21 CFR Part 314 — Applications for FDA Approval to Market a New Drug

PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 356, 356a, 356b, 356c, 356e, 360cc, 360ddd, 360ddd-1, 371, 374, 379e, 379k-1. Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. Editorial Note: Nomenclature changes to part 314 appear at 69 FR 13717, Mar. 24, 2004; 81 FR 69639, Oct. 6, 2016. 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 of applications and abbreviated applications to market a new drug under section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and postmarketing reports to them. (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. (c) The following provisions do not apply to designated medical gases, which are subject to the certification and postmarketing reporting requirements under part 230 of this chapter: (1) Sections 314.50 through 314.72; (2) Section 314.80; (3) Section 314.81, except paragraph (b)(3); (4) Section 314.90; (5) Subpart C of this part; (6) Sections 314.100 through 314.162; (7) Subpart H of this part; and (8) Subpart I of this part. (d) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted. [50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999; 89 FR 51782, June 18, 2024] § 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 an 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 Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part and part 320 of this chapter. (b) The following definitions of terms apply to this part and part 320 of this chapter: 180-day exclusivity period 505(b)(2) application Abbreviated application, abbreviated new drug application, or ANDA Acknowledgment letter Act et seq. et seq. Active ingredient Active moiety ANDA holder Applicant Application, new drug application, or NDA Approval letter Assess the effects of the change Authorized generic drug Bioavailability Bioequivalence Bioequivalence requirement Class 1 resubmission Class 2 resubmission Commercial marketing Complete response letter Component Date of approval Dosage form (1) The physical appearance of the drug product; (2) The physical form of the drug product prior to dispensing to the patient; (3) The way the product is administered; and (4) The design features that affect frequency of dosing. Drug product Drug substance Efficacy supplement (1) Add or modify an indication or claim; (2) Revise the dose or dose regimen; (3) Provide for a new route of administration; (4) Make a comparative efficacy claim naming another drug product; (5) Significantly alter the intended patient population; (6) Change the marketing status from prescription to over-the-counter use; (7) Provide for, or provide evidence of effectiveness necessary for, the traditional approval of a product originally approved under subpart H of this part; or (8) Incorporate other information based on at least one adequate and well-controlled clinical study. FDA or Agency First applicant Inactive ingredient Listed drug NDA holder Newly acquired information Original application or original NDA Paragraph IV acknowledgment letter Paragraph IV certification 4 4 Patent owner Pharmaceutical alternatives Pharmaceutical equivalents i.e., Postmark Reference listed drug Reference standard Resubmission, Right of reference or use Same drug product formulation Specification i.e., Strength (1)(i) The total quantity of drug substance in mass or units of activity in a dosage unit or container closure (e.g., weight/unit dose, weight/volume or weight/weight in a container closure, or units/volume or units/weight in a container closure); and/or, as applicable. (ii) The concentration of the drug substance in mass or units of activity per unit volume or mass (e.g., weight/weight, weight/volume, or units/volume); or (2) Such other criteria the Agency establishes for determining the amount of drug substance contained in, delivered, or deliverable from a drug product if the weights and measures described in paragraph (i) of this definition do not apply (e.g., certain drug-device combination products for which the amount of drug substance is emitted per use or unit time). Substantially complete application Tentative approval The list http://www.fda.gov/cder Therapeutic equivalents [81 FR 69636, Oct. 6, 2016] Subpart B—Applications § 314.50 Content and format of an NDA. NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA 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, including, if applicable, any Medication Guide required under part 208 of this chapter. Other NDAs will generally contain only some of those items, and information will be limited to that needed to support the particular submission. These include an NDA of the type described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, an amendment, and a supplement. The NDA 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 NDA that is received or otherwise obtained by the applicant from any source. FDA will maintain guidance documents on the format and content of NDAs to assist applicants in their preparation. (a) Application form. (1) The name and address of the applicant; the date of the NDA; the NDA number if previously issued (for example, if the NDA is a resubmission or an amendment or 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 INDs (as defined in § 312.3(b) of this chapter) that are referenced in the NDA; the identification numbers of all drug master files and other applications under this part that are referenced in the NDA; and the drug product's proposed indications for use. (2) A statement whether the submission is an original submission, a 505(b)(2) application, a resubmission, 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 must sign the NDA. If the person signing the NDA does not reside or have a place of business within the United States, the NDA 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. (c) Summary. (2) The summary is required to contain the following information: (i) The proposed text of the labeling, including, if applicable, any Medication Guide required under part 208 of this chapter, for the drug, with annotations to the information in the summary and technical sections of the NDA that support the inclusion of each statement in the labeling, and, if the NDA is for a prescription drug, statements describing the reasons for omitting a section or subsection of the labeling format in § 201.57 of this chapter. (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 NDA. (v) A summary of the nonclinical pharmacology and toxicology section of the NDA. (vi) A summary of the human pharmacokinetics and bioavailability section of the NDA. (vii) A summary of the microbiology section of the NDA (for anti-infective drugs only). (viii) A summary of the clinical data section of the NDA, 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. (1) Chemistry, manufacturing, and controls section. (i) Drug substance. (ii)( (a) Drug product. ( b a ( c (iii) Environmental impact. (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 NDA. FDA will review such early submissions as resources permit. (v) The applicant must include a statement certifying that the field copy of the NDA has been provided to the applicant's home FDA district office. (2) Nonclinical pharmacology and toxicology section. (i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic indication and studies that 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 subject to the good laboratory practice regulations under part 58 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. (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 procedures 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 NDA describes in the chemistry, manufacturing, and controls section tests, analytical procedures, and acceptance criteria 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 tests, analytical procedures, and acceptance criteria, 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. (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 procedures (for example, in vitro sensitivity discs) needed for effective use of the drug. (5) Clinical data section. (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 NDA, 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. The effectiveness data must be presented by gender, age, and racial subgroups and must identify any modifications of dose or dose interval needed for specific subgroups. Effectiveness data from other subgroups of the population of patients treated, when appropriate, such as patients with renal failure or patients with different levels of severity of the disease, also must be presented. (vi) A summary and updates of safety information, as follows: ( a ( b a 1 2 3 (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. (x) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted. (xi) If original subject records were audited or reviewed by the sponsor in the course of monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical study so audited or reviewed. (6) Statistical section. (i) A copy of the information submitted under paragraph (d)(5)(ii) of this section concerning the description and analysis of each controlled clinical study, and the documentation and supporting statistical analyses used in evaluating the controlled clinical studies. (ii) A copy of the information submitted under paragraph (d)(5)(vi)( a (7) Pediatric use section. (e) Samples and labeling. (i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to perform three times each test described in the NDA to determine whether the drug substance and the drug product meet the specifications given in the NDA: ( a ( b ( c (ii) Samples of the finished market package, if requested by FDA. (2) The applicant must submit the following in the archival copy of the NDA: (i) Three copies of the analytical procedures 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 procedures. 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 (including, if applicable, any Medication Guide required under part 208 of this chapter) for the drug product (4 copies of draft labeling or 12 copies of final printed labeling). (f) Case report forms and tabulations. (1) Case report tabulations. (2) Case report forms. (3) Additional data. (4) Presentation and format. (g) Other. (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 must submit an accurate and complete English translation of each part of the NDA that is not in English. The applicant must submit a copy of each original literature publication for which an English translation is submitted. (3) If an applicant who submits an NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act obtains a “right of reference or use,” as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act, the applicant must include in its NDA a written statement signed by the owner of the data from each such investigation that the applicant may rely on in support of the approval of its NDA, and provide FDA access to, the underlying raw data that provide the basis for the report of the investigation submitted in its NDA. (h) Patent information. (i) Patent certification Contents. (i) Patents claiming drug substance, drug product, or method of use. ( 1 ( 2 ( 3 ( 4 i I, ( name of applicant is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of name of proposed drug product ( ii (B) If the drug on which investigations that are relied upon by the applicant were conducted is itself a licensed generic drug of a patented drug first approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act, an appropriate patent certification or statement under this section with respect to each patent that claims the first-approved patented drug or that claims an approved use for such a drug. (C) If, before the date of submission of an original 505(b)(2) application, there is a drug product approved in an NDA that is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted, an appropriate patent certification or statement under this section with respect to each patent that claims the drug substance or drug product or that claims an approved use for one such drug product. (ii) No relevant patents. In the opinion and to the best knowledge of ( name of applicant (iii) Method-of-use patent. (B) If the labeling of the drug product for which the applicant is seeking approval includes an indication or other condition of use that, according to the patent information submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 or in the opinion of the applicant, is claimed by a method-of-use patent, the applicant must submit an applicable certification under paragraph (i)(1)(i) of this section. (2) [Reserved] (3) Licensing agreements. (4) Untimely filing of patent information. (A) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of patent issuance; (B) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of approval of a corresponding change to product labeling; or (C) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of a decision by the U.S. Patent and Trademark Office or by a Federal district court, the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent, and the amendment contains a copy of the decision. (ii) An applicant whose 505(b)(2) application is submitted after the NDA holder's untimely filing of patent information or whose 505(b)(2) application was previously filed but did not contain an appropriate patent certification or statement at the time of the patent submission must submit a certification under paragraph (i)(1)(i) of this section and/or a statement under paragraph (i)(1)(iii) of this section as to that patent. (5) Disputed patent information. (6) Amended certifications. (i) After finding of infringement. 3 (ii) After request to remove a patent or patent information from the list. (iii) Other amendments. ( 1 ( 2 (B) An applicant is not required to submit a supplement to change a submitted certification when information on an otherwise applicable patent is submitted after the approval of the 505(b)(2) application. (j) Claimed exclusivity. (1) A statement that the applicant is claiming exclusivity. (2) A reference to the appropriate paragraph under § 314.108 that supports its claim. (3) If the applicant claims exclusivity under § 314.108(b)(2), information to show that, to the best of its knowledge or belief, a drug has not previously been approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act containing any active moiety in the drug for which the applicant is seeking approval. (4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the following information to show that the NDA contains “new clinical investigations” that are “essential to approval of the NDA or supplement” and were “conducted or sponsored by the applicant:” (i) “New clinical investigations. (ii) “Essential to approval.” (iii) “Conducted or sponsored by.” (k) Financial certification or disclosure statement. (l) Format of an original NDA Archival copy. (i) Labeling. (ii) [Reserved] (2) Review copy. (3) Field copy. (4) Binding folders. (5) Electronic format submissions. [50 FR 7493, Feb. 22, 1985] Editorial Note: For Federal Register www.govinfo.gov. § 314.52 Notice of certification of invalidity, unenforceability, or noninfringement of a patent. (a) Notice of certification. (1) Each owner of the patent that is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the U.S. Patent and Trademark Office; and (2) The holder of the approved NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act for each drug product which is claimed by the patent or a use of which is claimed by the patent and for which the applicant is seeking approval, or, if the NDA holder does not reside or maintain a place of business within the United States, the NDA holder's attorney, agent, or other authorized official. The name and address of the NDA holder or its attorney, agent, or authorized official may be obtained by sending a written or electronic communication to the Central Document Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or to the Orange Book Staff at the email address listed on the Agency's Web site at http://www.fda.gov. (3) This paragraph (a) does not apply to a method-of-use patent that does not claim a use for which the applicant is seeking approval. (4) An applicant may send notice by an alternative method only if FDA has agreed in advance that the method will produce an acceptable form of documentation. (b) Sending the notice. (2) Any notice required by paragraph (a) of this section is invalid if it is sent before the date of filing described in § 314.101(a)(2) or, if FDA notifies the applicant that FDA has refused to file the 505(b)(2) application, before the date described in § 314.101(a)(3) on which the 505(b)(2) application is filed. The applicant will not have complied with this paragraph (b) until it sends valid notice. (3) The applicant must submit to FDA an amendment to its 505(b)(2) application that includes a statement certifying that the notice has been provided to each person identified under paragraph (a) of this section and that the notice met the content requirement under paragraph (c) of this section. A copy of the notice itself need not be submitted to the Agency. (c) Content of a notice. (1) A statement that a 505(b)(2) application that contains any required bioavailability or bioequivalence studies has been submitted by the applicant and filed by FDA. (2) The NDA number. (3) The established name, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act, of the proposed drug product. (4) The active ingredient, strength, and dosage form of the proposed drug product. (5) The patent number and expiration date of each patent on the list alleged to be invalid, unenforceable, or not infringed. (6) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed. The applicant must include in the detailed statement: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed. (ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation. (7) If the applicant alleges that the patent will not be infringed and the applicant seeks to preserve the option to later file a civil action for declaratory judgment in accordance with section 505(c)(3)(D) of the Federal Food, Drug, and Cosmetic Act, then the notice must be accompanied by an offer of confidential access to the 505(b)(2) application for the sole and limited purpose of evaluating possible infringement of the patent that is the subject of the paragraph IV certification. (8) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant. (d) Amendment or supplement to a 505(b)(2) application. (2) If, before the date of filing described in § 314.101(a)(2) or (3), as applicable, an applicant submits a paragraph IV certification in an amendment, the applicant must send the notice required by paragraph (a) of this section in accordance with the procedures in paragraph (b) of this section. (3) An applicant that submits an amendment or supplement to seek approval of a different strength must provide notice of any paragraph IV certification in accordance with paragraph (d)(1) or (2) of this section, as applicable. (e) Documentation of timely sending and receipt of notice. (f) Forty-five day period after receipt of notice. (g) Designated delivery services. (i) Is available to the general public throughout the United States; (ii) Records electronically to its database, kept in the regular course of its business, or marks on the cover in which any item referred to in this section is to be delivered, the date on which such item was given to such trade or business for delivery; and (iii) Provides overnight or 2-day delivery service throughout the United States. (2) FDA may periodically issue guidance regarding designated delivery services. [81 FR 69641, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019] § 314.53 Submission of patent information. (a) Who must submit patent information. (b) Patents for which information must be submitted and patents for which information must not be submitted General requirements. 3 (2) Test data for submission of patent information for patents that claim only a polymorph. (i) A full description of the polymorphic form of the drug substance, including its physical and chemical characteristics and stability; 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 polymorphic form of the drug substance; (ii) The executed batch record for a drug product containing the polymorphic form of the drug substance and documentation that the batch was manufactured under current good manufacturing practice requirements; (iii) Demonstration of bioequivalence between the executed batch of the drug product that contains the polymorphic form of the drug substance and the drug product as described in the NDA; (iv) A list of all components used in the manufacture of the drug product containing the polymorphic form and a statement of the composition of the drug product; a statement of the specifications and analytical methods for each component; 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 release and stability data complying with the approved product specifications to demonstrate pharmaceutical equivalence and comparable product stability; and (v) Comparative in vitro dissolution testing on 12 dosage units each of the executed test batch and the NDA product. (c) Reporting requirements General requirements. http://www.fda.gov (2) Drug substance (active ingredient), drug product (formulation or composition), and method-of-use patents Original declaration. (A) NDA number; (B) The NDA applicant's name, full address, phone number and, if available, fax number and email address; (C) Trade name (or proposed trade name) of new drug; (D) Active ingredient(s) of new drug; (E) Strength(s) of new drug; (F) Dosage form(s) and route(s) of administration of new drug, and whether the applicant proposes to market the new drug for prescription use or over-the-counter use; (G) U.S. patent number, issue date, and expiration date of patent submitted; (H) The patent owner's name, full address, phone number and, if available, fax number and email address; (I) The name, full address, phone number and, if available, fax number and email address of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification under section 505(b)(3) and (j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and §§ 314.52 and 314.95 (if patent owner or NDA applicant or holder does not reside or have a place of business within the United States); (J) Information on whether the patent has been submitted previously for the NDA or supplement; (K) If the patent has been submitted previously for listing, identify all change(s) from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action or procedure; (L) Information on whether the patent is a product-by-process patent in which the product claimed is novel; (M) Information on the drug substance (active ingredient) patent, including the following: ( 1 ( 2 ( 3 ( 4 ( 5 (N) Information on the drug product (composition/formulation) patent, including the following: ( 1 ( 2 (O) Information on each method-of-use patent, including the following: ( 1 ( 2 ( 3 (P) Whether there are no relevant patents that claim the drug substance (active ingredient), drug product (formulation or composition), or method(s) of use, for which the applicant is seeking approval and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product; (Q) A signed verification that states: The undersigned declares that this is an accurate and complete submission of patent information for the NDA, amendment, or supplement pending under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-sensitive patent information is submitted pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR 314.53 and this submission complies with the requirements of the regulation. I verify under penalty of perjury that the foregoing is true and correct. (R) Information on whether the applicant, patent owner or attorney, agent, representative, or other authorized official signed the form; the name of the person; and the full address, phone number and, if available, the fax number and email address; and (S) Exceptions to required submission of patent information: ( 1 ( 2 ( 3 (ii) Submission of patent information upon and after approval. (A) NDA number; (B) The NDA holder's name, full address, phone number and, if available, fax number and email address; (C) Trade name of new drug; (D) Active ingredient(s) of new drug; (E) Strength(s) of new drug; (F) Dosage form(s) and route(s) of administration of new drug, and whether the new drug is approved for prescription use or over-the-counter use; (G) Approval date of NDA or supplement; (H) U.S. patent number, issue date, and expiration date of patent submitted; (I) The patent owner's name, full address, phone number and, if available, fax number and email address; (J) The name, full address, phone number and, if available, fax number and email address of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification under section 505(b)(3) and (j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and §§ 314.52 and 314.95 (if patent owner or NDA applicant or holder does not reside or have a place of business within the United States); (K) Information on whether the patent has been submitted previously for the NDA or supplement; (L) If the patent has been submitted previously for listing, identify all change(s) from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action or procedure; (M) Information on whether the patent is a product-by-process patent in which the product claimed is novel; (N) Information on the drug substance (active ingredient) patent, including the following: ( 1 ( 2 ( 3 ( 4 ( 5 (O) Information on the drug product (composition/formulation) patent, including the following: ( 1 ( 2 (P) Information on each method-of-use patent, including the following: ( 1 ( 2 ( 3 ( 4 (Q) Whether there are no relevant patents that claim the approved drug substance (active ingredient), the approved drug product (formulation or composition), or approved method(s) of use and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product; (R) A signed verification that states: The undersigned declares that this is an accurate and complete submission of patent information for the NDA, amendment, or supplement approved under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-sensitive patent information or response to a request under 21 CFR 314.53(f)(1) is submitted pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR 314.53 and this submission complies with the requirements of the regulation. I verify under penalty of perjury that the foregoing is true and correct. (S) Information on whether the applicant, patent owner or attorney, agent, representative, or other authorized official signed the form; the name of the person; and the full address, phone number and, if available, the fax number and email address; and (T) Exceptions to required submission of patent information: ( 1 ( 2 ( 3 (3) No relevant patents. (4) Authorized signature. (d) When and where to submit patent information Original NDA. (2) Supplements. (A) To add or change the dosage form or route of administration; (B) To add or change the strength; or (C) To change the drug product from prescription use to over-the-counter use. (ii) If the applicant submits a supplement for a change other than one of the changes listed under paragraph (d)(2)(i) of this section (for example, to change the formulation, to add a new indication or other condition of use, or to make any other patented change regarding the drug substance, drug product, or any method of use), the following patent information submission requirements apply: (A) If existing patents for which information required by paragraph (c) of this section has already been submitted to FDA for the product approved in the original NDA claim the changed product, the applicant is not required to resubmit this patent information pursuant to paragraph (c) of this section unless the published description of the patented method of use would change upon approval of the supplement, and FDA will continue to list this patent information for the product; (B) If one or more existing patents for which information has already been submitted to FDA no longer claim the changed product, the applicant must submit a request under paragraph (f)(2)(iv) of this section to remove that patent information from the list at the time of approval of the supplement; (C) If one or more existing drug substance (active ingredient), drug product (formulation and composition), or method-of-use patents claim the changed product for which approval is sought in the supplement and such patent information has not been submitted to FDA, the applicant must submit the patent information required under paragraph (c) of this section. (3) Newly issued patents. (4) Submission of Forms FDA 3542a and 3542 Patent information submitted with the filing of an NDA, amendment, or supplement. (ii) Patent information submitted upon and after approval of an NDA or supplement. (5) Submission date. (6) Identification. i.e., (e) Public disclosure of patent information. 3 http://www.fda.gov (f) Correction of patent information errors Requests by persons other than the NDA holder. http://www.fda.gov (i) Communication with the NDA holder Drug substance or drug product claim. (B) Method-of-use claim. ( 1 ( 2 (ii) Patent certification or statement during and after patent listing dispute. (iii) Information on patent listing disputes. (2) Requests by the NDA holder Patents or patent claims that no longer meet the statutory requirements for listing. (ii) Patent term restoration. (iii) Submission of corrections or changes to patent information. (iv) Submission of patent withdrawals and requests to remove a patent from the list. (A) The NDA number to which the request applies; (B) Each product(s) approved in the NDA to which the request applies; and (C) The patent number. [81 FR 69643, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019] § 314.54 Procedure for submission of a 505(b)(2) application requiring investigations for approval of a new indication for, or other change from, a listed drug. (a) The Federal Food, Drug, and Cosmetic Act does not permit approval of an ANDA for a new indication, nor does it permit approval of other changes in a listed drug if investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the change. Any person seeking approval of a drug product that represents a modification of a listed drug (e.g., a new indication or new dosage form) and for which investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the changes may, except as provided in paragraph (b) of this section, submit a 505(b)(2) application. This 505(b)(2) application need contain only that information needed to support the modification(s) of the listed drug. (1) The applicant must submit a complete archival copy of the application that contains the following: (i) The information required under § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and (g), except that § 314.50(d)(1)(ii)( c (ii) The information required under § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support the safety and effectiveness of the drug product. (iii) Identification of each listed drug for which FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug's application holder, and listed drug's approved NDA number. The listed drug(s) identified as relied upon must include a drug product approved in an NDA that: (A) Is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted; and (B) Was approved before the original 505(b)(2) application was submitted. (iv) If the applicant is seeking approval only for a new indication and not for the indications approved for the listed drug on which the applicant relies, a certification so stating. (v) Any patent information required under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act with respect to any patent which claims the drug for which approval is sought or a method of using such drug and to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product. (vi) Any patent certification or statement required under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to any relevant patents that claim the listed drug(s) on which investigations relied on by the applicant for approval of the application were conducted, or that claim a use for the listed drug(s). A 505(b)(2) applicant seeking approval of a drug that is pharmaceutically equivalent to a listed drug approved in an NDA implicitly relies upon one such pharmaceutically equivalent listed drug. (vii) If the applicant believes the change for which it is seeking approval is entitled to a period of exclusivity, the information required under § 314.50(j). (2) The applicant must submit a review copy that contains the technical sections described in § 314.50(d)(1), except that the section described in § 314.50(d)(1)(ii)( c (3) The information required by § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on which the applicant relies must be satisfied by reference to the listed drug under paragraph (a)(1)(iii) of this section. (4) The applicant must submit a field copy of the 505(b)(2) application that contains the technical section described in § 314.50(d)(1), a copy of the information required under § 314.50(a) and (c), and certification that the field copy is a true copy of the technical section described in § 314.50(d)(1) contained in the archival and review copies of the 505(b)(2) application. (b) A 505(b)(2) application may not be submitted under this section for a drug product whose only difference from a listed drug is that: (1) The extent to which its active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the listed drug; or (2) The rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug. [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. 28, 1992, as amended at 58 FR 47351, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 81 FR 69647, Oct. 6, 2016] § 314.55 Pediatric use information. (a) Required assessment. (b) Deferred submission. (2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the drug product may be approved for use in adults subject to the requirement that the applicant submit the required assessments within a specified time. (c) Waivers General. (2) Full waiver. (i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used in a substantial number of pediatric patients; (ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or (iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in all pediatric age groups. (3) Partial waiver. (i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group; (ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed; (iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in that age group; or (iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed. (4) FDA action on waiver. (5) Definition of “meaningful therapeutic benefit”. (i) If approved, the drug would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population. Examples of how improvement might be demonstrated include, for example, evidence of increased effectiveness in treatment, prevention, or diagnosis of disease, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of compliance, or evidence of safety and effectiveness in a new subpopulation; or (ii) The drug is in a class of drugs or for an indication for which there is a need for additional therapeutic options. (d) Exemption for orphan drugs. [63 FR 66670, Dec. 2, 1998] § 314.56 Nonprescription drug product with an additional condition for nonprescription use (ACNU). (a) Definition. (1) Additional condition for nonprescription use (2) [Reserved] (b) Separate application required for a nonprescription drug product with an ACNU (c) Specific requirements for an application for a nonprescription drug product with an ACNU. (1) New drug application (NDA). (i) A statement regarding whether the purpose of the ACNU is to ensure appropriate self-selection or appropriate actual use, or both, by consumers of the nonprescription drug product with an ACNU without the supervision of a practitioner licensed by law to administer such drug; (ii) A statement regarding the necessity of the ACNU; (iii) A description of how the ACNU ensures appropriate self-selection or appropriate actual use, or both; (iv) A description of the key elements of the ACNU, including: (A) The additional condition implemented by the applicant to be fulfilled by the consumer to obtain the nonprescription drug product with an ACNU; (B) The labeling specifically associated with the ACNU; and (C) The criteria by which the consumer would successfully fulfill the ACNU, including a description of the specific actions to be taken by a consumer or required responses to be provided by a consumer; (v) Adequate data or other information that demonstrates the necessity of the ACNU to ensure appropriate self-selection or appropriate actual use, or both; (vi) Adequate data or other information that demonstrates the effect of the ACNU on the appropriate self-selection or appropriate actual use, or both; and (vii) A description of the specific way(s) the ACNU is operationalized. (2) Abbreviated new drug application (ANDA). (i) A statement regarding whether the purpose of the ACNU is to ensure appropriate self-selection or appropriate actual use, or both, by consumers of the nonprescription drug product with an ACNU without the supervision of a practitioner licensed by law to administer such drug, which must be the same as the purpose of the ACNU for its reference listed drug (RLD); (ii) Information demonstrating that the key elements of the ACNU are the same as the key elements of the ACNU for its RLD; and (iii) A description of the specific way(s) the ACNU is operationalized. If an applicant believes the ACNU is operationalized in the same way as the RLD, include information demonstrating that the ACNU is operationalized in the same way as the RLD. If a different way to operationalize the proposed ACNU is used, include information to show that this different way to operationalize the proposed ACNU achieves the same purpose as the ACNU for its RLD and that the differences from the RLD are otherwise acceptable in an ANDA. (d) Simultaneous marketing of nonprescription and prescription drug products. e.g., [89 FR 105330, Dec. 26, 2024] § 314.60 Amendments to an unapproved NDA, supplement, or resubmission. (a) Submission of NDA. (b) Submission of major amendment. (2) Submission of a major amendment to an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement more than 3 months before the end of the initial review cycle will not extend the cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle. (3) Submission of an amendment to an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement that is not a major amendment will not extend the initial review cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle. (4) Submission of a major amendment to a manufacturing supplement within 2 months of the end of the initial review cycle constitutes an agreement by the applicant under section 505(c) of the Federal Food, Drug, and Cosmetic Act to extend the initial review cycle by 2 months. FDA may instead defer review of the amendment until the subsequent review cycle. If the agency extends the initial review cycle for a manufacturing supplement under this paragraph, the division responsible for reviewing the supplement will notify the applicant of the extension. The initial review cycle for a manufacturing supplement may be extended only once due to submission of a major amendment. FDA may, at its discretion, review any subsequent major amendment during the initial review cycle (as extended) or defer review until the subsequent review cycle. (5) Submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not extend the initial review cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle. (6) A major amendment may not include data to support an indication or claim that was not included in the original NDA, supplement, or resubmission, but it may include data to support a minor modification of an indication or claim that was included in the original NDA, supplement, or resubmission. (7) When FDA defers review of an amendment until the subsequent review cycle, the agency will notify the applicant of the deferral in the complete response letter sent to the applicant under § 314.110 of this part. (c) Limitation on certain amendments. (i) The unapproved NDA is for a drug for which a previous NDA has been approved and granted a period of exclusivity in accordance with section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act that has not expired; (ii) The applicant seeks to amend the unapproved NDA to include a published report of an investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug; (iii) The applicant has not obtained a right of reference or use to the investigation described in paragraph (c)(1)(ii) of this section; and (iv) The report of the investigation described in paragraph (c)(1)(ii) of this section would be essential to the approval of the unapproved NDA. (2) The submission of an amendment described in paragraph (c)(1) of this section will cause the unapproved NDA to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt by FDA of the amendment. The amendment will be considered a resubmission of the NDA, which may not be accepted except as provided in accordance with section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act. (d) Field copy. (e) Different drug. (f) Patent certification requirements. (i) To add a new indication or other condition of use; (ii) To add a new strength; (iii) To make other than minor changes in product formulation; or (iv) To change the physical form or crystalline structure of the active ingredient. (2) If the amendment to the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in paragraph (f)(1) of this section. [50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. 8, 2004; 73 FR 39608, July 10, 2008; 81 FR 69648, Oct. 6, 2016] § 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. If, by the time it receives such notice, the agency has identified any deficiencies in the application, we will list such deficiencies in the letter we send the applicant acknowledging the withdrawal. 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 § 20.45 of FDA's public information regulations. [50 FR 7493, Feb. 22, 1985, as amended at 68 FR 25287, May 12, 2003; 73 FR 39609, July 10, 2008] § 314.70 Supplements and other changes to an approved NDA. (a) Changes to an approved NDA. (ii) The submission and grant of a written request for an exception or alternative under § 201.26 of this chapter satisfies the applicable requirements in paragraphs (a) through (c) of this section. However, any grant of a request for an exception or alternative under § 201.26 of this chapter must be reported as part of the annual report to the NDA under paragraph (d) of this section. (2) The NDA holder must assess the effects of the change before distributing a drug product made with a manufacturing change. (3) Notwithstanding the requirements of paragraphs (b) and (c) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the product or in an annual report). (4) The applicant must promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented in accordance with paragraphs (b) and (c) of this section. (5) Except for a supplement providing for a change in the labeling, the applicant must include in each supplement and amendment to a supplement providing for a change under paragraph (b) or (c) of this section a statement certifying that a field copy has been provided in accordance with § 314.440(a)(4). (6) A supplement or annual report must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the submission. (b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes). (2) These changes include, but are not limited to: (i) Except those described in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients, or in the specifications provided in the approved NDA; (ii) Changes requiring completion of studies in accordance with part 320 of this chapter to demonstrate the equivalence of the drug product to the drug product as manufactured without the change or to the reference listed drug; (iii) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product, or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation; (iv) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance; (v) The following labeling changes: (A) Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section; (B) If applicable, any change to a Medication Guide required under part 208 of this chapter, except for changes in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and (C) Any change to the information required by § 201.57(a) of this chapter, with the following exceptions that may be reported in an annual report under paragraph (d)(2)(x) of this section: ( 1 ( 2 (vi) Changes in a drug product container closure system that controls the drug product delivered to a patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride, vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component that may affect the impurity profile of the drug product. (vii) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following: (A) Changes in the virus or adventitious agent removal or inactivation method(s); (B) Changes in the source material or cell line; and (C) Establishment of a new master cell bank or seed. (viii) Changes to a drug product under an NDA that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that NDA. (3) The applicant must obtain approval of a supplement from FDA prior to distribution of a drug product made using a change under paragraph (b) of this section. Except for submissions under paragraph (e) of this section, the following information must be contained in the supplement: (i) A detailed description of the proposed change; (ii) The drug product(s) involved; (iii) The manufacturing site(s) or area(s) affected; (iv) A description of the methods used and studies performed to assess the effects of the change; (v) The data derived from such studies; (vi) For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; and (vii) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section. (4) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement should be plainly marked: “Prior Approval Supplement-Expedited Review Requested.” (c) Changes requiring supplement submission at least 30 days prior to distribution of the drug product made using the change (moderate changes). (2) These changes include, but are not limited to: (i) A change in the container closure system that does not affect the quality of the drug product, except those described in paragraphs (b) and (d) of this section; and (ii) Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including: (A) An increase or decrease in production scale during finishing steps that involves different equipment; and (B) Replacement of equipment with that of a different design that does not affect the process methodology or process operating parameters. (iii) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements. (3) A supplement submitted under paragraph (c)(1) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is to be made. The supplement must be labeled “Supplement—Changes Being Effected in 30 Days” or, if applicable under paragraph (c)(6) of this section, “Supplement—Changes Being Effected.” (4) Pending approval of the supplement by FDA, except as provided in paragraph (c)(6) of this section, distribution of the drug product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(3)(i) through (b)(3)(vii) of this section must be contained in the supplement. (5) The applicant must not distribute the drug product made using the change if within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either: (i) The change requires approval prior to distribution of the drug product in accordance with paragraph (b) of this section; or (ii) Any of the information required under paragraph (c)(4) of this section is missing; the applicant must not distribute the drug product made using the change until the supplement has been amended to provide the missing information. (6) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved NDA may commence distribution of the drug product involved upon receipt by the agency of a supplement for the change. These changes include, but are not limited to: (i) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess; (ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another; (iii) Changes in the labeling to reflect newly acquired information, except for changes to the information required in § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish any of the following: (A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter; (B) To add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage; (C) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product; (D) To delete false, misleading, or unsupported indications for use or claims for effectiveness; or (E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision. (7) If the agency disapproves the supplemental NDA, it may order the manufacturer to cease distribution of the drug product(s) made with the manufacturing change. (d) Changes to be described in an annual report (minor changes). (2) These changes include, but are not limited to: (i) Any change made to comply with a change to an official compendium, except a change described in paragraph (c)(2)(iii) of this section, that is consistent with FDA statutory and regulatory requirements. (ii) The deletion or reduction of an ingredient intended to affect only the color of the drug product; (iii) Replacement of equipment with that of the same design and operating principles except those equipment changes described in paragraph (c) of this section; (iv) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another; (v) A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the NDA or published in an official compendium; (vi) An extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the NDA; (vii) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved NDA, or deletion of an alternative analytical procedure; (viii) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint; (ix) 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; and (x) An editorial or similar minor change in labeling, including a change to the information allowed by paragraphs (b)(2)(v)(C)( 1 2 (3) For changes under this category, the applicant is required to submit in the annual report: (i) A statement by the holder of the approved NDA that the effects of the change have been assessed; (ii) A full description of the manufacturing and controls changes, including the manufacturing site(s) or area(s) involved; (iii) The date each change was implemented; (iv) Data from studies and tests performed to assess the effects of the change; and, (v) For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, a cross-reference to relevant validation protocols and/or standard operating procedures. (e) Protocols. (f) Patent information. (g) Claimed exclusivity. (h) Different drug. [69 FR 18764, Apr. 8, 2004, as amended at 71 FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 81 FR 69648, Oct. 6, 2016] § 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 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; except that a supplement for a change other than a change in labeling is required also to contain a field copy. (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 except as specified otherwise in this part. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, July 10, 2008] § 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 in 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 § 20.45 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. [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, 2003] § 314.80 Postmarketing reporting of adverse drug experiences. (a) Definitions. Adverse drug experience. Individual case safety report (ICSR). ICSR attachments. Disability. Life-threatening adverse drug experience. immediate i.e. Serious adverse drug experience. Unexpected adverse drug experience. i.e. (b) Review of adverse drug experiences. (c) Reporting requirements. (1)(i) Postmarketing 15-day “Alert reports”. (ii) Postmarketing 15-day “Alert reports”—followup. (iii) Submission of reports. (A) A copy of each adverse drug experience report; (B) The date the report was received by the nonapplicant; (C) The date the report was submitted to the applicant; and (D) The name and address of the applicant. (2) Periodic adverse drug experience reports. (ii) Each periodic report is required to contain: (A) Descriptive information. 1 ( 2 ( 3 ( 4 (B) ICSRs for serious, expected, and nonserious adverse drug experiences. (iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse drug experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience. (d) Scientific literature. i.e. (e) Postmarketing studies. (f) Information reported on ICSRs. (1) Patient information. (i) Patient identification code; (ii) Patient age at the time of adverse drug experience, or date of birth; (iii) Patient gender; and (iv) Patient weight. (2) Adverse drug experience. (i) Outcome attributed to adverse drug experience; (ii) Date of adverse drug experience; (iii) Date of ICSR submission; (iv) Description of adverse drug experience (including a concise medical narrative); (v) Adverse drug experience term(s); (vi) Description of relevant tests, including dates and laboratory data; and (vii) Other relevant patient history, including preexisting medical conditions. (3) Suspect medical product(s). (i) Name; (ii) Dose, frequency, and route of administration used; (iii) Therapy dates; (iv) Diagnosis for use (indication); (v) Whether the product is a prescription or nonprescription product; (vi) Whether the product is a combination product as defined in § 3.2(e) of this chapter; (vii) Whether adverse drug experience abated after drug use stopped or dose reduced; (viii) Whether adverse drug experience reappeared after reintroduction of drug; (ix) Lot number; (x) Expiration date; (xi) National Drug Code (NDC) number; and (xii) Concomitant medical products and therapy dates. (4) Initial reporter information. (i) Name, address, and telephone number; (ii) Whether the initial reporter is a health care professional; and (iii) Occupation, if a health care professional. (5) Applicant information. (i) Applicant name and contact office address; (ii) Telephone number; (iii) Report source, such as spontaneous, literature, or study; (iv) Date the report was received by applicant; (v) Application number and type; (vi) Whether the ICSR is a 15-day “Alert report”; (vii) Whether the ICSR is an initial report or followup report; and (viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s). (g) Electronic format for submissions. (2) An applicant or nonapplicant may request, in writing, a temporary waiver of the requirements in paragraph (g)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (g)(1) of this section. (h) Multiple reports. (i) Patient privacy. (j) Recordkeeping. (k) Withdrawal of approval. (l) Disclaimer. [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, 1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 62 FR 34168, June 25, 1997; 62 FR 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 1998; 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004; 74 FR 13113, Mar. 26, 2009; 79 FR 33088, June 10, 2014] § 314.81 Other postmarketing reports. (a) Applicability. (b) Reporting requirements. (1) 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 specification established for it in the application. (2) Annual report. (i) Summary. (ii)( a Distribution data. ( b Authorized generic drugs. [email protected] (iii) Labeling. a ( b i.e. ( c (iv) Chemistry, manufacturing, and controls changes. a ( b (v) Nonclinical laboratory studies. (vi) Clinical data. a ( b ( c (vii) Status reports of postmarketing study commitments. ( a Content of status report. ( 1 Applicant's name. ( 2 Product name. ( 3 NDA, ANDA, and supplement number. ( 4 Date of U.S. approval of NDA or ANDA. ( 5 Date of postmarketing study commitment. ( 6 Description of postmarketing study commitment. ( 7 Schedule for completion and reporting of the postmarketing study commitment. ( 8 Current status of the postmarketing study commitment. ( i Pending. ( ii Ongoing. a 7 ( iii Delayed. a 7 ( iv Terminated. ( v Submitted. ( 9 Explanation of the study's status. a 8 a 7 ( b Public disclosure of information. (viii) Status of other postmarketing studies. (ix) Log of outstanding regulatory business. (3) Other reporting Advertisements and promotional labeling. http://www.fda.gov/opacom/morechoices/fdaforms/cder.html. (ii) Special reports. (iii) Notification of a permanent discontinuance or an interruption in manufacturing. a ( 1 ( 2 ( b a ( 1 ( 2 ( c a ( 1 ( 2 ( 3 ( 4 ( 5 ( d 1 ( i ( ii ( iii ( iv ( 2 ( e a b ( 1 a c ( 2 e a ( f Drug shortage shortage Intended for use in the prevention or treatment of a debilitating disease or condition Life supporting or life sustaining Meaningful disruption (iv) Withdrawal of approved drug product from sale. a ( 1 ( 2 ( 3 ( 4 ( b a 1 4 ( c a (v) Report of an additional condition for nonprescription use (ACNU) failure for a nonprescription drug product with an ACNU ACNU failure. ( 1 ( 2 (B) Review of ACNU failure. (C) Report of ACNU failure. (D) Content of Report of ACNU failure. ( 1 Required information. ( 2 Additional information if available to the applicant. ( i ( ii ( iii ( iv ( v ( vi ( vii ( viii ( ix ( x (E) Submission. 1 ( 2 (F) Electronic format for submissions. 1 ( 2 1 (G) Recordkeeping. (c) General requirements Multiple applications. (2) Patient identification. (d) Withdrawal of approval. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0001) [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815, Feb. 20, 2001; 68 FR 69019, Dec. 11, 2003; 69 FR 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; 72 FR 58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, 2009; 74 FR 37167, July 28, 2009; 76 FR 78539, Dec. 19, 2011; 80 FR 38938, July 8, 2015; 81 FR 60221, Aug. 31, 2016; 89 FR 105331, Dec. 26, 2024] § 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 NDA, or in an amendment or supplement to an NDA. 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 NDA or compliance cannot be achieved; (2) The applicant's alternative submission satisfies the requirement; or (3) The applicant's submission otherwise justifies a waiver. (c) If FDA grants the applicant's waiver request with respect to a requirement under §§ 314.50 through 314.81, the waived requirement will not constitute a basis for refusal to approve an NDA under § 314.125. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, 2002; 81 FR 69649, Oct. 6, 2016] Subpart C—Abbreviated Applications Source: 57 FR 17983, Apr. 28, 1992, unless otherwise noted. § 314.92 Drug products for which abbreviated applications may be submitted. (a) Abbreviated applications are suitable for the following drug products within the limits set forth under § 314.93: (1) Drug products that are the same as a listed drug. A “listed drug” is defined in § 314.3. For determining the suitability of an abbreviated new drug application, the term “same as” means identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted. If a listed drug has been voluntarily withdrawn from or not offered for sale by its manufacturer, a person who wishes to submit an abbreviated new drug application for the drug shall comply with § 314.122. (2) [Reserved] (3) Drug products that have been declared suitable for an abbreviated new drug application submission by FDA through the petition procedures set forth under § 10.30 of this chapter and § 314.93. (b) FDA will publish in the list listed drugs for which abbreviated applications may be submitted. The list is available from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402, 202-783-3238. [57 FR 17983, Apr. 28, 1992, as amended at 64 FR 401, Jan. 5, 1999] § 314.93 Petition to request a change from a listed drug. (a) The only changes from a listed drug for which the agency will accept a petition under this section are those changes described in paragraph (b) of this section. Petitions to submit ANDAs for other changes from a listed drug will not be approved. (b) A person who wants to submit an ANDA for a drug product which is not identical to a listed drug in route of administration, dosage form, and strength, or in which one active ingredient is substituted for one of the active ingredients in a listed combination drug, must first obtain permission from FDA to submit such an ANDA. (c) To obtain permission to submit an ANDA for a change described in paragraph (b) of this section, a person must submit and obtain approval of a petition requesting the change. A person seeking permission to request such a change from a reference listed drug shall submit a petition in accordance with § 10.20 of this chapter and in the format specified in § 10.30 of this chapter. The petition shall contain the information specified in § 10.30 of this chapter and any additional information required by this section. If any provision of § 10.20 or § 10.30 of this chapter is inconsistent with any provision of this section, the provisions of this section apply. (d) The petitioner shall identify a listed drug and include a copy of the proposed labeling for the drug product that is the subject of the petition and a copy of the approved labeling for the listed drug. The petitioner may, under limited circumstances, identify more than one listed drug, for example, when the proposed drug product is a combination product that differs from the combination reference listed drug with regard to an active ingredient, and the different active ingredient is an active ingredient of a listed drug. The petitioner shall also include information to show that: (1) The active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those of the reference listed drug. (2) The drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use in the reference listed drug's labeling for which the applicant seeks approval. (3) If the proposed drug product is a combination product with one different active ingredient, including a different ester or salt, from the reference listed drug, that the different active ingredient has previously been approved in a listed drug or is a drug that does not meet the definition of “new drug” in section 201(p) of the Federal Food, Drug, and Cosmetic Act. (e) No later than 90 days after the date a petition that is permitted under paragraph (a) of this section is submitted, FDA will approve or disapprove the petition. (1) FDA will approve a petition properly submited under this section unless it finds that: (i) Investigations must be conducted to show the safety and effectiveness of the drug product or of any of its active ingredients, its route of administration, dosage form, or strength which differs from the reference listed drug; or (ii) For a petition that seeks to change an active ingredient, the drug product that is the subject of the petition is not a combination drug; or (iii) For a combination drug product that is the subject of the petition and has an active ingredient different from the reference listed drug: (A) The drug product may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted under § 314.94; or (B) The petition does not contain information to show that the different active ingredient of the drug product is of the same pharmacological or therapeutic class as the ingredient of the reference listed drug that is to be changed and that the drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use in the listed drug's labeling for which the applicant seeks approval; or (C) The different active ingredient is not an active ingredient in a listed drug or a drug that meets the requirements of section 201(p) of the Federal Food, Drug, and Cosmetic Act; or (D) The remaining active ingredients are not identical to those of the listed combination drug; or (iv) Any of the proposed changes from the listed drug would jeopardize the safe or effective use of the product so as to necessitate significant labeling changes to address the newly introduced safety or effectiveness problem; or (v) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons; or (vi) A drug product is approved in an NDA for the change described in the petition. (2) For purposes of this paragraph, “investigations must be conducted” means that information derived from animal or clinical studies is necessary to show that the drug product is safe or effective. Such information may be contained in published or unpublished reports. (3) If FDA approves a petition submitted under this section, the agency's response may describe what additional information, if any, will be required to support an ANDA for the drug product. FDA may, at any time during the course of its review of an ANDA, request additional information required to evaluate the change approved under the petition. (f)(1) FDA may withdraw approval of a petition if the agency receives any information demonstrating that the petition no longer satisfies the conditions under paragraph (e) of this section. (2) If, after approval of a petition and before approval of an ANDA submitted pursuant to the approved petition, a drug product is approved in an NDA for the change described in the petition, the petition and the listed drug identified in the petition can no longer be the basis for ANDA submission, irrespective of whether FDA has withdrawn approval of the petition. A person seeking approval for such drug product must submit a new ANDA that identifies the pharmaceutically equivalent reference listed drug as the basis for ANDA submission and comply with applicable regulatory requirements. [57 FR 17983, Apr. 28, 1992, as amended at 81 FR 69649, Oct. 6, 2016] § 314.94 Content and format of an ANDA. ANDAs are required to be submitted in the form and contain the information required under this section. Three copies of the ANDA are required, an archival copy, a review copy, and a field copy. FDA will maintain guidance documents on the format and content of ANDAs to assist applicants in their preparation. (a) ANDAs. (1) Application form. (2) Table of contents. (3) Basis for ANDA submission. (i) The name of the reference listed drug, including its dosage form and strength. For an ANDA based on an approved petition under § 10.30 of this chapter and § 314.93, the reference listed drug must be the same as the listed drug referenced in the approved petition. (ii) A statement as to whether, according to the information published in the list, the reference listed drug is entitled to a period of marketing exclusivity under section 505(j)(5)(F) of the Federal Food, Drug, and Cosmetic Act. (iii) For an ANDA based on an approved petition under § 10.30 of this chapter and § 314.93, a reference to the FDA-assigned docket number for the petition and a copy of FDA's correspondence approving the petition. (4) Conditions of use. (ii) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section. (5) Active ingredients. (A) A statement that the active ingredient of the proposed drug product is the same as that of the reference listed drug. (B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section. (ii) For a combination drug product, information to show that the active ingredients are the same as those of the reference listed drug except for any different active ingredient that has been the subject of an approved petition, as follows: (A) A statement that the active ingredients of the proposed drug product are the same as those of the reference listed drug, or if one of the active ingredients differs from one of the active ingredients of the reference listed drug and the ANDA is submitted under the approval of a petition under § 314.93 to vary such active ingredient, information to show that the other active ingredients of the drug product are the same as the other active ingredients of the reference listed drug, information to show that the different active ingredient is an active ingredient of another listed drug or of a drug that does not meet the definition of “new drug” in section 201(p) of the Federal Food, Drug, and Cosmetic Act, and such other information about the different active ingredient that FDA may require. (B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section. (6) Route of administration, dosage form, and strength. (A) A statement that the route of administration, dosage form, and strength of the proposed drug product are the same as those of the reference listed drug. (B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section. (ii) If the route of administration, dosage form, or strength of the drug product differs from the reference listed drug and the ANDA is submitted under an approved petition under § 314.93, such information about the different route of administration, dosage form, or strength that FDA may require. (7) Bioequivalence. (ii) If the ANDA is submitted pursuant to a petition approved under § 314.93, the results of any bioavailability or bioequivalence testing required by the Agency, or any other information required by the Agency to show that the active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those in the reference listed drug and that the proposed drug product can be expected to have the same therapeutic effect as the reference listed drug. If the proposed drug product contains a different active ingredient than the reference listed drug, FDA will consider the proposed drug product to have the same therapeutic effect as the reference listed drug if the applicant provides information demonstrating that: (A) There is an adequate scientific basis for determining that substitution of the specific proposed dose of the different active ingredient for the dose of the member of the same pharmacological or therapeutic class in the reference listed drug will yield a resulting drug product whose safety and effectiveness have not been adversely affected. (B) The unchanged active ingredients in the proposed drug product are bioequivalent to those in the reference listed drug. (C) The different active ingredient in the proposed drug product is bioequivalent to an approved dosage form containing that ingredient and approved for the same indication as the proposed drug product or is bioequivalent to a drug product offered for that indication which does not meet the definition of “new drug” under section 201(p) of the Federal Food, Drug, and Cosmetic Act. (iii) For each in vivo or in vitro bioequivalence study contained in the ANDA: (A) A description of the analytical and statistical methods used in each study; and (B) With respect to each study involving human subjects, a statement that the study either was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105 of this chapter, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter. (8) Labeling Listed drug labeling. (ii) Copies of proposed labeling. (iii) Statement on proposed labeling. (iv) Comparison of approved and proposed labeling. (9) Chemistry, manufacturing, and controls. c (ii) Inactive ingredients. (iii) Inactive ingredient changes permitted in drug products intended for parenteral use. (iv) Inactive ingredient changes permitted in drug products intended for ophthalmic or otic use. (v) Inactive ingredient changes permitted in drug products intended for topical use. (10) Samples. (11) Other. (12) Patent certification Patents claiming drug substance, drug product, or method of use. ( 1 ( 2 ( 3 ( 4 i I, ( name of applicant), is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of name of proposed drug product ( ii (B) If the ANDA refers to a listed drug that is itself a licensed generic product of a patented drug first approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act, an appropriate patent certification or statement under paragraph (a)(12)(i) and/or (iii) of this section with respect to each patent that claims the first-approved patented drug or that claims a use for such drug. (ii) No relevant patents. In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed drug referred to in this ANDA or that claim a use of the listed drug. (iii) Method-of-use patent. (B) If the labeling of the drug product for which the applicant is seeking approval includes an indication or other condition of use that, according to the patent information submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 or in the opinion of the applicant, is claimed by a method-of-use patent, an applicable certification under paragraph (a)(12)(i) of this section. (iv) [Reserved] (v) Licensing agreements. (vi) Untimely filing of patent information. ( 1 ( 2 ( 3 (B) An applicant whose ANDA is submitted after the NDA holder's untimely filing of patent information, or whose pending ANDA was previously submitted but did not contain an appropriate patent certification or statement at the time of the patent submission, must submit a certification under paragraph (a)(12)(i) of this section and/or a statement under paragraph (a)(12)(iii) of this section as to that patent. (vii) Disputed patent information. (viii) Amended certifications. (A) After finding of infringement. 3 (B) After request to remove a patent or patent information from the list. (C) Other amendments. 1 2 ( i ( ii ( 2 (13) Financial certification or disclosure statement. (b) Drug products subject to the Drug Efficacy Study Implementation (DESI) review. (c) [Reserved] (d) Format of an ANDA. (i) Format of submission. (ii) Labeling. (iii) Electronic format submissions. (2) For ANDAs, the applicant must submit a review copy of the ANDA that contains two separate sections. One section must contain the information described under paragraphs (a)(2) through (6) and (8) and (9) of this section and section 505(j)(2)(A)(vii) of the Federal Food, Drug, and Cosmetic Act and a copy of the analytical procedures and descriptive information needed by FDA's laboratories to perform tests on samples of the proposed drug product and to validate the applicant's analytical procedures. The other section must contain the information described under paragraphs (a)(3), (7), and (8) of this section. Each of the sections in the review copy is required to contain a copy of the application form described under paragraph (a) of this section. (3) [Reserved] (4) The applicant may obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the ANDA. (5) The applicant must submit a field copy of the ANDA that contains the technical section described in paragraph (a)(9) of this section, a copy of the application form required under paragraph (a)(1) of this section, and a certification that the field copy is a true copy of the technical section described in paragraph (a)(9) of this section contained in the archival and review copies of the ANDA. [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003; 69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, 2009; 76 FR 13880, Mar. 15, 2011; 81 FR 69649, Oct. 6, 2016] § 314.95 Notice of certification of invalidity, unenforceability, or noninfringement of a patent. (a) Notice of certification. (1) Each owner of the patent that is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the U.S. Patent and Trademark Office; and (2) The holder of the approved NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act for the listed drug that is claimed by the patent and for which the applicant is seeking approval, or, if the NDA holder does not reside or maintain a place of business within the United States, the NDA holder's attorney, agent, or other authorized official. The name and address of the NDA holder or its attorney, agent, or authorized official may be obtained by sending a written or electronic communication to the Central Document Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266 or to the Orange Book Staff at the email address listed on the Agency's Web site at http://www.fda.gov (3) This paragraph (a) does not apply to a method-of-use patent that does not claim a use for which the applicant is seeking approval. (4) An applicant may send notice by an alternative method only if FDA has agreed in advance that the method will produce an acceptable form of documentation. (b) Sending the notice. (2) Any notice required by paragraph (a) of this section is invalid if it is sent before the applicant's receipt of a paragraph IV acknowledgment letter, or before the first working day after the day the patent is published in the list. The applicant will not have complied with this paragraph (b) until it sends valid notice. (3) The applicant must submit to FDA an amendment to its ANDA that includes a statement certifying that the notice has been provided to each person identified under paragraph (a) of this section and that the notice met the content requirements under paragraph (c) of this section. A copy of the notice itself need not be submitted to the Agency. (c) Contents of a notice. (1) A statement that FDA has received an ANDA submitted by the applicant containing any required bioavailability or bioequivalence data or information. (2) The ANDA number. (3) A statement that the applicant has received the paragraph IV acknowledgment letter for the ANDA. (4) The established name, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act, of the proposed drug product. (5) The active ingredient, strength, and dosage form of the proposed drug product. (6) The patent number and expiration date of each listed patent for the reference listed drug alleged to be invalid, unenforceable, or not infringed. (7) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed. The applicant must include in the detailed statement: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed. (ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation. (8) If the applicant alleges that the patent will not be infringed and the applicant seeks to preserve the option to later file a civil action for declaratory judgment in accordance with section 505(j)(5)(C) of the Federal Food, Drug, and Cosmetic Act, then the notice must be accompanied by an offer of confidential access to the ANDA for the sole and limited purpose of evaluating possible infringement of the patent that is the subject of the paragraph IV certification. (9) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant. (d) Amendment or supplement to an ANDA. (2) If, before receipt of a paragraph IV acknowledgment letter, an applicant submits an amendment to its ANDA that includes a paragraph IV certification, the applicant must send the notice required by paragraph (a) of this section in accordance with the procedures in paragraph (b) of this section. If an ANDA applicant's notice of its paragraph IV certification is timely provided in accordance with paragraph (b) of this section and the applicant has not submitted a previous paragraph IV certification, FDA will base its determination of whether the applicant is a first applicant on the date of submission of the amendment containing the paragraph IV certification. (3) An applicant that submits an amendment or supplement to seek approval of a different strength must provide notice of any paragraph IV certification in accordance with paragraph (d)(1) or (2) of this section, as applicable. (e) Documentation of timely sending and receipt of notice. (f) Forty-five day period after receipt of notice. (g) Designated delivery services. (i) Is available to the general public throughout the United States; (ii) Records electronically to its database, kept in the regular course of its business, or marks on the cover in which any item referred to in this section is to be delivered, the date on which such item was given to such trade or business for delivery; and (iii) Provides overnight or 2-day delivery service throughout the United States. (2) FDA may periodically issue guidance regarding designated delivery services. [81 FR 69651, Oct. 6, 2016, as amended at 84 FR 6673, Feb. 28, 2019] § 314.96 Amendments to an unapproved ANDA. (a) ANDA. (2) Submission of an amendment containing significant data or information before the end of the initial review cycle constitutes an agreement between FDA and the applicant to extend the initial review cycle only for the time necessary to review the significant data or information and for no more than 180 days. (b) Field copy. (c) Different listed drug. (d)(1) Patent certification requirements. (i) To add a new indication or other condition of use; (ii) To add a new strength; (iii) To make other than minor changes in product formulation; or (iv) To change the physical form or crystalline structure of the active ingredient. (2) If the amendment to the ANDA does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in paragraph (d)(1) of this section. [57 FR 17983, Apr. 28, 1992, as amended at 58 FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999; 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16, 2009; 81 FR 69652, Oct. 6, 2016] § 314.97 Supplements and other changes to an approved ANDA. (a) General requirements. (b) Different listed drug. [81 FR 69653, Oct. 6, 2016] § 314.98 Postmarketing reports. (a) Each applicant having an approved abbreviated new drug application under § 314.94 that is effective must comply with the requirements of § 314.80 regarding the reporting and recordkeeping of adverse drug experiences. (b) Each applicant must make the reports required under § 314.81 and section 505(k) of the Federal Food, Drug, and Cosmetic Act for each of its approved abbreviated applications. [79 FR 33089, June 10, 2014] § 314.99 Other responsibilities of an applicant of an ANDA. (a) An applicant must comply with the requirements of § 314.65 regarding withdrawal by the applicant of an unapproved ANDA and § 314.72 regarding a change in ownership of an ANDA. (b) An applicant may ask FDA to waive under this section any requirement that applies to the applicant under §§ 314.92 through 314.99. The applicant must comply with the requirements for a waiver under § 314.90. If FDA grants the applicant's waiver request with respect to a requirement under §§ 314.92 through 314.99, the waived requirement will not constitute a basis for refusal to approve an ANDA under § 314.127. 81 FR 69653, Oct. 6, 2016] Subpart D—FDA Action on Applications and Abbreviated Applications Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992. § 314.100 Timeframes for reviewing applications and abbreviated applications. (a) Except as provided in paragraph (c) of this section, within 180 days of receipt of an application for a new drug under section 505(b) of the act or an abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the applicant either an approval letter under § 314.105 or a complete response letter under § 314.110. This 180-day period is called the “initial review cycle.” (b) At any time before approval, an applicant may withdraw an application under § 314.65 or an abbreviated application under § 314.99 and later submit it again for consideration. (c) The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in §§ 314.60 and 314.96, as the result of a major amendment. [73 FR 39609, July 10, 2008] § 314.101 Filing an NDA and receiving an ANDA. (a) Filing an NDA. (2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for refusing to file the NDA apply, the Agency will file the NDA and notify the applicant in writing. In the case of a 505(b)(2) application that contains a paragraph IV certification, the applicant will be notified via a paragraph IV acknowledgment letter. The date of filing will be the date 60 days after the date FDA received the NDA. The date of filing begins the 180-day period described in section 505(c) of the Federal Food, Drug, and Cosmetic Act. This 180-day period is called the “filing clock.” (3) If FDA refuses to file the NDA, 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 NDA 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 NDA. If, following the informal conference, the applicant requests that FDA file the NDA (with or without amendments to correct the deficiencies), the Agency will file the NDA over protest under paragraph (a)(2) of this section, notify the applicant in writing, and review it as filed. If the NDA 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 NDA that is filed over protest. If FDA refuses to file the NDA under paragraph (e) of this section, the applicant may amend the NDA and resubmit it, and the Agency will make a determination under this section whether it may be filed. (b)(1) Receiving an ANDA. (2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for considering the ANDA not to have been received applies, the ANDA is substantially complete and the Agency will receive the ANDA and notify the applicant in writing. If FDA determines, upon evaluation, that an ANDA was substantially complete as of the date it was submitted to FDA, FDA will consider the ANDA to have been received as of the date of submission. In the case of an ANDA that contains a paragraph IV certification, the applicant will be notified via a paragraph IV acknowledgment letter. (3) If FDA considers the ANDA not to have been received under paragraph (d) or (e) of this section, FDA will notify the applicant of the refuse-to-receive decision. The applicant may then: (i) Withdraw the ANDA under § 314.99; or (ii) Correct the deficiencies and resubmit the ANDA; or (iii) Take no action, in which case FDA may consider the ANDA withdrawn after 1 year. (c) [Reserved] (d) NDA or ANDA deficiencies. (1) The NDA or ANDA does not contain a completed application form. (2) The NDA or ANDA is not submitted in the form required under § 314.50 or § 314.94. (3) The NDA or ANDA is incomplete because it does not on its face contain information required under section 505(b) or section 505(j) of the Federal Food, Drug, and Cosmetic Act and § 314.50 or § 314.94. In determining whether an ANDA is incomplete on its face, FDA will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA. (4) The applicant fails to submit a complete environmental assessment, which addresses each of the items specified in the applicable format under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.31 of this chapter. (5) The NDA or ANDA does not contain an accurate and complete English translation of each part of the NDA or ANDA that is not in English. (6) The NDA or ANDA does not contain a statement for each nonclinical laboratory study that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, for each study not conducted in compliance with part 58 of this chapter, a brief statement of the reason for the noncompliance. (7) The NDA or ANDA does not contain a statement for each clinical study that the study was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to those regulations, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter, or, if the study was subject to but was not conducted in compliance with those regulations, the NDA or ANDA does not contain a brief statement of the reason for the noncompliance. (8) The drug product that is the subject of the submission is already covered by an approved NDA or ANDA and the applicant of the submission: (i) Has an approved NDA or ANDA for the same drug product; or (ii) Is merely a distributor and/or repackager of the already approved drug product. (9) The NDA is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act. (e) Regulatory deficiencies. (1) The drug product is subject to licensing by FDA under the Public Health Service Act (42 U.S.C. 201 et seq. (2) Submission of a 505(b)(2) application or an ANDA is not permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal Food, Drug, and Cosmetic Act. (f) Outcome of FDA review. (i) Approve the NDA; or (ii) Issue a notice of opportunity for a hearing if the applicant asked FDA to provide it an opportunity for a hearing on an NDA in response to a complete response letter. (2) Within 180 days after the date of receipt, plus the period of time the review clock was extended (if any), FDA will either approve or disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a notice of opportunity for hearing if the applicant asked FDA to provide it an opportunity for a hearing on an ANDA in response to a complete response letter. (3) This paragraph (f) does not apply to NDAs or ANDAs that have been withdrawn from FDA review by the applicant. [81 FR 69653, Oct. 6, 2016] § 314.102 Communications between FDA and applicants. (a) General principles. (b) Notification of easily correctable deficiencies. (c) Ninety-day conference. (d) End-of-review conference. (e) Other meetings. i.e. [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 73 FR 39609, July 10, 2008] § 314.103 Dispute resolution. (a) General. (b) Administrative and procedural issues. (c) Scientific and medical disputes. (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 or abrreviated 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 its standing advisory committees for its consideration and recommendations. [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 57 FR 17989, Apr. 28, 1992; 73 FR 39609, July 10, 2008] § 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 or abbreviated application is submitted for a drug that appears to have an abuse potential. [57 FR 17989, Apr. 28, 1992] § 314.105 Approval of an NDA and an ANDA. (a) FDA will approve an NDA and send the applicant an approval letter if none of the reasons in § 314.125 for refusing to approve the NDA applies. FDA will issue a tentative approval letter if an NDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is a 7-year period of orphan exclusivity for the listed drug under section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter, or if a 505(b)(2) application otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved until the conditions in § 314.107(b)(3) are met; because there is a period of exclusivity for the listed drug under § 314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the Federal Food, Drug, and Cosmetic Act; or because there is a period of exclusivity for the listed drug under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an approval after any necessary additional review of the NDA. FDA's tentative approval of a drug product is based on information available to FDA at the time of the tentative approval letter ( i.e., (b) FDA will approve an NDA and issue the applicant an approval letter on the basis of draft labeling if the only deficiencies in the NDA 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 NDA after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling, and an ANDA after it determines that the drug meets the statutory standards for manufacturing and controls, labeling, and, where applicable, bioequivalence. While the statutory standards apply to all drugs, the many kinds of drugs that are subject to the statutory standards 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 the statutory standards. FDA makes its views on drug products and classes of drugs available through guidance documents, recommendations, and other statements of policy. (d) FDA will approve an ANDA and send the applicant an approval letter if none of the reasons in § 314.127 for refusing to approve the ANDA applies. FDA will issue a tentative approval letter if an ANDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is a 7-year period of orphan exclusivity for the listed drug under section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter, or cannot be approved until the conditions in § 314.107(b)(3) or (c) are met; because there is a period of exclusivity for the listed drug under § 314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the Federal Food, Drug, and Cosmetic Act; or because there is a period of exclusivity for the listed drug under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an approval after any necessary additional review of the ANDA. FDA's tentative approval of a drug product is based on information available to FDA at the time of the tentative approval letter ( i.e., [81 FR 69654, Oct. 6, 2016] § 314.106 Foreign data. (a) General. (b) As sole basis for marketing approval. (c) Consultation between FDA and applicants. [50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11580, Mar. 29, 1990] § 314.107 Date of approval of a 505(b)(2) application or ANDA. (a) General. (b) Effect of patent(s) on the listed drug. (1) Timing of approval based on patent certification or statement. (i) Immediately, if the applicant certifies under § 314.50(i) or § 314.94(a)(12) that: (A) The applicant is aware of a relevant patent but the patent information required under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act has not been submitted to FDA; or (B) The relevant patent has expired; or (C) The relevant patent is invalid, unenforceable, or will not be infringed, except as provided in paragraphs (b)(3) and (c) of this section, and the 45-day period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired; or (D) There are no relevant patents. (ii) Immediately, if the applicant submits an appropriate statement under § 314.50(i) or § 314.94(a)(12) explaining that a method-of-use patent does not claim an indication or other condition of use for which the applicant is seeking approval, except that if the applicant also submits a paragraph IV certification to the patent, then the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(1)(i)(C) of this section. (iii) On the date specified, if the applicant certifies under § 314.50(i) or § 314.94(a)(12) that the relevant patent will expire on a specified date. (2) Patent information filed after submission of 505(b)(2) application or ANDA. 4 4 (3) Disposition of patent litigation Approval upon expiration of 30-month period or 7 1/2 (B) If the patented drug product qualifies for 5 years of exclusive marketing under § 314.108(b)(2) and the patent owner or its representative or the exclusive patent licensee brings suit for patent infringement during the 1-year period beginning 4 years after the date of approval of the patented drug and within 45 days of receipt of the notice of certification from the applicant under § 314.52 or § 314.95, the 505(b)(2) application or ANDA may be approved at the expiration of the 7 1/2 (ii) Federal district court decision of invalidity, unenforceability, or non-infringement. 1/2 (A) The date on which the court enters judgment reflecting the decision; or (B) The date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed. (iii) Appeal of Federal district court judgment of infringement. 1/2 (A) The date on which the mandate is issued by the court of appeals entering judgment that the patent is invalid, unenforceable, or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity); or (B) The date of a settlement order or consent decree signed and entered by the court of appeals stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed. (iv) Affirmation or non-appeal of Federal district court judgment of infringement. 1/2 (v) Grant of preliminary injunction by Federal district court. 1/2 (A) The patent is invalid, unenforceable, or not infringed, the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(3)(ii) of this section; or (B) The patent is infringed, the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(3)(iii) or (iv) of this section, whichever is applicable. (vi) Written consent to approval by patent owner or exclusive patent licensee. 1/2 (vii) Court order terminating 30-month or 7 1/2 1/2 1/2 (viii) Court order of dismissal without a finding of infringement. 1/2 (4) Tentative approval. (c) Timing of approval of subsequent ANDA. (2) A first applicant must submit correspondence to its ANDA notifying FDA within 30 days of the date of its first commercial marketing of its drug product or the reference listed drug. If an applicant does not notify FDA, as required in this paragraph (c)(2), of this date, the date of first commercial marketing will be deemed to be the date of the drug product's approval. (3) If FDA concludes that a first applicant is not actively pursuing approval of its ANDA, FDA may immediately approve an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for approval. (d) Delay due to exclusivity. (e) Notification of court actions or written consent to approval. (i) A copy of any judgment by the court (district court or mandate of the court of appeals) or settlement order or consent decree signed and entered by the court (district court or court of appeals) finding a patent described in paragraph (b)(3) of this section invalid, unenforceable, or not infringed, or finding the patent valid and infringed; (ii) Written notification of whether or not any action by the court described in paragraph (e)(1)(i) of this section has been appealed within the time permitted for an appeal; (iii) A copy of any order entered by the court terminating the 30-month or 7 1/2 (iv) A copy of any written consent to approval by the patent owner or exclusive patent licensee described in paragraph (b)(3)(vi) of this section; (v) A copy of any preliminary injunction described in paragraph (b)(3)(v) of this section, and a copy of any subsequent court order lifting the injunction; and (vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may be approved no earlier than the date specified (irrespective of whether the injunction relates to a patent described in paragraph (b)(3) of this section). (2) All information required by paragraph (e)(1) of this section must be sent to the applicant's NDA or ANDA, as appropriate, within 14 days of the date of entry by the court, the date of appeal or expiration of the time for appeal, or the date of written consent to approval, as applicable. (f) Forty-five day period after receipt of notice of paragraph IV certification Computation of 45-day time clock. (2) Notification of filing of legal action. (A) The 505(b)(2) application or ANDA number. (B) The name of the 505(b)(2) or ANDA applicant. (C) The established name of the drug product or, if no established name exists, the name(s) of the active ingredient(s), the drug product's strength, and dosage form. (D) A statement that an action for patent infringement, identified by court, case number, and the patent number(s) of the patent(s) at issue in the action, has been filed in an appropriate court on a specified date. (ii) A patent owner or NDA holder (or its representative(s)) may also notify FDA of the filing of any legal action for patent infringement. The notice should contain the information and be sent to the offices or divisions described in paragraph (f)(2)(i) of this section. (iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the NDA holder, or its representative(s) does not notify FDA in writing before the expiration of the 45-day time period or the completion of the Agency's review of the 505(b)(2) application or ANDA, whichever occurs later, that a legal action for patent infringement was filed within 45 days of receipt of the notice of paragraph IV certification, the 505(b)(2) application or ANDA may be approved upon expiration of the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a legal action for patent infringement has not been filed) or upon completion of the Agency's review of the 505(b)(2) application or ANDA, whichever is later. (3) Waiver. ( Name of patent owner or NDA holder who is an exclusive patent licensee or its representative(s) name of applicant section 505(b)(3) or 505(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act name of applicant name of drug date on which 45 days elapse Name of patent owner or NDA holder who is an exclusive patent licensee section 505(c)(3)(C) or 505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act name of applicant 505(b)(2) application or ANDA name of drug (g) Conversion of approval to tentative approval. [81 FR 69655, Oct. 6, 2016] § 314.108 New drug product exclusivity. (a) Definitions. Approved under section 505(b) Bioavailability study Clinical investigation Conducted or sponsored by the applicant Essential to approval New chemical entity New clinical investigation (b) Submission of and timing of approval of a 505(b)(2) application or ANDA. (2) If a drug product that contains a new chemical entity was approved after September 24, 1984, in an NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act, no person may submit a 505(b)(2) application or ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved NDA, except that the 505(b)(2) application or ANDA may be submitted after 4 years if it contains a certification of patent invalidity or noninfringement described in § 314.50(i)(1)(i)(A)( 4 4 (3) The approval of a 505(b)(2) application or ANDA described in paragraph (b)(2) of this section will occur as provided in § 314.107(b)(1) or (2), unless the owner of a patent that claims the drug, the patent owner's representative, or exclusive licensee brings suit for patent infringement against the applicant during the 1-year period beginning 48 months after the date of approval of the NDA for the new chemical entity and within 45 days after receipt of the notice described at § 314.52 or § 314.95, in which case, approval of the 505(b)(2) application or ANDA will occur as provided in § 314.107(b)(3). (4) If an NDA: (i) Was submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act; (ii) Was approved after September 24, 1984; (iii) Was for a drug product that contains an active moiety that has been previously approved in another NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act; and (iv) Contained reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the applicant that were essential to approval of the application, for a period of 3 years after the date of approval of the application, the Agency will not approve a 505(b)(2) application or an ANDA for the conditions of approval of the NDA, or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that relies on the information supporting the conditions of approval of an original NDA. (5) If a supplemental NDA: (i) Was approved after September 24, 1984; and (ii) Contained reports of new clinical investigations (other than bioavailability studies) that were conducted or sponsored by the applicant that were essential to approval of the supplemental NDA, for a period of 3 years after the date of approval of the supplemental application, the Agency will not approve a 505(b)(2) application or an ANDA for a change, or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that relies on the information supporting a change approved in the supplemental NDA. [59 FR 50368, Oct. 3, 1994, as amended at 81 FR 69657, Oct. 6, 2016] § 314.110 Complete response letter to the applicant. (a) Complete response letter. (1) Description of specific deficiencies. (2) Complete review of data. (3) Inadequate data. (4) Recommendation of actions for approval. (b) Applicant actions. (1) Resubmission. (i) A resubmission of an application or efficacy supplement that FDA classifies as a Class 1 resubmission constitutes an agreement by the applicant to start a new 2-month review cycle beginning on the date FDA receives the resubmission. (ii) A resubmission of an application or efficacy supplement that FDA classifies as a Class 2 resubmission constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission. (iii) A resubmission of an NDA supplement other than an efficacy supplement constitutes an agreement by the applicant to start a new review cycle the same length as the initial review cycle for the supplement (excluding any extension due to a major amendment of the initial supplement), beginning on the date FDA receives the resubmission. (iv) A major resubmission of an abbreviated application constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission. (v) A minor resubmission of an abbreviated application constitutes an agreement by the applicant to start a new review cycle beginning on the date FDA receives the resubmission. (2) Withdrawal. (3) Request opportunity for hearing. (c) Failure to take action. (2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application should not be withdrawn and to request an extension of time in which to resubmit the application. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application will be deemed to be withdrawn. [73 FR 39609, July 10, 2008] § 314.120 [Reserved] § 314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) petition that relies on, a listed drug that is no longer marketed. (a) An abbreviated new drug application that refers to, or a petition under section 505(j)(2)(C) of the act and § 314.93 that relies on, a listed drug that has been voluntarily withdrawn from sale in the United States must be accompanied by a petition seeking a determination whether the listed drug was withdrawn for safety or effectiveness reasons. The petition must be submitted under §§ 10.25(a) and 10.30 of this chapter and must contain all evidence available to the petitioner concerning the reasons for the withdrawal from sale. (b) When a petition described in paragraph (a) of this section is submitted, the agency will consider the evidence in the petition and any other evidence before the agency, and determine whether the listed drug is withdrawn from sale for safety or effectiveness reasons, in accordance with the procedures in § 314.161. (c) An abbreviated new drug application described in paragraph (a) of this section will be disapproved, under § 314.127(a)(11), and a 505(j)(2)(C) petition described in paragraph (a) of this section will be disapproved, under § 314.93(e)(1)(iv), unless the agency determines that the withdrawal of the listed drug was not for safety or effectiveness reasons. (d) Certain drug products approved for safety and effectiveness that were no longer marketed on September 24, 1984, are not included in the list. Any person who wishes to obtain marketing approval for such a drug product under an abbreviated new drug application must petition FDA for a determination whether the drug product was withdrawn from the market for safety or effectiveness reasons and request that the list be amended to include the drug product. A person seeking such a determination shall use the petition procedures established in § 10.30 of this chapter. The petitioner shall include in the petition information to show that the drug product was approved for safety and effectiveness and all evidence available to the petitioner concerning the reason that marketing of the drug product ceased. [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July 1, 1992] § 314.125 Refusal to approve an NDA. (a) The Food and Drug Administration will refuse to approve the NDA 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 NDA under section 505(d) of the Federal Food, Drug, and Cosmetic Act, if: (1) FDA sends the applicant a complete response letter under § 314.110; (2) The applicant requests an opportunity for hearing for a new drug on the question of whether the NDA is approvable; and (3) FDA finds that any of the reasons given in paragraph (b) of this section apply. (b) FDA may refuse to approve an NDA for any of the following reasons, unless the requirement has been waived under § 314.90: (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) of the Federal Food, Drug, and Cosmetic 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 NDA 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 NDA does not contain bioavailability or bioequivalence data required under part 320 of this chapter. (10) A reason given in a letter refusing to file the NDA under § 314.101(d), if the deficiency is not corrected. (11) The drug will be manufactured in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the Federal Food, Drug, and Cosmetic 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 NDA. (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 NDA 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 NDA that is received or otherwise obtained by the applicant from any source. (15) A nonclinical laboratory study that is described in the NDA 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 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. (16) Any clinical investigation involving human subjects described in the NDA, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected. (17) The applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the NDA refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA. (18) For a new drug, the NDA failed to contain the patent information required by section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act. (19) The 505(b)(2) application failed to contain a patent certification or statement with respect to each listed patent for a drug product approved in an NDA that: (i) Is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted; and (ii) Was approved before the original 505(b)(2) application was submitted. (20) For an NDA for a nonprescription drug product with an additional condition for nonprescription use under § 314.56, if FDA has determined the application failed to meet the requirements in § 314.56 applicable to NDAs. (c) For drugs intended to treat life-threatening or severely-debilitating illnesses that are developed in accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in paragraphs (b) (3), (4), and (5) of this section shall be applied according to the considerations contained in § 312.84 of this chapter. [50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28, 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766, Mar. 6, 2009; 81 FR 60221, Aug. 31, 2016; 81 FR 69658, Oct. 6, 2016; 89 FR 105331, Dec. 26, 2024] § 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 section 505 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. 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. (ii) Dose-comparison concurrent control. (iii) No treatment concurrent control. (iv) Active treatment concurrent control. (v) Historical control. (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 Drug Evaluation and Research 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. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. 4, 2002] § 314.127 Refusal to approve an ANDA. (a) FDA will refuse to approve an ANDA for a new drug under section 505(j) of the Federal Food, Drug, and Cosmetic Act for any of the following reasons, unless the requirement has been waived under § 314.99: (1) The methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity. (2) Information submitted with the ANDA is insufficient to show that each of the proposed conditions of use has been previously approved for the listed drug referred to in the ANDA. (3)(i) If the reference listed drug has only one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredient is the same as that of the reference listed drug; (ii) If the reference listed drug has more than one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredients are the same as the active ingredients of the reference listed drug; or (iii) If the reference listed drug has more than one active ingredient and if the ANDAis for a drug product that has an active ingredient different from the reference listed drug: (A) Information submitted with the ANDA is insufficient to show: ( 1 ( 2 (B) No petition to submit an ANDA for the drug product with the different active ingredient was approved under § 314.93. (4)(i) If the ANDA is for a drug product whose route of administration, dosage form, or strength purports to be the same as that of the listed drug referred to in the ANDA, information submitted in the abbreviated new drug application is insufficient to show that the route of administration, dosage form, or strength is the same as that of the reference listed drug; or (ii) If the ANDA is for a drug product whose route of administration, dosage form, or strength is different from that of the listed drug referred to in the application, no petition to submit an ANDA for the drug product with the different route of administration, dosage form, or strength was approved under § 314.93. (5) If the ANDA was submitted under the approval of a petition under § 314.93, the ANDA did not contain the information required by FDA with respect to the active ingredient, route of administration, dosage form, or strength that is not the same as that of the reference listed drug. (6)(i) Information submitted in the ANDA is insufficient to show that the drug product is bioequivalent to the listed drug referred to in the ANDA; or (ii) If the ANDA was submitted under a petition approved under § 314.93, information submitted in the ANDA is insufficient to show that the active ingredients of the drug product are of the same pharmacological or therapeutic class as those of the reference listed drug and that the drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use approved for the reference listed drug. (7) Information submitted in the ANDA is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the ANDA except for changes required because of differences approved in a petition under § 314.93 or because the drug product and the reference listed drug are produced or distributed by different manufacturers or because aspects of the listed drug's labeling are protected by patent, or by exclusivity, and such differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use. (8)(i) Information submitted in the ANDA or any other information available to FDA shows that: (A) The inactive ingredients of the drug product are unsafe for use, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug product; or (B) The composition of the drug product is unsafe, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the proposed labeling because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included. (ii)(A) FDA will consider the inactive ingredients or composition of a drug product unsafe and refuse to approve an ANDA under paragraph (a)(8)(i) of this section if, on the basis of information available to the agency, there is a reasonable basis to conclude that one or more of the inactive ingredients of the proposed drug or its composition raises serious questions of safety or efficacy. From its experience with reviewing inactive ingredients, and from other information available to it, FDA may identify changes in inactive ingredients or composition that may adversely affect a drug product's safety or efficacy. The inactive ingredients or composition of a proposed drug product will be considered to raise serious questions of safety or efficacy if the product incorporates one or more of these changes. Examples of the changes that may raise serious questions of safety or efficacy include, but are not limited to, the following: ( 1 ( 2 ( 3 ( 4 ( 5 ( 6 ( 7 (B) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug, and, if it differs from the listed drug in a preservative, buffer, or antioxidant, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product. (C) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for ophthalmic or otic use unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, substances to adjust tonicity, or thickening agents, in the same concentration as the listed drug, and if it differs from the listed drug in a preservative, buffer, substance to adjust tonicity, or thickening agent, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product and the labeling does not claim any therapeutic advantage over or difference from the listed drug. (9) Approval of the listed drug referred to in the ANDA has been withdrawn or suspended for grounds described in § 314.150(a) or FDA has published a notice of opportunity for hearing to withdraw approval of the reference listed drug under § 314.150(a). (10) Approval of the listed drug referred to in the ANDA has been withdrawn under § 314.151 or FDA has proposed to withdraw approval of the reference listed drug under § 314.151(a). (11) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons, or approval of the reference listed drug has been suspended under § 314.153, or the agency has issued an initial decision proposing to suspend the reference listed drug under § 314.153(a)(1). (12) The abbreviated new drug application does not meet any other requirement under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act. (13) The abbreviated new drug application contains an untrue statement of material fact. (14) For an ANDA submitted pursuant to an approved petition under § 10.30 of this chapter and § 314.93, an NDA subsequently has been approved for the change described in the approved petition. (15) For an ANDA for a nonprescription drug product with an additional condition for nonprescription use under § 314.56, if FDA has determined the application failed to meet the requirements in § 314.56 applicable to ANDAs. (b) FDA may refuse to approve an ANDA for a new drug if the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.63 of this chapter that is contained in the ANDA refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA. [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 67 FR 77672, Dec. 19, 2002; 81 FR 69658, Oct. 6, 2016; 89 FR 105331, Dec. 26, 2024] § 314.150 Withdrawal of approval of an application or abbreviated 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 314.151(a) of this chapter and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, if any of the following apply: (1) The Secretary of Health and Human Services has suspended the approval of the application or abbreviated 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 or abbreviated 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 or abbreviated application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when the application or abbreviated application was approved, evaluated together with the evidence available when the application or abbreviated 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 or abbreviated 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 or abbreviated 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 represented to have under the conditions of use prescribed, recommended, or suggested in its labeling; or (iv) That the application or abbreviated application contains any untrue statement of a material fact; or (v) That the patent information prescribed by section 505(c) of the act was not submitted within 30 days after the receipt of written notice from FDA specifying the failure to submit such information; or (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 or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, 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(k) or 507(g) of the act and § 314.80, § 314.81, or § 314.98, 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 or abbreviated 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 ensure 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 or abbreviated 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 of this chapter. (6) The application or abbreviated 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 or abbreviated 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 or abbreviated 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 of this chapter 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 or abbreviated application, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected. (9) That the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application or abbreviated application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA. (10) That the labeling for the drug product that is the subject of the abbreviated new drug application is no longer consistent with that for the listed drug referred to in the abbreviated new drug application, except for differences approved in the abbreviated new drug application or those differences resulting from: (i) A patent on the listed drug issued after approval of the abbreviated new drug application; or (ii) Exclusivity accorded to the listed drug after approval of the abbreviated new drug application that do not render the drug product less safe or effective than the listed drug for any remaining, nonprotected condition(s) of use. (c) FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal because the drug subject to the application or abbreviated application is no longer being marketed, provided none of the conditions listed in paragraphs (a) and (b) of this section applies to the drug. FDA will consider a written request for a 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 or abbreviated 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 or abbreviated 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 or abbreviated application in a notice published in the Federal Register [57 FR 17993, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 64 FR 402, Jan. 5, 1999] § 314.151 Withdrawal of approval of an abbreviated new drug application under section 505(j)(5) of the act. (a) Approval of an abbreviated new drug application approved under § 314.105(d) may be withdrawn when the agency withdraws approval, under § 314.150(a) or under this section, of the approved drug referred to in the abbreviated new drug application. If the agency proposed to withdraw approval of a listed drug under § 314.150(a), the holder of an approved application for the listed drug has a right to notice and opportunity for hearing. The published notice of opportunity for hearing will identify all drug products approved under § 314.105(d) whose applications are subject to withdrawal under this section if the listed drug is withdrawn, and will propose to withdraw such drugs. Holders of approved applications for the identified drug products will be provided notice and an opportunity to respond to the proposed withdrawal of their applications as described in paragraphs (b) and (c) of this section. (b)(1) The published notice of opportunity for hearing on the withdrawal of the listed drug will serve as notice to holders of identified abbreviated new drug applications of the grounds for the proposed withdrawal. (2) Holders of applications for drug products identified in the notice of opportunity for hearing may submit written comments on the notice of opportunity for hearing issued on the proposed withdrawal of the listed drug. If an abbreviated new drug application holder submits comments on the notice of opportunity for hearing and a hearing is granted, the abbreviated new drug application holder may participate in the hearing as a nonparty participant as provided for in § 12.89 of this chapter. (3) Except as provided in paragraphs (c) and (d) of this section, the approval of an abbreviated new drug application for a drug product identified in the notice of opportunity for hearing on the withdrawal of a listed drug will be withdrawn when the agency has completed the withdrawal of approval of the listed drug. (c)(1) If the holder of an application for a drug identified in the notice of opportunity for hearing has submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not requested or is settled, the submitted comments will be considered by the agency, which will issue an initial decision. The initial decision will respond to the comments, and contain the agency's decision whether there are grounds to withdraw approval of the listed drug and of the abbreviated new drug applications on which timely comments were submitted. The initial decision will be sent to each abbreviated new drug application holder that has submitted comments. (2) Abbreviated new drug application holders to whom the initial decision was sent may, within 30 days of the issuance of the initial decision, submit written objections. (3) The agency may, at its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions. (4) If there are no timely objections to the initial decision, it will become final at the expiration of 30 days. (5) If timely objections are submitted, they will be reviewed and responded to in a final decision. (6) The written comments received, the initial decision, the evidence relied on in the comments and in the initial decision, the objections to the initial decision, and, if a limited oral hearing has been held, the transcript of that hearing and any documents submitted therein, shall form the record upon which the agency shall make a final decision. (7) Except as provided in paragraph (d) of this section, any abbreviated new drug application whose holder submitted comments on the notice of opportunity for hearing shall be withdrawn upon the issuance of a final decision concluding that the listed drug should be withdrawn for grounds as described in § 314.150(a). The final decision shall be in writing and shall constitute final agency action, reviewable in a judicial proceeding. (8) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the Dockets Management Staff (HFA-305), Food and Drug Administration, room. 1-23, 12420 Parklawn Dr., Rockville, MD 20857, promptly upon receipt in that office. (d) If the agency determines, based upon information submitted by the holder of an abbreviated new drug application, that the grounds for withdrawal of the listed drug are not applicable to a drug identified in the notice of opportunity for hearing, the final decision will state that the approval of the abbreviated new drug application for such drug is not withdrawn. [57 FR 17994, Apr. 28, 1992, as amended at 88 FR 45066, July 14, 2023] § 314.152 Notice of withdrawal of approval of an application or abbreviated application for a new drug. If the Food and Drug Administration withdraws approval of an application or abbreviated application for a new drug, FDA will publish a notice in the Federal Register [57 FR 17994, Apr. 28, 1992] § 314.153 Suspension of approval of an abbreviated new drug application. (a) Suspension of approval. (1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of section 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred to in the abbreviated new drug application, for the period of the suspension; (2) The agency, in the notice described in paragraph (b) of this section, or in any subsequent written notice given an abbreviated new drug application holder by the agency, concludes that the risk of continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or suspend approval under § 314.151 or paragraph (b) of this section; or (3) The agency, under the procedures set forth in paragraph (b) of this section, issues a final decision stating the determination that the abbreviated application is suspended because the listed drug on which the approval of the abbreviated new drug application depends has been withdrawn from sale for reasons of safety or effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on the date stated in the decision and will remain in effect until the agency determines that the marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons. (b) Procedures for suspension of abbreviated new drug applications when a listed drug is voluntarily withdrawn for safety or effectiveness reasons. (2) Each abbreviated new drug application holder will have 30 days from the issuance of the initial decision to present, in writing, comments and information bearing on the initial decision. If no comments or information is received, the initial decision will become final at the expiration of 30 days. (3) Comments and information received within 30 days of the issuance of the initial decision will be considered by the agency and responded to in a final decision. (4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions. (5) If the final decision affirms the agency's initial decision that the listed drug was withdrawn for reasons of safety or effectiveness, the decision will be published in the Federal Register (6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of safety or effectiveness but, based upon information submitted by the holder of an abbreviated new drug application, also determines that the reasons for the withdrawal of the listed drug are not relevant to the safety and effectiveness of the drug subject to such abbreviated new drug application, the final decision will state that the approval of such abbreviated new drug application is not suspended. (7) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the Dockets Management Staff (address in paragraph (b)(1) of this section) promptly upon receipt in that office. [57 FR 17995, Apr. 28, 1992, as amended at 88 FR 45066, July 14, 2023] § 314.160 Approval of an application or abbreviated 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 or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the Federal Register [57 FR 17995, Apr. 28, 1992] § 314.161 Determination of reasons for voluntary withdrawal of a listed drug. (a) A determination whether a listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or effectiveness reasons may be made by the agency at any time after the drug has been voluntarily withdrawn from sale, but must be made: (1) Prior to approving an abbreviated new drug application that refers to the listed drug; (2) Whenever a listed drug is voluntarily withdrawn from sale and abbreviated new drug applications that referred to the listed drug have been approved; and (3) When a person petitions for such a determination under §§ 10.25(a) and 10.30 of this chapter. (b) Any person may petition under §§ 10.25(a) and 10.30 of this chapter for a determination whether a listed drug has been voluntarily withdrawn for safety or effectiveness reasons. Any such petition must contain all evidence available to the petitioner concerning the reason that the drug is withdrawn from sale. (c) If the agency determines that a listed drug is withdrawn from sale for safety or effectiveness reasons, the agency will, except as provided in paragraph (d) of this section, publish a notice of the determination in the Federal Register. (d) If the agency determines under paragraph (a) of this section that a listed drug is withdrawn from sale for safety and effectiveness reasons and there are approved abbreviated new drug applications that are subject to suspension under section 505(j)(5) of the act, FDA will initiate a proceeding in accordance with § 314.153(b). (e) A drug that the agency determines is withdrawn for safety or effectiveness reasons will be removed from the list, under § 314.162. The drug may be relisted if the agency has evidence that marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons. A determination that the drug is not withdrawn for safety or effectiveness reasons may be made at any time after its removal from the list, upon the agency's initiative, or upon the submission of a petition under §§ 10.25(a) and 10.30 of this chapter. If the agency determines that the drug is not withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this determination in the Federal Register. [57 FR 17995, Apr. 28, 1992] § 314.162 Removal of a drug product from the list. (a) FDA will remove a previously approved new drug product from the list for the period stated when: (1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug application under § 314.150(a) or § 314.151 or under the imminent hazard authority of section 505(e) of the act, for the same period as the withdrawal or suspension of the application; or (2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA will publish in the Federal Register (c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this section, FDA will relist a drug that has been removed from the list. The agency will publish in the Federal Register [57 FR 17996, Apr. 28, 1992] § 314.170 Adulteration and misbranding of an approved drug. All drugs, including those the Food and Drug Administration approves under section 505 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 by regulations issued through informal rulemaking under sections 501, 502, and 503 of the act. [50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992, and amended at 64 FR 402, Jan. 5, 1999] Subpart E—Hearing Procedures for New Drugs Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992. § 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. (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 (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 (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: (1) To any person who has submitted an application or abbreviated application, by delivering the notice in person or by sending it by registered or certified mail to the last address shown in the application or abbreviated application. (2) To any person who has not submitted an application or abbreviated application but who is subject to the notice under § 310.6 of this chapter, by publication of the notice in the Federal Register. (c)(1) Notice of participation and request for a hearing, and submission of studies and comments. (2) FDA will not consider data or analyses submitted after 60 days in determining whether a hearing is warranted unless they are derived from well-controlled studies begun before the date of the notice of opportunity for hearing and the results of the studies were not available within 60 days after the date of publication of the notice. Nevertheless, FDA may consider other studies on the basis of a showing by the person requesting a hearing of inadvertent omission and hardship. The person requesting a hearing shall list in the request for hearing all studies in progress, the results of which the person intends later to submit in support of the request for a hearing. The person shall submit under paragraph (c)(1)(ii) of this section a copy of the complete protocol, a list of the participating investigators, and a brief status report of the studies. (3) Any other interested person who is not subject to the notice of opportunity for a hearing may also submit comments on the proposal to withdraw approval of the application or abbreviated application. The comments are requested to be submitted within the time and under the conditions specified in this section. (d) The person requesting a hearing is required to submit under paragraph (c)(1)(ii) of this section the studies (including all protocols and underlying raw data) on which the person relies to justify a hearing with respect to the drug product. Except, a person who requests a hearing on the refusal to approve an application is not required to submit additional studies and analyses if the studies upon which the person relies have been submitted in the application and in the format and containing the summaries required under § 314.50. (1) If the grounds for FDA's proposed action concern the effectiveness of the drug, each request for hearing is required to be supported only by adequate and well-controlled clinical studies meeting all of the precise requirements of § 314.126 and, for combination drug products, § 300.50, or by other studies not meeting those requirements for which a waiver has been previously granted by FDA under § 314.126. Each person requesting a hearing shall submit all adequate and well-controlled clinical studies on the drug product, including any unfavorable analyses, views, or judgments with respect to the studies. No other data, information, or studies may be submitted. (2) The submission is required to include a factual analysis of all the studies submitted. If the grounds for FDA's proposed action concern the effectiveness of the drug, the analysis is required to specify how each study accords, on a point-by-point basis, with each criterion required for an adequate well-controlled clinical investigation established under § 314.126 and, if the product is a combination drug product, with each of the requirements for a combination drug established in § 300.50, or the study is required to be accompanied by an appropriate waiver previously granted by FDA. If a study concerns a drug or dosage form or condition of use or mode of administration other than the one in question, that fact is required to be clearly stated. Any study conducted on the final marketed form of the drug product is required to be clearly identified. (3) Each person requesting a hearing shall submit an analysis of the data upon which the person relies, except that the required information relating either to safety or to effectiveness may be omitted if the notice of opportunity for hearing does not raise any issue with respect to that aspect of the drug; information on compliance with § 300.50 may be omitted if the drug product is not a combination drug product. A financial certification or disclosure statement or both as required by part 54 of this chapter must accompany all clinical data submitted. FDA can most efficiently consider submissions made in the following format. I. Safety data. A. Animal safety data. 1. Individual active components. a. Controlled studies. b. Partially controlled or uncontrolled studies. 2. Combinations of the individual active components. a. Controlled studies. b. Partially controlled or uncontrolled studies. B. Human safety data. 1. Individual active components. a. Controlled studies. b. Partially controlled or uncontrolled studies. c. Documented case reports. d. Pertinent marketing experiences that may influence a determination about the safety of each individual active component. 2. Combinations of the individual active components. a. Controlled studies. b. Partially controlled or uncontrolled studies. c. Documented case reports. d. Pertinent marketing experiences that may influence a determination about the safety of each individual active component. II. Effectiveness data. A. Individual active components: Controlled studies, with an analysis showing clearly how each study satisfies, on a point-by-point basis, each of the criteria required by § 314.126. B. Combinations of individual active components. 1. Controlled studies with an analysis showing clearly how each study satisfies on a point-by-point basis, each of the criteria required by § 314.126. 2. An analysis showing clearly how each requirement of § 300.50 has been satisfied. III. A summary of the data and views setting forth the medical rationale and purpose for the drug and its ingredients and the scientific basis for the conclusion that the drug and its ingredients have been proven safe and/or effective for the intended use. If there is an absence of controlled studies in the material submitted or the requirements of any element of § 300.50 or § 314.126 have not been fully met, that fact is required to be stated clearly and a waiver obtained under § 314.126 is required to be submitted. IV. A statement signed by the person responsible for such submission that it includes in full (or incorporates by reference as permitted in § 314.200(c)(2)) all studies and information specified in § 314.200(d). ( Warning: (e) Contentions that a drug product is not subject to the new drug requirements. (1) A contention that a drug product is generally recognized as safe and effective within the meaning of section 201(p) of the act is required to be supported by submission of the same quantity and quality of scientific evidence that is required to obtain approval of an application for the product, unless FDA has waived a requirement for effectiveness (under § 314.126) or safety, or both. The submission should be in the format and with the analyses required under paragraph (d) of this section. A person who fails to submit the required scientific evidence required under paragraph (d) waives the contention. General recognition of safety and effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data and information. (2) A contention that a drug product is exempt from part or all of the new drug provisions of the act under the exemption for products marketed before June 25, 1938, contained in section 201(p) of the act, or under section 107(c) of the Drug Amendments of 1962, is required to be supported by evidence of past and present quantitative formulas, labeling, and evidence of marketing. A person who makes such a contention should submit the formulas, labeling, and evidence of marketing in the following format. I. Formulation. A. A copy of each pertinent document or record to establish the exact quantitative formulation of the drug (both active and inactive ingredients) on the date of initial marketing of the drug. B. A statement whether such formulation has at any subsequent time been changed in any manner. If any such change has been made, the exact date, nature, and rationale for each change in formulation, including any deletion or change in the concentration of any active ingredient and/or inactive ingredient, should be stated, together with a copy of each pertinent document or record to establish the date and nature of each such change, including, but not limited to, the formula which resulted from each such change. If no such change has been made, a copy of representative documents or records showing the formula at representative points in time should be submitted to support the statement. II. Labeling. A. A copy of each pertinent document or record to establish the identity of each item of written, printed, or graphic matter used as labeling on the date the drug was initially marketed. B. A statement whether such labeling has at any subsequent time been discontinued or changed in any manner. If such discontinuance or change has been made, the exact date, nature, and rationale for each discontinuance or change and a copy of each pertinent document or record to establish each such discontinuance or change should be submitted, including, but not limited to, the labeling which resulted from each such discontinuance or change. If no such discontinuance or change has been made, a copy of representative documents or records showing labeling at representative points in time should be submitted to support the statement. III. Marketing. A. A copy of each pertinent document or record to establish the exact date the drug was initially marketed. B. A statement whether such marketing has at any subsequent time been discontinued. If such marketing has been discontinued, the exact date of each such discontinuance should be submitted, together with a copy of each pertinent document or record to establish each such date. IV. Verification. A statement signed by the person responsible for such submission, that all appropriate records have been searched and to the best of that person's knowledge and belief it includes a true and accurate presentation of the facts. (Warning: (3) The Food and Drug Administration will not find a drug product, including any active ingredient, which is identical, related, or similar, as described in § 310.6, to a drug product, including any active ingredient for which an application is or at any time has been effective or deemed approved, or approved under section 505 of the act, to be exempt from part or all of the new drug provisions of the act. (4) A contention that a drug product is not a new drug for any other reason is required to be supported by submission of the factual records, data, and information that are necessary and appropriate to support the contention. (5) It is the responsibility of every person who manufactures or distributes a drug product in reliance upon a “grandfather” provision of the act to maintain files that contain the data and information necessary fully to document and support that status. (f) Separation of functions. (g) Summary judgment. (1) Where a specific notice of opportunity for hearing (as defined in paragraph (a)(1) of this section) is used, the Commissioner will enter summary judgment against a person who requests a hearing, making findings and conclusions, denying a hearing, if it conclusively appears from the face of the data, information, and factual analyses in the request for the hearing that there is no genuine and substantial issue of fact which precludes the refusal to approve the application or abbreviated application or the withdrawal of approval of the application or abbreviated application; for example, no adequate and well-controlled clinical investigations meeting each of the precise elements of § 314.126 and, for a combination drug product, § 300.50 of this chapter, showing effectiveness have been identified. Any order entering summary judgment is required to set forth the Commissioner's findings and conclusions in detail and is required to specify why each study submitted fails to meet the requirements of the statute and regulations or why the request for hearing does not raise a genuine and substantial issue of fact. (2) When following a general notice of opportunity for a hearing (as defined in paragraph (a)(1) of this section) the Director of the Center for Drug Evaluation and Research concludes that summary judgment against a person requesting a hearing should be considered, the Director will serve upon the person requesting a hearing by registered mail a proposed order denying a hearing. This person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing. (3) When following a general or specific notice of opportunity for a hearing a person requesting a hearing submits data or information of a type required by the statute and regulations, and the Director of the Center for Drug Evaluation and Research concludes that summary judgment against the person should be considered, the Director will serve upon the person by registered mail a proposed order denying a hearing. The person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing. (4) If review of the data, information, and analyses submitted show that the grounds cited in the notice are not valid, for example, that substantial evidence of effectiveness exists, the Commissioner will enter summary judgment for the person requesting the hearing, and rescind the notice of opportunity for hearing. (5) If the Commissioner grants a hearing, it will begin within 90 days after the expiration of the time for requesting the hearing unless the parties otherwise agree in the case of denial of approval, and as soon as practicable in the case of withdrawal of approval. (6) The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact or if the Commissioner concludes that a hearing would otherwise be in the public interest. (7) If the manufacturer or distributor of an identical, related, or similar drug product requests and is granted a hearing, the hearing may consider whether the product is in fact identical, related, or similar to the drug product named in the notice of opportunity for a hearing. (8) A request for a hearing, and any subsequent grant or denial of a hearing, applies only to the drug products named in such documents. (h) FDA will issue a notice withdrawing approval and declaring all products unlawful for drug products subject to a notice of opportunity for a hearing, including any identical, related, or similar drug product under § 310.6, for which an opportunity for a hearing is waived or for which a hearing is denied. The Commissioner may defer or stay the action pending a ruling on any related request for a hearing or pending any related hearing or other administrative or judicial proceeding. [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004; 74 FR 13113, Mar. 26, 2009; 88 FR 45066, July 14, 2023] § 314.201 Procedure for hearings. Parts 10 through 16 apply to hearings relating to new drugs under section 505 (d) and (e) of the act. § 314.235 Judicial review. (a) The Commissioner of Food and Drugs will certify the transcript and record. In any case in which the Commissioner enters an order without a hearing under § 314.200(g), the record certified by the Commissioner is required to include the requests for hearing together with the data and information submitted and the Commissioner's findings and conclusion. (b) A manufacturer or distributor of an identical, related, or similar drug product under § 310.6 may seek judicial review of an order withdrawing approval of a new drug application, whether or not a hearing has been held, in a United States court of appeals under section 505(h) of the act. Subpart F [Reserved] Subpart G—Miscellaneous Provisions Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992. § 314.410 Imports and exports of new drugs. (a) Imports. (2) A drug substance intended for use in the manufacture, processing, or repacking of a new drug may be imported into the United States if it complies with the labeling exemption in § 201.122 pertaining to shipments of drug substances in domestic commerce. (b) Exports. (2) A new drug substance that is covered by an application approved under this part for use in the manufacture of an approved drug product may be exported by the applicant or any person listed as a supplier in the approved application, provided the drug substance intended for export meets the specification of, and is shipped with a copy of the labeling required for, the approved drug product. (3) Insulin or an antibiotic drug may be exported without regard to the requirements in section 802 of the act if the insulin or antibiotic drug meets the requirements of section 801(e)(1) of the act. [50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992, and amended at 64 FR 402, Jan. 5, 1999; 69 FR 18766, Apr. 8, 2004] § 314.420 Drug master files. (a) A drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder) who intends it to be used for one of the following purposes: To permit the holder to incorporate the information by reference when the holder submits an investigational new drug application under part 312 or submits an application or an abbreviated application or an amendment or supplement to them under this part, or to permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person. FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file. Instead, the agency customarily reviews the information only in the context of an application under part 312 or this part. A drug master file may contain information of the kind required for any submission to the agency, including information about the following: (1) [Reserved] (2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug product; (3) Packaging materials; (4) Excipient, colorant, flavor, essence, or materials used in their preparation; (5) FDA-accepted reference information. (A person wishing to submit information and supporting data in a drug master file (DMF) that is not covered by Types II through IV DMF's must first submit a letter of intent to the Drug Master File Staff, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.) FDA will then contact the person to discuss the proposed submission. (b) An investigational new drug application or an application, abbreviated application, amendment, or supplement may incorporate by reference all or part of the contents of any drug master file in support of the submission if the holder authorizes the incorporation in writing. Each incorporation by reference is required to describe the incorporated material by name, reference number, volume, and page number of the drug master file. (c) A drug master file is required to be submitted in two copies. The agency has prepared guidance that provides information about how to prepare a well-organized drug master file. If the drug master file holder adds, changes, or deletes any information in the file, the holder shall notify in writing, each person authorized to reference that information. Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file. (d) The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate. If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies. (e) The public availability of data and information in a drug master file, including the availability of data and information in the file to a person authorized to reference the file, is determined under part 20 and § 314.430. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 53 FR 33122, Aug. 30, 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, Jan. 12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004] § 314.430 Availability for public disclosure of data and information in an application or abbreviated application. (a) The Food and Drug Administration will determine the public availability of any part of an application or abbreviated application under this section and part 20 of this chapter. For purposes of this section, the application or abbreviated application includes all data and information submitted with or incorporated by reference in the application or abbreviated application, including investigational new drug applications, drug master files under § 314.420, supplements submitted under § 314.70 or § 314.97, reports under § 314.80 or § 314.98, and other submissions. For purposes of this section, safety and effectiveness data include all studies and tests of a drug on animals and humans and all studies and tests of the drug for identity, stability, purity, potency, and bioavailability. (b) FDA will not publicly disclose the existence of an application or abbreviated application before an approval letter is sent to the applicant under § 314.105 or tentative approval letter is sent to the applicant under § 314.107, unless the existence of the application or abbreviated application has been previously publicly disclosed or acknowledged. (c) If the existence of an unapproved application or abbreviated application has not been publicly disclosed or acknowledged, no data or information in the application or abbreviated application is available for public disclosure. (d)(1) If the existence of an application or abbreviated application has been publicly disclosed or acknowledged before the agency sends an approval letter to the applicant, no data or information contained in the application or abbreviated application is available for public disclosure before the agency sends an approval letter, but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the safety and effectiveness data that are appropriate for public consideration of a specific pending issue; for example, for consideration of an open session of an FDA advisory committee. (2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the investigational new drug application that was required to be filed in Docket Number 95S-0158 in the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act. (e) After FDA sends an approval letter to the applicant, the following data and information in the application or abbreviated application are immediately available for public disclosure, unless the applicant shows that extraordinary circumstances exist. A list of approved applications and abbreviated applications, entitled “Approved Drug Products with Therapeutic Equivalence Evaluations,” is available from the Government Printing Office, Washington, DC 20402. This list is updated monthly. (1) [Reserved] (2) If the application applies to a new drug, all safety and effectiveness data previously disclosed to the public as set forth in § 20.81 and a summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the application. The summaries do not constitute the full reports of investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) on which the safety or effectiveness of the drug may be approved. The summaries consist of the following: (i) For an application approved before July 1, 1975, internal agency records that describe safety and effectiveness data and information, for example, a summary of the basis for approval or internal reviews of the data and information, after deletion of the following: ( a ( b (ii) For an application approved on or after July 1, 1975, a Summary Basis of Approval (SBA) document that contains a summary of the safety and effectiveness data and information evaluated by FDA during the drug approval process. The SBA is prepared in one of the following ways: ( a ( b (3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61. (4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information after deletion of the following: (i) Names and any information that would identify the person using the product. (ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution. (5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as set forth in § 20.81. (6) An assay procedure or other analytical procedure, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61. (7) All correspondence and written summaries of oral discussions between FDA and the applicant relating to the application, under the provisions of part 20. (f) All safety and effectiveness data and information which have been submitted in an application and which have not previously been disclosed to the public are available to the public, upon request, at the time any one of the following events occurs unless extraordinary circumstances are shown: (1) No work is being or will be undertaken to have the application approved. (2) A final determination is made that the application is not approvable and all legal appeals have been exhausted. (3) Approval of the application is withdrawn and all legal appeals have been exhausted. (4) A final determination has been made that the drug is not a new drug. (5) For applications submitted under section 505(b) of the act, the effective date of the approval of the first abbreviated application submitted under section 505(j) of the act which refers to such drug, or the date on which the approval of an abbreviated application under section 505(j) of the act which refers to such drug could be made effective if such an abbreviated application had been submitted. (6) For abbreviated applications submitted under section 505(j) of the act, when FDA sends an approval letter to the applicant. (g) The following data and information in an application or abbreviated application are not available for public disclosure unless they have been previously disclosed to the public as set forth in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they do not represent a trade secret or confidential commercial or financial information under § 20.61 of this chapter: (1) Manufacturing methods or processes, including quality control procedures. (2) Production, sales distribution, and similar data and information, except that any compilation of that data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure. (3) Quantitative or semiquantitative formulas. (h) The compilations of information specified in § 20.117 are available for public disclosure. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68 FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, 2004; 73 FR 39610, July 10, 2008; 88 FR 45066, July 14, 2023] § 314.440 Addresses for applications and abbreviated applications. (a) Applicants shall send applications, abbreviated applications, and other correspondence relating to matters covered by this part, except for products listed in paragraph (b) of this section, to the appropriate office identified below: (1) Except as provided in paragraph (a)(4) of this section, an application under § 314.50 or § 314.54 submitted for filing should be directed to the Central Document Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Applicants may obtain information about folders for binding applications on the Internet at http://www.fda.gov/cder/ddms/binders.htm. (2) Except as provided in paragraph (a)(4) of this section, an abbreviated application under § 314.94, and amendments, supplements, and resubmissions should be directed to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. This includes items sent by parcel post or overnight courier service. Correspondence not associated with an abbreviated application also should be addressed to 5901-B Ammendale Rd., Beltsville, MD 20705-1266. (3) A request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds for denying approval of an application, except an application under paragraph (b) of this section, should be directed to the Associate Director for Policy (HFD-5). (4) The field copy of an application, an abbreviated application, amendments, supplements, resubmissions, requests for waivers, and other correspondence about an application and an abbreviated application shall be sent to the applicant's home FDA district office, except that a foreign applicant shall send the field copy to the appropriate address identified in paragraphs (a)(1) and (a)(2) of this section. (b) Applicants shall send applications and other correspondence relating to matters covered by this part for the drug products listed below to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, except applicants shall send a request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds for denying approval of an application to the Center for Biologics Evaluation and Research, ATTN: Director, at the same address. (1) Ingredients packaged together with containers intended for the collection, processing, or storage of blood and blood components; (2) Plasma volume expanders and hydroxyethyl starch for leukapheresis; (3) Blood component processing solutions and shelf life extenders; and (4) Oxygen carriers. [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11581, Mar. 29, 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005; 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. 26, 2009; 75 FR 37295, June 29, 2010; 80 FR 18091, Apr. 3, 2015; 84 FR 6673, Feb. 28, 2019] § 314.445 Guidance documents. (a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain requirements of this part. (b) The Center for Drug Evaluation and Research (CDER) maintains a list of guidance documents that apply to CDER's regulations. The list is maintained on the Internet and is published annually in the Federal Register. [65 FR 56480, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009] Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses Source: 57 FR 58958, Dec. 11, 1992, unless otherwise noted. § 314.500 Scope. This subpart applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy). [57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999] § 314.510 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence. § 314.520 Approval with restrictions to assure safe use. (a) If FDA concludes that a drug product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the drug product, such as: (1) Distribution restricted to certain facilities or physicians with special training or experience; or (2) Distribution conditioned on the performance of specified medical procedures. (b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug product. § 314.530 Withdrawal procedures. (a) For new drugs approved under §§ 314.510 and 314.520, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if: (1) A postmarketing clinical study fails to verify clinical benefit; (2) The applicant fails to perform the required postmarketing study with due diligence; (3) Use after marketing demonstrates that postmarketing restrictions are inadequate to assure safe use of the drug product; (4) The applicant fails to adhere to the postmarketing restrictions agreed upon; (5) The promotional materials are false or misleading; or (6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use. (b) Notice of opportunity for a hearing. (c) Submission of data and information. (2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register (3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing. (d) Separation of functions. (e) Procedures for hearings. (1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs. (2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation. (f) Judicial review. [57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999] § 314.540 Postmarketing safety reporting. Drug products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved drug products, as provided in §§ 314.80 and 314.81. § 314.550 Promotional materials. For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement. § 314.560 Termination of requirements. If FDA determines after approval that the requirements established in § 314.520, § 314.530, or § 314.550 are no longer necessary for the safe and effective use of a drug product, it will so notify the applicant. Ordinarily, for drug products approved under § 314.510, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the drug product's clinical benefit and the drug product would be appropriate for approval under traditional procedures. For drug products approved under § 314.520, the restrictions would no longer apply when FDA determines that safe use of the drug product can be assured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30. Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible Source: 67 FR 37995, May 31, 2002, unless otherwise noted. § 314.600 Scope. This subpart applies to certain new drug products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. This subpart applies only to those new drug products for which: Definitive human efficacy studies cannot be conducted because it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance; and field trials to study the product's effectiveness after an accidental or hostile exposure have not been feasible. This subpart does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation for the products to which it does apply. § 314.610 Approval based on evidence of effectiveness from studies in animals. (a) FDA may grant marketing approval for a new drug product for which safety has been established and for which the requirements of § 314.600 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the sufficiency of animal data, the agency may take into account other data, including human data, available to the agency. FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when: (1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product; (2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans; (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and (4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans. (b) Approval under this subpart will be subject to three requirements: (1) Postmarketing studies. (2) Approval with restrictions to ensure safe use. (i) Distribution restricted to certain facilities or health care practitioners with special training or experience; (ii) Distribution conditioned on the performance of specified medical procedures, including medical followup; and (iii) Distribution conditioned on specified recordkeeping requirements. (3) Information to be provided to patient recipients. § 314.620 Withdrawal procedures. (a) Reasons to withdraw approval. (1) A postmarketing clinical study fails to verify clinical benefit; (2) The applicant fails to perform the postmarketing study with due diligence; (3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the drug product; (4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this subpart; (5) The promotional materials are false or misleading; or (6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use. (b) Notice of opportunity for a hearing. (c) Submission of data and information. (2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register (3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing. (d) Separation of functions. (e) Procedures for hearings. (1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs. (2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of CDER may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation. (f) Judicial review. § 314.630 Postmarketing safety reporting. Drug products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting requirements applicable to all approved drug products, as provided in §§ 314.80 and 314.81. § 314.640 Promotional materials. For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement. § 314.650 Termination of requirements. If FDA determines after approval under this subpart that the requirements established in §§ 314.610(b)(2), 314.620, and 314.630 are no longer necessary for the safe and effective use of a drug product, FDA will so notify the applicant. Ordinarily, for drug products approved under § 314.610, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the drug product's clinical benefit. For drug products approved under § 314.610, the restrictions would no longer apply when FDA determines that safe use of the drug product can be ensured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30 of this chapter.

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