deficiencies concerning CMC issues. This early communication is
intended to permit applicants to correct readily identified
deficiencies relatively early in the review process and to submit an
amendment before the review period has elapsed. Section 314.102(b)
further states that such early communication would not ordinarily apply
to major scientific issues; instead, major scientific issues will
ordinarily be addressed in an action letter.
We propose to revise Sec. 314.102(b) to clarify that major
scientific issues will ordinarily be addressed in a complete response
letter, even though they may have been addressed earlier in a
discipline review letter in accordance with user fee performance goals.
Current Sec. 314.102(d) discusses end-of-review conferences. It
states that at the conclusion of our review of an application or
abbreviated application as designated by the issuance of an approvable
or not approvable letter, we will provide applicants 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
[[Page 43359]]
before the application or abbreviated application can be approved.
Section 314.102(d) further states that this meeting will be available
on all applications or abbreviated applications, with priority given to
applications for new chemical entities and major new indications for
marketed drugs and for the first duplicates for such drugs. Requests
for such meetings must be directed to the director of the division
responsible for reviewing the application or abbreviated application.
We propose to revise Sec. 314.102(d) by replacing ``an approvable
or not approvable letter'' with ``a complete response letter.'' In
addition, we propose to delete the references to abbreviated
applications because the Office of Generic Drugs, which reviews such
applications, does not routinely provide end-of-review conferences for
ANDAs. Finally, because we virtually always agree to requests for end-
of-review conferences for NDAs and do not prioritize the scheduling of
such conferences for particular types of NDAs, we propose to remove the
reference to priority status for certain types of NDAs.
4. Approval (Proposed Sec. 314.105)
Current Sec. 314.105(b), concerning approval of applications and
abbreviated applications, states that FDA will approve an application
and issue the applicant an approval letter (rather than an approvable
letter under Sec. 314.110) on the basis of draft labeling if only
minor labeling deficiencies remain. We propose to delete the reference
to approvable letters. Substituting a reference to complete response
letters would not be appropriate because issuance of such a letter
would not necessarily signify that we believe that an application is
basically approvable provided that certain issues are resolved or that
the application substantially meets the requirements of part 314, as is
the case with approvable letters issued under current Sec. 314.110.
5. Public Disclosure of Existence of Applications (Proposed Sec.
314.430)
Current Sec. 314.430(b) states that we will not publicly disclose
the existence of an application or abbreviated application before we
send an approvable letter to the applicant unless the existence of the
application or abbreviated application has been previously publicly
disclosed or acknowledged. The provision further states that CDER will
maintain and make available for public disclosure a list of
applications or abbreviated applications for which we have sent an
approvable letter to the applicant.
We propose to revise Sec. 314.430(b) to allow for FDA disclosure
of the existence of an NDA or ANDA after issuance of an approval letter
or tentative approval letter. Proposed Sec. 314.430 (b) states that we
will not publicly disclose the existence of an application or
abbreviated application before we send the applicant an approval letter
under Sec. 314.105 or a tentative approval letter under Sec. 314.107,
unless the existence of the application or abbreviated application has
been previously publicly disclosed or acknowledged. We do not believe
that it is necessary to include a provision stating that the agency
will maintain and make available for public disclosure a list of
approved applications and abbreviated applications because we already
make this information available by routinely announcing the approval of
NDAs and ANDAs within days of their approval and publishing an annual
list (with monthly supplements) of ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' (known as the ``Orange Book'').
We issue a tentative approval letter when an application meets the
scientific and technical requirements for approval under section 505(b)
or (j) of the act but marketing exclusivity (e.g., pediatric
exclusivity, orphan drug exclusivity) or patent rights prevent final
approval of the drug product. As stated in Sec. 314.107(b)(3)(v),
tentative approval of an application does not constitute an approval of
an application and cannot, absent a final approval letter from the
agency, result in an effective approval of an application. However,
because we only issue tentative approval letters when an application
has met the scientific and technical approval requirements, tentative
approval letters do not present the same disclosure concerns as
correspondence regarding other unapproved applications. Therefore, we
intend to follow our past practice of acknowledging the existence of
applications that have received tentative approval letters and making
those letters publicly available.
Because current Sec. 314.107(b)(3) does not explicitly refer to
our practice of issuing a letter notifying an applicant of a tentative
approval, we propose to revise Sec. 314.107(b)(3)(v) to state that we
will issue a tentative approval letter when tentative approval is
appropriate in accordance with Sec. 314.107 (b)(3).
The changes that we are proposing to the disclosure provisions
would mean that FDA disclosure of the existence of an NDA or ANDA might
result in later disclosure than sometimes occurs under the current
regulation (i.e., with respect to those applications for which FDA now
issues approvable letters). However, we believe that this effect would
be limited because most applicants (at least for NDAs) publicly reveal
the existence of their applications before agency issuance of an
approval letter. Moreover, the proposed change would be consistent with
the agency's long-standing presumption that, before approval (and
absent evidence to the contrary), the existence of an application is
confidential commercial information under 21 CFR 20.61. For example,
under Sec. 601.51, FDA will not disclose the existence of a biological
product file before a BLA has been approved unless it has previously
been publicly disclosed or acknowledged.
However, we specifically invite comment on whether it would be
appropriate for FDA to disclose the existence of an NDA or ANDA
following issuance of a complete response letter and if so, what
conditions, if any, should be placed on such disclosure. For example,
one alternative to the proposed approach would be that FDA would
publicly disclose the existence of an NDA or ANDA following issuance of
a complete response letter unless the applicant notified the agency (by
some specified deadline) that the applicant had not publicly disclosed
or acknowledged the existence of the application or abbreviated
application. This approach would allow applicants to prevent agency
disclosure of the existence of an application despite the issuance of a
complete response letter. However, it also would create the potential
for inadvertent disclosure and necessitate the establishment of a
system to record and track applicants' positions regarding disclosure.
This could be burdensome to applicants and the agency.
6. Other Technical Revisions (Proposed Sec. Sec. 312.84, 314.103,
314.125, and 314.440)
We are proposing to revise other sections of the regulations to
replace references to approvable and/or not approvable letters with
references to complete response letters. These revisions would be made
to Sec. 312.84 (Risk-benefit analysis in review of marketing
applications for drugs to treat life-threatening and severely-
debilitating illnesses), Sec. 314.103 (Dispute resolution), Sec.
314.125 (Refusal to approve an application), and Sec. 314.440
(Addresses for applications and abbreviated applications). (The
proposed rule also revises this section by providing the current
address to
[[Page 43360]]
which an NDA must be submitted and the address for applications
regarding certain products reviewed by CBER.)
D. Amendments to Unapproved NDAs, ANDAs, and Unapproved Supplements to
Approved NDAs
The other principal purpose of this proposed rule, besides the
adoption of complete response letters and related changes to
resubmissions, is to revise the regulations in Sec. Sec. 314.60 and
314.96 on amendments to unapproved NDAs and ANDAs, respectively.
1. Amendments to Unapproved NDAs, Supplements, and Resubmissions
(Proposed Sec. 314.60)
Amendments to unapproved NDAs are addressed in Sec. 314.60.
Current Sec. 314.60(a) states that except as provided in Sec. 314.60
(b), the applicant may submit an amendment to an application that is
filed under Sec. 314.100, but not yet approved. (The reference to
Sec. 314.100 is in error; Sec. 314.101 not Sec. 314.100 addresses
the filing of applications.) Section 314.60(a) further states that the
submission of a major amendment (e.g., one that contains significant
new data from a previously unreported study or detailed new analyses of
earlier data) constitutes an agreement by the applicant under section
505(c) of the act to extend the date by which we are required to decide
on the application. The section adds that we ordinarily will extend the
review period but only for the time needed to review the new
information, and we may not extend the period for more than 180 days.
If we extend the review period for the application, the director of the
division responsible for reviewing the application will notify the
applicant of the length of the extension. The submission of an
amendment that is not a major amendment will not extend the review
period.
We propose to revise Sec. 314.60(a) to state that we generally
assume that when an original application (i.e., original NDA)
supplement to an approved application or resubmission of an application
or supplement is submitted to the agency for review, the applicant
believes that we can approve the application, supplement, or
resubmission as submitted. However, the applicant may submit an
amendment to an application or supplement that has been filed under
Sec. 314.101 but is not yet approved.
In place of the provisions in current Sec. 314.60(a), we propose
to add new Sec. 314.60(b). 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 constitutes an
agreement by the applicant under section 505(c) of the act to extend
the review cycle by 3 months. However, the proposed regulation states
that we may instead defer review of such an amendment until the
subsequent review cycle. The subsequent review cycle would run from the
resubmission of the application, efficacy supplement, or resubmission
following receipt of the complete response letter to the issuance of
either a second complete response letter or an approval letter. Under
proposed Sec. 314.60(b)(1), if we extend the initial review cycle for
an original application, efficacy supplement, or resubmission of an
application or efficacy supplement under this paragraph (b)(1), the
division responsible for reviewing the application, supplement, or
resubmission will notify the applicant of the extension. Proposed Sec.
314.60(b)(1) further states 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
submission of a major amendment. Finally, proposed Sec. 314.60(b)(1)
states that 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.
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 will not extend the cycle. We may, at our
discretion, review such an amendment during the initial review cycle or
defer review until the subsequent review cycle.
Under proposed Sec. 314.60(b)(3), submission of a minor amendment
to an original application, efficacy supplement, or resubmission of an
application or efficacy supplement will not extend the initial review
cycle. We may, at our discretion, review such an amendment during the
initial review cycle or defer review until the subsequent review cycle.
Under proposed Sec. 314.60(b)(4), submission of an amendment to a
supplement other than an efficacy supplement will not extend the
initial review cycle. We may, at our discretion, review such an
amendment during the initial review cycle or defer review until the
subsequent review cycle.
Proposed Sec. 314.60 (b)(5) specifies that a major amendment may
not include data to support an indication for a use that was not
included in the original application, supplement, or resubmission.
These proposed regulations would codify for all NDAs, efficacy
supplements, and resubmissions of NDAs and efficacy supplements, our
current policy on extending the review period for human drug
applications when a major amendment is submitted before FDA issuance of
an action letter. As stated in the previous paragraphs, we believe that
it is appropriate to treat amendments to unapproved efficacy
supplements and amendments to resubmissions of applications and
efficacy supplements, the same as amendments to unapproved NDAs.
Amendments to ANDAs submitted before FDA issuance of an action letter
are addressed in Sec. 314.96, discussed in section III.D.3 of this
document.
2. Procedures for Submission of a Supplement to an Approved Application
(Proposed Sec. 314.71)
The references to different types of supplemental applications in
proposed Sec. Sec. 314.60 and 314.110 necessitate a change to Sec.
314.71, which addresses procedures for submission of supplements to
approved applications. Current Sec. 314.71(c) states that all
procedures and actions that apply to applications under part 314,
including actions by applicants and the agency, also apply to
supplements. Under proposed Sec. Sec. 314.60 and 314.110, a certain
type of NDA supplement (i.e., efficacy supplements) will be treated the
same as an NDA, while other types will be treated differently. To
reflect this different treatment of certain supplements, we propose to
revise Sec. 314.71(c) to clarify that all procedures and actions that
apply to applications under part 314 also apply to supplements ``except
as specified otherwise in this part.''
3. Amendments to Unapproved ANDAs (Proposed Sec. 314.96)
Our regulations on submitting amendments to unapproved abbreviated
applications are set forth in Sec. 314.96. Current Sec. 314.96(a)(2)
states that submission of an amendment containing significant data or
information constitutes an agreement to extend the review period only
for the time necessary to review the information and for no more than
180 days. Under Sec. 314.96(a)(3), the submission of an amendment
containing significant data or information to resolve deficiencies
specified in a not approvable letter will extend the date by which we
must reach a decision on the abbreviated
[[Page 43361]]
application only for the time necessary to review the information and
for no more than 180 days.
We propose to revise Sec. 314.96(a)(2) to substitute the term
``initial review cycle'' for ``review period.'' Our proposed revision
would also clarify that an amendment to an ANDA submitted before the
end of the initial review cycle that contains significant data or
information could extend the initial review cycle for as many as 180
days. Thus, we are proposing to retain the Office of Generic Drugs'
current approach to amendments to ANDAs.
We propose to delete Sec. 314.96(a)(3) because the submission of
an amendment to an abbreviated application following receipt of a
complete response letter (i.e., a resubmission of an abbreviated
application) is addressed in proposed Sec. 314.110.
IV. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act (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 proposed rule is not a significant regulatory action as defined by
the Executive order.
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule 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.
We believe that this proposed rule is consistent with the
regulatory philosophy and principles identified in Executive Order
12866. Because the proposed rule does not impose mandates on State,
local, or tribal governments, or the private sector, that would result
in an expenditure in any one year of $100,000,000 or more, we are not
required to perform a cost-benefit analysis under the Unfunded Mandates
Reform Act of 1995.
With respect to the Regulatory Flexibility Act, we do not believe
that this proposed rule would have a significant economic impact on a
substantial number of small entities. We are taking this action to
amend our regulations governing applications for approval to market new
drugs, generic drugs, and biological products. This action is necessary
to meet a user fee performance goal to replace approvable and not
approvable letters with complete response letters. The proposed rule
also would revise regulations governing amendments to unapproved
applications and codify terminology used in user fee performance goals
affecting resubmissions of applications. As discussed in greater detail
in the following paragraphs, the economic impact of these regulatory
changes is not expected to be significant for any affected entity.
A. Impact of the Proposed Rule
As described in detail in sections II and III of this document, the
proposed rule would do the following: (1) For NDAs and ANDAs, replace
the two types of action letters currently used (approvable and not
approvable letters) with complete response letters; (2) for BLAs,
incorporate into the regulations an existing policy on complete
response letters; (3) incorporate into regulations the terminology and
procedures used in the user fee performance goals regarding NDA
resubmissions; and (4) revise 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 proposed rule largely would
codify current agency practices. For ANDAs, the proposed rule would
revise regulations to be consistent with current practice or, where
appropriate, with the provisions governing NDAs. The most significant
impact of the proposed rule would be on efficacy supplements to
approved NDAs and on resubmissions of applications and efficacy
supplements. The impact of specific provisions of this proposed rule on
NDAs, ANDAs, efficacy supplements, and resubmissions is described in
greater detail in the following paragraphs.
1. Complete Response Letter
We are proposing regulatory changes that would replace approvable
and not approvable letters with complete response letters. Both
approvable and not approvable letters indicate that an NDA or ANDA is
not approvable in its current form, and that changes are necessary or
that we require additional information. A complete response letter
would describe the deficiencies in an NDA or ANDA and, where
appropriate, the actions necessary to place the application in
condition for approval. In the past, some drug manufacturers have
expressed concern that a not approvable letter sends an unintended
message that a marketing application will 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 have already adopted a
policy of issuing complete response letters for BLAs, and the proposed
rule would simply codify 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 proposing 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
would codify agency practices regarding NDA resubmissions in place
since 1998.
We are proposing to apply 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 proposed
application of the Class 1 and Class 2 provisions to resubmissions of
efficacy supplements would represent a regulatory change because under
PDUFA II, all resubmissions of efficacy supplements would start a new
6-month review cycle. Under the proposed rule, a Class 1 resubmission
of an efficacy supplement would extend the review
[[Page 43362]]
cycle by only 2 months, rather than 6 months, as occurred under PDUFA
II. Review times for Class 2 efficacy supplement resubmissions would be
largely unaffected by the proposed 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 proposed rule generally would maintain
current agency practice (review within 6 months) with respect to the
review of other types of NDA supplements, i.e., for CMC or labeling
changes (although under PDUFA III, our goal is to review within 4
months resubmissions of certain CMC supplements for which prior
approval is required). For ANDA resubmissions, the proposal would
codify the current practice of 6-month review.
3. Amendments to Unapproved Drug Marketing Applications
We also are proposing to revise our regulations on extending the
initial review cycle following the submission of an amendment to an
unapproved drug marketing application. Current regulations state, for
unapproved NDAs and efficacy supplements, that submission of a major
amendment extends the review cycle for the amount of time necessary to
review the new information but not by more than 180 days. The proposed
rule generally would extend the review cycle by 3 months if a major
amendment to an application, efficacy supplement, or resubmission of an
application or efficacy supplement were submitted within 3 months of
the end of the initial review cycle. (The proposed rule states that we
may defer review until a subsequent review cycle.) If a major amendment
were submitted more than 3 months before the end of the initial review
cycle, the review cycle would not be extended. These changes would
codify the practice for NDAs that has been in place since 1998.
However, we have 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 proposed change regarding
resubmissions of efficacy supplements, we believe that it is
appropriate to treat the proposed change regarding amendments to
unapproved efficacy supplements as a regulatory change for purposes of
this analysis.
These provisions of the proposed rule might slightly increase
review times for efficacy supplements for which at least one major
amendment was received during 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 might exercise our review
discretion.
With respect to amendments to ANDAs, the proposed changes to
regulations would codify FDA's current approach.
B. Summary of Impacts
Based on the preceding analysis, the proposed changes to provisions
governing resubmissions could result in reduced review times for up to
40 percent of efficacy supplements resubmitted annually. However, the
proposed provisions governing major amendments could slightly increase
review times for up to 11 percent of efficacy 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 might exercise
our discretion to defer review until the next cycle. ANDAs will not be
significantly affected by the proposed changes to regulations.
Because this proposed rule generally amends current 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 previously noted), we certify that the
proposed 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 proposed 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 proposed rule would substitute complete response
letters for approvable and not approvable letters (in current
Sec. Sec. 314.110 and 314.120, respectively) when we take action on
marketing applications. The proposed rule would retain the provisions
requiring the recipient of the action letter (a complete response
letter under the proposed rule) to either amend the application
(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 proposed rule also would revise 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 would not change the
information required in such amendments and resubmissions. OMB has
approved the information collection previously discussed concerning
responses to action letters under OMB control number 0910-0001, which
expires on March 31, 2005.
The proposed rule would also establish regulations on the issuance
of complete response letters to biologics license applicants and
supplement applicants. The proposed rule would codify 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 August 31, 2005.
FDA tentatively concludes that this proposed rule contains no new
collection of information. Therefore, OMB clearance under the PRA is
not required.
VII. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have 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 order and, consequently, a federalism summary impact
statement is not required.
[[Page 43363]]
VIII. Proposed Effective Date
We propose that any final rule that may issue based on this
proposal become effective 30 days after the date of its publication in
the Federal Register.
IX. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments on this proposal. Submit
a single copy of electronic comments or two paper copies of any mailed
comments, except that individuals may submit one paper copy. Comments
are to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the Division
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
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.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 312, 314, 600, and 601 be amended as
follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
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, 371; 42
U.S.C. 262.
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 (for a drug) or Sec. 601.3 of this
chapter (for a biologic). * * *
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
3. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 371, 374, 379e.
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,
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.
Class 2 resubmission means the resubmission of an application,
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 identifying all of the deficiencies 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
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.
* * * * *
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.
* * * * *
Sec. 314.50 [Amended]
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''.
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. 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,
[[Page 43364]]
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 an amendment to a supplement other than an
efficacy 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.
(5) A major amendment may not include data to support an indication
for a use that was not included in the original application,
supplement, or resubmission.
(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.* * *
* * * * *
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]
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.
Sec. 314.96 [Amended]
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.
* * * * *
10. Section 314.100 is revised to read as follows:
Sec. 314.100 Timeframes for reviewing applications and abbreviated
applications.
(a)(1) Except as provided in paragraph (a)(2) 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.''
(2) For 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.
(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 review cycle may be extended 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.
11. Section 314.101 is amended as follows:
a. By revising paragraph (f)(1)(ii);
b. By redesignating paragraphs (f)(2) and (f)(3) as paragraphs
(f)(3) and (f)(4), respectively;
c. By adding new paragraph (f)(2); and
d. By revising the second sentence of newly redesignated paragraph
(f)(3) 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 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) For 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 180-day
period specified in paragraph (f)(1) of this section will be adjusted
to be consistent with the agency's user fee performance goals for
reviewing such applications and supplements.
(3) * * * 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.
* * * * *
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
[[Page 43365]]
by removing the phrase ``or Sec. 314.120, respectively''.
Sec. 314.105 [Amended]
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)''.
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.* * *
* * * * *
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 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 for which the review cycle was extended. The complete
response letter will identify any amendments for which the review cycle
was not extended that FDA 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) Description of actions necessary for approval. Where
appropriate, a complete response letter will describe the actions
necessary 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:
(1) Resubmission. Resubmit the application or abbreviated
application, addressing all deficiencies identified in the complete
response letter. For purposes of this section, a resubmission means
submission by the applicant of all materials needed to fully address
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 6-
month review cycle 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 (HFD-5), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857. 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 under section 505(d) or (j)(4) of the act.
(c) Failure to take action. An applicant agrees to extend the
review period under section 505(c)(1) of the act until it takes any of
the actions listed in paragraph (b) of this section. For an
application, FDA may consider an applicant's failure to take any of
such actions within 1 year after receiving a complete response letter
to be a request by the applicant to withdraw the application. For an
abbreviated application, FDA may consider an applicant's failure to
take any of the actions listed in paragraph (b) of this section within
6 months after receiving a complete response letter to be a request by
the applicant to withdraw the abbreviated application.
Sec. 314.120 [Removed and Reserved]
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 by 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.
20. Section 314.440 is amended in paragraph (a)(1) by removing the
phrase ``Document and Records Section, 5901-B Ammendale Rd.,
Beltsville, MD 20705-1266'' and by adding in its place the phrase
``Central Document Room, 12229 Wilkins Ave., Rockville, MD 20852-
1833''; in paragraph (a)(3) by removing the phrase ``or Sec.
314.120''; and by revising the introductory text of paragraph (b) to
read as follows:
Sec. 314.440 Addresses for applications and abbreviated applications.
* * * * *
(b) Applicants must send applications and other correspondence
relating to matters covered by this part for the drug products listed
below to the Center for Biologics Evaluation and Research (HFM-99),
Food and Drug
[[Page 43366]]
Administration, 1401 Rockville Pike, Rockville, MD 20852, except
applicants must send a request for an opportunity for a hearing under
Sec. 314.110 on the question of whether there are grounds for denying
approval of an application to the Director, Center for Biologics
Evaluation and Research (HFM-1), at the same address.
* * * * *
PART 600--BIOLOGICAL PRODUCTS: GENERAL
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.
22. Section 600.3 is amended by revising paragraph (jj) to read as
follows:
Sec. 600.3 Definitions.
* * * * *
(jj) Complete response letter means a written communication to an
applicant from FDA usually identifying all of the deficiencies in a
biologics license application or supplement that must be satisfactorily
addressed before it can be approved.
* * * * *
PART 601--LICENSING
23. The authority 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).
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.
(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. 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 receiving a
complete response letter to be a request by the applicant to withdraw
the application or supplement.
Dated: July 9, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-16476 Filed 7-19-04; 8:45 am]
BILLING CODE 4160-01-S