PART 601—LICENSING Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note), sec 7002(e), Pub. L. 111-148, 124 Stat. 817, as amended by sec. 607, Division N, Pub. L. 116-94, 133 Stat. 3127. Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted. Cross References: For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111. Subpart A—General Provisions § 601.2 Applications for biologics licenses; procedures for filing. (a) General. (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 (4) Therapeutic recombinant DNA-derived products. (b) [Reserved] (c)(1) To obtain marketing approval for a biological product subject to licensure which is a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product, an applicant shall submit a biologics license application in accordance with paragraph (a) of this section except that the following sections in parts 600 through 680 of this chapter shall not be applicable to such products: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, 610.53, and 610.62 of this chapter. (2) To the extent that the requirements in this paragraph (c) conflict with other requirements in this subchapter, this paragraph (c) shall supersede other requirements. (d) Approval of a biologics license application or issuance of a biologics license shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure the continued safety, purity, and potency of such products. Applicable requirements for the maintenance of establishments for the manufacture of a product subject to this section shall include but not be limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter. (e) Any establishment and product license for a biological product issued under section 351 of the Public Health Service Act (42 U.S.C. 201 et seq. (f) Withdrawal from sale of approved biological products. (g) Master files Biologics license applications under section 351 of the Public Health Service Act not permitted to incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file (2) Former approved applications deemed to be licenses for biological products pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (i) Is a former approved application under section 505 of the Federal Food, Drug, and Cosmetic Act that, pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009, has been deemed to be a license for the biological product under section 351 of the Public Health Service Act; and (ii) At the time it was so deemed, incorporated by reference drug substance, drug substance intermediate, and/or drug product information contained in a drug master file submitted under § 314.420 of this chapter, may continue to incorporate by reference the information contained in that drug master file. Amendments and supplements to such applications may also continue to incorporate by reference the information contained in that drug master file. (3) Non-biological product constituent parts of combination products regulated under biologics license applications under section 351 of the Public Health Service Act (4) Biologics license applications under section 351 of the Public Health Service Act permitted to incorporate by reference information contained in a master file that is not drug substance, drug substance intermediate, or drug product information (5) Investigational new drug applications. [64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015; 80 FR 37974, July 2, 2015; 81 FR 60221, Aug. 31, 2016; 89 FR 9756, Feb. 12, 2024] § 601.3 Complete response letter to the applicant. (a) Complete response letter. (1) Description of specific deficiencies. (2) Inadequate data. (3) Recommendation of actions for approval. (b) Applicant actions. (1) Resubmission. (2) Withdrawal. (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 or supplement should not be withdrawn and to request an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn. [73 FR 39611, July 10, 2008] § 601.4 Issuance and denial of license. (a) A biologics license shall be issued upon a determination by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research that the establishment(s) and the product meet the applicable requirements established in this chapter. A biologics license shall be valid until suspended or revoked. (b) If the Commissioner determines that the establishment or product does not meet the requirements established in this chapter, the biologics license application shall be denied and the applicant shall be informed of the grounds for, and of an opportunity for a hearing on, the decision. If the applicant so requests, the Commissioner shall issue a notice of opportunity for hearing on the matter pursuant to § 12.21(b) of this chapter. [42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar. 24, 2005] § 601.5 Revocation of license. (a) A biologics license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products manufactured under such license or to discontinue the manufacture of a particular product for which a license is held and waiving an opportunity for a hearing on the matter. (b)(1) The Commissioner shall notify the licensed manufacturer of the intention to revoke the biologics license, setting forth the grounds for, and offering an opportunity for a hearing on the proposed revocation if the Commissioner finds any of the following: (i) Authorized Food and Drug Administration employees after reasonable efforts have been unable to gain access to an establishment or a location for the purpose of carrying out the inspection required under § 600.21 of this chapter, (ii) Manufacturing of products or of a product has been discontinued to an extent that a meaningful inspection or evaluation cannot be made, (iii) The manufacturer has failed to report a change as required by § 601.12 of this chapter, (iv) The establishment or any location thereof, or the product for which the license has been issued, fails to conform to the applicable standards established in the license and in this chapter designed to ensure the continued safety, purity, and potency of the manufactured product, (v) The establishment or the manufacturing methods have been so changed as to require a new showing that the establishment or product meets the requirements established in this chapter in order to protect the public health, or (vi) The licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use. (2) Except as provided in § 601.6 of this chapter, or in cases involving willfulness, the notification required in this paragraph shall provide a reasonable period for the licensed manufacturer to demonstrate or achieve compliance with the requirements of this chapter, before proceedings will be instituted for the revocation of the license. If compliance is not demonstrated or achieved and the licensed manufacturer does not waive the opportunity for a hearing, the Commissioner shall issue a notice of opportunity for hearing on the matter under § 12.21(b) of this chapter. [64 FR 56451, Oct. 20, 1999] § 601.6 Suspension of license. (a) Whenever the Commissioner has reasonable grounds to believe that any of the grounds for revocation of a license exist and that by reason thereof there is a danger to health, the Commissioner may notify the licensed manufacturer that the biologics license is suspended and require that the licensed manufacturer do the following: (1) Notify the selling agents and distributors to whom such product or products have been delivered of such suspension, and (2) Furnish to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research, complete records of such deliveries and notice of suspension. (b) Upon suspension of a license, the Commissioner shall either: (1) Proceed under the provisions of § 601.5(b) of this chapter to revoke the license, or (2) If the licensed manufacturer agrees, hold revocation in abeyance pending resolution of the matters involved. [64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005] § 601.7 Procedure for hearings. (a) A notice of opportunity for hearing, notice of appearance and request for hearing, and grant or denial of hearing for a biological drug pursuant to this part, for which the exemption from the Federal Food, Drug, and Cosmetic Act in § 310.4 of this chapter has been revoked, shall be subject to the provisions of § 314.200 of this chapter except to the extent that the notice of opportunity for hearing on the matter issued pursuant to § 12.21(b) of this chapter specifically provides otherwise. (b) Hearings pursuant to §§ 601.4 through 601.6 shall be governed by part 12 of this chapter. (c) When a license has been suspended pursuant to § 601.6 and a hearing request has been granted, the hearing shall proceed on an expedited basis. [42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12, 1977] § 601.8 Publication of revocation. The Commissioner, following revocation of a biologics license under 21 CFR 601.5(b), will publish a notice in the Federal Register [74 FR 20585, May 5, 2009] § 601.9 Licenses; reissuance. (a) Compliance with requirements. (b) Exclusion of noncomplying location. (c) Exclusion of noncomplying product(s). [64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005] Subpart B [Reserved] Subpart C—Biologics Licensing § 601.12 Changes to an approved application. (a) General. (2) Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or nonclinical laboratory studies the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. (3) Notwithstanding the requirements of paragraphs (b), (c), and (f) 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 (f)(1) and (f)(2) of this section. (5) 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 cover letter. (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 as provided in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation, including inactive ingredients, or in the specifications provided in the approved application; (ii) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product; (iii) Changes in the virus or adventitious agent removal or inactivation method(s); (iv) Changes in the source material or cell line; (v) Establishment of a new master cell bank or seed; and (vi) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s), or an addition, deletion, or substitution of steps in an aseptic processing operation. (3) The applicant must obtain approval of the supplement from FDA prior to distribution of the product made using the change. Except for submissions under paragraph (e) of this section, the following shall be contained in the supplement: (i) A detailed description of the proposed change; (ii) The product(s) involved; (iii) The manufacturing site(s) or area(s) affected; (iv) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product; (v) The data derived from such studies; (vi) Relevant validation protocols and data; and (vii) A reference list of relevant standard operating procedures (SOP's). (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 and its mailing cover should be plainly marked: “Prior Approval Supplement-Expedited Review Requested. (c) Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change. (2) These changes include, but are not limited to: (i) [Reserved] (ii) An increase or decrease in production scale during finishing steps that involves different equipment; and (iii) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters. (iv) 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) Pending approval of the supplement by FDA, and except as provided in paragraph (c)(5) of this section, distribution of the product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of this section shall be contained in the supplement. (4) 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 product in accordance with paragraph (b) of this section; or (ii) Any of the information required under paragraph (c)(3) of this section is missing; the applicant shall not distribute the product made using the change until FDA determines that compliance with this section is achieved. (5) In certain circumstances, FDA may determine that, based on experience with a particular type of change, the supplement for such change is usually complete and provides the proper information, and on particular assurances that the proposed change has been appropriately submitted, the product made using the change may be distributed immediately upon receipt of the supplement by FDA. These circumstances may include substantial similarity with a type of change regularly involving a “Supplement—Changes Being Effected” supplement or a situation in which the applicant presents evidence that the proposed change has been validated in accordance with an approved protocol for such change under paragraph (e) of this section. (6) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the products 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)(iv) of this section, that is consistent with FDA statutory and regulatory requirements. (ii) The deletion or reduction of an ingredient intended only to affect the color of the product, except that a change intended only to affect Blood Grouping Reagents requires supplement submission and approval prior to distribution of the product made using the change in accordance with the requirements set forth in paragraph (b) of this section; (iii) An extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the application; (iv) A change within the container closure system for a nonsterile product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium; (v) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form product, without a change from one container closure system to another; (vi) The addition by embossing, debossing, or engraving of a code imprint to a solid dosage form biological product other than a modified release dosage form, or a minor change in an existing code imprint; and (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 application, or deletion of an alternative analytical procedure. (3) The following information for each change shall be contained in the annual report: (i) A list of all products involved; and (ii) A full description of the manufacturing and controls changes including: the manufacturing site(s) or area(s) involved; the date the change was made; a cross-reference to relevant validation protocols and/or SOP's; and relevant data from studies and tests performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. (iii) A statement by the holder of the approved application or license that the effects of the change have been assessed. (4) The applicant shall submit the report to the FDA office responsible for reviewing the application. The report shall include all the information required under this paragraph for each change made during the annual reporting interval which ends on the anniversary date in the order in which they were implemented. (e) An applicant may submit one or more protocols describing the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect. (f) Labeling changes. (2) Labeling changes requiring supplement submission—product with a labeling change that may be distributed before FDA approval. (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 abuse, dependence, psychological effect, or overdosage; (C) To add or strengthen an instruction about dosage and administration that is intended to increase the safety of the use of the product; and (D) To delete false, misleading, or unsupported indications for use or claims for effectiveness. (E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the product that FDA specifically requests be submitted under this provision. (ii) Pending approval of the supplement by FDA, the applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the supplement is submitted. The supplement shall clearly identify the change being made and include necessary supporting data. The supplement and its mailing cover shall be plainly marked: “Special Labeling Supplement—Changes Being Effected.” (3) Labeling changes requiring submission in an annual report. (A) Editorial or similar minor changes; (B) A change in the information on how the product is supplied that does not involve a change in the dosage strength or dosage form; (C) A change in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter for a Medication Guide; and (D) A change to the information required in § 201.57(a) of this chapter as follows: ( 1 ( 2 (E) A change made pursuant to an exception or alternative granted under § 201.26 or § 610.68 of this chapter. (ii) The applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the change is made. (4) Advertisements and promotional labeling. (5) The submission and grant of a written request for an exception or alternative under § 201.26 or § 610.68 of this chapter satisfies the requirements in paragraphs (f)(1) through (f)(2) of this section. (6) For purposes of paragraph (f)(2) of this section, information will be considered newly acquired if it consists of data, analyses, or other information not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA. (g) Failure to comply. (h) Administrative review. [62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998. Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766, Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov. 18, 2008; 80 FR 18092, Apr. 3, 2015] § 601.14 Regulatory submissions in electronic format. (a) General. (b) Labeling. [68 FR 69020, Dec. 11, 2003] § 601.15 Foreign establishments and products: samples for each importation. Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter) must be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment must accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c)). For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Center for Biologics Evaluation and Research or Center for Drug Evaluation and Research accompanies each shipment. [70 FR 14983, Mar. 24, 2005, as amended at 80 FR 18092, Apr. 3, 2015] § 601.20 Biologics licenses; issuance and conditions. (a) Examination—compliance with requirements. (b) Availability of product. (1) The product intended for introduction into interstate commerce is available for examination, and (2) Such product is available for inspection during all phases of manufacture. (c) Manufacturing process—impairment of assurances. (d) Inspection—compliance with requirements. (e) One biologics license to cover all locations. [64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005] § 601.21 Products under development. A biological product undergoing development, but not yet ready for a biologics license, may be shipped or otherwise delivered from one State or possession into another State or possession provided such shipment or delivery is not for introduction or delivery for introduction into interstate commerce, except as provided in sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, as amended, and the regulations thereunder (21 CFR parts 312 and 812). [64 FR 56451, Oct. 20, 1999] § 601.22 Products in short supply; initial manufacturing at other than licensed location. A biologics license issued to a manufacturer and covering all locations of manufacture shall authorize persons other than such manufacturer to conduct at places other than such locations the initial, and partial manufacturing of a product for shipment solely to such manufacturer only to the extent that the names of such persons and places are registered with the Commissioner of Food and Drugs and it is found upon application of such manufacturer, that the product is in short supply due either to the peculiar growth requirements of the organism involved or to the scarcity of the animal required for manufacturing purposes, and such manufacturer has established with respect to such persons and places such procedures, inspections, tests or other arrangements as will ensure full compliance with the applicable regulations of this subchapter related to continued safety, purity, and potency. Such persons and places shall be subject to all regulations of this subchapter except §§ 601.2 to 601.6, 601.9, 601.10, 601.20, 601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and places authorized under this section to conduct the initial and partial manufacturing of a product for shipment solely to a manufacturer of a product subject to licensure under § 601.2(c), the following additional regulations shall not be applicable: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, and 610.53 of this chapter. Failure of such manufacturer to maintain such procedures, inspections, tests, or other arrangements, or failure of any person conducting such partial manufacturing to comply with applicable regulations shall constitute a ground for suspension or revocation of the authority conferred pursuant to this section on the same basis as provided in §§ 601.6 to 601.8 with respect to the suspension and the revocation of licenses. [42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64 FR 56452, Oct. 20, 1999; 80 FR 37974, July 2, 2015] § 601.27 Pediatric studies. (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 product may be licensed 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 product does not represent a meaningful therapeutic benefit over existing therapies 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 product would be ineffective or unsafe in all pediatric age groups. (3) Partial waiver. (i) The product does not represent a meaningful therapeutic benefit over existing therapies 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 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 product 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, e.g., 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 product is in a class of products or for an indication for which there is a need for additional therapeutic options. (d) Exemption for orphan drugs. [63 FR 66671, Dec. 2, 1998] § 601.28 Annual reports of postmarketing pediatric studies. Sponsors of licensed biological products shall submit the following information each year within 60 days of the anniversary date of approval of each product under the license 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): (a) Summary. (b) Clinical data. (c) Status reports. [65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015] § 601.29 Guidance documents. (a) FDA has made available guidance documents under § 10.115 of this chapter to help you comply with certain requirements of this part. (b) The Center for Biologics Evaluation and Research (CBER) maintains a list of guidance documents that apply to the center's regulations. The lists are maintained on the Internet and are published annually in the Federal Register. [65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015] Subpart D—Diagnostic Radiopharmaceuticals Source: 64 FR 26668, May 17, 1999, unless otherwise noted. § 601.30 Scope. This subpart applies to radiopharmaceuticals intended for in vivo administration for diagnostic and monitoring use. It does not apply to radiopharmaceuticals intended for therapeutic purposes. In situations where a particular radiopharmaceutical is proposed for both diagnostic and therapeutic uses, the radiopharmaceutical must be evaluated taking into account each intended use. § 601.31 Definition. For purposes of this part, diagnostic radiopharmaceutical (a) An article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons; or (b) Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such article as defined in paragraph (a) of this section. § 601.32 General factors relevant to safety and effectiveness. FDA's determination of the safety and effectiveness of a diagnostic radiopharmaceutical includes consideration of the following: (a) The proposed use of the diagnostic radiopharmaceutical in the practice of medicine; (b) The pharmacological and toxicological activity of the diagnostic radiopharmaceutical (including any carrier or ligand component of the diagnostic radiopharmaceutical); and (c) The estimated absorbed radiation dose of the diagnostic radiopharmaceutical. § 601.33 Indications. (a) For diagnostic radiopharmaceuticals, the categories of proposed indications for use include, but are not limited to, the following: (1) Structure delineation; (2) Functional, physiological, or biochemical assessment; (3) Disease or pathology detection or assessment; and (4) Diagnostic or therapeutic patient management. (b) Where a diagnostic radiopharmaceutical is not intended to provide disease-specific information, the proposed indications for use may refer to a biochemical, physiological, anatomical, or pathological process or to more than one disease or condition. § 601.34 Evaluation of effectiveness. (a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria: (1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy. (2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es). (3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology. (4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management. (5) For a claim that does not fall within the indication categories identified in § 601.33, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim. (b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient followup. § 601.35 Evaluation of safety. (a) Factors considered in the safety assessment of a diagnostic radiopharmaceutical include, among others, the following: (1) The radiation dose; (2) The pharmacology and toxicology of the radiopharmaceutical, including any radionuclide, carrier, or ligand; (3) The risks of an incorrect diagnostic determination; (4) The adverse reaction profile of the drug; (5) Results of human experience with the radiopharmaceutical for other uses; and (6) Results of any previous human experience with the carrier or ligand of the radiopharmaceutical when the same chemical entity as the carrier or ligand has been used in a previously studied product. (b) The assessment of the adverse reaction profile includes, but is not limited to, an evaluation of the potential of the diagnostic radiopharmaceutical, including the carrier or ligand, to elicit the following: (1) Allergic or hypersensitivity responses, (2) Immunologic responses, (3) Changes in the physiologic or biochemical function of the target and nontarget tissues, and (4) Clinically detectable signs or symptoms. (c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA may require, among other information, the following types of data: (A) Pharmacology data, (B) Toxicology data, (C) Clinical adverse event data, and (D) Radiation safety assessment. (2) The amount of new safety data required will depend on the characteristics of the product and available information regarding the safety of the diagnostic radiopharmaceutical, and its carrier or ligand, obtained from other studies and uses. Such information may include, but is not limited to, the dose, route of administration, frequency of use, half-life of the ligand or carrier, half-life of the radionuclide, and results of clinical and preclinical studies. FDA will establish categories of diagnostic radiopharmaceuticals based on defined characteristics relevant to risk and will specify the amount and type of safety data that are appropriate for each category (e.g., required safety data may be limited for diagnostic radiopharmaceuticals with a well established, low-risk profile). Upon reviewing the relevant product characteristics and safety information, FDA will place each diagnostic radiopharmaceutical into the appropriate safety risk category. (d) Radiation safety assessment. Subpart E—Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses Source: 57 FR 58959, Dec. 11, 1992, unless otherwise noted. § 601.40 Scope. This subpart applies to certain biological 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). § 601.41 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 biological product on the basis of adequate and well-controlled clinical trials establishing that the biological 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 biological product 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. § 601.42 Approval with restrictions to assure safe use. (a) If FDA concludes that a biological 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 biological 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 biological product. § 601.43 Withdrawal procedures. (a) For biological products approved under § 601.41 or § 601.42, 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 ensure safe use of the biological 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 biological 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 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003; 70 FR 14984, Mar. 24, 2005] § 601.44 Postmarketing safety reporting. Biological products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products. § 601.45 Promotional materials. For biological 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. § 601.46 Termination of requirements. If FDA determines after approval that the requirements established in § 601.42, § 601.43, or § 601.45 are no longer necessary for the safe and effective use of a biological product, it will so notify the applicant. Ordinarily, for biological products approved under § 601.41, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the biological product's clinical benefit and the biological product would be appropriate for approval under traditional procedures. For biological products approved under § 601.42, the restrictions would no longer apply when FDA determines that safe use of the biological 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 F—Confidentiality of Information § 601.50 Confidentiality of data and information in an investigational new drug notice for a biological product. (a) The existence of an IND notice for a biological product will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information in an IND file for a biological product shall be handled in accordance with the provisions established in § 601.51. (c) Notwithstanding the provisions of § 601.51, the Food and Drug Administration shall disclose upon request to an individual on whom an investigational biological product has been used a copy of any adverse reaction report relating to such use. [39 FR 44656, Dec. 24, 1974] § 601.51 Confidentiality of data and information in applications for biologics licenses. (a) For purposes of this section the biological product file includes all data and information submitted with or incorporated by reference in any application for a biologics license, IND's incorporated into any such application, master files, and other related submissions. The availability for public disclosure of any record in the biological product file shall be handled in accordance with the provisions of this section. (b) The existence of a biological product file will not be disclosed by the Food and Drug Administration before a biologics license application has been approved unless it has previously been publicly disclosed or acknowledged. The Food and Drug Administration will maintain a list available for public disclosure of biological products for which a license application has been approved. (c) If the existence of a biological product file has not been publicly disclosed or acknowledged, no data or information in the biological product file is available for public disclosure. (d)(1) If the existence of a biological product file has been publicly disclosed or acknowledged before a license has been issued, no data or information contained in the file is available for public disclosure before such license is issued, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government. (2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IND 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 a license has been issued, the following data and information in the biological product file are immediately available for public disclosure unless extraordinary circumstances are shown: (1) All safety and effectiveness data and information. (2) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial or financial information in § 20.61 of this chapter. (3) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of: (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. (4) A list of all active ingredients and any inactive ingredients previously disclosed to the public, as defined in § 20.81 of this chapter. (5) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and it is shown to fall within the exemption established in § 20.61 of this chapter. (6) All correspondence and written summaries of oral discussions relating to the biological product file, in accordance with the provisions of part 20 of this chapter. (7) All records showing the manufacturer's testing of a particular lot, after deletion of data or information that would show the volume of the drug produced, manufacturing procedures and controls, yield from raw materials, costs, or other material falling within § 20.61 of this chapter. (8) All records showing the testing of and action on a particular lot by the Food and Drug Administration. (f) The following data and information in a biological product file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 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 such 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. (g) For purposes of this regulation, safety and effectiveness data include all studies and tests of a biological product on animals and humans and all studies and tests on the drug for identity, stability, purity, potency, and bioavailability. [39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR 13717, Mar. 24, 2004; 70 FR 14984, Mar. 24, 2005; 88 FR 45066, July 14, 2023] Subpart G—Postmarketing Studies Source: 65 FR 64618, Oct. 30, 2000, unless otherwise noted. § 601.70 Annual progress reports of postmarketing studies. (a) General requirements. (1) Clinical safety; (2) Clinical efficacy; (3) Clinical pharmacology; and (4) Nonclinical toxicology. (b) What to report. (1) Applicant's name. (2) Product name. (3) Biologics license application (BLA) and supplement number. (4) Date of U.S. approval of BLA. (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. (iii) Delayed. (iv) Terminated. (v) Submitted. (9) Explanation of the study's status. (c) When to report. (d) Where to report. (e) Public disclosure of information. [65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015] Subpart H—Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible Source: 67 FR 37996, May 31, 2002, unless otherwise noted. § 601.90 Scope. This subpart applies to certain biological 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 biological 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 efficacy 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. § 601.91 Approval based on evidence of effectiveness from studies in animals. (a) FDA may grant marketing approval for a biological product for which safety has been established and for which the requirements of § 601.90 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the biological 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. § 601.92 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 biological 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 biological 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 CBER 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. [67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005] § 601.93 Postmarketing safety reporting. Biological products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products. § 601.94 Promotional materials. For biological 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. § 601.95 Termination of requirements. If FDA determines after approval under this subpart that the requirements established in §§ 601.91(b)(2), 601.92, and 601.93 are no longer necessary for the safe and effective use of a biological product, FDA will so notify the applicant. Ordinarily, for biological products approved under § 601.91, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the biological product's clinical benefit. For biological products approved under § 601.91, the restrictions would no longer apply when FDA determines that safe use of the biological 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.