§25.31. Human drugs and biologics. — Inbound Citations

(a) All applications or petitions requesting agency action require the submission of an EA or a claim of categorical exclusion. A claim of categorical exclusion shall include a statement of compliance with the categorical exclusion criteria and shall state that to the applicant's knowledge, no extraordinary circumstances exist. Failure to submit an adequate EA for an application or petition requesting action by the agency of a type specified in § 25.20, unless the agency can determine that the action qualifies for exclusion under §§ 25.30, 25.31, 25.32, 25.33, 25.34, or 25.35 is sufficient grounds for FDA to refuse to file or approve the application or petition. An EA adequate for filing is one that addresses the relevant environmental issues. An EA adequate for approval is one that contains sufficient information to enable the agency to determine whether the proposed action may significantly affect the quality of the human environment.

Any proposed action of a type specified in this section normally requires at least the preparation of an EA, unless it is an action in a specific class that qualifies for exclusion under §§ 25.30, 25.31, 25.32, 25.33, 25.34, or 25.35:

The classes of actions listed in this section and §§ 25.31 through 25.35 are categorically excluded and, therefore, ordinarily do not require the preparation of an EA or an EIS:

(a) As defined by CEQ in 40 CFR 1508.9, an EA is a concise public document that serves to provide sufficient evidence and analysis for an agency to determine whether to prepare an EIS or a FONSI. The EA shall include brief discussions of the need for the proposal, of alternatives as required by section 102(2)(E) of NEPA, of the environmental impacts of the proposed action and alternatives, and a listing of agencies and persons consulted. An EA shall be prepared for each action not categorically excluded in § 25.30, § 25.31, § 25.32, § 25.33, or § 25.34, or § 25.35. The EA shall focus on relevant environmental issues relating to the use and disposal from use of FDA-regulated articles and shall be a concise, objective, and well-balanced document that allows the public to understand the agency's decision. If potentially adverse environmental impacts are identified for an action or a group of related actions, the EA shall discuss any reasonable alternative course of action that offers less environmental risk or that is environmentally preferable to the proposed action. The use of a scientifically justified tiered testing approach, in which testing may be stopped when the results suggest that no significant impact will occur, is an acceptable approach.

(iv) Reflecting the distinctions described in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to contain the following:

(a) Drug substance. A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy relevant requirements in this paragraph.

(b) Drug product. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain requirements in this paragraph.

(c) A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial.

(d) Labeling. A copy of all labels and labeling to be provided to each investigator.

(e) Environmental analysis requirements. A claim for categorical exclusion under § 25.30 or 25.31 or an environmental assessment under § 25.40.

(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.

(iii) The NDA is required to contain either a claim for categorical exclusion under § 25.30 or 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter.

(viii) The submission does not contain a complete environmental assessment 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.

(a) To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter), on forms prescribed for such purposes, and shall submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance; statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter; or was not subject to such requirements in accordance with § 56.104 or § 56.105, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter. A full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product for introduction or delivery for introduction into interstate commerce; summaries of results of tests performed on the lot(s) represented by the submitted sample(s); specimens of the labels, enclosures, and containers, and if applicable, any Medication Guide required under part 208 of this chapter proposed to be used for the product; and the address of each location involved in the manufacture of the biological product shall be listed in the biologics license application. The applicant shall also include a financial certification or disclosure statement(s) or both for clinical investigators as required by part 54 of this chapter. An application for a biologics license shall not be considered as filed until all pertinent information and data have been received by the Food and Drug Administration. The applicant shall also include either a claim for categorical exclusion under § 25.30 or § 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter. The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. An application for any of the following specified categories of biological products subject to licensure shall be handled as set forth in paragraph (c) of this section:

(1) Therapeutic DNA plasmid products;

(2) Therapeutic synthetic peptide products of 40 or fewer amino acids;

(3) Monoclonal antibody products for in vivo use; and

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(h) Withdrawal of existing approvals of FDA-approved articles, unless categorically excluded in §§ 25.31 (d) or (k), 25.32(m), or 25.33 (g) or (h).

(l) Approval of NDA's, abbreviated applications, applications for marketing approval of a biologic product, supplements to such applications, and actions on IND's, unless categorically excluded in § 25.31 (a), (b), (c), (e), or (l).

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(f) Establishment by regulation of labeling requirements, a standard, or a monograph, unless categorically excluded in §§ 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) or (p).

(h) Withdrawal of existing approvals of FDA-approved articles, unless categorically excluded in §§ 25.31 (d) or (k), 25.32(m), or 25.33 (g) or (h).

(l) Approval of NDA's, abbreviated applications, applications for marketing approval of a biologic product, supplements to such applications, and actions on IND's, unless categorically excluded in § 25.31 (a), (b), (c), (e), or (l).