We address all of the comments in section III of this document.

After considering the comments, we have concluded that it is appropriate to make several revisions to the proposed rule. The final rule deletes the reference in proposed Sec. 314.100(a)(2) to the adjustment of the initial review cycle for human drug applications and supplements to such applications. Adjustment of the initial review cycle to fewer or greater than 180 days for human drug applications and supplements, accepted by mutual agreement between industry and FDA under the agency's user fee performance goals, is provided for under the adjustment by mutual agreement provision in revised Sec. 314.100(c) (see the response to comment 7 in section III.C.1 of this document).

The final rule also revises Sec. 314.110(c) to allow applicants an extension of time in which to resubmit an application, to avoid having the applicant's failure to resubmit within 1 year be regarded as a request to withdraw the application. This revision addresses some comments' concerns that 1 year might not be enough time in which to resubmit an application after receipt of a complete response letter. The final rule also revises Sec. 314.110(b)(1)(iii) to state that resubmission of an NDA supplement other than an efficacy supplement constitutes an agreement by the applicant to start a new review cycle, beginning on the date we receive the resubmission, that is the same length as the initial review cycle for the supplement (excluding any extension due to a major amendment of the initial supplement).

In addition to these revisions, the final rule includes other changes to the proposed rule in response to comments.

Several comments objected to the regulations in proposed Sec. 314.60(b) that give FDA the option to defer review of different types of amendments until the subsequent review cycle. However, we have determined that we need to have the ability to defer review of amendments to the next review cycle under appropriate circumstances. Although our policy, as reflected in guidance, is to try to review most amendments during the initial review cycle, there are circumstances under which deferral is necessary and appropriate, as discussed in section III.G.1 of this document.

On our own initiative, we also have revised Sec. 314.60(b) to correct an inadvertent omission of a user fee performance goal regarding major amendments to manufacturing supplements. Revised Sec. 314.60(b)(4) now specifies that submission of a major amendment to a manufacturing supplement submitted within 2 months of the end of the initial review cycle constitutes an agreement to extend the cycle by 2 months.

Also on our own initiative, we have revised the proposed rule to clarify the definition of ``efficacy supplement'' in Sec. 314.3(b) (21 CFR 314.3(b)), to state the correct address to which requests for a hearing on the denial of approval of an NDA or ANDA must be submitted in Sec. 314.110(b)(3), and to state the correct addresses to which NDAs and ANDAs must be submitted in Sec. 314.440(a)(1) and (a)(2) (21 CFR 314.440(a)(1) and (a)(2)), respectively.
II. Summary of the Final Rule

A. Complete Response Letters

We are revising our regulations to substitute complete response letters for approvable and not approvable letters at the completion of the review cycle for an NDA or ANDA. Under revised Sec. 314.110, we will send a complete response letter if we determine that we will not approve an NDA or ANDA in its present form for one or more reasons. A complete response letter usually will describe all of the specific deficiencies that the agency has identified in an application. Table 1 of this document summarizes the changes to our regulations that we are making related to the adoption of complete response letters: [[Page 39590]]
Table 1.Summary of Changes Regarding Substitution of Complete Response Letters for Approvable and Not Approvable Letters Revised Regulations (changes to proposed rule in Previous Regulations italics) Approvable Letter for NDA Complete Response Letter

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

We are revising our regulations on the extension of the review period due to resubmission of an NDA or ANDA after receipt of a complete response letter. A class 2 resubmission of an NDA following receipt of a complete response letter starts a new 6month review cycle. A class 1 resubmission of an NDA starts a new 2month review cycle.

These provisions on class 1 and class 2 resubmissions also apply to efficacy supplements to NDAs. For other types of NDA supplements, resubmission starts a new review cycle the same length as the initial review cycle of the supplement under Sec. 314.100(a), excluding any extension due to a major amendment of the initial supplement.

A ``major'' resubmission of an ANDA following receipt of a complete response letter starts a new 6month review cycle. A ``minor'' resubmission of an ANDA starts a new review cycle of an unspecified length; under current FDA guidance, a minor resubmission usually starts a new review cycle of between 30 to 60 days.

The changes to our regulations on applicants' responses to action letters are summarized in the following Table 2.
Table 2.Summary of Changes to Regulations Regarding Applicant's Response to Agency Action Letters Revised Regulations (changes to proposed rule in Previous Regulations italics) Applicant's Response to Approvable Letter or Not NDA or ANDA Applicant's Response to Complete Response Approvable Letter for NDA (or NDA Supplement) Letter Within 10 days of date of letter, NDA applicant must do Review period is extended until applicant takes one of one of following: following actions:

C. Amendments to Unapproved Applications

We are also revising our regulations in Sec. 314.60 on extending the review cycle following the submission of an amendment to an unapproved NDA. Under revised Sec. 314.60(b)(1), submission of a major amendment within 3 months of the end of the initial review cycle constitutes an agreement to extend the review cycle by 3 months. Under Sec. 314.60(b)(2), submission of a major amendment more than 3 months before the end of the initial review cycle will not extend the cycle; nor will the initial review cycle for a nonmajor amendment be extended under Sec. 314.60(b)(3). These provisions apply to
[[Page 39591]]
amendments to original applications, efficacy supplements, and resubmissions of applications and efficacy supplements. Under Sec. 314.60(b)(4), submission of a major amendment to a manufacturing supplement within 2 months of the end of the initial review cycle constitutes an agreement to extend the review cycle by 2 months. Under Sec. 314.60(b)(5), submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not extend the review cycle. For all of these amendments, we may, at our discretion, defer review of the amendment until the subsequent review cycle, rather than extend the initial cycle or review the amendment during the initial cycle.

Table 3 of this document summarizes the changes to our regulations on amendments submitted before an action letter.
Table 3.Summary of Changes to Regulations on Amendments Submitted Before Action Letter Revised Regulations (changes to proposed rule in Previous Regulations italics) Amendments to Unapproved NDAs and NDA Supplements Amendments to Unapproved NDAs, Efficacy Supplements,

We received written comments from 6 drug manufacturers; 4 associations representing the drug, biologic, and medical device industries; and an individual (11 comments in all). A summary of the comments received and our responses follow.
A. General Comments
(Comment 1) One comment stated that throughout the proposed rule the word ``response'' is used without identifying whose response. As an example, the comment cites proposed Sec. 314.101(f)(1)(ii), under which we would issue a notice of opportunity for hearing if an applicant asked us to provide it an opportunity for a hearing on an application ``in response to a complete response letter.'' To clarify whose response is being referenced in a particular provision, the comment recommended that the provision always identify the respondent (e.g., use ``an applicant's response to a complete response letter'' in the above example).
(Response) We do not believe that it is necessary to revise Sec. 314.101(f)(1)(ii) as requested because only an applicant (not FDA) can respond to a complete response letter as defined in Sec. 314.3(b). We reviewed the other provisions in the proposed rule to ensure that the language does not suggest that the agency might respond to a complete response letter and that the use of the term ``response'' is not otherwise confusing. We conclude that it is unnecessary to revise the regulations in parts 314, 600, and 601 (21 CFR parts 314, 600, and 601) to identify who is responding to a complete response letter, as it is always the applicant who is responding.
(Comment 2) One comment encouraged us to consider an approval process whereby once we issue an approval letter, the applicant may begin marketing upon notification of approval and not have to address any additional regulatory hurdles, other than perhaps waiting for the exclusivity period of a previously approved drug to end.
(Response) The comment is beyond the scope of this rulemaking. With the exception of Sec. 314.430 on public disclosure of information in applications, this rule does not address approval or postapproval regulatory matters.
B. Definitions (Proposed Sec. 314.3(b))

1. Class 1 and Class 2 Resubmissions

Proposed Sec. 314.3(b) would have defined ``Class 1 resubmission'' as the resubmission of an application, following receipt of a complete response letter, that contains final printed labeling, draft labeling, certain safety updates, stability updates to support provisional or final dating periods, commitments to perform Phase 4 studies (including proposals for such studies), assay validation data, final release testing on the last lots used to support approval, minor reanalyses of previously submitted data, and other comparatively minor information. (Comment 3) Two comments stated that the proposed definition of class 1 resubmission lists items that qualify a resubmission as class 1 and concludes the list with the conjunction ``and,'' implying that a class 1 resubmission contains all of the listed items. The comments recommended that a class 1 resubmission be defined as a
[[Page 39592]]
resubmission that ``contains one or more of the following'' listed items.
(Response) We agree that this change is appropriate and have revised the definition of class 1 resubmission accordingly. Also, on our own initiative, but in a similar spirit of clarifying what was proposed, we are further revising the definition of class 1 resubmission to state that it includes not only the resubmission of an application but also the resubmission of an efficacy supplement. We are making a corresponding revision to the definition of ``Class 2 resubmission'' in Sec. 314.3. This makes these definitions consistent with the provisions on class 1 and class 2 resubmissions of applications and efficacy supplements in Sec. 314.110(b)(1)(i) and (b)(1)(ii). In addition, because we now refer to Phase 4 studies as ``postmarketing'' studies (see 21 CFR 314.81(b)(2)(viii)), we are revising the definition of class 1 resubmission accordingly. (Comment 4) One comment asked how we intended to ensure consistency across review divisions regarding the classification of resubmissions. (Response) We believe that the definition of class 1 resubmission provides adequate information on the types of resubmissions that are regarded as class 1 resubmissions and, by omission, the types of resubmissions that are regarded as class 2 resubmissions. For several years, CDER review divisions have been applying these definitions in reviewing resubmissions of applications that are subject to user fees. Nevertheless, CDER will provide training and information to help ensure that the final rule is applied consistently among the review divisions. 2. Complete Response Letter

Proposed Sec. 314.3(b) would have defined ``complete response letter'' as a written communication to an applicant from FDA usually identifying all of the deficiencies in an application or abbreviated application that must be satisfactorily addressed before it can be approved.
(Comment 5) One comment stated that absent unusual circumstances, a complete response letter should clearly define the specific deficiencies in an application to avoid presentation of new issues at a later date and minimize the potential for cycles of complete response letters. Two comments stated that specifying that a complete response letter ``usually'' identifies all of the deficiencies in an application is contrary to the plain meaning of ``complete response'' because any response that does not identify all of the deficiencies in an application is not complete. The comments stated that the use of vague language makes the regulation impossible to interpret and leaves the regulatory process open to inconsistencies across divisions. The comments stated that the user fee goals do not include similarly vague language but instead reflect FDA's commitment to review and act on certain percentages of applications within specified timeframes. The comments noted that the user fee goals state that the term ``review and act on'' means the issuance of a complete action letter after the complete review of a filed complete application. The comments acknowledged that, for drug products, we might issue a complete response letter without first conducting inspections or reviewing labeling (under proposed Sec. 314.110(a)(3)), but the comments requested that we revise the definition of complete response letter to specify which aspects of a complete review might be postponed while allowing the agency to issue a complete response letter. One of the comments suggested that the definition specify that we may issue a complete response letter ``without first conducting required inspections and/or reviewing proposed product labeling when FDA determines that the data submitted are inadequate to support approval as described in Sec. 314.110(a)(3).''
(Response) We do not agree that the definition of complete response letter should be revised as suggested. The statement that a complete response letter ``usually'' identifies all of the deficiencies in an application is appropriate because Sec. 314.110(a)(1) states that a complete response letter will describe all of the deficiencies ``except as stated in paragraph (a)(3) * * *'' In turn, paragraph (a)(3) states that if we determine that the data submitted are inadequate to support approval, we might issue a complete response letter without first conducting required inspections and/or reviewing proposed product labeling. Those are the only circumstances under which the complete response letter would not describe all of the known deficiencies in an application. We do not believe that it is necessary for the definition of complete response letter to specify which particular aspects of a complete review might be postponed.

However, we believe that it is necessary to revise the definition of complete response letter to make clear that a complete response letter is a communication ``usually describing all of the deficiencies that the agency has identified in an application or abbreviated application that must be satisfactorily addressed before it can be approved'' (Sec. 314.3(b)). This addresses the possibility that an applicant's response to a deficiency that we have identified in an application might reveal other deficiencies that we had not identified and which we accordingly had been unable to describe in the complete response letter. Although we seek to identify all deficiencies during the initial review period, we sometimes become aware of deficiencies only during a subsequent review period. It would be inconsistent with section 505(d) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(d)) and FDA regulations to approve an application despite an applicant's failure to address deficiencies solely because those deficiencies were identified only after issuance of a complete response letter, and we do not intend to allow this result. (Comment 6) One comment recommended that we add to the definition of complete response letter the following statement: ``Where appropriate, a complete response letter will describe the actions necessary to place the application in condition for approval.'' (Response) Because this statement appears in revised Sec. 314.110(a)(4), we do not believe that it is necessary to add this statement to the definition of complete response letter in Sec. 314.3. 3. Efficacy Supplement

Proposed Sec. 314.3(b) would have defined ``efficacy supplement'' as a supplement to an approved application proposing to make one or more of the following changes to product labeling:

1. Add or modify an indication for use;

2. Revise the dose or dose regimen;

3. Provide for a new route of administration;

4. Make a comparative efficacy claim naming another drug product;

5. Significantly alter the intended patient population;

6. Change the marketing status from prescription to overthe 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 wellcontrolled clinical study.

On our own initiative, we are making three changes to the proposed definition of efficacy supplement. First, we are revising the definition to state that an efficacy supplement means a supplement to an approved application proposing ``to make one or more related changes from among the following changes to product labeling * * *''. [[Page 39593]]
This change makes the definition consistent with our user fee ``bundling'' policy, which allows certain related changes (such as a change in indication and a related change in dose regimen) to be made in the same supplement with only one fee (see the FDA guidance for industry entitled ``Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees'').

The second change that we are making to the definition of efficacy supplement is to replace the term ``indication for use'' (in the first listed change) with the term ``indication or claim.'' The definition of ``human drug application'' in section 735(1) of the act (21 U.S.C. 379g(1)) includes the term ``indication for a use.'' As part of our user fee assessment policy, we have interpreted the term ``indication for a use'' more broadly than the term ``indication,'' as the latter term is commonly used (i.e., to mean a claim that a drug is effective for a particular use, for purposes of complying with the requirements on the content and format of labeling for prescription drugs in 21 CFR 201.57(c). This change clarifies that an efficacy supplement can be submitted to add or modify an indication or claim.

The third change that we are making to the definition of efficacy supplement concerns efficacy supplements that involve the traditional approval of a product that was originally approved under part 314, subpart H, regarding accelerated approval for drugs for serious or lifethreatening illnesses. It is possible that an efficacy supplement might be intended to provide evidence of effectiveness for the traditional approval of a subpart H drug but not actually complete the traditional approval of the drug. Therefore, we are revising the definition of efficacy supplement to clarify that such a supplement can be submitted to provide for the traditional approval of a product originally approved under subpart H or to provide evidence of effectiveness necessary for traditional approval of such a product. C. Timeframes for Review (Proposed Sec. 314.100)

1. Initial Review Cycle

Proposed Sec. 314.100(a)(1) stated that, except as provided in Sec. 314.100(a)(2), within 180 days of receipt of an NDA or ANDA, we will review the application and send the applicant an approval letter or a complete response letter; this 180day period is called the initial review cycle. Proposed Sec. 314.100(a)(2) stated that, for drug applications that are human drug applications, as defined in section 735(1)(A) and (B) of the act, or supplements to such applications, as defined in section 735(2) of the act, the initial review cycle will be adjusted to be consistent with the agency's user fee performance goals for reviewing such applications and supplements. (Comment 7) One comment objected to proposed Sec. 314.100(a)(2), stating that although the user fee goals recognize that we typically do not meet the 180day statutory review deadline, this should not be memorialized in a regulation. The comment stated that even though the statutory review period is regarded mainly as aspirational, it is important to maintain it within the regulations.
(Response) We agree with the comment that a specific provision solely addressing the adjustment of the initial review cycle for human drug applications and supplements to these applications is not necessary. Therefore, we have deleted proposed Sec. 314.100(a)(2). However, we note that, since the enactment of the Prescription Drug User Fee Act of 1992 (PDUFA) (Public Law 102571), there has been a mutual understanding between industry and the agency that the review cycle for an application or supplement subject to user fees may be adjusted (either shortened or lengthened) in accordance with the user fee performance goals. Previous Sec. 314.100(c) provided for an extension of the review cycle by mutual agreement between FDA and an applicant (as well as an extension as a result of a major amendment under Sec. Sec. 314.60 or 314.96). Consistent with the longstanding approach to applications subject to user fees, we have revised Sec. 314.100(c) to state that the initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in Sec. Sec. 314.60 and 314.96.

Correspondingly, the final rule also deletes proposed Sec. 314.101(f)(2). Current Sec. 314.101(f)(1) states that within 180 days after the date of filing, plus the period of time the review period was extended (if any), FDA will either approve the application or issue a notice of opportunity for hearing. Proposed Sec. 314.101(f)(2) stated that, for human drug applications and supplements, the 180day period after the date of filing would be adjusted to be consistent with the user fee performance goals. Proposed Sec. 314.101(f)(2) is not needed because Sec. 314.101(f)(1) encompasses extension of the review period beyond 180 days as well as circumstances under which FDA might approve an application in less than 180 days, regardless of whether such actions are the result of conformance to user fee performance goals. 2. Withdrawal and Later Submission

Proposed Sec. 314.100(b) stated that at any time before approval, an applicant may withdraw an application under Sec. 314.65 (21 CFR 314.65) or an abbreviated application under Sec. 314.99 (21 CFR 314.99) and later submit it again for consideration.
(Comment 8) Two comments stated that Sec. 314.100(b) should be revised to address the withdrawal of an application after receipt of a complete response letter. The comments stated that if a complete response letter is followed by withdrawal of the application, the subsequent submission of ``the same'' application would also constitute a ``resubmission.'' The comments suggested adding the following to Sec. 314.100(b): ``Except when preceded by a complete response letter, applications withdrawn prior to approval that are submitted again for the same product are not considered resubmissions as defined in Sec. 314.3(b) of this part.''
(Response) We do not agree with the comments because we regard an application that is withdrawn at any time before approval and submitted again for the same product as an original application, rather than a resubmission. The final rule defines ``original application'' (in Sec. 314.3(b)) as a pending application for which FDA has never issued a complete response letter or approval letter, or an application that was submitted again after FDA had refused to file it or after it was withdrawn without being approved. Under the proposed rule, a ``resubmission'' was defined (in proposed Sec. 314.110(b)(1)) as ``submission by the applicant of all materials needed to fully address all deficiencies identified in the complete response letter.'' Consistent with our approach to applications that are withdrawn before approval and later submitted again, we have added the following statement to the definition of resubmission: ``An application or abbreviated application for which FDA issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.'' For clarity, we are moving the definition of resubmission to Sec. 314.3 from Sec. 314.110(b)(1). D. Complete Response Letters (Proposed Sec. 314.110)

1. Content of Complete Response Letters

Proposed Sec. 314.110(a) would have required us to send an applicant a
[[Page 39594]]
complete response letter if we determined that we will not approve the application or abbreviated application in its present form for one or more of the reasons given in Sec. 314.125 or Sec. 314.127, respectively.
(Comment 9) One comment stated that it concurred with our view that the complete response letter should be a neutral mechanism to convey that an application cannot be approved in its present form. The comment agreed that use of the complete response letter will ensure consistency in how sponsors are informed of changes needed for approval, without implying anything about ultimate approvability. One comment stated that use of the complete response letter will provide a more efficient mechanism for application review.
(Response) As stated in the preamble to the proposed rule, we agree that the use of complete response letters will provide a more neutral and consistent mechanism than the use of approvable and not approvable letters to convey that an application cannot be approved in its present form.

a. Specific deficiencies. Under proposed Sec. 314.110(a)(1), a complete response letter would have described all of the specific deficiencies in an application or abbreviated application, except as stated in Sec. 314.110(a)(3).
(Comment 10) One comment stated that we should clearly identify and define the specific deficiencies in an application when drafting a complete response letter, adding that one purpose of the complete response letter is to minimize paperwork and delays between an applicant and the agency.
(Response) We agree with the comment. The intent of Sec. 314.110(a)(1) is that we will identify and describe all of the known deficiencies (except as provided in Sec. 314.110(a)(3)) to enable applicants to provide appropriate responses. However, consistent with our response to comment 5, we have revised Sec. 314.110(a)(1) to state that a complete response letter will describe all of the specific deficiencies that we have identified in an application at the time we issue the complete response letter. This change reflects the possibility that we might become aware of certain deficiencies only during a subsequent review period, such as while reviewing an applicant's response to a previously identified deficiency. (Comment 11) One comment asked that we clarify what mechanisms of communication we will use during the review cycle to convey to sponsors potential deficiencies that we have discovered to enable sponsors to address these deficiencies as quickly as possible. The comment stated that there would be few, if any, applications that would completely satisfy FDA reviewers in the first review cycle.
(Response) Because this comment concerns communication before issuance of the complete response letter, it is beyond the scope of this rulemaking. Nevertheless, it is worth noting that the user fee goals include mechanisms to improve communications about potential deficiencies during the review cycle. For example, the Goals Letter (2002) states that it is the intention of CDER and CBER to notify a sponsor of deficiencies in an application when each discipline has finished its initial review of its section of the pending application. In addition, the Goals Letter states that the review division and the safety group assigned to the review of a particular application will try to communicate their comments on a proposed risk management tool and plan, as well as on protocols for observational studies, as early in the review process as possible.

b. Complete review of data. Proposed Sec. 314.110(a)(2) stated that a complete response letter reflects our complete review of the data submitted in an original application or abbreviated application (or, where appropriate, a resubmission) and any amendments for which the review cycle was extended. It further stated that the complete response letter will identify any amendments for which the review cycle was not extended that we have not yet reviewed.
(Comment 12) Two comments stated that it was unclear whether complete review of the data includes review of information submitted in major amendments submitted more than 3 months before the end of the initial cycle or nonmajor amendments (which do not trigger extensions under the user fee goals or the proposed rule). The comments stated that the regulation should not define the scope of material included in a complete response letter as ``amendments for which the review cycle was extended.''
(Response) We agree that Sec. 314.110(a)(2) should include any amendments that we have reviewed, whether or not they resulted in an extension of the review cycle. Therefore, we are revising Sec. 314.110(a)(2) to state that a complete response letter reflects our complete review of the data submitted in an original application or abbreviated application (or, where appropriate, a resubmission) and any amendments that we have reviewed. Correspondingly, we are also revising Sec. 314.110(a)(2) to state that the complete response letter will identify any amendments that we have not yet reviewed.

c. Determination that data are inadequate. Under proposed Sec. 314.110(a)(3), if we determined, after an application is filed or an abbreviated application is received, that the data submitted are inadequate to support approval, we might issue a complete response letter without first conducting required inspections and/or reviewing proposed product labeling.
(Comment 13) One comment maintained that stating that we ``might'' issue a complete response letter without conducting required inspections and/or reviewing labeling adds ambiguity to agency actions. The comment stated that if we determine that the data are inadequate during the first half of the review cycle, it might be acceptable for us to issue a complete response letter without conducting inspections or reviewing labeling; however, a complete response letter sent toward the end of the cycle should thoroughly evaluate all components of the NDA. The comment stated that leaving to the review divisions the decision on whether we issue a complete response letter before we conduct inspections and review the labeling would unintentionally encourage inconsistency. The comment recommended that we revise Sec. 314.110(a)(3) to state that if we determine ``early in the review cycle'' or ``within the first half of the review cycle'' that the data are inadequate, we might issue a complete response letter without conducting inspections or a labeling review.
(Response) We understand the comment's concern about possible uncertainty as to the timing of a decision to issue a complete response letter without conducting an inspection or labeling review. However, it is possible that we might not determine until later in the review cycle that the data in the application are inadequate. Therefore, we believe that it is not appropriate to specify in Sec. 314.110(a)(3) a time after which we could no longer conclude that the data submitted are inadequate to support approval.
(Comment 14) One comment stated no objection to this proposal under the circumstances described but maintained that the complete response letter should indicate the status of each review team (labeling, chemistry and manufacturing, microbiology, bioequivalence, and/or clinical reviews and inspection status).
(Response) Rather than having the complete response letter state the status of each review team, we believe that it is appropriate for the letter to specify what portions, if any, of the review are [[Page 39595]]
incomplete, as review of a portion of an application may require input from more than one review team, and it is the status of the portion of a review, not the status of the review team, that is most relevant. This is the approach that we currently use in issuing approvable and not approvable letters.
(Comment 15) One comment asked us to comment on the future of CDER's PreApproval Inspection Program and how it would be incorporated into the proposed new review scheme.
(Response) Inspection of the facilities used in the manufacture of a proposed drug product is an essential part of the application review process. The PreApproval Inspection Program will not be affected by this rulemaking.

d. Actions to place application in condition for approval. Proposed Sec. 314.110(a)(4) stated, ``Where appropriate,'' a complete response letter will describe the actions necessary to place the application or abbreviated application in condition for approval.
(Comment 16) One comment stated that we should delete ``Where appropriate'' from Sec. 314.110(a)(4). The comment stated that a complete response letter should describe the actions and/or specify the data needed to place the application in condition for approval. One comment stated that we should specify precisely the amendments or procedures we will require as an appropriate reply to a complete response letter so that an applicant does not have to guess what is necessary to remedy the deficiencies cited in the letter. The comment stated that this would help applicants address FDA concerns more effectively.
(Response) We agree with the comments that the complete response letter should provide an applicant with information, whenever possible, on what the applicant could do to obtain approval. However, there may be times when what the applicant has submitted to the agency simply does not permit us to specify what the applicant would need to do to put the application in a position for approval. The intent of Sec. 314.110(a)(4) is for us to provide the applicant with sufficient detail on what actions might be necessary to resolve the deficiencies cited in the complete response letter. Providing clear guidance to applicants in the complete response letter will be helpful both to applicants and the agency.

However, at the time of issuance of the complete response letter, we may not have enough information to be certain about precisely what actions, including possibly conducting studies and/or submitting data, may ultimately be necessary to place an application in condition for approval. For example, we might have determined that there is a problem with the formulation of a proposed drug product but not be able to tell the applicant what it could do to resolve the problem, except in a general sense. Because of such potential circumstances, we have replaced ``Where appropriate'' with ``When possible'' in Sec. 314.110(a)(4).

In addition, we recognize that although it is appropriate for us to recommend actions that an applicant might take to place its application in condition for approval, we cannot require an applicant to take specific actionsand only those actionsto obtain approval. There might be multiple acceptable approaches that an applicant could take to remedy a deficiency in its application, and we might lack information that would affect our views on what actions an applicant should take. Therefore, we have revised Sec. 314.110(a)(4) to state that, when possible, a complete response letter will, rather than describe the actions necessary to place an application or abbreviated application in condition for approval, ``recommend actions that the applicant might take to place the application or abbreviated application in condition for approval.''

2. Responses to Complete Response Letters

Under proposed Sec. 314.110(b)(1) to (b)(3), an applicant was required to take one of three actions after receiving a complete response letter: Resubmit the application, withdraw the application, or request an opportunity for a hearing on whether there are grounds for denying approval of the application.

a. Resubmission. Under proposed Sec. 314.110(b)(1), an applicant could, in response to a complete response letter, resubmit the application or abbreviated application, addressing all deficiencies identified in the complete response letter. Proposed Sec. 314.110(b)(1) further stated that, for purposes of Sec. 314.110, a resubmission would mean submission by the applicant of all materials needed to fully address all deficiencies identified in the complete response letter.

As stated in our response to comment 8, we are relocating the definition of resubmission to Sec. 314.3 from Sec. 314.110(b)(1) and adding a sentence clarifying that an application or abbreviated application for which we issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.

i. Resubmission of an NDA supplement other than an efficacy supplement. Under proposed Sec. 314.110(b)(1)(iii), a resubmission of an NDA supplement other than an efficacy supplement would constitute an agreement by the applicant to start a new 6month review cycle beginning on the date we receive the resubmission.
(Comment 17) Three comments objected to the proposed 6month cycle for resubmissions of otherthanefficacy supplements. One comment stated that it seemed unreasonable that a resubmission not requiring clinical data would require an additional 6 months for review. Two comments stated that because one of our user fee goals is to act on 90 percent of manufacturing supplements that require prior approval within 4 months, a 6month review time for a resubmission of such a supplement would be longer than the review time for the original supplement. The comments stated that this is inappropriate because many of these resubmissions need only include data necessary to answer questions from the initial cycle and do not require as much review time as the initial supplement. The comments recommended that we revise Sec.
314.110(b)(1)(iii) to state that the length of the review cycle for the resubmission of an otherthanefficacy supplement will not exceed that for the original supplement. The comments further recommended that we establish a ``Type 1/Type 2'' scheme for resubmissions of prior approval chemistry and manufacturing supplements that would be similar to the approach for resubmissions of original applications and efficacy supplements, but with a 2month review cycle for Type 1 resubmissions and a 4month cycle for Type 2 resubmissions.
(Response) We agree with the comments that the review cycle for the resubmission of a supplement that is not an efficacy supplement should be the same as the initial review cycle for the original supplement. Therefore, we have revised Sec. 314.110(b)(1)(iii) to state that a resubmission of an NDA supplement other than an efficacy supplement constitutes an agreement by the applicant to start a new review cycle the same length as the initial review cycle for the supplement (excluding any extension due to a major amendment), beginning on the date FDA receives the resubmission. Under Sec. 314.100(a), the initial review cycle for a supplement other than an efficacy supplement is 180 days, unless it is adjusted by mutual agreement or as a result of a major amendment under Sec. 314.100(c). Under revised Sec. 314.110(b)(1)(iii), because the initial review cycle for a manufacturing supplement requiring prior approval is 4 months under the user fee goals, the
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review cycle for a resubmission of a manufacturing supplement would be 4 months (it would not be increased to reflect any extension of the initial review cycle for the manufacturing supplement resulting from a major amendment of the initial supplement). Given this change to Sec. 314.110(b)(1)(iii), we believe that establishing a separate ``Type 1/ Type 2'' classification scheme for resubmissions of prior approval chemistry and manufacturing supplements is not needed to ensure appropriate review cycles for these resubmissions and would create unnecessary administrative burdens.

ii. Minor resubmission of an ANDA. Proposed Sec. 314.110(b)(1)(v) stated that a minor resubmission of an ANDA constitutes an agreement by the applicant to start a new review cycle beginning on the date we receive the resubmission.
(Comment 18) One comment opposed this provision, stating that the failure to specify the length of the new review cycle would seriously hinder an applicant's ability to predict the approval date for its application, resulting in substantial commercial disadvantage. The comment stated that any delay in the onset of launch preparation due to an unpredictable approval date could harm the manufacturer's ability to prepare for the initial marketing of their products. The comment maintained that without a target date for completion of review, an applicant would be forced to follow up with FDA continually, contrary to requests by CDER's Office of Generic Drugs that applicants follow up only at the targeted time. The comment claimed that the statement in the preamble that the review cycle for a minor resubmission of an ANDA might last ``from 30 days to a few months'' was contrary to the guidance on ``Major, Minor and Telephone Amendments to Abbreviated New Drug Applications'' (ANDA amendments guidance), which purportedly was revised to produce more minor amendments and fewer major amendments to move applications through the review process more quickly. The comment maintained that without a definition of ``a few months,'' performance standards would be reduced as much as 50 percent or more, and the distinction between major and minor amendments would blur.

The comment also disagreed with the statement in the preamble that the proposed revisions for ANDA resubmissions are ``similar'' to those for NDA resubmissions. The comment stated that user fee goals apparently are being implemented at the expense of generic drug manufacturers by reducing the transparency of the review process and extending review times for minor resubmissions. The comment asked that we revise Sec. 314.110(b)(1)(v) to state that minor resubmissions of ANDAs are reviewed 30 to 60 days from receipt. The comment also stated that we should assess the issuance and classification of all complete response letters to uphold the intent to reduce ANDA approval times and resolve more deficiencies by telephone rather than complete a response letter.
(Response) We do not agree that the provision on minor resubmissions of ANDAs will interfere with generic drug manufacturers' ability to market their products in a timely manner. Under the ANDA amendments guidance, which the Office of Generic Drugs applies to major and minor resubmissions of ANDAs, we attempt to review minor resubmissions within 30 to 60 days, although not all can be reviewed within 60 days. In accordance with the ANDA amendments guidance, we will continue to work closely with ANDA sponsors to provide them with sufficient information about our review of ANDA resubmissions to enable sponsors to plan for the marketing of approved products. We agree with the comment that resolving deficiencies by telephone rather than by complete response letter benefits both applicants and the agency, and we will seek to do so where appropriate in accordance with the ANDA amendments guidance.

b. Request for a hearing. Under proposed Sec. 314.110(b)(3), after receiving a complete response letter, an applicant could ask us to provide it with an opportunity for a hearing on the question of whether there are grounds for denying approval of the NDA or ANDA.

On our own initiative, we have revised Sec. 314.110(b)(3) to update the information on the address to which requests for a hearing on the denial of approval of an NDA or ANDA must be submitted, as a result of the recent relocation of certain CDER offices.
(Comment 19) One comment stated that we should consider having an independent evaluator within FDA attend the hearings to confirm or negate grounds for denying approval. The comment also asked whether these hearings would be open public hearings.
(Response) With respect to the nature of hearings on the denial of approval of applications, Sec. 314.201 states that parts 10 through 16 (21 CFR parts 10 through 16) apply to these hearings. These hearings are not open public hearings; appearance and participation are governed by Sec. 12.40 through Sec. 12.45.

We do not believe that an independent evaluator is needed for hearings on grounds for denial of approval. Section 314.200(f) provides for separation of functions between CDER and the Commissioner of Food and Drugs (the Commissioner) upon receipt of a request for a hearing. CDER prepares an analysis of the request and a proposed order ruling on the issue and submits them to the Commissioner for review and decision. When CDER recommends denial of a hearing on all issues, no CDER representative will participate or advise in the review and decision by the Commissioner. When CDER recommends that a hearing be granted on one or more issues, separation of functions terminates as to those issues. The Commissioner may modify the text of those issues but may not deny a hearing on those issues. Separation of functions continues with respect to issues on which CDER has recommended denial of a hearing. The Commissioner will neither evaluate nor rule on CDER's recommendation on such issues, and such issues will not be included in the notice of hearing. Participants in the hearing may make a motion to the presiding officer for the inclusion of any such issue in the hearing. Under Sec. 12.60, the presiding officer of any hearing will be the Commissioner, a member of the Commissioner's office to whom responsibility for the matter has been delegated, or an administrative law judge qualified under 5 U.S.C. 3105. Separation of functions on all issues resumes upon issuance of a notice of a hearing. We believe that these provisions provide an adequate means of ensuring that the Commissioner makes an independent assessment of the evidence for and against approval of an application. Therefore, no independent evaluator is needed. 3. Failure to Take Action

Under proposed Sec. 314.110(c), an applicant would be considered to agree to extend the review period under section 505(c)(1) of the act until it takes any of the actions listed in Sec. 314.110(b) (i.e., resubmission of the application, withdrawal, or request for a hearing). Proposed Sec. 314.110(c) further stated that for an NDA, we might consider an applicant's failure to take any of these actions within 1 year after receiving a complete response letter to be a request by the applicant to withdraw the NDA (for an ANDA, the specified period was 6 months).
(Comment 20) Several comments objected to the elimination of the opportunity, available in previous Sec. Sec. 314.110(a)(5) and 314.120(a)(5), for
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an applicant to notify us within 10 days of receipt of an action letter that it agrees to an extension of the review period so that it can determine how to respond further. One comment stated that it was not clear whether any sponsor communication with us regarding an intent to resubmit or amend an application would cancel or postpone the proposed 1year timeframe. The comment stated that if an applicant believed that it must resubmit within 1 year to avoid automatic withdrawal, the result could be a lessthancomplete resubmission. Three comments stated that the absence of a resubmission within 1 year of receipt of a complete response letter cannot reasonably be characterized as failure to take action. Several comments stated that it might take several months for an applicant to reach agreement with us on what studies are needed for approval and then more time to conduct the studies and submit the results.

The comments suggested several ways to revise the regulations to allow applicants to request an extension of the review period. One comment stated that we should expand the first option in Sec. 314.110(b) (resubmission) to permit a sponsor to resubmit its application addressing all deficiencies or state its intent to do so (if the sponsor estimates that it will take more than 1 year to address all deficiencies).

Several comments recommended revisions to Sec. 314.110(c). One comment stated that Sec. 314.110(c) should be revised to clarify that additional time for resubmission will be granted if the applicant is diligently working to address all deficiencies. The comment stated that inaction for 1 year should be regarded as a request to withdraw the application if the applicant has not communicated an intent to resubmit or submitted evidence of progress being made toward the completion of work needed to address all deficiencies.

One comment stated that Sec. 314.110(c) should be revised to allow an applicant to notify us, within a specified time, of its intent to resubmit or to agree to a specified extension of time to reflect an agreedupon action plan to address deficiencies; absent such notification, we could consider the application withdrawn if it was not resubmitted within 1 year. The comment further stated that if an additional study was required, we should allow an extension beyond the 1year period.

Two comments recommended that Sec. 314.110(c) be revised in one of two ways. One approach would be to add an option for the applicant to notify us, within a specified time after receipt of a complete response letter, of an intent to resubmit. If the application is not resubmitted within 1 year, the applicant would be required to provide annual confirmation of its intent to resubmit; if the applicant provided no such notification, we could consider the application withdrawn. The alternative approach would require us to notify the applicant requesting a reply within a specified time regarding its intention to resubmit; failure to respond within the specified time would constitute a request for withdrawal.

One comment recommended that applicants be given the option to state their intention to address deficiencies as well as how and when this will be done. The comment suggested that we would use the target date as the closing date for the application. If the applicant later determined that it could not meet this deadline, it could seek another extension, which we could grant or deny at our discretion.
(Response) We agree that proposed Sec. 314.110(c) should be revised to allow applicants to request an extension of time in which to submit a resubmission. We acknowledge that in some circumstances it might take more than 1 year after issuance of a complete response letter for an applicant to reach agreement with us on what clinical studies might be needed, to conduct any required studies, and to provide the results in a resubmission. Therefore, we are revising Sec. 314.110(c) (renumbered as Sec. 314.110(c)(1)) to state that, for an NDA or ANDA, we may consider an applicant's failure to take any of

FOR FURTHER INFORMATION CONTACT Brian L. Pendleton, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6304, Silver Spring, MD 20993, 301796 3504; or

Stephen Ripley, Center for Biologics Evaluation and Research (HFM 17), Food and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 208521448, 3018276210.