Source: https://www.federalregister.gov/documents/2008/07/10/E8-15608/applications-for-approval-to-market-a-new-drug-complete-response-letter-amendments-to-unapproved
Timestamp: 2017-09-26 00:55:57
Document Index: 433575552

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A Rule by the Food and Drug Administration on 07/10/2008
39588-39611 (24 pages)
B. Definitions (Proposed § 314.3(b))
C. Timeframes for Review (Proposed § 314.100)
D. Complete Response Letters (Proposed § 314.110)
2. Definitions (Proposed § 600.3)
3. Complete Response Letter (Proposed § 601.3)
3. Public Disclosure of Existence of Applications (Proposed § 314.430)
4. Addresses for Applications and Abbreviated Applications (Proposed § 314.440)
G. Amendments to NDAs (Proposed § 314.60)
2. Major Amendment Within 3 Months of the End of the Cycle (Proposed § 314.60(b)(1))
3. Major Amendment More Than 3 Months Before the End of the Cycle (Proposed § 314.60(b)(2))
4. Nonmajor Amendment (Proposed § 314.60(b)(3))
5. Amendment to Supplement Other Than Efficacy Supplement (Proposed § 314.60(b)(4))
6. Contents of Major Amendment (Proposed § 314.60(b)(5))
H. Amendments to ANDAs (Proposed § 314.96)
https://www.federalregister.gov/d/E8-15608 https://www.federalregister.gov/d/E8-15608
In the Federal Register of July 20, 2004 (69 FR 43351), we published a proposed rule to replace approvable and not approvable letters with complete response letters and to make other changes to our regulations on NDAs, ANDAs, and BLAs. Previous § 314.110 (21 CFR 314.110) set forth provisions on the issuance of and response to approvable letters; § 314.120 (21 CFR 314.120) addressed the issuance of and response to not approvable letters. The proposed rule proposed to replace those provisions with a revised § 314.110 regarding the issuance of complete response letters upon completion of our review of NDAs and ANDAs.
The preamble to the proposed rule stated that the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) agreed to revise their regulations and procedures to provide for the issuance of complete response letters as part of our prescription drug Start Printed Page 39589user fee performance goals. We first made the commitment regarding complete response letters as part of the user fee performance goals established in conjunction with the enactment of the Food and Drug Administration Modernization Act of 1997 (Public Law 105-115) (the user fee provisions of this act are known as “PDUFA II”). We repeated this commitment in the performance goals developed in conjunction with the enactment of the Prescription Drug User Fee Amendments of 2002 (PDUFA III), set forth in title V, subtitle A, of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Public Law 107-188). Section 502 of PDUFA III states that user fees will be dedicated to expediting the drug development process and the process for review of human drug applications in accordance with the new performance goals, which are set forth in an enclosure to letters from Tommy Thompson, Secretary of Health and Human Services, to the Chairman of the House Committee on Energy and Commerce and the Ranking Member of the Senate Committee on Health, Education, Labor, and Pensions (June 4, 2002) (Goals Letter).
The proposed rule stated that, because there are no provisions on action letters in the biological product regulations, CBER had only to change its standard operating procedures to incorporate the issuance of a complete response letter at the end of a review cycle for a biological product. We noted that although CBER had already done this, we proposed to add a regulation (proposed § 601.3) on the issuance of complete response letters concerning BLAs and BLA supplements.
The codification of different initial review cycles for human drug applications and supplements to such applications (proposed § 314.100);
The absence of a provision to allow applicants to request an extension of time in which to submit a resubmission following receipt of a complete response letter (proposed § 314.110(c));
The review cycle applicable to a resubmission of a supplement other than an efficacy supplement (proposed § 314.110(b)(1)(iii));
FDA's discretion to defer review of an amendment until the next review cycle (proposed § 314.60(b)).
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 § 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 § 314.100(c) (see the response to comment 7 in section III.C.1 of this document).
The final rule also revises § 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 § 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).
Several comments objected to the regulations in proposed § 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 § 314.60(b) to correct an inadvertent omission of a user fee performance goal regarding major amendments to manufacturing supplements. Revised § 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 § 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 § 314.110(b)(3), and to state the correct addresses to which NDAs and ANDAs must be submitted in § 314.440(a)(1) and (a)(2) (21 CFR 314.440(a)(1) and (a)(2)), respectively.
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 § 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:Start Printed Page 39590
Approvable Letter for NDA • States that NDA is basically approvable if certain issues are resolved. • Indicates that NDA substantially meets requirements of part 314 and FDA can approve it if applicant submits additional information or agrees to specific conditions (e.g., labeling changes). Approvable Letter for ANDA • Indicates that ANDA substantially meets requirements of part 314 and is approvable if minor deficiencies are corrected. • Describes deficiencies and states when applicant must respond. Not Approvable Letter for NDA or ANDA • States that NDA cannot be approved for one of reasons in § 314.125 or ANDA cannot be approved for one of reasons in § 314.127. • Describes deficiencies in NDA or ANDA. Complete Response Letter • States that FDA will not approve NDA or ANDA in its present form. • Describes all specific deficiencies that FDA has identified in the application (except when the agency determines that data submitted are inadequate to support approval and issues a complete response letter without first conducting required inspection and/or reviewing labeling). Deficiencies could be minor (e.g., requiring labeling changes) or major (e.g., requiring additional clinical trials). • Reflects complete review of data in NDA or ANDA and any amendments FDA has reviewed. • When possible, recommends actions applicant might take to place application in condition for approval.
For products for which approval of a BLA is required for marketing, we are adopting a new regulation, § 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.
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 § 314.100(a), excluding any extension due to a major amendment of the initial supplement.
Applicant's Response to Approvable Letter or Not Approvable Letter for NDA (or NDA Supplement) Within 10 days of date of letter, NDA applicant must do one of following: • Amend application or notify FDA of intent to file amendment. • Withdraw application. • Request opportunity for hearing. • Agree to extend review period to decide which of above actions to take. Response to Approvable Letter for ANDA (or ANDA Supplement) • Correct deficiencies by specified date or FDA will refuse to approve ANDA or ANDA supplement. • Request opportunity for hearing within 10 days. Response to Not Approvable Letter for ANDA (or ANDA supplement) • Same as for NDAs except that 10-day period does not apply (with exception of request for opportunity for hearing). • FDA may regard failure to respond within 180 days as request to withdraw. NDA or ANDA Applicant's Response to Complete Response Letter Review period is extended until applicant takes one of following actions: • Resubmit NDA or ANDA, addressing identified deficiencies. —Class 1 resubmission of NDA or efficacy supplement starts new 2-month review cycle —Class 2 resubmission of NDA or efficacy supplement starts new 6-month cycle —Resubmission of NDA supplement other than efficacy supplement starts new cycle same length as initial review cycle for supplement (excluding any extension due to major amendment) —Major resubmission of ANDA or ANDA supplement starts new 6-month cycle —Minor resubmission of ANDA or ANDA supplement starts new cycle of variable length • Withdraw NDA or ANDA. • Request opportunity for hearing. FDA may consider failure to take action within 1 year to be request to withdraw, unless applicant has requested extension of time in which to resubmit.
We are also revising our regulations in § 314.60 on extending the review cycle following the submission of an amendment to an unapproved NDA. Under revised § 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 § 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 § 314.60(b)(3). These provisions apply to Start Printed Page 39591amendments to original applications, efficacy supplements, and resubmissions of applications and efficacy supplements. Under § 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 § 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.
Amendments to Unapproved NDAs and NDA Supplements • Submission of major amendment constitutes agreement to extend deadline for FDA decision. • FDA may not extend review period more than 180 days. • Submission of nonmajor amendment will not extend review period. Amendments to Unapproved ANDAs and ANDA Supplements • Submission of amendment containing significant data or information constitutes agreement to extend review period up to 180 days. • Same for amendments to unapproved ANDA supplements. Amendments to Unapproved NDAs, Efficacy Supplements, and Resubmissions of NDAs and Efficacy Supplements • Submission of major amendment within 3 months of end of initial review cycle may extend cycle by 3 months; FDA may instead defer review to subsequent cycle. • Initial review cycle may be extended only once for major amendment. • Submission of major amendment more than 3 months before end of initial review cycle will not extend cycle; FDA may instead defer review. • Submission of nonmajor amendment will not extend review cycle; FDA may instead defer review. Amendments to Unapproved Manufacturing Supplements • Submission of major amendment within 2 months of end of initial review cycle may extend cycle by 2 months; FDA may instead defer review. Amendments to Unapproved NDA Supplements Other Than Efficacy and Manufacturing Supplements • Submission of any amendment will not extend initial review cycle; FDA may instead defer review. Amendments to Unapproved ANDAs • Unchanged.
(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 § 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 § 314.101(f)(1)(ii) as requested because only an applicant (not FDA) can respond to a complete response letter as defined in § 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.
(Response) The comment is beyond the scope of this rulemaking. With the exception of § 314.430 on public disclosure of information in applications, this rule does not address approval or post-approval regulatory matters.
Proposed § 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 Start Printed Page 39592resubmission 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 § 314.3. This makes these definitions consistent with the provisions on class 1 and class 2 resubmissions of applications and efficacy supplements in § 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.
Proposed § 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 § 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 § 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 § 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” (§ 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.
(Response) Because this statement appears in revised § 314.110(a)(4), we do not believe that it is necessary to add this statement to the definition of complete response letter in § 314.3.
Proposed § 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:
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 * * *”. Start Printed Page 39593This 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”).
Proposed § 314.100(a)(1) stated that, except as provided in § 314.100(a)(2), within 180 days of receipt of an NDA or ANDA, we will review the application and send the applicant an approval letter or a complete response letter; this 180-day period is called the initial review cycle. Proposed § 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 § 314.100(a)(2), stating that although the user fee goals recognize that we typically do not meet the 180-day statutory review deadline, this should not be memorialized in a regulation. The comment stated that even though the statutory review period is regarded mainly as aspirational, it is important to maintain it within the regulations.
(Response) We agree with the comment that a specific provision solely addressing the adjustment of the initial review cycle for human drug applications and supplements to these applications is not necessary. Therefore, we have deleted proposed § 314.100(a)(2). However, we note that, since the enactment of the Prescription Drug User Fee Act of 1992 (PDUFA) (Public Law 102-571), there has been a mutual understanding between industry and the agency that the review cycle for an application or supplement subject to user fees may be adjusted (either shortened or lengthened) in accordance with the user fee performance goals. Previous § 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 §§ 314.60 or 314.96). Consistent with the long-standing approach to applications subject to user fees, we have revised § 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 §§ 314.60 and 314.96.
Correspondingly, the final rule also deletes proposed § 314.101(f)(2). Current § 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 § 314.101(f)(2) stated that, for human drug applications and supplements, the 180-day period after the date of filing would be adjusted to be consistent with the user fee performance goals. Proposed § 314.101(f)(2) is not needed because § 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.
Proposed § 314.100(b) stated that at any time before approval, an applicant may withdraw an application under § 314.65 (21 CFR 314.65) or an abbreviated application under § 314.99 (21 CFR 314.99) and later submit it again for consideration.
(Comment 8) Two comments stated that § 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 § 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 § 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 § 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 § 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 § 314.3 from § 314.110(b)(1).
Proposed § 314.110(a) would have required us to send an applicant a Start Printed Page 39594complete 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 § 314.125 or § 314.127, respectively.
a. Specific deficiencies. Under proposed § 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 § 314.110(a)(3).
(Response) We agree with the comment. The intent of § 314.110(a)(1) is that we will identify and describe all of the known deficiencies (except as provided in § 314.110(a)(3)) to enable applicants to provide appropriate responses. However, consistent with our response to comment 5, we have revised § 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.
b. Complete review of data. Proposed § 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.
(Response) We agree that § 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 § 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 § 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 § 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 § 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 § 314.110(a)(3) a time after which we could no longer conclude that the data submitted are inadequate to support approval.
(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 Start Printed Page 39595incomplete, 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.
d. Actions to place application in condition for approval. Proposed § 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 § 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 § 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 § 314.110(a)(4).
In addition, we recognize that although it is appropriate for us to recommend actions that an applicant might take to place its application in condition for approval, we cannot require an applicant to take specific actions—and only those actions—to obtain approval. There might be multiple acceptable approaches that an applicant could take to remedy a deficiency in its application, and we might lack information that would affect our views on what actions an applicant should take. Therefore, we have revised § 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.”
Under proposed § 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 § 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 § 314.110(b)(1) further stated that, for purposes of § 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 § 314.3 from § 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 § 314.110(b)(1)(iii), a resubmission of an NDA supplement other than an efficacy supplement would constitute an agreement by the applicant to start a new 6-month review cycle beginning on the date we receive the resubmission.
(Comment 17) Three comments objected to the proposed 6-month cycle for resubmissions of other-than-efficacy supplements. One comment stated that it seemed unreasonable that a resubmission not requiring clinical data would require an additional 6 months for review. Two comments stated that because one of our user fee goals is to act on 90 percent of manufacturing supplements that require prior approval within 4 months, a 6-month review time for a resubmission of such a supplement would be longer than the review time for the original supplement. The comments stated that this is inappropriate because many of these resubmissions need only include data necessary to answer questions from the initial cycle and do not require as much review time as the initial supplement. The comments recommended that we revise § 314.110(b)(1)(iii) to state that the length of the review cycle for the resubmission of an other-than-efficacy supplement will not exceed that for the original supplement. The comments further recommended that we establish a “Type 1/Type 2” scheme for resubmissions of prior approval chemistry and manufacturing supplements that would be similar to the approach for resubmissions of original applications and efficacy supplements, but with a 2-month review cycle for Type 1 resubmissions and a 4-month cycle for Type 2 resubmissions.
(Response) We agree with the comments that the review cycle for the resubmission of a supplement that is not an efficacy supplement should be the same as the initial review cycle for the original supplement. Therefore, we have revised § 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 § 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 § 314.100(c). Under revised § 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 Start Printed Page 39596review 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 § 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 § 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.
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 § 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.
b. Request for a hearing. Under proposed § 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 § 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.
(Response) With respect to the nature of hearings on the denial of approval of applications, § 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 § 12.40 through § 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 § 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.
Under proposed § 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 § 314.110(b) (i.e., resubmission of the application, withdrawal, or request for a hearing). Proposed § 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 §§ 314.110(a)(5) and 314.120(a)(5), for Start Printed Page 39597an applicant to notify us within 10 days of receipt of an action letter that it agrees to an extension of the review period so that it can determine how to respond further. One comment stated that it was not clear whether any sponsor communication with us regarding an intent to resubmit or amend an application would cancel or postpone the proposed 1-year timeframe. The comment stated that if an applicant believed that it must resubmit within 1 year to avoid automatic withdrawal, the result could be a less-than-complete resubmission. Three comments stated that the absence of a resubmission within 1 year of receipt of a complete response letter cannot reasonably be characterized as failure to take action. Several comments stated that it might take several months for an applicant to reach agreement with us on what studies are needed for approval and then more time to conduct the studies and submit the results.
The comments suggested several ways to revise the regulations to allow applicants to request an extension of the review period. One comment stated that we should expand the first option in § 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 § 314.110(c). One comment stated that § 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 § 314.110(c) should be revised to allow an applicant to notify us, within a specified time, of its intent to resubmit or to agree to a specified extension of time to reflect an agreed-upon action plan to address deficiencies; absent such notification, we could consider the application withdrawn if it was not resubmitted within 1 year. The comment further stated that if an additional study was required, we should allow an extension beyond the 1-year period.
Two comments recommended that § 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.
(Response) We agree that proposed § 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 § 314.110(c) (renumbered as § 314.110(c)(1)) to state that, for an NDA or ANDA, we may consider an applicant's failure to take any of the actions in § 314.110(b) within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application, unless the applicant has requested an extension of time in which to resubmit the application. Section 314.110(c) further states that we will grant any reasonable request for such an extension. In addition, § 314.110(c) states that we may consider an applicant's failure to resubmit the application within the extended time period or to request an additional extension to be a request by the applicant to withdraw the application.
Although, as stated in the proposed rule, ANDA resubmissions usually do not involve generation of clinical data, for consistency we have decided to apply the 1-year period (subject to extension) to ANDA resubmissions as well as NDA resubmissions. In addition, we have revised § 314.110(c)(1) to state that the applicant's 1-year deadline for taking action begins “after issuance of a complete response letter” rather than “after [the applicant] receiv[es]” the complete response letter. This change provides certainty as to the start of the 1-year period. In addition, on our own initiative we have revised the first sentence of § 314.110(c)(1) to make clear that this paragraph addresses extension of the review period (until any of the actions listed in § 314.110(b) are taken) for an NDA under section 505(c)(1) of the act or an ANDA under section (j)(5)(A) of the act (the proposed rule inadvertently referred only to section 505(c)(1) for NDA applicants).
(Comment 21) Two comments stated that because deeming an application withdrawn is optional under proposed § 314.110(c), differences between and within centers might create an uneven playing field in which some applications are withdrawn while similarly situated applications are not. The comments stated that the decision to withdraw should rest with the applicant.
(Response) We believe that it is reasonable and within the scope of our authority to consider an applicant's failure to take any significant action within a reasonable period of time to be a request to withdraw the application. Nevertheless, we do not believe that § 314.110(c) should require us to deem an application to be withdrawn under these circumstances. Although we agree with the comments that there should not be significant differences across CDER regarding this matter, decisions on whether to regard an applicant's failure to take action as a request to withdraw the application will reflect the circumstances surrounding each particular application.
(Comment 22) One comment stated that we should notify an applicant before deeming an application withdrawn within 1 year for failure to take action under § 314.110(c), and applicants should have reasonable time to respond.
(Response) We agree that it is appropriate for us to notify an applicant that we intend to regard an application as withdrawn for failure to take action. Therefore, we are adding § 314.110(c)(2), which states that if we consider an applicant's failure to take action in accordance with § 314.110(c)(1) to be a request to withdraw the application, we will notify the applicant in writing. Section 314.110(c)(2) further states that the applicant will have 30 days from the date of the notification to explain why the application should not be withdrawn and request an extension of time in which to resubmit the application. Additionally, § 314.110(c)(2) states that we will grant any reasonable request for an extension. Finally, § 314.110(c)(2) states that if the Start Printed Page 39598applicant does not respond to the notification within 30 days, the application will be deemed to be withdrawn.
To incorporate the use of complete response letters into the biologics regulations, the proposed rule added a definition of complete response letter to § 600.3 and added § 601.3 regarding complete response letters. We received comments on these proposed regulations as well as on the lack of regulations on other matters related to BLAs.
(Comment 23) One comment stated that although we proposed many changes to § 314.110 regarding complete response letters for NDAs and ANDAs, we proposed only select changes for the corresponding regulations for BLAs in § 601.3. The comment specifically noted the lack of a definition of resubmission in § 601.3 and the fact that NDA and ANDA applicants have three options for responding to a complete response letter under § 314.110(b) while BLA applicants have only two options under § 601.3(b). The comment recommended that we revise § 601.3 to include the topics in § 314.110 or explain the brevity of the biologics regulations. One comment recommended that we revise the biologics regulations to be consistent with the procedures and timeframes for review of resubmissions and amendments of drug applications in part 314.
With respect to the two examples of inconsistency noted by one comment, we are adding a definition of resubmission to the biologics regulations at § 600.3 (see the response to comment 27), and we have concluded that it is not necessary that § 601.3(b) specify the right to request a hearing because that right is stated elsewhere in the biologics regulations (see the response to comment 26).
Proposed § 600.3(jj) would have defined “complete response letter” as a written communication to an applicant from FDA usually identifying all of the deficiencies in a BLA or BLA supplement that must be satisfactorily addressed before it can be approved.
(Comment 24) Three comments objected to the definition of complete response letter for essentially the same reasons that two of those comments provided for objecting to the definition of complete response letter for NDAs and ANDAs in § 314.3(b). Specifically, the comments maintained that stating that a complete response letter “usually” identifies all of the deficiencies in a BLA that must be satisfactorily addressed is contrary to the plain meaning of “complete response,” makes the regulation too vague and open to varying interpretation across review divisions, and is inconsistent with statements in the user fee goals. One comment stated that according to CBER's Standard Operating Procedures and Policies (SOPP) 8405, “Complete Review and Issuance of Action Letters,” the complete response letter will summarize all of the deficiencies remaining in a BLA. The comments stated that there might be circumstances when it would be reasonable for us to postpone certain aspects of a complete review; these circumstances, which are set forth in SOPP 8405, are limited to testing of submitted product lots, pre-licensing inspections, and evaluation of final printed labeling.
(Response) We agree with the comments that, generally, a complete response letter will identify all of the deficiencies in a BLA. Consistent with our response to comment 5, we have revised the definition of complete response letter in § 600.3 to state that a complete response letter is a communication “usually describing all of the deficiencies that the agency has identified in a biologics license application or supplement that must be satisfactorily addressed before it can be approved.” (The definition of complete response letter is set forth in § 600.3(ll), rather than § 600.3(jj) as proposed, because two other definitions have been added to § 600.3 since the issuance of the proposed rule.) We also agree with the comments that exceptions to this general rule include when the complete response letter concerns a BLA with respect to which we have not conducted required inspections, tested product lots, and/or reviewed proposed product labeling. Therefore, we are revising § 601.3(a) (rather than the definition of complete response letter in § 600.3) to state in § 601.3(a)(1) that a complete response letter will describe all of the deficiencies that the agency has identified in a BLA or BLA supplement, except as stated in § 601.3(a)(2). Section 601.3(a)(2) states that if we determine, after a BLA or BLA supplement is filed, that the data are inadequate to support approval, we might issue a complete response letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed product labeling. The provision refers to proposed product labeling rather than the suggested final printed labeling because we generally review the latter only after an applicant has addressed Start Printed Page 39599any major deficiencies in an application.
(Response) Consistent with § 314.110(a)(4) (see our response to comment 16), we have added the following statement in § 601.3(a)(3) (rather than to the definition of complete response letter in § 600.3): “When possible, a complete response letter will recommend actions that the applicant might take to place its biologics license application or supplement in condition for approval.”
a. Complete response letter. Proposed § 601.3(a) stated that we would send the BLA applicant or BLA supplement applicant a complete response letter if we determined that we would not approve the application or supplement in its present form. As stated in our response to comment 24, we have added § 601.3(a)(1) stating that a complete response letter will describe all of the deficiencies that the agency has identified in a BLA or BLA supplement, except as stated in § 601.3(a)(2). As discussed in our response to comment 25, we also are adding § 601.3(a)(3) stating that, when possible, a complete response letter will recommend actions that the applicant might take to place its BLA or BLA supplement in condition for approval.
b. Applicant actions. i. General. Under proposed § 601.3(b), after receiving a complete response letter, the biologics license applicant or supplement applicant was required to either resubmit the application or supplement or withdraw it.
(Comment 26) One comment stated that although NDA and ANDA applicants have three options following receipt of a complete response letter (resubmit the application, withdraw it, or request a hearing), BLA applicants have only two options (resubmit or withdraw the application). The comment recommended that we either revise § 601.3 or explain this omission from the biologics regulations.
(Response) We do not believe that it is necessary to include, in § 601.3, a reference to the option to request a hearing. Under § 601.4(b) (21 CFR 601.4(b)), if we determine that an establishment or product that is the subject of a BLA does not meet the requirements for approval, we will deny the BLA and inform the applicant of the grounds for, and of an opportunity for a hearing on, the decision. Section 601.4(b) further states that if the applicant requests, we will issue a notice of opportunity for a hearing on the matter pursuant to § 12.21(b). Because the right to request a hearing regarding a denial of approval is set forth in § 601.4(b), we do not believe that it is necessary to revise § 601.3 as requested.
ii. Resubmission. Under proposed § 601.3(b)(1), after receiving a complete response letter, a BLA applicant or supplement applicant could resubmit the application or supplement, addressing all deficiencies identified in the complete response letter.
(Response) We agree that the regulations should define “resubmission.” Therefore, we have added a definition of resubmission in § 600.3(mm), stating that a resubmission is a submission by the biologics license applicant or supplement applicant of all materials needed to fully address all deficiencies identified in the complete response letter. This parallels the definition of resubmission in § 314.3(b).
(Response) We agree. Therefore, consistent with the definition of resubmission in § 314.3(b) for NDAs and ANDAs (see the response to comment 8), the definition of resubmission in § 600.3(mm) includes the statement, “A biologics license application or supplement for which FDA issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.”
c. Failure to take action. Under proposed § 601.3(c), we could consider a BLA applicant or BLA supplement applicant's failure to either resubmit or withdraw the application or supplement within 1 year after receiving a complete response letter to be a request by the applicant to withdraw the application or supplement.
(Comment 29) As with proposed § 314.110(c) concerning complete response letters to NDA and ANDA applicants, several comments objected to the lack of an option in § 601.3(c) to seek an extension of time in which to resubmit an application or supplement. Two comments stated that the absence of a resubmission within 1 year of receipt of a complete response letter cannot reasonably be characterized as failure to take action. Three comments stated that it might take at least several months for an applicant to reach agreement with us on what studies are needed for approval and then more time to conduct the studies and submit the results. One comment maintained that although the preamble to the proposed rule stated that § 601.3 is intended to incorporate current CBER policy, § 601.3(c) does not reflect current policy and does not afford applicants the opportunity to notify us of their intent to resubmit an application to prevent us from considering it withdrawn.
Four comments suggested revisions to § 601.3(c). One comment recommended that it be revised to state as follows: “FDA may consider a biologics license applicant or supplement applicant's failure to resubmit, amend the application to request an extension of time to respond, or withdraw the application or supplement within 1 year after receiving a complete response letter to be a request by the applicant to withdraw the application or supplement.” One comment recommended that the first option in proposed § 601.3(b) be revised to permit sponsors to resubmit the BLA or supplement addressing all deficiencies or state their intention to do so (if they conclude that it will take more than 1 year to address all deficiencies).
Two comments recommended that § 601.3(c) be revised in one of two ways. One approach would be to add an option for the BLA or BLA supplement applicant to notify us, within a specified time after receipt of a complete response letter, of an intent to resubmit. If the resubmission is not submitted within 1 year, the applicant would be required to provide annual confirmation of its intent to resubmit; if the applicant provides no such notification, we could consider the application or supplement withdrawn. The alternative approach would require us to notify the applicant requesting a reply within a specified time regarding its intention to resubmit; failure to respond within the specified time would constitute a request for withdrawal.
(Response) For the reasons stated in the discussion of § 314.110(c) (see the response to comments 20 and 22), we Start Printed Page 39600agree that § 601.3(c) should be revised to, among other things, allow applicants to seek an extension of time in which to resubmit an application (beyond 1 year after issuance of the complete response letter), and to notify applicants when we decide to consider an applicant's failure to take action as required under § 601.3 to be a request to withdraw the application. Therefore, we are revising § 601.3(c) to state, in § 601.3(c)(1), that we may consider a BLA applicant or BLA supplement applicant's failure to either resubmit or withdraw the application or supplement within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application or supplement, unless the applicant has requested an extension of time in which to resubmit the application or supplement. Section 601.3(c)(1) further states that we will grant any reasonable request for such an extension. Finally, § 601.3(c)(1) states that we may consider an applicant's failure to resubmit the application or supplement within the extended time period or to request an additional extension to be a request by the applicant to withdraw the application.
We also are adding § 601.3(c)(2), which states that if we consider an applicant's failure to take action in accordance with § 601.3(c)(1) to be a request to withdraw the application, we will notify the applicant in writing. Section 601.3(c)(2) further states that the applicant will have 30 days from the date of the notification to explain why the application or supplement should not be withdrawn and request an extension of time in which to resubmit the application or supplement, and we will grant any reasonable request for an extension. Finally, § 601.3(c)(2) states that if the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn.
As with revised § 314.110(c)(1), we are substituting the phrase “after issuance of a complete response letter” for the phrase “after receiving a complete response letter” to provide certainty about the start of the 1-year period.
Proposed § 314.50(d)(5)(vi)(b) would have required NDA applicants to submit safety update reports 4 months after the initial submission, in a resubmission following receipt of a complete response letter, and at other times as requested by us. Previous § 314.50(d)(5)(vi)(b) had required the submission of safety updates 4 months after the initial submission, after receiving an approvable letter, and when otherwise requested by us.
Proposed § 314.65 stated in part that if, by the time we received notice of an applicant's request to withdraw an unapproved application, we had identified any deficiencies in the application, we would list such deficiencies in the letter we sent the applicant acknowledging the withdrawal.
(Comment 31) One comment stated that all communications before the issuance of approval or tentative approval should remain confidential. Therefore, the comment recommended that the following statement be added to § 314.65: “This communication, like all communications prior to approval or tentative approval, will not be publicly disclosed.”
(Response) We agree with the comment that the letter to an applicant acknowledging the withdrawal of its application is a confidential communication. However, we do not believe that it is necessary to add to § 314.65 the language suggested by the comment. The confidential nature of such communications is already addressed in § 314.430.
Proposed § 314.430(b) stated that we would not publicly disclose the existence of an application or abbreviated application before an approval letter was sent to the applicant under § 314.105 or a tentative approval letter was sent to the applicant under § 314.107, unless the existence of the application or abbreviated application had been previously publicly disclosed or acknowledged. Previous § 314.430(b) stated that we would not make such a disclosure before issuance of an approvable letter. In the proposed rule, we acknowledged that our proposed change might result in later disclosure than sometimes occurred under the previous regulation with respect to those applications for which we issued approvable letters. But we stated that the proposed change was consistent with our presumption that, before approval, the existence of an application is confidential commercial information under § 20.61 (21 CFR 20.61). However, we invited comment on whether it would be appropriate for us to disclose the existence of an application following issuance of a complete response letter and, if so, under what conditions.
(Comment 32) Six comments agreed with the proposal to not disclose the existence of an NDA or ANDA before we send an approval letter or tentative approval letter unless the existence of the application has been previously publicly disclosed or acknowledged. Two comments stated that it was appropriate to continue our current policy on disclosure; one comment stated that this was consistent with the presumption that the existence of an application is confidential commercial information. One comment specifically opposed the alternative approach we suggested in the proposed rule, under which we could disclose the existence of an NDA or ANDA following issuance of a complete response letter unless the applicant notified us by a specified date that the applicant had not publicly disclosed or acknowledged the application's existence. The comment stated that such disclosure could be harmful, particularly in the generic drug sector, to any competitive advantage that a sponsor might have in a race to product launch. The comment also agreed with the statement in the proposed rule that requiring applicants to notify us to prevent our disclosing the existence of their applications would Start Printed Page 39601create the potential for error and would be burdensome.
The proposed rule would have revised § 314.440(a)(1) to state that, except as provided in § 314.440(a)(4), an application under § 314.50 or § 314.54 submitted for filing should be directed to the Central Document Room, 12229 Wilkins Ave., Rockville, MD 20852-1833.
The proposed rule correctly revised the title of the office to which applications must be submitted under § 314.440(a)(1) from “Document and Records Section” to “Central Document Room,” but it inadvertently changed the address for the office. The final rule states the correct address to which these applications must be submitted as follows: Central Document Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.
In addition, on our own initiative we are revising § 314.440(a)(2) concerning addresses for ANDAs to specify the current address for the Office of Generic Drugs and to update related information.
We proposed several revisions to § 314.60 concerning amendments to unapproved NDAs. Previous § 314.60 stated in part that submission of a major amendment ordinarily would extend the application's review period only for the time necessary to review the new information, but not more than 180 days; submission of an amendment that was not a major amendment would not extend the review period. We proposed to revise § 314.60 to, among other things, specify how long the review cycle would be extended for several types of amendments. In addition, proposed § 314.60(b) would allow us to defer all of these amendments to the next review cycle.
As the GRMP guidance states, although we strive to review amendments during the initial review cycle for an application, there are circumstances under which this is not possible or would not be an efficient use of resources. Although the GRMP guidance specifies some of the circumstances in which deferral of review of an amendment to the next review cycle might be appropriate, we do not believe that we can codify in the regulations all of the circumstances under which we might defer review of an amendment. Therefore, we conclude that § 314.60 must provide us with the Start Printed Page 39602discretion to defer review of various types of amendments until the subsequent review cycle, when appropriate.
(Comment 34) Two comments stated that § 314.60 should require us to provide written notification to the applicant when we defer an amendment to the next cycle because deferral is essentially an action decision. The comments stated that such notification should describe the deficiencies that preclude approval.
(Response) We agree with the comments that we should provide written notification to an applicant when we defer review of an amendment to the subsequent review cycle. We currently provide such notice in our approvable and not approvable letters. Therefore, we have added a new § 314.60(b)(7) stating as follows: “When FDA defers review of an amendment until the subsequent review cycle, the agency will notify the applicant of the deferral in the complete response letter sent to the applicant under § 314.110.” We do not believe that it is necessary to codify in the regulations that we will provide a reason for the deferral. Usually, the reasons for deferral are general in nature (e.g., the amendment contains substantial new information or does not address a known deficiency). We would be willing to discuss the reasons for deferral after the applicant receives the complete response letter.
Under proposed § 314.60(b)(1), submission of a major amendment to an original application, efficacy supplement, or resubmission of an application or efficacy supplement within 3 months of the end of the initial review cycle constituted an agreement by the applicant under section 505(c) of the act to extend the initial review cycle by 3 months. Proposed § 314.60(b)(1) further stated that we might instead defer review of the amendment until the subsequent review cycle. Proposed § 314.60(b)(1) also stated that the initial review cycle for an original application, efficacy supplement, or resubmission of an application or efficacy supplement may be extended only once due to the submission of a major amendment. It further stated that we might, at our discretion, review any subsequent major amendment during the initial review cycle (as extended) or defer review to the subsequent cycle.
On our own initiative, we are revising § 314.60(b)(1) with respect to amendments to resubmissions. Unlike applications and supplements (21 CFR 314.71(c)), resubmissions are not subject to the “initial review cycle” provision in § 314.100(a); they just have a “review cycle.” Therefore, we are adding to § 314.60(b)(1) a statement clarifying that, for references to a resubmission of an application or efficacy supplement in § 314.60(b), the timeframe for reviewing the resubmission is the “review cycle” rather than the “initial review cycle.”
(Response) We do not believe that it is necessary to include a definition of major amendment in the regulations. Previous § 314.60(a) did not define a major amendment; it only gave an example of a major amendment (i.e., “an amendment that contains significant new data from a previously unreported study or detailed new analyses of previously submitted data”). Because we are uncertain that we can define major amendment in a way that encompasses all types of amendments that should be treated as major amendments, we decline to add a definition to the regulations.
(Comment 36) Two comments recommended not codifying the 3-month extension for a major amendment submitted within 3 months of the end of the initial review cycle because, although this is consistent with current user fee goals, those goals could change as a result of future negotiations on user fees. The comments stated that the timeframes agreed upon in the user fee negotiations historically have taken precedence over existing regulatory timeframes, as was recognized in proposed § 314.100(a)(2). The comments stated that if we believed it was necessary to codify user fee goals on extensions, we should revise § 314.60(b) to state that for human drug applications, any extension of review due to a major amendment will be consistent with the user fee goals, similar to proposed § 314.100(a)(2).
(Response) As stated in the preamble to the proposed rule, we are revising § 314.60 to state that submission of a major amendment within 3 months of the end of the review cycle will extend the review cycle by 3 months because we want to make the regulation consistent with the current user fee goal on these amendments. At present, we do not anticipate a change in this goal. If this goal does in fact change as a result of a future user fee agreement, we could issue a proposed rule proposing to make the regulation match the user fee goal on this matter.
(Comment 37) Four comments specifically addressed the provision in proposed § 314.60(b)(1) allowing deferral of review of a major amendment submitted within 3 months of the end of the initial review cycle. One comment stated that the option to defer review was arbitrary and inconsistent with the user fee goals. The comment stated that neither the proposed codified provision nor the preamble gave examples of when it might be appropriate to defer review. The comment claimed that because the overwhelming majority of these amendments are submitted in response to FDA requests, it would be unreasonable to penalize applicants by deferring review of the amendments. The comment also stated that early communication of information and data requests in accordance with GRMP principles will ordinarily result in receipt of responses early in the initial cycle, giving us more time to complete our review by the goal date. Therefore, the comment recommended that § 314.60(b)(1) be revised to state that the agency will make every effort to complete its review of the full application, including amendments, by the user fee goal date. The comment maintained that review of these major amendments should only be deferred when the amount of new information and the timing of the submission make it impossible to review the amendment in the initial cycle.
One comment recommended revising § 314.60(b)(1) to state that we would not be required to review a major amendment that pertains to one section of the application if we have previously identified deficiencies in another section that prevent first-cycle approval. Two comments recommended revising § 314.60(b)(1) to state that we may defer review of a major amendment submitted within the last 3 months of the initial cycle that meets any of the following criteria: (1) It amends technical sections of an application in which we have identified deficiencies that prohibit approval during the initial cycle and that do not contain information needed to put the application in condition for approval; (2) it amends a technical section other than sections in which we have identified deficiencies preventing approval, where review of the amendment will not result in approval during the current cycle; or (3) it is an amendment for which, under the user fee goals, we could not extend the review cycle (e.g., a second major amendment submitted within the last 3 months of the initial cycle).
(Response) We do not agree with any of the proposed revisions to § 314.60(b)(1). As stated in the GRMP guidance, we usually seek to review Start Printed Page 39603amendments, including major amendments, during the initial review cycle. However, we do not believe that it is necessary to codify this intent in § 314.60(b)(1) or elsewhere in this section. As stated in our response to comment 33, we do not believe that we can codify all of the circumstances under which it might be appropriate to defer review of major amendments. In addition, we do not agree with the claim that the overwhelming majority of amendments are submitted in response to agency requests, and the comment provides no evidence supporting this statement. For these reasons, we believe that it is appropriate to include in § 314.60(b)(1) a statement that we can defer review of a major amendment submitted within 3 months of the end of the initial review cycle rather than extend the cycle by 3 months.
(Comment 38) One comment stated that § 314.60(b)(1) also should specify that we would not be required to review a second major amendment submitted within 3 months of the goal date with no accompanying extension of the review clock.
(Response) We do not agree with the suggested change. Proposed § 314.60(b)(1) stated that the initial review cycle may be extended only once due to the submission of a major amendment, and any subsequent major amendment would either be reviewed during the initial review cycle or deferred. We believe that it is appropriate that § 314.60(b)(1) include these provisions to make clear that we will not extend the review cycle for a second major amendment.
Under proposed § 314.60(b)(2), submission of a major amendment to an original application, efficacy supplement, or resubmission of an application or efficacy supplement more than 3 months before the end of the initial review cycle would not have extended the cycle. Proposed § 314.60(b)(2) further stated that we might, at our discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.
(Comment 39) One comment stated that the deferral provision in § 314.60(b)(2) would have the unintended effect of widening differences among review divisions regarding when review of these major amendments is deferred and would seem to discourage the possibility of dialogue on the merits of submission of a major amendment. Two comments stated that, because the user fee goals do not address major amendments submitted more than 3 months before the end of the review period, the implication is that review can be accommodated during the initial cycle. One comment stated that we should not defer the review of major amendments submitted well in advance of the goal date, so this option should be deleted from the rule. One comment recommended that § 314.60(b)(2) state that we will ordinarily make every effort to complete our review of an application or efficacy supplement, including any amendments submitted more than 3 months before the end of the initial cycle, by the user fee goal date.
Several comments stated that the regulation should specify the criteria under which we could defer review of these major amendments. Two comments recommended that § 314.60(b)(2) state that we may defer review of a major amendment submitted more than 3 months before the end of the initial cycle when we have already identified at least one major deficiency (such as a failed pivotal trial) that is not addressed by the amendment and is unlikely to be addressed during the current cycle due to a need for significant additional research or development.
(Response) We do not agree with any of the proposed revisions to § 314.60(b)(2). For the reasons stated in our response to comment 33, we do not believe that we can codify all of the circumstances under which it might be appropriate to defer review of these major amendments. Consequently, we have retained the provision in § 314.60(b)(2) giving us the discretion to defer review of these amendments to the next review cycle.
Under proposed § 314.60(b)(3), the submission of an amendment to an original application, efficacy supplement, or resubmission of an application or efficacy supplement that is not a major amendment would not have extended the initial review cycle. Proposed § 314.60(b)(3) further stated that we might, at our discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.
(Comment 40) One comment stated that § 314.60(b)(3) would have the unintended effect of widening differences in interpretation among review divisions regarding these nonmajor amendments. The comment added that § 314.60(b)(3) seemed contrary to § 314.102(b), which encourages reviewers to communicate promptly to applicants easily correctable deficiencies so that the deficiencies can be corrected through amendments before the review period ends. One comment stated that by their very nature, these amendments are less complex and require less time to review, which provides even more reason to expect that they be reviewed in the initial cycle. Therefore, the comment maintained that § 314.60(b)(3) should state that we will ordinarily review all nonmajor amendments by the user fee goal date.
Several comments stated that § 314.60(b)(3) should set forth the criteria for deferral of review. One comment recommended that § 314.60(b)(3) state that we could defer review of a nonmajor amendment that is submitted close to the end of the cycle and which could not contribute to an approval decision because other major deficiencies cannot be satisfactorily addressed. One comment suggested that the regulation state that we could defer review if a nonmajor amendment is submitted late in the review cycle (such as 1 to 2 months before the end) or if the amendment does not provide information that addresses easily correctable deficiencies, provided other major deficiencies prevent approval at the end of the initial cycle. Similarly, two comments recommended that § 314.60(b)(3) state that we may defer review of a nonmajor amendment that is received within 1 month of the end of the initial cycle or that does not contain information adequate to put the application in condition for approval during the current cycle. One comment recommended stating that we could defer review of a nonmajor amendment that is received late in the review cycle (e.g., within weeks of the goal date) when review of the amendment is not expected to impact the outcome of the application review.
(Response) We do not agree with any of the proposed revisions to § 314.60(b)(3). For the reasons stated in our response to comment 33, we do not believe that we can codify all of the circumstances under which it might be appropriate to defer review of these nonmajor amendments. Consequently, we have retained the provision in § 314.60(b)(3) giving us the discretion to defer review of these amendments to the next review cycle.
Under proposed § 314.60(b)(4), submission of an amendment to a supplement other than an efficacy Start Printed Page 39604supplement would not have extended the initial review cycle. Proposed § 314.60(b)(4) further stated that we might, at our discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.
On our own initiative, we have revised § 314.60(b)(4) to ensure that the regulation is consistent with the user fee performance goal regarding major amendments to manufacturing supplements. In PDUFA III, industry and the agency agreed that submission of a major amendment to a manufacturing supplement submitted within 2 months of the goal date would extend the goal date for acting on the supplement by 2 months, and that there can be only one such extension per review cycle. Although industry and the agency have been acting in accordance with this user fee goal since the enactment of PDUFA III in 2002, we inadvertently failed to incorporate this practice into the proposed rule issued in 2004. Consequently, we have revised § 314.60(b)(4) to state that submission of a major amendment to a manufacturing supplement within 2 months of the end of the initial review cycle constitutes an agreement by the applicant under section 505(c) of the act to extend the initial review cycle by 2 months. Consistent with the approach to major amendments in § 314.60(b)(2), revised § 314.60(b)(4) further states: FDA may instead defer review of a major amendment to a manufacturing supplement until the subsequent review cycle; if we extend the initial review cycle, the division responsible for reviewing the supplement will notify the applicant of the extension; the initial review cycle for a manufacturing supplement may be extended only once due to submission of a major amendment; and we may, at our discretion, review any subsequent major amendment during the initial review cycle (as extended) or defer review until the subsequent review cycle.
In accordance with the change to § 314.60(b)(4), revised § 314.60(b)(5) states that submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not extend the initial review cycle, and we have discretion to review or defer review of such an amendment. Proposed § 314.60(b)(5) has been renumbered as § 314.60(b)(6).
(Comment 41) One comment recommended that we revise proposed § 314.60(b)(4) to state that we might consider deferring review of other-than-efficacy supplements that are received late in the review cycle (e.g., within weeks of the goal date) when their review is not expected to impact the outcome of the application review. Two comments stated that the regulation should permit us to defer review of any other-than-efficacy supplement that either is received within 1 month of the end of the initial cycle or contains information that is inadequate to put the application in condition for approval during the current cycle.
(Response) We do not agree with either of the suggested revisions to proposed § 314.60(b)(4) (now § 314.60(b)(5)). For the reasons stated in our response to comment 33, we do not believe that we can codify all of the circumstances under which it might be appropriate to defer review of amendments to supplements other than efficacy or manufacturing supplements. Consequently, we have retained the provision in § 314.60(b)(5) giving us the discretion to defer review of these amendments to the next review cycle.
Under proposed § 314.60(b)(5) (now § 314.60(b)(6)), a major amendment could not include data to support an indication for a use that was not included in the original application, supplement, or resubmission.
(Comment 42) One comment stated that it would be unfair in most cases to expect us to meet the goal date for review of an application if a major amendment was submitted for a completely new indication in the middle of the initial review cycle. However, the comment stated that sometimes we request additional data or safety updates, which can lead to the expansion or modification of an indication (e.g., submission of long-term safety data supporting chronic use). The comment added that there might be a significant public health reason to allow the submission of a major amendment to support a new indication. Therefore, the comment recommended that § 314.60(b)(6) be modified to allow exceptions when data to support a new or expanded indication are either requested by us or submitted with our prior concurrence.
(Response) We agree with the comment that it is appropriate to allow a major amendment to include data to support a slightly modified indication (e.g., increasing or decreasing the age range, increasing the severity of the disease) but not a completely new indication, regardless of whether the data supporting the new indication were submitted at the applicant's initiative or at our request. Therefore, we have revised § 314.60(b)(6) to state as follows: “A major amendment may not include data to support an indication or claim that was not included in the original application, supplement, or resubmission, but it may include data to support a minor modification of an indication or claim that was included in the original application, supplement, or resubmission.” In addition, for the reasons stated in section III.B.3 of this document regarding § 314.3, we are substituting the phrase “indication or claim” for “indication for a use.”
Proposed § 314.96(a)(2) stated that submission of an amendment containing significant data or information before the end of the initial review cycle constitutes an agreement between FDA and the applicant to extend the initial review cycle only for the time necessary to review the significant data or information and for no more than 180 days.
(Comment 43) One comment objected to proposed § 314.96(a)(2) and recommended several changes. First, the comment stated that it appeared that the only proposed change to § 314.96 was the removal of the condition that the cycle will be extended only for the time necessary to review the data. The comment maintained that this was not consistent with the intent to reduce ANDA approval times as stated in the ANDA amendments guidance. Second, the comment stated that § 314.96(a)(2) does not provide a definition of “significant.” The comment recommended that the term “major amendment” be substituted for “amendment containing significant data or information” in § 314.96(a)(2). Third, the comment stated that § 314.96 lacks a provision regarding the submission of an amendment that contains data or information not considered significant. Finally, the comment stated that, in contrast to the provisions on major and nonmajor amendments to NDAs in § 314.60, it appeared that any amendment of an ANDA submitted at any time during the initial cycle constitutes an agreement to extend the review cycle by 6 months. The comment maintained that the provisions on NDA amendments that take into consideration the timing and content of amendments were fair and appropriate and recommended that a similar approach be taken with ANDA amendments. To address all of these concerns, the comment recommended that § 314.96 be revised to state as follows: “The submission of a major amendment to an original ANDA at any time within the initial review cycle constitutes an agreement between the Start Printed Page 39605FDA and the applicant to extend the cycle only by the time necessary to review the data, and for no more than 180 days. A major amendment is defined as any new or revised information or data that, if it were to be submitted post-approval, would be categorized as a Prior Approval Supplement as defined in 314.70(b). The submission of a minor amendment to an original ANDA within 3 months of the end of the initial review cycle constitutes an agreement between the FDA and the applicant to extend the cycle by 30 to 60 days. The submission of a minor amendment more than 3 months before the close of the initial review cycle would not extend the review cycle. A minor amendment is defined as any new or revised information that, if it were to be submitted post-approval, would be categorized as a Changes Being Effected or Changes Being Effected in 30 Days supplement as defined in 314.70(c).”
(Response) Contrary to the comment, revised § 314.96(a)(2) retains the provision in previous § 314.96(a)(2) that the submission of an amendment to an ANDA containing significant data or information before the end of the review cycle constitutes an agreement to extend the review cycle “only for the time necessary to review the significant data or information and for no more than 180 days.”
We do not agree with the comment's recommended changes to § 314.96. We do not believe that it is necessary to add a definition of major amendment in § 314.96. The ANDA amendments guidance does not provide a definition of major amendment but provides a listing of types of amendments that we regard as major amendments. These include, but are not limited to, amendments relating to the manufacture of a new batch of drug product, a new bioequivalence study that is unrelated to the manufacture of a new batch of the drug product, and new analytical methods and validation data. We believe that the guidance provides adequate information to applicants about the types of amendments that we regard as “containing significant data or information” under § 314.96(a)(2). We do not agree with the comment's suggested definition of major amendment because the matters that are the subject of supplements submitted under § 314.70 do not necessarily correlate with matters that are the subject of amendments submitted under § 314.96, and the regulatory environment in which we review supplements differs from that in which we review amendments (e.g., we have much more information about a drug product after approval than we do before approval). For these reasons, we conclude that it is appropriate to retain the flexibility provided in § 314.96(a)(2) concerning what constitutes an amendment containing significant data or other information.
We also do not believe that it is necessary to include provisions on “minor” amendments to ANDAs in § 314.96. The ANDA amendments guidance states that, except for those amendments that are classified as “major” or “telephone,” amendments will be designated as “minor,” and the guidance provides examples of minor amendments (e.g., deficiencies in a drug master file, problems regarding good manufacturing practices). (According to the guidance, an amendment can be classified as a “telephone” amendment at the agency's discretion if the amendment would otherwise be classified as “minor” but the deficiencies are of a limited number or complexity (e.g., a need for clarification of data already submitted, a request for a postapproval commitment).) The guidance states that we attempt to review minor amendments within 30 to 60 days but notes that we cannot review all of these amendments within 60 days. We believe that the comment's proposed definition of minor amendment is not appropriate for the reasons we stated for not adopting the proposed definition of major amendment. In addition, we decline to adopt the specific provisions on minor amendments suggested by the comment. The regulations in previous § 314.94 on amendments to pending ANDAs did not address minor amendments and did not parallel the provisions in § 314.60 on NDA amendments. Because ANDA amendments often differ in subject matter from NDA amendments, we do not believe it is necessary that the provisions on the content and timing of ANDA amendments match those for NDA amendments. We believe that the ANDA amendments guidance provides adequate information to ANDA applicants on minor amendments, and we do not find it necessary to codify our policy in the regulations at this time.
As described in sections II and III of this document, the final rule makes the following changes: (1) For NDAs and ANDAs, replaces the two types of action letters currently used (approvable and not approvable letters) with complete response letters; (2) for BLAs, incorporates into the regulations an existing policy on complete response letters; (3) incorporates into the regulations the terminology and procedures used in the user fee performance goals regarding NDA resubmissions; and (4) revises regulations governing extension of the initial review cycle in response to major amendments to unapproved applications, supplements, and resubmissions. For NDAs (with respect to resubmissions and amendments) and BLAs, the final rule codifies current agency practices. For ANDAs, the final rule revises regulations to be consistent with current practice or, where appropriate, with the provisions governing NDAs. The most significant impact of the final rule is on efficacy supplements to approved NDAs and on Start Printed Page 39606resubmissions of applications and efficacy supplements. The impact of specific provisions of the final rule on NDAs, ANDAs, efficacy supplements, manufacturing supplements, and resubmissions is described in greater detail in the following paragraphs.
Based on the preceding analysis, the changes to provisions governing resubmissions could result in reduced review times for up to 40 percent of efficacy supplements resubmitted annually. However, the provisions governing major amendments could slightly increase review times for up to 11 percent of efficacy supplements and 6 percent of manufacturing supplements (for which at least one major amendment was received during the initial review cycle) filed annually. The full impact of this rule would be affected by the number of future submissions and the extent to which we exercise our discretion to defer review until the next cycle. ANDAs will not be Start Printed Page 39607significantly affected by the changes to regulations.
This final rule does not contain new information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). The final rule substitutes complete response letters for approvable and not approvable letters (in previous §§ 314.110 and 314.120, respectively) when we take action on marketing applications. The final rule retains the provisions requiring the recipient of the action letter (a complete response letter under the final rule) to amend the application (i.e., resubmit it), withdraw it, or ask us to provide an opportunity for a hearing on whether there are grounds for denying approval of the application. The final rule also revises the regulations (§§ 314.60, 314.96, 314.110, and 314.120) on extending the review cycle due to the submission of amendments before we issue an action letter and due to resubmissions, but does not change the information required in such amendments and resubmissions. OMB already has approved the information collection discussed earlier concerning responses to action letters under OMB control number 0910-0001, which expires on May 31, 2011.
(c) If FDA concludes that the data presented are not sufficient for marketing approval, FDA will issue a complete response letter under § 314.110 of this chapter or the biological product licensing procedures. * * *
Class 1 resubmission means the resubmission of an application or efficacy supplement, following receipt of a complete response letter, that Start Printed Page 39608contains one or more of the following: Final printed labeling, draft labeling, certain safety updates, stability updates to support provisional or final dating periods, commitments to perform postmarketing studies (including proposals for such studies), assay validation data, final release testing on the last lots used to support approval, minor reanalyses of previously submitted data, and other comparatively minor information.
5. Section 314.50 is amended in paragraph (d)(5)(vi)(
(7) When FDA defers review of an amendment until the subsequent review cycle, the agency will notify the applicant of the deferral in the complete response letter sent to the applicant under § 314.110 of this part.Start Printed Page 39609
(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 § 314.65 on the date of receipt by FDA of the amendment. * * *
(a) Except as provided in paragraph (c) of this section, within 180 days of receipt of an application for a new drug under section 505(b) of the act or an abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the applicant either an approval letter under § 314.105 or a complete response letter under § 314.110. This 180-day period is called the “initial review cycle.”
(c) The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in §§ 314.60 and 314.96, as the result of a major amendment.
11. Section 314.101 is amended by revising paragraph (f)(1)(ii) and by revising the last sentence of paragraph (f)(2) to read as follows:
13. Section 314.103 is amended in paragraph (c)(1) in the first sentence by removing the phrase “an approvable or not approvable” and adding in its place the phrase “a complete response” and by removing the phrase “or § 314.120, respectively”.
(b) Applicant actions. After receiving a complete response letter, the applicant must take one of following actions:Start Printed Page 39610
(3) Request opportunity for hearing. Ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively. The applicant must submit the request to the Associate Director for Policy, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the date of the request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree, the agency will either approve the application or abbreviated application under § 314.105, or refuse to approve the application under § 314.125 or abbreviated application under § 314.127 and give the applicant written notice of an opportunity for a hearing under § 314.200 and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively.
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 § 314.120”.
19. Section 314.430 is amended in paragraph (b) in the first sentence by removing the phrase “approvable letter is sent to the applicant under § 314.110” and adding in its place the phrase “approval letter is sent to the applicant under § 314.105 or tentative approval letter is sent to the applicant under § 314.107”; and by removing the last sentence.
20. Section 314.440 is amended as follows:
a. In paragraph (a)(1) by removing the phrase “Document and Records Section” and by adding in its place the phrase “Central Document Room”;
b. In paragraph (a)(3) by removing the phrase “or § 314.120”;
c. In the introductory text of paragraph (b) by removing the phrase “or § 314.120”; and
(2) Except as provided in paragraph (a)(4) of this section, an abbreviated application under § 314.94, and amendments, supplements, and resubmissions should be directed to the Office of Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food and Drug Administration, Metro Park North II, 7500 Standish Place, rm. 150, Rockville, MD 20855. This includes items sent by parcel post or overnight courier service. Correspondence not associated with an abbreviated application should be addressed specifically to the intended office or division and to the person as follows: Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Attn: [insert name of person], Metro Park North II, HFD-[insert mail code of office or division], 7500 Standish Place, rm. 150, Rockville, MD 20855. The mail code for the Office of Generic Drugs is HFD-600, the mail codes for the Divisions of Chemistry I, II, and III are HFD-620, HFD-640, and HFD-630, respectively, and the mail code for the Division of Bioequivalence is HFD-650.
(mm) Resubmission means a submission by the biologics license applicant or supplement applicant of all Start Printed Page 39611materials needed to fully address all deficiencies identified in the complete response letter. A biologics license application or supplement for which FDA issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.