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U.S. Department of Health and Human Services

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New Drug and Antibiotic Regulations: part 3

21 CFR Parts 71, 170, 171, 180, 201, 310, 312, 314, 330, 430, 431, 433, 510, 511, 514, 570, 571, 601, 812, 1003, and 1010
New Drug and Antibiotic Regulations
[Docket No. 82N-0293]
50 FR 7452 (continued)

138. One comment urged that the changes in the regulation on drug master files should apply only to information added to the master file after the date of publication of the final rule. Another comment urged that the changes apply only to applications submitted after the effective date which incorporate a drug master file reference.

FDA believes that a uniform effective date for changes in the regulation on drug master files is necessary. Applying the regulations only to information added to a file after publication of the final rule, or applications submitted after the effective date of the final rule, would lead to continual confusion about what part of the file is subject to the rule.

139. Designated journals (§ 310.9). One comment objected to FDA removing its list of designated journals from the regulations. The comment urged FDA to retain a list of journals that are available to it and waive requirements for submission or reprints and summaries of reports in those journals.

As discussed elsewhere in this preamble, FDA does not believe it to be a wise expenditure of its resources to retrieve copies of referenced journals from its library, given the minimal burden on applicants to submit relevant copies. FDA notes that the change is more likely to expedite rather than delay review of applications. In addition to removing § 310.9, FDA also is deleting the references to § 310.9 that appear in 21 CFR 510.3(1) and 510.95.

140. Public information (§ 314.430). One comment contended that FDA's classification of what constitutes confidential safety and effectiveness data in an application is overbroad and that, instead, the agency should require the applicant to index confidential records within its application in a manner similar to the procedure in § 20.53 (21 CFR 20.53) of FDA's public information regultions. If a person requests a copy of a record the applicant considers confidential, the applicant's reasons for considering it confidential could be forwarded to the requestor, who may then ask the agency to determine whether the record is disclosable.

FDA does not agree with this comment. An applicant is required to itemize and index its records under § 20.53 only in a legal action contesting an FDA denial of a request for records because they are exempt from public disclosure as a trade secret or confidential commercial or financial data and information. The agency believes that the comment's suggestion that this procedure be established absent litigation, and before FDA makes an initial determination about the status of a document, would impose a significant burden on applicants to index large numbers of records whose confidential status will never be disputed. It would also add to FDA's already heavy workload in responding to freedom of information requests by requiring the agency to provide the requestor with a preliminary response detailing the applicant's reasons for considering a record nondisclosable.

141. In § 314.430(f) of the proposal, FDA proposed to modify § 314.14(f) of the current regulations in identifying the situations in which safety and effectiveness data and information are available for public disclosure. Consideration of that proposal, as it relates to disclosure rules for drugs submitted under section 505(b) of the act, was rendered moot, however, by section 104 of the Drug Price Competition and Patent Term Restoration Act of 1984, enacted on September 24, 1984, because the new law itself provides when data and information in such submissions are publicly disclosable. Accordingly, FDA has conformed this final rule (§ 314.430(f)) to be consistent with section 104 of the new law.

In doing so, FDA calls attention to one specific point. Section 314.14(f)(5) of the current regulations provides that safety and effectiveness data and information are publicly disclosable when a final determination has been made that the drug may be approved without the submission of such data and information. In the past, "final determination" (for drugs approved under section 505) was interpreted to require publication of a final Federal Register notice under the Drug Efficacy Study Implementation (DESI) program. Under the new law, however, this provision means such data and information are publicly disclosable as soon as an abbreviated application under section 505(j) of the act for the product can be made effective, and that point in time will be identifiable through the list pubished monthly in accordance with section 505(j)(6) of the act.

For applications submitted under sections 505(j), 506, and 507 of the act, FDA has added § 314.430(f)(6) which states that safety and effectiveness data and information will be publicly disclosable when FDA sends an approval letter to the applicant. To prevent redundancy, FDA had deleted proposed § 314.430(e)(1) for the final rule.

142. Waivers (§ 314.90). One comment suggested that FDA not issue a final provision permitting it to waive requirements for the submission of information in an application. This comment feared that the waiver provision would permit applicants to market new products without having to submit adequate clinical information and other data about its safety and efficacy.

FDA believes this comment misunderstands the scope of the waiver provision, which is intended to give applicants the flexibility to seek alternative ways of complying with the regulatory requirements for drug approval. FDA is unable, and does not view the provision as authorizing it, to waive statutory requirements.

143. Other changes. On its own initiative, FDA has revised the final rule to retain current requirements, described below, that were inadvertently omitted from the proposal in the sections concerning contents of an application (§ 314.50), refusal to file an application (§ 314.101(d)), refusal to approve an application (§ 314.125), and/or withdrawal of approval of an application (§ 314.150).

First, the final rule provides that an application must contain reports of all investigations of the drug sponsored by the applicant, and all other information pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source. To correspond to this requirement, the final rule also provides that FDA may refuse to approve (or withdraw approval of) an application if it does not explain the omission of a report of any investigation of a drug sponsored by the applicant, or the omission of other information pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source. Although the proposal contained a requirement that the applicant submit all information pertinent to the evaluation of the application, it did not clearly require an applicant to submit reports of all the studies it sponsors nor did it provide for FDA to refuse to file or approve, or to withdraw approval of, an application that omits required reports or an explanation of the omission (all of which are current requirements).

Second, the final rule underscores the importance of conducting clinical investigations involving human subjects in compliance with the institutional review board regulations in Part 56 and the informed consent regulations in Part 50. In this regard, the final rule provides that the application must contain a statement for each clinical study subject to those regulations that the study was conducted in compliance with them. The agency may refuse to file an application, under the final rule, if the requisite statement is not provided. Also under the final rule, FDA may refuse to approve (or withdraw approval of) an application if the noncompliance results in the rights or safety of human subjects not being adequately protected. These requirements were added to the current regulations in the Federal Register of January 27, 1981 (46 FR 8942, 8954), but they were inadvertently omitted from the proposal. The language used in the final rule constitutes a minor change from current regulations to clarify that FDA would not refuse to approve (or withdraw approval of) an application because of minor technical deviations from these regulations not affecting the rights of safety of human subjects. For purposes of consistency, FDA is also revising § 312.1(d)(11) to conform the provision respecting termination of an IND to the language used in this final rule.

Similarly, the final rule, like the current regulations and the proposal, underscores the importance of conducting nonclinical laboratory studies in compliance with the good laboratory practice regulations in Part 58. The language in the final rule has been revised to state that for each nonclinical study not conducted in compliance with these regulations, the application must contain a brief statement of the reason for the noncompliance (rather than a detailed description of all differences between the practices used in the study and those in the regulations). The language used in the final rule reflects advice that FDA has been providing to applicants with respect to interpretation of the current regulatory provision. The section on refusing to file an application has been conformed accordingly. For purposes of consistency, FDA is also revising the following sections of Title 21 of the Code of Federal Regulations with respect to applications submitted to FDA for research or marketing permits where the submission includes the results of nonclinical laboratory studies subject to Part 58, in order to conform those sections to the language used in this final rule: § § 71.1, 71.6, 170.35, 171.1, 171.6, 180.1, 312.1, 330.10, 511.1, 514.1, 514.8, 514.15, 514.110, 570.35, 571.1, 571.6, 602.1, 812.27, 1003.31, 1010.4, and 1010.5.

Finally, also with respect to compliance with Part 58, the final rule, like the proposal, provides that FDA may refuse to approve an application if the nature of the noncompliance does not support the validity of the study. This language is intended to clarify that FDA would not refuse to approve an application because of minor technical deviations from these regulations. The final rule also contains a parallel provision in the section on withdrawal of approval, which was inadvertently omitted from the proposal. For purposes of consistency, FDA is also revising § § 312.1(d)(12), 514.111(a)(11), and 514.115(b)(4) to conform these provisions governing investigational new drug and new animal drug applications to the language used in this final rule.

List of Subjects

21 CFR Part 71

Administrative practice and procedure, Color additive certification, Color additive petitions, Color additives, Cosmetics, Drugs.

21 CFR Part 170

Administrative practice and procedure, Definitions, Food additives, Food additive safety.

21 CFR Part 171

Administrative practice and procedure, Food additive petitions, Food additives.

21 CFR Part 180

Food additives, Interim listed food additives.

21 CFR Part 201

Drugs, Labeling.

21 CFR Part 310

Administrative practice and procedure, Drugs, Medical devices, Reporting requirements.

21 CFR Part 312

Drugs, Medical research.

21 CFR Part 314

Administrative practice and procedure, Drugs.

21 CFR Part 330

Over-the-counter drugs.

21 CFR Part 430

Administrative practice and procedure, Antibiotics.

21 CFR Part 431

Administrative practice and procedure, Antibiotics.

21 CFR Part 433

Antibiotics, Labeling.

21 CFR Part 510

Administrative practice and procedure, Animal drugs, Labeling, Reporting requirements.

21 CFR Part 511

Animal drugs, Medical research.

21 CFR Part 514

Administrative practice and procedure, Animal drugs.

21 CFR Part 570

Animal feeds, Animal foods, Food additives.

21 CFR Part 571

Administrative practice and procedure, Animal feeds, Animal foods, Food additives.

21 CFR Part 601

Biologics.

21 CFR Part 812

Health records, Investigational device exemptions, Medical devices, Medical device research, Reporting requiements.

21 CFR Part 1003

Administrative practice and procedure, Defects, Electronic products, Noncompliance, Radiation protection.

21 CFR Part 1010

Administrative practice and procedure, Electronic products, Exemptions, Exports, Radiation protection, Standards, Variances.

Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 409, 501, 502, 503, 505, 506, 507, 512-516, 520, 701, 706, 52 Stat. 1049-1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463 as amended, 72 Stat. 1785-1788 as amended, 74 Stat. 399-407 as amended, 82 Stat. 343-351, 90 Stat. 540-560 (21 U.S.C. 348, 351, 352, 353, 355, 356, 357, 360b-360f, 371, 376)) and the Public Health Service Act (secs. 215, 301, 351, 354-360f, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended (42 U.S.C. 216, 241, 262, 263b-263n)) and under 21 CFR 5.11, Parts 71, 170, 171, 180, 201, 310, 312, 314, 430, 431, 433, 510, 511, 514, 570, 601, 812, 1003, and 1010 are amended as follows:

PART 71 -- COLOR ADDITIVE PETITIONS

1. Part 71 is amended:

a. In § 71.1 by revising paragraph (g), to read as follows:

§ 71.1 Petitions.

* * * * *

(g) If nonclinical laboratory studies are involved, petitions filed with the Commissioner under section 706(b) of the act shall include with respect to each nonclinical study contained in the petition, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in Part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * *

b. In § 71.6 by revising the third sentence of paragraph (b), to read as follows:

§ 71.6 Extension of time for studying petitions; substantive amendments; withdrawal of petitions without prejudice.

* * * * *

(b) * * * If nonclinical laboratory studies are involved, additional information and data submitted in support of filed petitions shall include, with respect to each nonclinical laboratory study contained in the petition, either a statement that the study was conducted in compliance with the requirements set forth in Part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * * * * *

PART 170 -- FOOD ADDITIVES

2. Part 170 is amended in § 170.35 by revising paragraph (c)(1)(vi), to read as follows:

§ 170.35 Affirmation of generally recognized as safe (GRAS) status.

* * * * *

(c) * * *

(1) * * *

(vi) If nonclinical laboratory studies are involved, additional information and data submitted in support of filed petitions shall include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in Part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * *

PART 171 -- FOOD ADDITIVE PETITIONS

3. Part 171 is amended:

a. In § 171.1 by revising paragraph (k), to read as follows:

§ 171.1 Petitions.

* * * * *

(k) If nonclinical laboratory studies are involved, petitions filed with the Commissioner under section 409(b) of the act shall include, with respect to each nonclinical study contained in the petition, either a statement that the study has been, or will be, conducted in compliance with the good laboratory practice regulations as set forth in Part 58 of this chapter, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * *

b. By revising § 171.6, to read as follows:

§ 171.6 Amendment of petition.

After a petition has been filed, the petitioner may submit additional information or data in support thereof. In such cases, if the Commissioner determines that the additional information or data amount to a substantive amendment, the petition as amended will be given a new filing date, and the time limitation will begin to run anew. Where the substantive amendment proposes a substantial change to any petition that may affect the quality of the human environment, the petitioner is required to submit an environmental analysis report pursuant to § 25.1 of this chapter. If nonclinical laboratory studies are involved, additional information and data submitted in support of filed petitions shall include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in Part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

PART 180 -- FOOD ADDITIVES PERMITTED IN FOOD ON AN INTERIM BASIS OR IN CONTACT WITH FOOD PENDING ADDITIONAL STUDY

4. Part 180 is amended in § 180.1 by revising paragraph (c)(4), to read as follows:

§ 180.1 General.

* * * * *

(c) * * *

(4) If nonclinical laboratory studies are involved, studies filed with the Commissioner shall include, with respect to each study, either a statement that the study has been or will be conducted in compliance with the good laboratory practice regulations as set forth in Part 58 of this chapter, or, if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * *

PART 201 -- LABELING

5. Part 201 is amended in § 201.122 by revising paragraph (a), to read as follows:

§ 201.122 Drugs for processing, repacking, or manufacturing.

* * * * *

(a) An approved new drug application or new animal drug application covers the production and delivery of the drug substance to the application holder by persons named in the application, and, for a new drug substance, the export of it by such persons under § 314.410 of this chapter; or

* * * * *

PART 310 -- NEW DRUGS

6. Part 310 is amended:

§ 310.3 [Amended]

a. In § 310.3 Definitions and interpretations by removing and reserving paragraph (m).

§ 310.9 [Removed]

b. By removing § 310.9 Designated journals.

§ 310.300 [Removed]

c. By removing § 310.300 Records and reports concerning experience on drugs for which an approval is in effect.

§ 310.301 [Removed]

d. By removing § 310.301 Reporting of adverse drug experiences.

§ 310.302 [Removed]

e. By removing § 310.302 Records and reports on new drugs and antibiotics for use by man for which applications or certification forms 5 and 6 became effective or were approved prior to June 20, 1963.

PART 312 -- NEW DRUGS FOR INVESTIGATIONAL USE 7.

Part 312 is amended:

a. In § 312.1 by revising item 16 in Form FD-1571 in paragraph (a)(2) and by revising paragraph (d) (11) and (12), to read as follows:

§ 312.1 Conditions for exemption of new drugs for investigational use.

(a) * * *

(2) * * *

Form FD-1571 * * *

16. A statement that all nonclinical laboratory studies have been, or will be, conducted in compliance with the good laboratory practice regulations set forth in Part 58 of this chapter, or, if such studies have not been conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

* * * * *

(d) * * *

(11) Any clinical investigation involving human subjects, subject to the institutional review board regulations in Part 56 of this chapter or informed consent regulations in Part 50 of this chapter, is not being conducted in compliance with those regulations such that the rights or safety of human subjects are not adequately protected; or

(12) Any nonclinical laboratory study that is described in the notice of claimed investigational exemption and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations as set forth in Part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study; or

* * * * *
b. In § 312.20 by revising paragraph (c), to read as follows:

§ 312.20 Clinical data generated outside the United States and not subject to a "Notice of Claimed Investigational Exemption for a New Drug."

* * * * *

(c) Data from studies performed outside the United States and conducted in accordance with the requirements of this section may be utilized without duplication of the studies in the United States, as appropriate.
* * * * *

8. By revising Part 314 to read as follows:

PART 314 -- APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN ANTIBIOTIC DRUG
Subpart A -- General Provisions

Sec.
314.1 Scope of this part.
314.2 Purpose.
314.3 Definitions.

Subpart B -- Applications

314.50 Content and format of an application.
314.55 Abbreviated application.
314.56 Drug products for which abbreviated applications are suitable.
314.60 Amendments to an unapproved application.
314.65 Withdrawal by the applicant of an unapproved application.
314.70 Supplements and other changes to an approved application.
314.71 Procedures for submission of a supplement to an approved application.
314.72 Change in ownership of an application.
314.80 Postmarketing reporting of adverse drug experiences.
314.81 Other postmarketing reports.
314.90 Waivers.

Subpart C -- FDA Action on Applications

314.100 Time frames for reviewing applications.
314.101 Filing and application.
314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an application.
314.106 Foreign data.
314.110 Approvable letter to the applicant.
314.120 Not approvable letter to the applicant.
314.125 Refusal to approve an application.
314.126 Adequate and well-controlled studies.
314.150 Withdrawal of approval of an application.
314.152 Notice of withdrawal of approval of an application for a new drug.

Sec.
314.160 Approval of an application for which approval was previously refused, suspended, or withdrawn.
314.170 Adulteration and misbranding of an approved drug.

Subpart D -- Hearing Procedures for New Drugs

314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or denial of hearing. 314.201 Procedure for hearings.
314.235 Judicial review.

Subpart E -- Administrative Procedures for Antibiotics

314.300 Procedure for the issuance, amendment, or repeal of regulations.

Subpart F -- Miscellaneous Provisions

314.410 Imports and exports of new drugs and antibiotics.
314.420 Drug master files.
314.430 Availability for public disclosure of data and information in an application.
314.440 Addresses for applications.
314.445 Guidelines.

Authority: Secs. 409, 501, 502, 503, 505, 506, 507, 512-516, 520, 701, 706, 52 Stat. 1049-1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 stat. 463 as amended, 72 Stat. 1785-1788 as amended, 74 Stat. 399-407 as amended, 82 Stat. 343-351, 90 Stat. 540-560 (21 U.S.C. 351, 352, 353, 355, 356, 357, 360b-360f, 371, 376); sec. 215, 301, 351, 354-360F, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended (42 U.S.C. 216, 241, 262, 263b-263n).

Subpart A -- General Provisions
§ 314.1 Scope of this part.

(a) This part sets forth procedures and requirements for the submission to, and the review by, the Food and Drug Administration fo applications and abbreviated applications, as well as amendments, supplements, and postmarketing reports to them, by persons seeking or holding approval from FDA of the following:

(1) An application under section 505 of the Federal Food, Drug, and Cosmetic Act to market a new drug.

(2) An application under section 507 of the Federal Food, Drug, and Cosmetic Act to market an antibiotic drug.

(b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and Subchapter F of Chapter I of Title 21 of the Code of Federal Regulations.

(c) References in this part to regulations in the Code of Federal Regulations are to Chapter I of Title 21, unless otherwise noted.

§ 314.2 Purpose.

The purpose of this part is to establish an efficient and thorough drug review process in order to: (a) Facilitate the approval of drugs shown to be safe and effective; and (b) ensure the disapproval of drugs not shown to be safe and effective. These regulations are also intended to establish and effective system for FDA's surveillance of marketed drugs. These regulations shall be construed in light of these objectives.

§ 314.3 Definitions.

(a) The definitions and interpretations contained in section 201 of the act apply to those terms when used in this part.

(b) The following definitions of terms apply to this part:

"Act" means the Federal Food, Drug, and Cosmetic Act (sections 201-901, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

"Applicant" means any person who submits an application or abbreviated application or an amendment or supplement to them under this part to obtain Food and Drug Administration approval of a new drug or an antibiotic drug and any person who owns an approved application.

"Application" means both the application described under § 314.50 and the abbreviated application under § 314.55, including all amendments and supplements.

"Approvable letter" means a written communication to an applicant from FDA stating that the agency will approve the application if specific additional information or material is submitted or specific conditions are met. An approvable letter does not constitute approval of any part of an application and does not permit marketing of the drug that is the subject of the application.

"Approval letter" means a written communication to an applicant from FDA approving an application. An approval letter permits marketing of the drug product that is the subject of the application.

"Drug product" means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

"Drug substance" means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure of any function of the human body, but does not include intermediates used in the synthesis of such ingredient.

"FDA" means the Food and Drug Administration.

"Not approvable letter" means a written communication to an applicant from FDA stating that the agency does not consider the application approvable because one or more deficiencies in the application preclude the agency from approving it.

Subpart B -- Applications
§ 314.50 Content and format of an application.

Applications, including abbreviated applications, and supplements to approved applications are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Two copies of the application are required, an archival copy and a review copy. An application for a new chemical entity will generally contain an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labeling. Other applications will generally contain only some of those items, and information will be limited to that needed to support the particular submission. These include an application for a duplicate of a marketed drug product (such as a "paper NDA," which relies primarily on published literature to provide substantial evidence of effectiveness and adequate scientific evidence of safety for the claimed indications), an abbreviated application, an amendment, and a supplement. The application is required to contain reports of all investigations of the drug product sponsored by the applicant, and all other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source. The Food and Drug Administration will maintain guidelines on the format and content of applications to assist applicants in their preparation.

(a) Application form. The applicant shall submit a completed and signed application form that contains the following:

(1) The name and address of the applicant; the date of the application; the application number if previously issued (for example, if the application is a resubmission, an amendment, or a supplement); the name of the drug product, including its established, proprietary, code, and chemical names; the dosage form and strength; the route of administration; the identification numbers of all investigational new drug applications that are referenced in the application; the identification numbers of all drug master files and other applications under this part that are referenced in the application; and the drug product's proposed indications for use.

(2) A statement whether the submission is an original submission, a resubmission, an abbreviated application under § 314.55, or a supplement to an application under § 314.70.

(3) A statement whether the applicant proposes to market the drug product as a prescription or an over-the-counter product.

(4) A check-list identifying what enclosures required under this section the applicant is submitting.

(5) The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. If the person signing the application does not reside or have a place of business within the United States, the application is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.

(b) Index. The archival copy of the application is required to contain a comprehensive index by volume number and page number to the summary under paragraph (c) of this section, the technical sections under paragraph (d) of this section, and the supporting information under paragraph (f) of this section.

(c) Summary. (1) An application is required to contain a summary of the application in enough detail that the reader may gain a good general understanding of the data and information in the application, including an understanding of the quantitative aspects of the data. The summary is not required for abbreviated applications under § 314.55 and supplements under § 314.70. Resubmissions of an application should contain an updated summary, as appropriate. The summary should discuss all aspects of the application, and synthesize the information into a well-structured and unified document. The summary should be written at approximately the level of detail required for publication in, and meet the editorial standards generally applied by, refereed scientific and medical journals. In addition to the agency personnel reviewing the summary in the context of their review of the application, FDA may furnish the summary to FDA advisory committee members and agency officials whose duties require an understanding of the application. To the extent possible, data in the summary should be presented in tabular and graphic forms. FDA has prepared a guideline under § 10.90(b) that provides information about how to prepare a summary. The summary required under this paragraph may be used by FDA or the applicant to prepare the Summary Basis of Approval document for public disclosure (under § 314.430(e)(2)(ii)) when the application is approved.

(2) The summary is required to contain the following information:

(i) The proposed text of the labeling for the drug, with annotations to the information in the summary and technical sections of the application that support the inclusion of each statement in the labeling, and, if the application is for a prescription drug, statements describing the reasons for omitting a section or subsection of the labeling format in § 201.57.

(ii) A statement identifying the pharmacologic class of the drug and a discussion of the scientific rationale for the drug, its intended use, and the potential clinical benefits of the drug product.

(iii) A brief description of the marketing history, if any, of the drug outside the United States, including a list of the countries in which the drug has been marketed, a list of any countries in which the drug has been withdrawn from marketing for any reason related to safety or effectiveness, and a list of countries in which applications for marketing are pending. The description is required to describe both marketing by the applicant and, if known, the marketing history of other persons.

(iv) A summary of the chemistry, manufacturing, and controls section of the application.

(v) A summary of the nonclinical pharmacology and toxicology section of the application.

(vi) A summary of the human pharmacokinetics and bioavailability section of the application.

(vii) A summary of the microbiology section of the application (for anti-infective drugs only).

(viii) A summary of the clinical data section of the application, including the results of statistical analyses of the clinical trials.

(ix) A concluding discussion that presents the benefit and risk considerations related to the drug, including a discussion of any proposed additional studies or surveillance the applicant intends to conduct postmarketing.

(d) Technical sections. The application is required to contain the technical sections described below. Each technical section is required to contain data and information in sufficient detail to permit the agency to make a knowledgeable judgment about whether to approve the application or whether grounds exist under section 505(d) or 507 of the act to refuse to approve the application. The required technical sections are as follows:

(1) Chemistry, manufacturing, and controls section. A section describing the composition, manufacture, and specification of the drug substance and the drug product, including the following:

(i) Drug substance. A full description of the drug substance including its physical and chemical characteristics and stability; the name and address of its manufacturer; the method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and such specifications and analytical methods as are necessary to assure the identity, strength, quality, and purity of the drug substance and the bioavailability of the drug products made from the substance, including, for example, specifications relating to stability, sterility, particle size, and crystalline form. The application may provide additionally for the use of alternatives to meet any of these requirements, including alternative sources, process controls, methods, and specifications. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may satisfy relevant requirements in this paragraph.

(ii) Drug product. A list of all components used in the manufacture of the drug product (regardless of whether they appear in the drug product); and a statement of the composition of the drug product; a statement of the specifications and analytical methods for each component; the name and address of each manufacturer the drug product; a description of the manufacturing and packaging procedures and in-process controls for the drug product; such specifications and analytical methods as are necessary to assure the identity, strength, quality, purity, and bioavailability of the drug product, including, for example, specifications relating to sterility, dissolution rate, containers and closure systems; and stability data with proposed expiration dating. The application may provide additionally for the use of alternatives to meet any of these requirements, including alternative components, manufacturing and packaging procedures, in-process controls, methods, and specifications. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may satisfy relevant requirements in this paragraph.

(iii) Environmental impact analysis report. An environmental impact analysis report under § 25.1 analyzing the environmental impact of the manufacturing process and the ultimate use of the drug product.

(iv) The applicant may, at its option, submit a complete chemistry, manufacturing, and controls section 90 to 120 days before the anticipated submission of the remainder of the application. FDA will review such early submissions as resources permit.

(2) Nonclinical pharmacology and toxicology section. A section describing, with the aid of graphs and tables, the nonclinical laboratory studies with the drug, including the following:

(i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic indication and studies otherwise define the pharmacologic properties of the drug or are pertinent to possible adverse effects.

(ii) Studies of the toxicological effects of the drug as they relate to the drug's intended clinical uses, including, as appropriate, studies assessing the drug's acute, subacute, and chronic toxicity; carcinogenicity; and studies of toxicities related to the drug's particular mode of administration or conditions of use.

(iii) Studies, as appropriate, of the effects of the drug on reproduction and on the developing fetus.

(iv) Any studies of the absorption, distribution, metabolism, and excretion of the drug in animals.

(v) For each nonclinical laboratory study a statement that it was conducted in compliance with the good laboratory practice regulations in Part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.

(3) Human pharmacokinetics and bioavailability section. A section describing the human pharmacokinetic data and human bioavailability data, or information supporting a waiver of the submission of in vivo bioavailability data under Subpart B of Part 320, including the following:

(i) A description of each of the bioavailability and pharmacokinetic studies of the drug in humans performed by or on behalf of the applicant that includes a description of the analytical and statistical methods used in each study and a statement with respect to each study that it either was conducted in compliance with the institutional review board regulations in Part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in Part 50.

(ii) If the application describes in the chemistry, manufacturing, and controls section specifications or analytical methods needed to assure the bioavailability of the drug product or drug substance, or both, a statement in this section of the rationale for establishing the specification or analytical methods, including data and information supporting the rationale.

(iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of the active ingredients and the bioavailability or bioequivalence, or both, of the drug product.

(4) Microbiology section. If the drug is an anti-infective drug, a section describing the microbiology data, including the following:

(i) A description of the biochemical basis of the drug's action on microbial physiology.

(ii) A description of the antimicrobial spectra of the drug, including results of in vitro preclinical studies to demonstrate concentrations of the drug required for effective use.

(iii) A description of any known mechanisms of resistance to the drug, including results of any known epidemiologic studies to demonstrate prevalence of resistance factors.

(iv) A description of clinical microbiology laboratory methods (for example, in vitro sensitivity discs) needed for effective use of the drug.

(5) Clinical data section. A section describing the clinical investigations of the drug, including the following:

(i) A description and analysis of each clinical pharmacology study of the drug, including a brief comparison of the results of the human studies with the animal pharmacology and toxicology data.

(ii) A description and analysis of each controlled clinical study pertinent to a proposed use of the drug, including the protocol and a description of the statistical analyses used to evaluate the study. If the study report is an interim analysis, this is to be noted and a projected completion date provided. Controlled clinical studies that have not been analyzed in detail for any reason (e.g., because they have been discontinued or are incomplete) are to be included in this section, including a copy of the protocol and a brief description of the results and status of the study.

(iii) A description of each uncontrolled clinical study, a summary of the results, and a brief statement explaining why the study is classified as uncontrolled.

(iv) A description and analysis of any other data or information relevant to an evaluation of the safety and effectiveness of the drug product obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from clinical investigations, including controlled and uncontrolled studies of uses of the drug other than those proposed in the application, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers.

(v) An integrated summary of the data demonstrating substantial evidence of effectiveness for the claimed indications. Evidence is also required to support the dosage and administration section of the labeling, including support for the dosage and dose interval recommended, and modifications for specific subgroups (for example, pediatrics, geriatrics, patients with renal failure).

(vi) A summary and updates of safety information, as follows:

(a) The applicant shall submit an integrated summary of all available information about the safety of the drug product, including pertinent animal data, demonstrated or potential adverse effects of the drug, clinically significant drug/drug interactions, and other safety considerations, such as data from epidemiological studies of related drugs. A description of any statistical analyses performed in analyzing safety data should also be included, unless already included under paragraph (a)(5)(ii) of this section.

(b) The applicant shall, under section 505(i) of the act, update periodically its pending application with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling. These "safety update reports" are required to include the same kinds of information (from clinical studies, animal studies, and other sources) and are required to be submitted in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition, the reports are required to include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived). The applicant shall submit these reports (1) 4 months after the initial submission; (2) following receipt of an approvable letter; and (3) at other times as requested by FDA. Prior to the submission of the first such report, applicants are encouraged to consult with FDA regarding further details on its form and content.

(vii) If the drug has a potential for abuse, a description and analysis of studies or information related to abuse of the drug, including a proposal for scheduling under the Controlled Substances Act. A description of any studies related to overdosage is also required, including information on dialysis, antidotes, or other treatments, if known.

(viii) An integrated summary of the benefits and risks of the drug, including a discussion of why the benefits exceed the risks under the conditions stated in the labeling.

(ix) A statement with respect to each clinical study involving human subjects that it either was conducted in compliance with the institutional review board regulations in Part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in Part 50.

(6) Statistical section. A section describing the statistical evaluation of clinical data, including the following:

(i) A copy of the information submitted under paragraph (d)(5)(ii) of this section concerning the description and analyses of each controlled clinical study, and the documentation and supporting statistical analysis used in evaluating the controlled clinical studies.

(ii) A copy of the information submitted under paragraph (d)(5)(vi)(a) of this section concerning a summary of information about the safety of the drug product, and the documentation and supporting statistical analyses used in evaluating the safety information.

(e) Samples and labeling. (1) Upon request from FDA, the applicant shall submit the samples described below to the places identified in the agency's request. FDA will generally ask applicants to submit samples directly to two or more agency laboratories that will perform all necessary tests on the samples and validate the applicant's analytical methods.

(i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to perform three times each test described in the application to determine whether the drug substance and the drug product meet the specifications given in the application:

(a) The drug product proposed for marketing;

(b) The drug substance used in the drug product from which the samples of the drug product were taken; and

(c) Reference standards and blanks (except that reference standards recognized in an official compendium need not be submitted).

(ii) Samples of the finished market package, if requested by FDA.

(2) The applicant shall submit the following in the archival copy of the application:

(i) Three copies of the analytical methods and related descriptive information contained in the chemistry, manufacturing, and controls section under paragraph (d)(1) of this section for the drug substance and the drug product that are necessary for FDA's laboratories to perform all necessary tests on the samples and to validate the applicant's analytical methods. The related descriptive information includes a description of each sample; the proposed regulatory specifications for the drug; a detailed description of the methods of analysis; supporting data for accuracy, specificity, precision and ruggedness; and complete results of the applicant's tests on each sample.

(ii) Copies of the label and all labeling for the drug product (4 copies of draft labeling or 12 copies of final printed labeling).

(f) Case report forms and tabulations. The archival copy of the application is required to contain the following case report tabulations and case report forms:

(1) Case report tabulations. The application is required to contain tabulations of the data from each adequate and well-controlled study under § 314.126 (Phase 2 and Phase 3 studies as described in § 312.1(a)(2), Form FDA-1571), tabulations of the data from the earliest clinical pharmacology studies (Phase 1 studies as described in § 312.1(a)(2), Form FDA-1517), and tabulations of the safety data from other clinical studies. Routine submission of other patient data from uncontrolled studies is not required. The tabulations are required to include the data on each patient in each study, except that the applicant may delete those tabulations which the agency agrees, in advance, are not pertinent to a review of the drug's safety or effectiveness. Upon request, FDA will discuss with the applicant in a "pre-NDA" conference those tabulations that may be appropriate for such deletion. Barring unforeseen circumstances, tabulations agreed to be deleted at such a conference will not be requested during the conduct of FDA's review of the application. If such unforeseen circumstances do occur, any request for deleted tabulations will be made by the director of the FDA division responsible for reviewing the application, in accordance with paragraph (f)(3) of this section.

(2) Case report forms. The application is required to contain copies of individual case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event, whether believed to be drug related or not, including patients receiving reference drugs or placebo. This requirement may be waived by FDA for specific studies if the case report forms are unnecessary for a proper review of the study.

(3) Additional data. The applicant shall submit to FDA additional case report forms and tabulations needed to conduct a proper review of the application, as requested by the director of the FDA division responsible for reviewing the application. The applicant's failure to submit information requested by FDA within 30 days after receipt of the request may result in the agency viewing any eventual submission as a major amendment under § 314.60 and extending the review period as necessary. If desired by the applicant, the FDA division director will verify in writing any request for additional data that was made orally.

(4) Applicants are invited to meet with FDA before submitting an application to discuss the presentation and format of supporting information. If the applicant and FDA agree, the applicant may submit tabulations of patient data and case report forms in a form other than hard copy, for example, on microfiche or computer tapes.

(g) Other. The following general requirements apply to the submission of information within the summary under paragraph (c) of this section and within the technical sections under paragraph (d) of this section.

(1) The applicant ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously is required to identify the file by name, reference number, volume, and page number in the agency's records where the information can be found. A reference to information submitted to the agency by a person other than the applicant is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.

(2) The applicant shall submit an accurate and complete English translation of each part of the application that is not in English. The applicant shall submit a copy of each original literature publication for which an English translation is submitted.

(h) Format of an original application. (1) The applicant shall submit a complete archival copy of the application that contains the information required under paragraphs (a) through (f) of this section. FDA will maintain the archival copy during the review of the application to permit individual reviewers to refer to information that is not contained in their particular technical sections of the application, to give other agency personnel access to the application for official business, and to maintain in one place a complete copy of the application. An applicant may submit on microfiche the portions of the archival copy of the application described in paragraphs (b) through (d) of this section. Information relating to samples and labeling, described in paragraph (e) of this section, is required to be submitted in hard copy. Tabulations of patient data and case report forms, described in paragraph (f) of this section, may be submitted on microfiche only if the applicant and FDA agree. If FDA agrees, the applicant may use another suitable microform system.

(2) The applicant shall submit a review copy of the application. Each of the technical sections (described in paragraph (d) (1) through (6) of this section) in the review copy is required to be separately bound with a copy of the application form required under paragraph (a) of this section and a copy of the summary required under paragraph (c) of this section. The applicant may obtain from FDA sufficient folders to bind the archival and review copies of the application.

§ 314.55 Abbreviated application.

(a) An abbreviated application is an application in which reports of nonclinical laboratory studies and reports of clinical investigations (except those pertaining to in vivo bioavailability of the drug product) may be omitted. The information may be omitted when the Food and Drug Administration has determined that the information already available to it is adequate to establish that a particular dosage form of a drug meets the statutory standards for safety and effectiveness. An abbreviated application will usually be reserved for duplicates of drug products previously approved under a full application under § 314.50. An abbreviated application is not required to comply with the requirements in § 314.50 (c), (d)(2), (4), (5), (6), and (f).

(b) FDA will file an abbreviated application only if it has made a finding that an abbreviated application is suitable for a drug product. If FDA finds that a drug product may be approved for marketing on the basis of an abbreviated application, it will make that finding publicly available, as follows:

(1) If the finding applies to a broad category of drug products, the agency will amend § 314.56 to identify the category in that section.

(2) If the finding applies to a drug product because it is so closely related to a product for which an abbreviated application is suitable that the same conclusions about safety and effectiveness apply to it, the agency will make the finding public by updating its list of drug products for which abbreviated applications are suitable. The list is available from the National Technical Information Service, Department of Commerce, 5285 Port Royal Rd., Springfield, VA 22161.

(3) If the finding applies to duplicates of a drug product that is subject to FDA's Drug Efficacy Study Implementation program (a review of drug products approved as safe between 1938 and 1962), the agency will make that finding public through a notice published in the Federal Register.

(c)(1) A finding by FDA that an abbreviated application is suitable for a drug product applies only to a product that is the same in active ingredient, dosage form and strength, route of administration, and conditions of use as the drug product that was the subject of the finding. For drug product that is similar but different in one or more of these characteristics, an abbreviated application will be accepted only if FDA has made a separate finding of suitability. However, filing of an abbreviated application for a drug product does not signify that the product is safe and effective until the application is approved.

(2) A finding that a drug product is a new drug because it is similar to a product that is a new drug, and is therefore subject to the requirements of this part, does not include a finding that an abbreviated application is suitable for the similar product.

(3) A finding that a single-active-entity drug product is safe and effective and that an abbreviated application is suitable is not a basis for determining that a combination drug product containing that entity as one of its ingredients is either safe or effective or that an abbreviated application is suitable. The finding also is not a basis for determining that the combination drug product meets all of the requirements for combination drugs as described in § 300.50.

(d) (1) A person may seek a determination of the suitability of an abbreviated application for a product that the person believes is similar or related to a drug product that has been declared to be suitable for an abbreviated application. Extension of the finding that a drug product is safe and effective to another product will ordinarily be limited to other dosage forms for the same route of administration or to closely related ingredients. If preclinical or clinical evidence is needed to support the safety, or if clinical evidence is needed to support the effectiveness, of the proposed product, then an abbreviated application is not appropriate for the similar or related drug product.

(2) A person seeking a determination that an abbreviated application is suitable for a similar or related drug product shall use the petition procedures established in § 10.30. The petitioner shall set forth the reasons that justify extending the finding that an abbreviated application is suitable for one product to the similar or related product proposed to be marketed.

(3) An application submitted in the form of an abbreviated application for a drug product that has not been the subject of a finding that allows an abbreviated application for the product will be considered to be a petition under § 10.30 and will be processed as such.

(e) Each abbreviated application is required to contain a reference to FDA's finding that an abbreviated application is suitable for the specific product that is the subject of the application and to contain both an archival and a review copy of the application.

(1) The applicant shall submit a complete archival copy of the application that contains the information required under § 314.50 (a), (b), (d)(1) and (3), (e), and (g). An applicant may submit the archival copy of the application on microfiche or, if FDA agrees, another suitable microform system.

(2) The applicant shall submit a review copy that contains the technical sections described in § 314.50(d)(1) and (3). Each of the technical sections in the review copy is required to be separately bound with a copy of the application form required under § 314.50(a).

(3) The applicant may obtain from FDA sufficient folders to bind the archival and the review copies of the application.

§ 314.56 Drug products for which abbreviated applications are suitable.

Abbreviated applications are suitable for the following drugs within the limits set forth in § 314.55(c):

(a) Duplicates of drug products that were first approved before October 10, 1962, and reformulations of these products, if the original or reformulated product has been evaluated as part of the drug efficacy study and announced by notice in the Federal Register as effective for one or more indications, and if the Food and Drug Administration has made a finding that an abbreviated application is suitable.

(b) [Reserved]

(c) Drug products that are very closely related to a product described in paragraph (a) of this section and that are subject to a separate finding of suitability for marketing under an abbreviated application.

(d) Drug products that contain a chlorofluorocarbon determined to be an essential use and identified in § 2.125(h)(2) as suitable for an abbreviated application.

(e) Duplicates of an antibiotic drug for which FDA has approved an application.

§ 314.60 Amendments to an unapproved application.

The applicant may submit an amendment to an application that is filed under § 314.100, but not yet approved. The submission of a major amendment (for example, an amendment that contains significant new data from a previously unreported study or detailed new analyses of previously submitted data), whether on the applicant's own initiative or at the invitation of the agency, constitutes an agreement by the applicant under section 505(c) of the act to extend the date by which the agency is required to reach a decision on the application. Ordinarily, the agency will extend the review period for a major amendment but only for the time necessary to review the new information. However, the agency may not extend the review period more than 180 days. If the agency extends the review period for the application, the director of the division responsible for reviewing the application will notify the applicant of the length of the extension. The submission of an amendment that is not a major amendment will not extend the review period.

§ 314.65 Withdrawal by the applicant of an unapproved application.

An applicant may at any time withdraw an application that is not yet approved by notifying the Food and Drug Administration in writing. The agency will consider an applicant's failure to respond within 10 days to an approvable letter under § 314.110 or a not approvable letter under § 314.120 to be a request by the applicant to withdraw the application. A decision to withdraw the application is without prejudice to refiling. The agency will retain the application and will provide a copy to the applicant on request under the fee schedule in § 20.42 of FDA's public information regulations.

§ 314.70 Supplements and other changes to an approved application.

(a) Changes to an approved application. The applicant shall notify the Food and Drug Administration about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant shall notify FDA about it in a supplemental application under paragraph (b) or (c) of this section or by inclusion of the information in the annual report to the application under paragraph (d) of this section. Notwithstanding the requirements of paragraphs (b) and (c) of this section, an applicant shall make a change provided for in those paragraphs (for example, the deletion of an ingredient common to many drug products) in accordance with a guideline, notice, or regulation published in the Federal Register that provides for a less burdensome notification of the change (for example, by notification at the time a supplement is submitted or in the next annual report).

(b) Supplements requiring FDA approval before the change is made. An applicant shall submit a supplement, and obtain FDA approval of it, before making the changes listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. An applicant may ask FDA to expedite its review of a supplement if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked: "Supplement -- Expedited Review Requested."

(1) Drug substance. A change affecting the drug substance to accomplish any of the following:

(i) To relax the limits for a specification;

(ii) To establish a new regulatory analytical method;

(iii) To delete a specification or regulatory analytical method;

(iv) To change the synthesis of the drug substance, including a change in solvents and a change in the route of synthesis.

(v) To use a different facility or establishment to manufacture the drug substance, where: (a) the manufacturing process in the new facility or established differs materially from that in the former facility or establishment, or (b) the new facility or establishment has not received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(2) Drug product. A change affecting the drug product to accomplish any of the following:

(i) To add or delete an ingredient, or otherwise to change the composition of the drug product, other than deletion of an ingredient intended only to affect the color of the drug product;

(ii) To relax the limits for a specification;

(iii) To establish a new regulatory analytical method;

(iv) To delete a specification or regulatory analytical method;

(v) To change the method of manufacture of the drug product, including changing or relaxing an in-process control;

(vi) To use a different facility or establishment, including a different contract laboratory or labeler, to manufacture, process, or pack the drug product;

(vii) To change the container and closure system for the drug product (for example, glass to high density polyethylene (HDPE), or HDPE to polyvinyl chloride) or change a specification or regulatory analytical method for the container and closure system;

(viii) To change the size of the container, except for solid dosage forms, without a change in the container and closure system.

(ix) To extend the expiration date of the drug product based on data obtained under a new or revised stability testing protocol that has not been approved in the application.

(x) To establish a new procedure for reprocessing a batch of the drug product that fails to meet specifications.

(3) Labeling. Any change in labeling, except one described in paragraph (c)(2) or (d) of this section.

(c) Supplements for changes that may be made before FDA approval. An applicant shall submit a supplement at the time the applicant makes any kind of change listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. A supplement under this paragraph is required to give a full explanation of the basis for the change, identify the date on which the change is made, and, if the change concerns labeling, include 12 copies of final printed labeling. The applicant shall promptly revise all promotional labeling and drug advertising to make it consistent with any change in the labeling. The supplement and its mailing cover should be plainly marked: "Special Supplement -- Changes Being Effected."

(1) Adds a new specification or test method or changes in the methods, facilities (except a change to a new facility), or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess;

(2) Changes labeling to accomplish any of the following:

(i) To add or strengthen a contraindication, warning, precaution, or adverse reaction;

(ii) To add or strengthen a statement about drug abuse, dependence, or overdosage; or

(iii) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the product. (iv) To delete false, misleading, or unsupported indications for use or claims for effectiveness.

(3) To use a different facility or establishment to manufacture the drug substance, where: (i) The manufacturing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and (ii) the new facility or establishment has received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(d) Changes described in the annual report. An applicant shall not submit a supplement to make any change in the conditions in an approved application, unless otherwise required under paragraph (b) or (c) of this section, but shall describe the change in the next annual report required under § 314.81. Some examples of changes that can be described in the annual report are the following:

(1) Any change made to comply with an official compendium.

(2) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form.

(3) An editorial or similar minor change in labeling.

(4) The deletion of an ingredient intended only to affect the color of the drug product.

(5) An extension of the expiration date based upon full shelf-life data obtained from a protocol approved in the application.

6) A change within the container and closure system for the drug product (for example, a change from one high density polyethylene (HDPE) to another HDPE), except a change in container size for nonsolid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium.

(7) The addition or deletion of an alternate analytical method.

(8) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another.

§ 314.71 Procedures for submission of a supplement to an approved application.

(a) Only the applicant may submit a supplement to an application.

(b) All procedures and actions that apply to an application under § 314.50 and an abbreviated application under § 314.55 also apply to supplements, except that the information required in the supplement is limited to that needed to support the change. A supplement is required to contain an archival copy and a review copy that include an application form and appropriate technical sections, samples, and labeling.

(c) All procedures and actions that apply to applications under this part, including actions by applicants and the Food and Drug Administration, also apply to supplements.

§ 314.72 Change in ownership of an application.

(a) An applicant may transfer ownership of its application. At the time of transfer the new and former owners are required to submit information to the Food and Drug Administration as follows:

(1) The former owner shall submit a letter or other document that states that all rights to the application have been transferred to the new owner.

(2) The new owner shall submit an application form signed by the new owner and a letter or other document containing the following:

(i) The new owner's commitment to agreements, promises, and conditions made by the former owner and contained in the application;

(ii) The date that the change is ownership is effective; and

(iii) Either a statement that the new owner has a complete copy of the approved application, including supplements and records that are required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.42 of FDA's public information regulations.

(b) The new owner shall advise FDA about any change in the conditions in the approved application under § 314.70, except the new owner may advise FDA in the next annual report about a change in the drug product's label or labeling to change the product's brand or the name of its manufacturer, packer, or distributor.

§ 314.80 Postmarketing reporting of adverse drug experiences.

(a) Definitions. The following definitions of terms apply to this section:

"Adverse drug experience" means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: an adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose, whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any significant failure of expected pharmacological action.

"Increased frequency" means an absolute increase in the number of reports of an adverse drug experience received during a specified time period compared to the number of similar adverse drug experience reports received during an equivalent time period in the past.

"Serious" means an adverse drug experience that is life threatening, is permanently disabling, requires inpatient hospitalization, or requires prescription drug therapy. In addition, an adverse drug experience with one of the following outcomes is always considered serious: death, congenital anomaly, cancer, or overdose.

"Unexpected" means an adverse drug experience that is not listed in the current labeling for the drug and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents.

(b) Review of adverse drug experiences. Each applicant having an approved application under § 314.50 or § 314.55 shall promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers.

(c) Reporting requirements. The applicant shall report to FDA adverse drug experience information, as described in this section. The applicant shall submit two copies of each report described in this section to the Division of Drug and Biological Product Experience (HFN-70), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. FDA may waive the requirement for the second copy in appropriate instances.

(1) Fifteen-day "Alert reports." (i) The applicant shall report each adverse drug experience that is both serious and unexpected, regardless of source, as soon as possible but in any case within 15 working days of initial receipt of the information. These reports are required to be submitted on Form FDA-1639 (Drug Experience Report). The applicant shall promptly investigate all adverse drug experiences that are the subject of these 15-day Alert reports and shall submit followup reports within 15 working days of receipt of new information or as requested by FDA. If additional information is not obtainable, a followup report may be required that describes briefly the steps taken to seek additional information and the reasons why it could not be obtained. These 15-day Alert reports and followups to them are required to be submitted under separate cover and may not be included, except for summary or tabular purposes, in a periodic report.

(ii) The applicant shall review periodically (at least as often as the periodic reporting cycle) the frequency of reports of adverse drug experiences that are both serious and expected, regardless of source, and report any significant increase in frequency as soon as possible but in any case within 15 working days of determining that a significant increase in frequency exists. Upon written notice, FDA may require that applicants review the frequency of reports of serious, expected adverse drug experiences at intervals different than the periodic reporting cycle. Reports of a significant increase in frequency are required to be submitted in narrative form (including the time period on which the increased frequency is based, the method of analysis, and the interpretation of the results), rather than using Form FDA-1639. Fifteen-day Alert reports based on increased frequency are required to be submitted under separate cover and may not be included, except for summary purposes, in a periodic report.

(iii) The requirements of paragraph (c)(1) (i) and (ii) of this section, concerning the submission of 15-day alert reports, shall also apply to any person (other than the applicant) whose name appears on the label of an approved drug product as a manufacturer, packer, or distributor. However, in order to avoid unnecessary duplication in the submission to FDA, and followup to, reports required by paragraph (c)(1) (i) and (ii) of this section, obligations of a nonapplicant may be met by submission of all reports of serious adverse drug experiences to the applicant. If a nonapplicant elects to submit adverse drug experience reports to the applicant rather than to FDA, it shall submit each report to the applicant within 3 working days of its receipt by the nonapplicant, and the applicant shall then comply with the requirements of this section. Under this circumstance, the nonapplicant shall maintain a record of this action which shall include:

(a) A copy of the drug experience report.

(b) Date the report was received by the nonapplicant.

c) Date the report was submitted to the applicant.

(d) Name and address of the applicant.

(iv) Each report submitted under this paragraph shall bear prominent identification as to its contents, i.e., "15-day Alert report" or "15-day Alert report -- followup."

(2) Periodic adverse drug experience reports. (i) The applicant shall report each adverse drug experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years from the date of approval of the application, and then at annual intervals. The applicant shall submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of approval of the application) and each annual report within 60 days of the anniversary date of approval of the application. Upon written notice, FDA may extend or reestablish the requirement that an applicant submit quarterly reports, or require that the applicant submit reports under this section at different times than those stated. For example, the agency may reestablish a quarterly reporting requirement following the approval of a major supplement. Followup information to adverse drug experiences submitted in a periodic report may be submitted in the next periodic report.

(ii) Each periodic report is required to contain: (a) a narrative summary and analysis of the information in the report and an analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the applicant's patient identification number, adverse reaction term(s), and date of submission to FDA); (b) a Form FDA-1639 (Drug Experience Report) for each adverse drug experience not reported under paragraph (c)(1)(i) of this section (with an index consisting of a line listing of the applicant's patient identification number and adverse reaction term(s); and (c) a history of actions taken since the last report because of adverse drug experiences (for example, labeling changes or studies initiated).

(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse drug experience information obtained from postmarketing clinical trials (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.

(d) Scientific literature. (1) A 15-day Alert report based on information from the scientific literature is required to be accompanied by a copy of the published article. The 15-day reporting requirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse drug experiences) apply only to reports found in scientific and medical journals either as case reports or as the result of a formal clinical trial. The 15-day reporting requirements in paragraph (c)(1)(ii) of this section (i.e., a significant increase in frequency of a serious, expected adverse drug experience) apply only to reports found in scientific and medical journals either as the result of a formal clinical trial, or from epidemiologic studies or analyses of experience in a monitored series of patients.

(2) As with all reports submitted under paragraph (c)(1)(i) of this section, reports based on the scientific literature shall be submitted on Form FDA-1639 or comparable format as prescribed by paragraph (f) of this section. In cases where the applicant believes that preparing the Form FDA-1639 constitutes an undue hardship, the applicant may arrange with the Division of Drug and Biological Product Experience for an acceptable alternative reporting format.

(e) Postmarketing epidemiological/surveillance studies. Adverse drug experiences from postmarketing epidemiological/surveillance studies, except for 15-day Alert reports, may be submitted following the completion of the study in the next periodic report. (A study is considered completed 1 year after it is concluded.) The applicant shall separate and clearly mark reports of adverse drug experiences that occur during such a postmarketing study as being distinct from those experiences that are being reported spontaneously to the applicant. Applicants are encouraged to submit such reports utilizing an alternative format to Form FDA-1639, as provided in paragraph (f)(3) of this section.

(f) Reporting Form FDA-1639. (1) Except as provided in paragraphs (c)(1)(ii) and (f)(3) of this section, the applicant shall complete a Form FDA-1639 (Drug Experience Report) for each report of an adverse drug experience.

(2) Each completed Form FDA-1639 should refer only to an individual patient or a single attached publication.

(3) Instead of using Form FDA-1639, an applicant may use a computer-generated FDA-1639 or other alternative format (e.g., a computer-generated tape or tabular listing) provided that: (i) The content of the alternative format is equivalent in all elements of information to those specified in Form FDA-1639; and (ii) the format is agreed to in advance by the Division of Drug and Biological Experience (HFN-730).

(4) Single copies of Form FDA-1639 may be obtained from the Division of Drug and Biological Product Experience (HFN-730), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857.

(g) Multiple reports. An applicant should not include in reports under this section any adverse drug experiences that occurred in clinical trials if they were previously submitted as part of the approved application. If a report applies to a drug for which an applicant holds more than one approved application, the applicant should submit the report to the application that was first approved. If a report refers to more than one drug marketed by an applicant, the applicant should submit the report to the application for the drug listed first in the report.

(h) Patient privacy. An applicant should not include in reports under this section the names and addresses of individual patients; instead, the applicant should assign a unique code number to each report, preferably not more than eight characters in length. The applicant should include the name of the reporter from whom the information was received. Names of patients, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not resaleable to the public under FDA's public information regulations in Part 20.

(i) Recordkeeping. The applicant shall maintain for a period of 10 years records of all adverse drug experiences known to the applicant, including raw data and any correspondence relating to adverse drug experiences.

(j) Guideline. FDA has prepared under § 10.90(b) a guideline for the submission of reports of adverse drug experiences and suggested followup investigation of reports.

(k) Withdrawal of approval. If an applicant fails to establish and maintain records and make reports required under this section, FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.

(l) Disclaimer. A report or information submitted by an applicant under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. An applicant need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect. For purposes of this provision, the term "applicant" also includes any person reporting under paragraph (c)(1)(iii) of this section.

§ 314.81 Other postmarketing reports.

(a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and sections 505(j) and 507(g) of the act.

(b) Reporting requirements. The applicant shall submit to the Food and Drug Administration at the specified times two copies of the following reports:

(1) NDA -- Field alert report. The applicant shall submit information of the following kinds about distributed drug products and articles to the FDA district office that is responsible for the facility involved within 3 working days of receipt by the applicant. The information may be provided by telephone or other rapid communication means, with prompt written followup. The report and its mailing cover should be plainly marked: "NDA -- Field Alert Report."

(i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article.

(ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application.

(2) Annual report. The applicant shall submit the following information in the order listed each year within 60 days of the anniversary date of approval of the application. The applicant shall submit the report to the FDA division responsible for reviewing the application. Each annual report is required to be accompanied by a completed transmittal Form FDA-2252 (Transmittal of Periodic Reports for Drugs for Human Use) which may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857, and is required to include all the information required under this section that the applicant received or otherwise obtained during the annual reporting interval which ends on the anniversary date. The report is required to contain the following:

(i) Summary. A brief summary of significant new information from the previous year that might affect the safety, effectiveness, or labeling of the drug product. The report is also required to contain a brief description of actions the applicant has taken or intends to take as a result of the new information, for example, submit a labeling supplement, add a warning to the labeling, or initiate a new study.

(ii) Distribution data. Information about the quantity of the drug product distributed under the approved application, including that distributed to distributors. The information is required to include the National Drug Code (NDC) number, the total number of dosage units of each strength or potency distributed (e.g., 100,000/5 milligram tablets, 50,000/10 milliliter vials), and the quantities distributed for domestic use and the quantities distributed for foreign use. Disclosure of financial or pricing data is not required.

(iii) Labeling. Currently used professional labeling, patient brochures or package inserts (if any), a representative sample of the package labels, and a summary of any changes in labeling that have been made since the last report listed by date in the order in which they were implemented, or if no changes, a statement of that fact.

(iv) Chemistry, manufacturing, and controls changes. ( a ) Reports of experiences, investigations, studies, or tests involving chemical or physical properties, or any other properties of the drug (such as the drug's behavior or properties in relation to microorganisms, including both the effects of the drug on microorganisms and the effects of microorganisms on the drug). These reports are only required for new information that may affect FDA's previous conclusions about the safety or effectiveness of the drug product.

( b ) A full description of the manufacturing and controls changes not requiring a supplemental application under § 314.70 (b) and (c), listed by date in the order in which they were implemented.

(v) Nonclinical laboratory studies. Copies of unpublished reports and summaries of published reports of new toxicological findings in animal studies and in vitro studies (e.g., mutagenicity) conducted by, or otherwise obtained by, the applicant concerning the ingredients in the drug product. The applicant shall submit a copy of a published report if requested by FDA.

(vi) Clinical data. ( a ) Published clinical trials of the drug (or abstracts of them), including clinical trials on safety and effectiveness; clinical trials on new uses; biopharmaceutic, pharmacokinetic, and clinical pharmacology studies; and reports of clinical experience pertinent to safety (for example, epidemiologic studies or analyses of experience in a monitored series of patients) conducted by or otherwise obtained by the applicant. Review articles, papers describing the use of the drug product in medical practice, papers and abstracts in which the drug is used as a research tool, promotional articles, press clippings, and papers that do not contain tabulations or summaries of original data should not be reported.

( b ) Summaries of completed unpublished clinical trials, or prepublication manuscripts if available, conducted by, or otherwise obtained by, the applicant. Supporting information should not be reported. (A study is considered completed 1 year after it is concluded.)

(vii) Status reports. A statement on the current status of any postmarketing studies performed by, or on behalf of, the applicant. To facilitate communications between FDA and the applicant, the report may, at the applicant's discretion, also contain a list of any open regulatory business with FDA concerning the drug product subject to the application.

(3) Other reporting -- (i) Advertisements and promotional labeling. . The applicant shall submit specimens of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Mailing pieces and labeling that are designed to contain samples of a drug product are required to be complete, except the sample of the drug product may be omitted. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product's current professional labeling. Form FDA-2253 may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857.

(ii) Special reports. Upon written request the agency may require that the applicant submit the reports under this section at different times than those stated.

(c) General requirements -- (1) Multiple applications. For all reports required by this section, the applicant shall submit the information common to more than one application only to the application first approved, and shall not report separately on each application. The submission is required to identify all the applications to which the report applies.

(2) Patient identification. Applicants should not include in reports under this section the names and addresses of individual patients; instead, the applicant should code the patient names whenever possible and retain the code in the applicant's files. The applicant shall maintain sufficient patient identification information to permit FDA, by using that information alone or along with records maintained by the investigator of a study, to identify the name and address of individual patients; this will ordinarily occur only when the agency needs to investigate the reports further or when there is reason to believe that the reports do not represent actual results obtained.

(d) Withdrawal of approval. If an applicant fails to make reports required under this section, FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.

§ 314.90 Waivers.

(a) An applicant may ask the Food and Drug Administration to waive under this section any requirement that applies to the applicant under § § 314.50 through 314.81. An applicant may ask FDA to waive under § 314.126(c) any criteria of an adequate and well-controlled study described in § 314.126(b). A waiver request under this section is required to be submitted with supporting documentation in an application, or in an amendment or supplement to an application. The waiver request is required to contain one of the following:

(1) An explanation why the applicant's compliance with the requirement is unnecessary or cannot be achieved;

(2) A description of an alternative submission that satisfies the purpose of the requirement; or

(3) Other information justifying a waiver.

(b) FDA may grant a waiver if it finds one of the following:

(1) The applicant's compliance with the requirement is unnecessary for the agency to evaluate the application or compliance cannot be achieved;

(2) The applicant's alternative submission satisfies the requirement; or

(3) The applicant's submission otherwise justifies a waiver.

Subpart C -- FDA Action on Applications
§ 314.100 Time frames for reviewing applications.

(a) Within 180 days of receipt of an application, the Food and Drug Administration will review it and send the applicant either an approval letter under § 314.105, an approvable letter under § 314.110, or a not approvable letter under § 314.120. This 180-day period is called the "review clock."

(b) During the review period an applicant may withdraw an application under § 314.65 and later resubmit it. FDA will then follow the same procedure as if a new application were submitted.

(c) The time period may be extended by mutual agreement between FDA and an applicant or, as provided in § 314.60, as the result of a major amendment.

§ 314.101 Filing an application.

(a) Within 60 days after the Food and Drug Administration receives an application, the agency will determine whether the application may be filed. The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to permit a substantive review.

(b) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for refusing to file the application apply, the agency will file the application and notify the applicant in writing. The date of filing will be the date 60 days after the date FDA received the application. The date of filing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the "filing clock."

(c) If FDA refuses to file the application, the agency will notify the applicant in writing and state the reason under paragraph (d) or (e) of this section for the refusal. If FDA refuses to file the application under paragraph (d) of this section, the applicant may request in writing within 30 days of the date of the agency's notification an informal conference with the agency about whether the agency should file the application. If following the informal conference the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest under paragraph (b) of this section, notify the applicant in writing, and review it as filed. If the application is filed over protest, the date of filing will be the date 60 days after the date the applicant requested the informal conference. The applicant need not resubmit a copy of an application that is filed over protest. If FDA refuses to file the application under paragraph (e) of this section, the applicant may amend the application and resubmit it and the agency will make a determination under this section whether it may be filed.

(d) FDA may refuse to file an application if any of the following applies.

(1) The application does not contain a completed application form.

(2) The application is not submitted in the form required under § 314.50 or § 314.55.

(3) The application is incomplete because it does not on its face contain information required under section 505(b) (1), (2), (3), (4), (5), and (6) or section 507 of the act and § 314.50 or § 314.55.

(4) The application does not contain an environmental impact analysis report analyzing under § 25.1 the environmental impact of the manufacturing process and the ultimate use or consumption of the drug.

(5) The application does not contain an accurate and complete English translation of each part of the application that is not in English.

(6) The application does not contain a statement for each nonclinical laboratory study that it was conducted in compliance with the requirements set forth in Part 58, or, for each study not conducted in compliance with Part 58, a brief statement of the reason for the noncompliance.

(7) The application does not contain a statement for each clinical study that it was conducted in compliance with the institutional review board regulations in Part 56, or was not subject to those regulations, and that it was conducted in compliance with the informed consent regulations in Part 50; or, if the study was subject to but was not conducted in compliance with those regulations, the application does not contain a brief statement of the reason for the noncompliance.

(e) The agency will refuse to file an application if any of the following applies:

(1) The drug product that is the subject of the submission is already coverd by an approved application.

(2) The submission purports to be an abbreviated application under § 314.55, but the drug product is not one for which FDA has made a finding that an abbreviated application is acceptable under § 314.55(b). FDA will file a copy of the application as a citizen petition under § 10.30 seeking a finding under § 314.55 that an abbreviated application is acceptable for the drug product, and so notify the applicant in writing.

(3) The drug product is subject to licensing by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and Subchapter F of Chapter I of Title 21 of the Code of Federal Regulations.

(f) (1) Within 180 days after the date of filing, plus the period of time the review period was extended (if any), FDA will either (i) approve the application or (ii) issue a notice of opportunity for hearing if the applicant asked FDA to provide it an opportunity for a hearing on an application in response to an approvable letter or a not approvable letter.

(2) This paragraph does not apply to applications that have been withdrawn from FDA review by the applicant.

§ 314.102 Communication between FDA and applicants.

(a) General principles. During the course of reviewing an application, FDA shall communicate with applicants about scientific, medical, and procedural issues that arise during the review process. Such communication may take the form of telephone conversations, letters, or meetings, whichever is most appropriate to discuss the particular issue at hand. Communications shall be appropriately documented in the application in accordance with § 10.65. Further details on the procedures for communication between FDA and applicants are contained in a staff manual guide that is publicly available.

(b) Notification of easily correctable deficiencies. FDA reviewers shall make every reasonable effort to communicate promptly to applicants easily correctable deficiencies found in an application when those deficiencies are discovered, particularly deficiencies concerning chemistry, manufacturing, and controls issues. The agency will also inform applicants promptly of its need for more data or information or for technical changes in the application needed to facilitate the agency's review. This early communication is intended to permit applicants to correct such readily identified deficiencies relatively early in the review process and to submit an amendment before the review period has elapsed. Such early communication would not ordinarily apply to major scientific issues, which require consideration of the entire pending application by agency managers as well as reviewing staff. Instead, these major scientific issues will ordinarily be addressed in an action letter.

(c) Ninety-day conference. Approximately 90 days after the agency receives the application, FDA will provide applicants with an opportunity to meet with agency reviewing officials. The purpose of the meeting will be to inform applicants of the general progress and status of their applications, and to advise applicants of deficiencies which have been identified by that time and which have not already been communicated. This meeting will be available on applications for all new chemical entities and major new indications of marketed drugs. Such meetings will be held at the applicant's option, and may be held by telephone if mutually agreed upon.

(d) End-of-review conference. At the conclusion of FDA's review of an application, as designated by the issuance of an approvable or not approvable letter, FDA will provide applicants with an opportunity to meet with agency reviewing officials. The purpose of the meeting will be to discuss what further steps need to be taken by the applicant before the application can be approved. This meeting will be available on all applications, with priority given to applications for new chemical entities and major new indications for marketed drugs. Requests for such meetings shall be directed to the director of the division responsible for reviewing the application.

(e) Other meetings. Other meetings between FDA and applicants may be held, with advance notice, to discuss scientific, medical, and other issues that arise during the review process. Requests for meetings shall be directed to the director of the division responsible for reviewing the application. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times. However, "drop-in" visits (i.e., an unannounced and unscheduled visit by a company representative) are discouraged except for urgent matters, such as to discuss an important new safety issue.

§ 314.103 Dispute resolution.

(a) General. The Food and Drug Administration is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications as quickly and amicably as possible through the cooperative exchange of information and views.

(b) Administrative and procedural issues. When administrative or procedural disputes arise, the applicant should first attempt to resolve the matter with the division responsible for reviewing the application, beginning with the consumer safety officer assigned to the application. If resolution is not achieved, the applicant may raise the matter with the person designated as ombudsman, whose function shall be to investigate what has happened and to facilitate a timely and equitable resolution. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings, obtaining timely replies to inquiries, and obtaining timely completion of pending reviews. Further details on this procedure are contained in a staff manual guide that is publicly available under FDA's public information regulations in Part 20.

(c) Scientific and medical disputes. (1) Because major scientific issues are ordinarily communicated to applicants in an approvable or not approvable letter pursuant to § 314.110 or § 314.120, respectively, the "end-of-review conference" described in § 314.102(d) will provide a timely forum for discussing and resolving, if possible, scientific and medical issues on which the applicant disagrees with the agency. In addition, the "ninety-day conference" described in § 314.102(c) will provide a timely forum for discussing and resolving, if possible, issues identified by that date.

(2) When scientific or medical disputes arise at other times during the review process, applicants should discuss the matter directly with the responsible reviewing officials. If necessary, applicants may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Ordinarily, such meetings would be held first with the Division Director, then with the Office Director, and finally with the Center Director if the matter is still unresolved. Requests for such meetings shall be directed to the director of the division responsible for reviewing the application. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.

(3) In requesting a meeting designed to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other consultants, as designated by the agency. Applicants may also bring their own consultants. For major scientific and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of is standing advisory committees for its consideration and recommendations.

§ 314.104 Drugs with potential for abuse.

The Food and Drug Administration will inform the Drug Enforcement Administration under section 201(f) of the Controlled Substances Act (21 U.S.C. 801) when an application is submitted for a drug that appears to have an abuse potential.

§ 314.105 Approval of an application.

(a) The Food and Drug Administration will approve an application and send the applicant an approval letter if none of the reasons in § 314.125 for refusing to approve the application apply. The date of the agency's approval letter is the date of approval of the application. When FDA sends an applicant an approval letter for an antibiotic, it will promulgate a regulation under § 314.300 providing for certification of the drug, if necessary. A new drug product or antibiotic may not be marketed until an approval letter is issued. Marketing of an antibiotic need not await the promulgation of a regulation under § 314.300.

(b) FDA will approve an application and issue the applicant an approval letter (rather than an approvable letter under § 314.110) on the basis of draft labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed labeling prior to marketing.

(c) FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling. While the statutory standards apply to all drugs, the many kinds of drugs that are subject to them and the wide range of uses for those drugs demand flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet them. FDA makes its views on drug products and classes of drugs available through guidelines, recommendations, and other statements of policy.

§ 314.106 Foreign data.

(a) General. The acceptance of foreign data in an application generally is governed by § 312.20.

(b) As sole basis for marketing approval. An application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if: (1) The foreign data are applicable to the U.S. population and U.S. medical practice; (2) the studies have been performed by clinical investigators of recognized competence; and (3) the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. Failure of an application to meet any of these criteria will result in the application not being approvable based on the foreign data alone. FDA will apply this policy in a flexible manner according to the nature of the drug and the data being considered.

(c) Consultation between FDA and applicants. Applicants are encouraged to meet with agency officials in a "presubmission" meeting when approval based solely on foreign data will be sought.

§ 314.110 Approvable letter to the applicant.

In selected circumstances it is useful at the end of the review period for the Food and Drug Administration to indicate to the applicant that the application is basically approvable providing certain issues are resolved. An approvable letter may be issued in such circumstances. FDA will send the applicant an approvable letter if the application substantially meets the requirements of this part and the agency believes that it can approve the application if specific additional information or material is submitted or specific conditions (for example, certain changes in labeling) are agreed to by the applicant. The approvable letter will describe the information or material FDA requires or the conditions the applicant is asked to meet. As a practical matter, the approvable letter will serve in most instances as a mechanism for resolving outstanding issues on drugs that are about to be approved and marketed. Within 10 days after the date of the approvable letter, the applicant shall either:

(a) Amend the application or notify FDA of an intent to file an amendment. The filing of an amendment or notice of intent to file an amendment constitutes an agreement by the applicant to extend the review period for 45 days after the date FDA receives the amendment. The extension is to permit the agency to review the amendment.

(b) Withdraw the application. FDA will consider the applicant's failure to respond within 10 days to an approvable letter to be a request by the applicant to withdraw the application under § 314.65. A decision to withdraw an application is without prejudice to a refiling.

(c) For a new drug, 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 under section 505(d) of the act. The applicant shall submit the request to the Division of Regulatory Affairs (HFN-360), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60 days of the date of the approvable letter, or within a different time period to which FDA and the applicant agree, the agency will either approve the application under § 314.105 or refuse to approve the application under § 314.125 and give the applicant written notice of an opportunity for a hearing under § 314.200 and section 505(c)(2) of the act on the question of whether there are grounds for denying approval of the application under section 505(d) of the act.

(d) For an antibiotic, file a petition or notify FDA of an intent to file a petition proposing the issuance, amendment, or repeal of a regulation under § 314.300 and section 507(f) of the act.

(e) Notify FDA that the applicant agrees to an extension of the review period under section 505(c) of the act, so that the applicant can determine whether to respond further under paragraph (a), (b), (c), or (d) of this section. The applicant's notice is required to state the length of the extension. FDA will honor any reasonable request for such an extension. FDA will consider the applicant's failure to respond further within the extended review period to be a request to withdraw the application under § 314.65. A decision to withdraw an application is without prejudice to a refiling.

§ 314.120 Not approvable letter to the applicant.

The Food and Drug Administration will send the applicant a not approvable letter if the agency believes that the application may not be approved for one of the reasons given in § 314.125. The not approvable letter will describe the deficiencies in the application. Within 10 days after the date of the not approvable letter, the applicant shall either:

(a) Amend the application or notify FDA of an intent to file an amendment. The filing of an amendment or a notice of intent to file an amendment constitutes an agreement by the applicant to extend the review period under § 314.60.

(b) Withdraw the application. FDA will consider the applicant's failure to respond within 10 days to a not approvable letter to be a request by the applicant to withdraw the application under § 314.65. A decision to withdraw the application is without prejudice to refiling.

(c) For a new drug, 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 under section 505(d) of the act. The applicant shall submit the request to the Division of Regulatory Affairs (HFN-360), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60 days of the date of the not approvable letter, or within a different time period to which FDA and the applicant agree, the agency will either approve the application under § 314.105 or refuse to approve the application under § 314.125 and give the applicant written notice of an opportunity for a hearing under § 314.200 and section 505(c)(2) of the act on the question of whether there are grounds for denying approval of the application under section 505(d) of the act.

(d) For an antibiotic, file a petition or notify FDA of an intent to file a petition proposing the issuance, amendment, or repeal of a regulation under § 314.300 and section 507(f) of the act.

(e) Notify FDA that the applicant agrees to an extension of the review period under section 505(c) of the act, so that the applicant can determine whether to respond further under paragraph (a), (b), (c), or (d) of this section. The applicant's notice is required to state the length of the extension. FDA will honor any reasonable request for such an extension. FDA will consider the applicant's failure to respond further within the extended review period to be a request to withdraw the application under § 314.65. A decision to withdraw an application is without prejudice to a refiling.

§ 314.125 Refusal to approve an application.

(a) The Food and Drug Administration will refuse to approve the application and for a new drug give the applicant written notice of an opportunity for a hearing under § 314.200 on the question of whether there are grounds for denying approval of the application under section 505(d) of the act, or for an antibiotic publish a proposed regulation based on an acceptable petition under § 314.300, if: (1) FDA sends the applicant an approvable or a not approvable letter under § 314.110 or § 314.120; (2) The applicant requests an opportunity for hearing for a new drug on the question of whether the application is approvable or files a petition for an antibiotic proposing the issuance, amendment, or repeal of a regulation; and (3) FDA finds that any of the reasons given in paragraph (b) of this section apply.

(b) FDA may refuse to approve an application for any of the following reasons:

(1) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product are inadequate to preserve its identity, strength, quality, purity, stability, and bioavailability.

(2) The investigations required under section 505(b) or 507 of the act do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.

(3) The results of the tests show that the drug is unsafe for use under the conditions prescribed, recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for use under those conditions.

(4) There is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.

(5) There is a lack of substantial evidence consisting of adequate and well-controlled investigations, as defined in § 314.126, that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling.

(6) The proposed labeling is false or misleading in any particular.

(7) The application contains an untrue statement of a material fact.

(8) The drug product's proposed labeling does not comply with the requirements for labels and labeling in Part 201.

(9) The application does not contain bioavailability or bioequivalence data required under Part 320.

(10) A reason given in a letter refusing to file the application under § 314.101(d), if the deficiency is not corrected.

(11) The drug will be manufactured or processed in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the act and Part 207.

(12) The applicant does not permit a properly authorized officer or employee of the Department of Health and Human Services an adequate opportunity to inspect the facilities, controls, and any records relevant to the application.

(13) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product do not comply with the current good manufacturing practice regulations in Parts 210 and 211.

(14) The application does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source.

(15) A nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations in Part 58 and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.

(16) Any clinical investigation involving human subjects described in the application, subject to the institutional review board regulations in Part 56 or informed consent regulations in Part 50, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.

§ 314.126 Adequate and well-controlled studies.

(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been developed over a period of years and are recognized by the scientific community as the essentials of an adequate and well-controlled clinical investigation. The Food and Drug Administration considers these characteristics in determining whether an investigation is adequate and well-controlled for purposes of sections 505 and 507 of the act. Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is "substantial evidence" to support the claims of effectiveness for new drugs and antibiotics. Therefore, the study report should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.

(b) An adequate and well-controlled study has the following characteristics:

(1) There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results. In addition, the protocol should contain a description of the proposed methods of analysis, and the study report should contain a description of the methods of analysis ultimately used. If the protocol does not contain a description of the proposed methods of analysis, the study report should describe how the methods used were selected.

(2) The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized:

(i) Placebo concurrent control. The test drug is compared with an inactive preparation designed to resemble the test drug as far as possible. A placebo-controlled study may include additional treatment groups, such as an active treatment control or a dose-comparison control, and usually includes randomization and blinding of patients or investigators, or both.

(ii) Dose-comparison concurrent control. At least two doses of the drug are compared. A dose-comparison study may include additional treatment groups, such as placebo control or active control. Dose-comparison trials usually include randomization and blinding of patients or investigators, or both.

(iii) No treatment concurrent control. Where objective measurements of effectiveness are available and placebo effect is negligible, the test drug is compared with no treatment. No treatment concurrent control trials usually include randomization.

(iv) Active treatment concurrent control. The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. An active treatment study may include additional treatment groups, however, such as a placebo control or a dose-comparison control. Active treatment trials usually include randomization and blinding of patients or investigators, or both. If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug.

(v) Historical control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (for example, certain malignancies) and studies in which the effect of the drug is self-evident (general anesthetics, drug metabolism).

(3) The method of selection of subjects provides adequate assurance that they have the disease or condition being studied, or evidence of susceptibility and exposure to the condition against which prophylaxis is directed.

(4) The method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups with respect to pertinent variables such as age, sex, severity of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for the study and the report of its results should describe how subjects were assigned to groups. Ordinarily, in a concurrently controlled study, assignment is by randomization, with or without stratification.

(5) Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data. The protocol and report of the study should describe the procedures used to accomplish this, such as blinding.

(6) The methods of assessment of subjects' response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation, and criteria used to assess response.

(7) There is an analysis of the results of the study adequate to assess the effects of the drug. The report of the study should describe the results and the analytic methods used to evaluate them, including any appropriate statistical methods. The analysis should assess, among other things, the comparability of test and control groups with respect to pertinent variables, and the effects of any interim data analyses performed.

(c) The Director of the Center for Drugs and Biologics may, on the Director's own initiative or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph (b) of this section with respect to a specific clinical investigation, either prior to the investigation or in the evaluation of a completed study. A petition for a waiver is required to set forth clearly and concisely the specific criteria from which waiver is sought, why the criteria are not reasonably applicable to the particular clinical investigation, what alternative procedures, if any, are to be, or have been employed, and what results have been obtained. The petition is also required to state why the clinical investigations so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.

(d) For an investigation to be considered adequate for approval of a new drug, it is required that the test drug be standardized as to identity, strength, quality, purity, and dosage form to give significance to the results of the investigation.

(e) Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness. Such studies carefully conducted and documented, may provide corroborative support of well-controlled studies regarding efficacy and may yield valuable data regarding safety of the test drug. Such studies will be considered on their merits in the light of the principles listed here, with the exception of the requirement for the comparison of the treated subjects with controls. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.

§ 314.150 Withdrawal of approval of an application.

(a) The Food and Drug Administration will notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6, and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application under section 505(e) of the act and under the procedure in § 314.200, or, for an antibiotic, rescind a certification or release, or amend or repeal a regulation providing for certification under section 507 of the act under the procedure in § 314.300, if any of the following applies:

(1) The Secretary of Health and Human Services has suspended the approval of the application for a new drug on a finding that there is an imminent hazard to the public health. FDA will promptly afford the applicant an expedited hearing following summary suspension on a finding of imminent hazard to health.

(2) FDA finds:

(i) That clinical or other experience, tests, or other scientific data show that the drug is unsafe for use under the conditions of use upon the basis of which the application was approved; or

(ii) That new evidence of clinical experience, not contained in the application or not available to FDA until after the application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when the application was approved, evaluated together with the evidence available when the application was approved, reveal that the drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved; or

(iii) Upon the basis of new information before FDA with respect to the drug, evaluated together with the evidence available when the application was approved, that there is a lack of substantial evidence from adequate and well-controlled investigations as defined in § 314.126, that the drug will have the effect it is purported or is represented to have under the conditions of use prescribed, recommended, or suggested in its labeling; or

(iv) That the application contains any untrue statement of a material fact.

(b) FDA may notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6, and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application under section 505(e) of the act and under the procedure in § 314.200, or, for an antibiotic, rescind a certification or release, or amend or repeal a regulation providing for certification under section 507 of the act and the procedure in § 314.300, if the agency finds:

(1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain required records or to make required reports under section 505(j) or 507(g) of the act and § § 314.80 and 314.81, or that the applicant has refused to permit access to, or copying or verification of, its records.

(2) That on the basis of new information before FDA, evaluated together with the evidence available when the application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the agency.

(3) That on the basis of new information before FDA, evaluated together with the evidence available when the application was approved, the labeling of the drug, based on a fair evaluation of all material facts, is false or misleading in any particular; and the labeling was not corrected by the applicant within a reasonable time after receipt of written notice from the agency.

(4) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the act.

(5) That the applicant has failed to submit bioavailability or bioequivalence data required under Part 320.

(6) The application does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source.

(7) That any nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its labeling was not conducted in compliance with the good laboratory practice regulations in Part 58 and no reason for the noncompliance was provided or, if it was, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.

(8) Any clinical investigation involving human subjects described in the application, subject to the institutional review board regulations in Part 56 or informed consent regulations in Part 50, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.

(c) FDA will withdraw approval of an application if the applicant requests its withdrawal because the drug subject to the application is no longer being marketed, provided none of the conditions listed in paragraphs (a) and (b) of this section apply to the drug. FDA will consider a written request for withdrawal under this paragraph to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal of approval of an application under this paragraph is without prejudice to refiling.

(d) FDA may notify an applicant that it believes a potential problem associated with a drug is sufficiently serious that the drug should be removed from the market and may ask the applicant to waive the opportunity for hearing otherwise provided for under this section, to permit FDA to withdraw approval of the application for the product, and to remove voluntarily the product from the market. If the applicant agrees, the agency will not make a finding under paragraph (b) of this section, but will withdraw approval of the application in a notice published in the Federal Register that contains a brief summary of the agency's and the applicant's views of the reasons for withdrawal.

§ 314.152 Notice of withdrawal of approval of an application for a new drug.

If the Food and Drug Administration withdraws approval of an application for a new drug, FDA will publish a notice in the Federal Register announcing the withdrawal of approval.

§ 314.160 Approval of an application for which approval was previously refused, suspended, or withdrawn.

Upon the Food and Drug Administration's own initiative or upon request of an applicant, FDA may, on the basis of new data, approve an application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the Federal Register announcing the approval.

§ 314.170 Adulteration and misbranding of an approved drug.

All drugs, including those the Food and Drug Administration approves, or provides for certification of, under sections 505, 506, and 507 of the act and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503 of the act. FDA is authorized to regulate approved new drugs and approved antibiotic drugs by regulations issued through informal rulemaking under sections 501, 502, and 503 of the act.

Subpart D -- Hearing Procedures for New Drugs
§ 314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or denial of hearing.

(a) Notice of opportunity for hearing. The Director of the Center for Drugs and Biologics, Food and Drug Administration, will give the applicant, and all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6, notice and an opportunity for a hearing on the Center's proposal to refuse to approve an application or to withdraw the approval of an application. The notice will state the reasons for the action and the proposed grounds for the order.

(1) The notice may be general (that is, simply summarizing in a general way the information resulting in the notice) or specific (that is, either referring to specific requirements in the statute and regulations with which there is a lack of compliance, or providing a detailed description and analysis of the specific facts resulting in the notice).

(2) FDA will publish the notice in the Federal Register and will state that the applicant, and other persons subject to the notice under § 310.6, who wishes to participate in a hearing, has 30 days after the date of publication of the notice to file a written notice of participation and request for hearing. The applicant, or other persons subject to the notice under § 310.6, who fails to file a written notice of participation and request for hearing within 30 days, waives the opportunity for a hearing.

(3) It is the responsibility of every manufacturer and distributor of a drug product to review every notice of opportunity for a hearing published in the Federal Register to determine whether it covers any drug product that person manufactures or distributes. Any person may request an opinion of the applicability of a notice to a specific product that may be identical, related, or similar to a product listed in a notice by writing to the Division of Drug Labeling Compliance (HFN-310), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. A person shall request an opinion within 30 days of the date of publication of the notice to be eligible for an opportunity for a hearing under the notice. If a person requests an opinion, that person's time for filing an appearance and request for a hearing and supporting studies and analyses begins on the date the person receives the opinion from FDA.

(b) FDA will provide the notice of opportunity for a hearing to applicants and to other persons subject to the notice under § 310.6, as follows:

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