21 C.F.R. Subpart C—Biologics Licensing
Title 21 - Food and Drugs
(a) General. (1) As provided by this section, an applicant must inform the Food and Drug Administration (FDA) (see mailing addresses in §600.2 of this chapter) about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s). (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). (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. (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. (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. The supplement shall be labeled “Supplement—Changes Being Effected in 30 Days” or, if applicable under paragraph (c)(5) of this section, “Supplement—Changes Being Effected.” (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). (1) Changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product shall be documented by the applicant in an annual report submitted each year within 60 days of the anniversary date of approval of the application. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, may approve a written request for an alternative date to combine annual reports for multiple approved applications into a single annual report submission. (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. (1) Labeling changes requiring supplement submission—FDA approval must be obtained before distribution of the product with the labeling change. Except as described in paragraphs (f)(2) and (f)(3) of this section, an applicant shall submit a supplement describing a proposed change in the package insert, package label, container label, or, if applicable, a Medication Guide required under part 208 of this chapter, and include the information necessary to support the proposed change. An applicant cannot use paragraph (f)(2) of this section to make any change to the information required in §201.57(a) of this chapter. An applicant may report the minor changes to the information specified in paragraph (f)(3)(i)(D) of this section in an annual report. The supplement shall clearly highlight the proposed change in the labeling. The applicant shall obtain approval from FDA prior to distribution of the product with the labeling change. (2) Labeling changes requiring supplement submission—product with a labeling change that may be distributed before FDA approval. (i) An applicant shall submit, at the time such change is made, a supplement for any change in the package insert, package label, or container label, except for changes to the package insert required in §201.57(a) of this chapter (which must be made pursuant to paragraph (f)(1) of this section), to accomplish any of the following: (A) To add or strengthen a contraindication, warning, precaution, or adverse reaction; (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. (i) An applicant shall submit any final printed package insert, package label, container label, or Medication Guide required under part 208 of this chapter incorporating the following changes in an annual report submitted to FDA each year as provided in paragraph (d)(1) of this section: (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) Removal of a listed section(s) specified in §201.57(a)(5) of this chapter; and (2) Changes to the most recent revision date of the labeling as specified in §201.57(a)(15) 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. Advertisements and promotional labeling shall be submitted to the Center for Biologics Evaluation and Research or Center for Drug Evaluation and Research in accordance with the requirements set forth in §314.81(b)(3)(i) of this chapter, except that Form FDA–2567 (Transmittal of Labels and Circulars) or an equivalent form shall be used. (g) Failure to comply. In addition to other remedies available in law and regulations, in the event of repeated failure of the applicant to comply with this section, FDA may require that the applicant submit a supplement for any proposed change and obtain approval of the supplement by FDA prior to distribution of the product made using the change. (h) Administrative review. Under §10.75 of this chapter, an applicant may request internal FDA review of FDA employee decisions under this section. [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] (a) General. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files.) (b) Labeling. The content of labeling required under §201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format as described in paragraph (a) of this section. This requirement is in addition to the provisions of §§601.2(a) and 601.12(f) that require applicants to submit specimens of the labels, enclosures, and containers, or to submit other final printed labeling. Submissions under this paragraph must be made in accordance with part 11 of this chapter except for the requirements of §11.10(a), (c) through (h), and (k), and the corresponding requirements of §11.30. [68 FR 69020, Dec. 11, 2003] 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 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). 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] (a) Examination—compliance with requirements. A biologics license application shall be approved only upon examination of the product and upon a determination that the product complies with the standards established in the biologics license application and the requirements prescribed in the regulations in this chapter including but not limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter. (b) Availability of product. No biologics license shall be issued unless: (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. No product shall be licensed if any part of the process of or relating to the manufacture of such product, in the judgment of the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, would impair the assurances of continued safety, purity, and potency as provided by the regulations contained in this chapter. (d) Inspection—compliance with requirements. A biologics license shall be issued or a biologics license application approved only after inspection of the establishment(s) listed in the biologics license application and upon a determination that the establishment(s) complies with the standards established in the biologics license application and the requirements prescribed in applicable regulations. (e) One biologics license to cover all locations. One biologics license shall be issued to cover all locations meeting the establishment standards identified in the approved biologics license application and each location shall be subject to inspection by FDA officials. [64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005] 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] 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, 610.11, 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] For purposes of reviewing biological products that have been licensed prior to July 1, 1972, to determine that they are safe and effective and not misbranded, the following regulations shall apply. Prior administrative action exempting biological products from the provisions of the Federal Food, Drug, and Cosmetic Act is superseded to the extent that these regulations result in imposing requirements pursuant to provisions therein for a designated biological product or category of products. (a) Advisory review panels. The Commissioner of Food and Drugs shall appoint advisory review panels (1) to evaluate the safety and effectiveness of biological products for which a license has been issued pursuant to section 351 of the Public Health Service Act, (2) to review the labeling of such biological products, and (3) to advise him on which of the biological products under review are safe, effective, and not misbranded. An advisory review panel shall be established for each designated category of biological product. The members of a panel shall be qualified experts, appointed by the Commissioner, and shall include persons from lists submitted by organizations representing professional, consumer, and industry interests. Such persons shall represent a wide divergence of responsible medical and scientific opinion. The Commissioner shall designate the chairman of each panel, and summary minutes of all meetings shall be made. (b) Request for data and views. (1) The Commissioner of Food and Drugs will publish a notice in the (2) Data and information submitted pursuant to a published notice, and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory review panel and the Food and Drug Administration as confidential until publication of a proposed evaluation of the biologics under review and the full report or reports of the panel. Thirty days thereafter such data and information shall be made publicly available and may be viewed at the Division of Dockets Management of the Food and Drug Administration, except to the extent that the person submitting it demonstrates that it still falls within the confidentiality provisions of one or more of those statutes. (3) To be considered, 12 copies of the submission on any marketed biological product within the class shall be submitted, preferably bound, indexed, and on standard sized paper, approximately 8
Biological Products Review Information I. Label or labels and all other labeling (preferably mounted. Facsimile labeling is acceptable in lieu of actual container labeling), including labeling for export. II. Representative advertising used during the past 5 years. III. The complete quantitative composition of the biological product. IV. Animal safety data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. C. Finished biological product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. V. Human safety data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component. 5. Pertinent medical and scientific literature. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components. 5. Pertinent medical and scientific literature. C. Finished biological product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of the finished biological product. 5. Pertinent medical and scientific literature. VI. Efficacy data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component. 5. Pertinent medical and scientific literature. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the effectiveness of combinations of the individual active components. 5. Pertinent medical and scientific literature. C. Finished biological product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the effectiveness of the finished biological product. 5. Pertinent medical and scientific literature. VII. A summary of the data and views setting forth the medical rational and purpose (or lack thereof) for the biological product and its components and the scientific basis (or lack thereof) for the conclusion that the biological product, including its components, has been proven safe and effective and is properly labeled for the intended use or uses. If there is an absence of controlled studies in the materials submitted, an explanation as to why such studies are not considered necessary or feasible shall be included. VIII. If the submission is by a licensed manufacturer, a statement signed by the authorized official of the licensed manufacturer shall be included, stating that to the best of his or her knowledge and belief, it includes all information, favorable and unfavorable, pertinent to an evaluation of the safety, effectiveness, and labeling of the product, including information derived from investigation, commercial marketing, or published literature. If the submission is by an interested person other than a licensed manufacturer, a statement signed by the person responsible for such submission shall be included, stating that to the best of his knowledge and belief, it fairly reflects a balance of all the available information, favorable and unfavorable available to him, pertinent to an evaluation of the safety, effectiveness, and labeling of the product. (c) Deliberations of an advisory review panel. An advisory review panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner of Food and Drugs with respect to the safety, effectiveness, and labeling of the biological products in the designated category under review. (1) A panel may also consult any individual or group. (2) Any interested person may request in writing an opportunity to present oral views to the panel. Such written requests for oral presentations should include a summarization of the data to be presented to the panel. Such request may be granted or denied by the panel. (3) Any interested person may present written data and views which shall be considered by the panel. This information shall be presented to the panel in the format set forth in paragraph (b)(3) of this section and within the time period established for the biological product category in the notice for review by a panel. (d) Standards for safety, effectiveness, and labeling. The advisory review panel, in reviewing the submitted data and preparing the panel's conclusions and recommendations, and the Commissioner of Food and Drugs, in reviewing and implementing the conclusions and recommendations of the panel, shall apply the following standards to determine that a biological product is safe and effective and not misbranded. (1) Safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the biological product is safe under the prescribed conditions of use, including results of significant human experience during use. (2) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product, when used under adequate directions, for use and warnings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Proof of effectiveness shall consist of controlled clinical investigations as defined in §314.126 of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the biological product or essential to the validity of the investigation, and that an alternative method of investigation is adequate to substantiate effectiveness. Alternate methods, such as serological response evaluation in clinical studies and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness already exists. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered. (3) The benefit-to-risk ratio of a biological product shall be considered in determining safety and effectiveness. (4) A biological product may combine two or more safe and effective active components: (i) When each active component makes a contribution to the claimed effect or effects; (ii) when combining of the active ingredients does not decrease the purity, potency, safety, or effectiveness of any of the individual active components; and (iii) if the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent preventive therapy or treatment for a significant proportion of the target population. (5) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall comply with section 351 of the Public Health Service Act and sections 502 and 503 of the Federal Food, Drug, and Cosmetic Act, and in particular with the applicable requirements of §§610.60 through 610.65 and subpart D of part 201 of this chapter. (e) Advisory review panel report to the Commissioner. An advisory review panel shall submit to the Commissioner of Food and Drugs a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category covered by the panel. Included within this report shall be: (1) A statement which designates those biological products determined by the panel to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness. (2) A statement which designates those biological products determined by the panel to be unsafe or ineffective, or to be misbranded. The statement shall include the panel's reasons for each such determination. (3) A statement which designates those biological products determined by the panel not to fall within either paragraph (e) (1) or (2) of this section on the basis of the panel's conclusion that the available data are insufficient to classify such biological products, and for which further testing is therefore required. The report shall recommend with as must specificity as possible the type of further testing required and the time period within which it might reasonably be concluded. The report shall also recommend whether the product license should or should not be revoked, thus permitting or denying continued manufacturing and marketing of the biological product pending completion of the testing. This recommendation will be based on an assessment of the present evidence of the safety and effectiveness of the product and the potential benefits and risks likely to result from the continued use of the product for a limited period of time while the questions raised concerning the product are being resolved by further study.2 2 As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under §601.26 of this chapter. The superseded text is included for the convenience of the user only. (f) Proposed order. After reviewing the conclusions and recommendations of the advisory review panel, the Commissioner of Food and Drugs shall publish in the (1) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness, and may propose corresponding amendments in other regulations under this subchapter F. (2) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be unsafe or ineffective, or to be misbranded, together with the reasons therefor. All licenses for such products shall be proposed to be revoked. (3) A statement designating the biological products not included in either of the above two statements on the basis of the Commissioner of Food and Drugs determination that the available data are insufficient to classify such biological products under either paragraph (f) (1) or (2) of this section. Licenses for such products may be proposed to be revoked or to remain in effect on an interim basis. Where the Commissioner determines that the potential benefits outweigh the potential risks, the proposed order shall provide that the biologics license for any biological product, falling within this paragraph, will not be revoked but will remain in effect on an interim basis while the data necessary to support its continued marketing are being obtained for evaluation by the Food and Drug Administration. The tests necessary to resolve whatever safety or effectiveness questions exist shall be described.2 2 As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under §601.26 of this chapter. The superseded text is included for the convenience of the user only. (4) The full report or reports of the panel to the Commissioner of Food and Drugs.
The summary minutes of the panel meeting or meetings shall be made available to interested persons upon request. Any interested person may within 90 days after publication of the proposed order in the (g) Final order. After reviewing the comments, the Commissioner of Food and Drugs shall publish in the (h) [Reserved] (i) Court Appeal. The final order(s) published pursuant to paragraph (g) of this section, and any notice published pursuant to paragraph (h) of this section, constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at his discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication. [38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974; 40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071, Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 64 FR 56452, Oct. 20, 1999] This regulation establishes procedures for the reclassification of all biological products that have been classified into Category IIIA. A Category IIIA biological product is one for which an advisory review panel has recommended under §601.25(e)(3), the Commissioner of Food and Drugs (Commissioner) has proposed under §601.25(f)(3), or the Commissioner has finally decided under §601.25(g) that available data are insufficient to determine whether the product license should be revoked or affirmed and which may be marketed pending the completion of further testing. All of these Category IIIA products will either be reclassified into Category I (safe, effective, and not misbranded) or Category II (unsafe, ineffective, or misbranded) in accordance with the procedures set forth below. (a) Advisory review panels. The Commissioner will appoint advisory review panels and use existing advisory review panels to (1) evaluate the safety and effectiveness of all Category IIIA biological products; (2) review the labeling of such products; and (3) advise the Commissioner on which Category IIIA biological products are safe, effective, and not misbranded. These advisory review panels will be established in accordance with procedures set forth in §601.25(a). (b) Deliberations of advisory review panels. The deliberations of advisory review panels will be conducted in accordance with §601.25(d). (c) Advisory review panel report to the Commissioner. An advisory review panel shall submit to the Commissioner a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category of products reviewed by the panel. The panel report shall include: (1) A statement designating the biological products in the category under review in accordance with either §601.25(e)(1) or §601.25(e)(2). (2) A statement identifying those biological products designated under §601.25(e)(2) that the panel recommends should be designated as safe and presumptively effective and should remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent that is available in sufficient quantities to meet current medical needs. For the products or categories of products so recommended, the report shall include: (i) A description and evaluation of the available evidence concerning effectiveness and an explanation why the evidence shows that the product has any benefit; and (ii) A description of the alternative therapeutic, prophylactic, or diagnostic agents considered and a statement of why such alternatives are not suitable. In making this recommendation the panel shall also take into account the seriousness of the condition intended to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing and new test development. The report shall also recommend with as much specificity as possible the type of further testing required and the time period within which it might reasonably be concluded. (d) Proposed order. After reviewing the conclusions and recommendations of the advisory review panels, the Commissioner shall publish in the (1) A statement designating the biological products in the category under review in accordance with either §601.25(e)(1) or 601.25(e)(2); (2) A notice of availability of the full panel report or reports. The full panel report or reports shall be made publicly available at the time of publication of the proposed order. (3) A proposal to accept or reject the findings of the advisory review panel required by §601.26(c)(2)(i) and (ii). (4) A statement identifying those biological products that the Commissioner proposes should be designated as safe and presumptively effective under §601.26(c)(2) and should be permitted to remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for the product that is available in sufficient quantities to meet current medical needs. In making this proposal, the Commissioner shall take into account the seriousness of the condition to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing. (e) Final order. After reviewing the comments on the proposed order, the Commissioner shall publish in the (f) Additional studies and labeling. (1) Within 60 days following publication of the final order, each licensed manufacturer for a biological product designated as requiring further study to justify continued marketing on an interim basis, under paragraph (e) of this section, shall submit to the Commissioner a written statement intended to show that studies adequate and appropriate to resolve the questions raised about the product have been undertaken. The Federal Government may undertake the studies. Any study involving a clinical investigation that involves human subjects shall be conducted in compliance with the requirements for informed consent under part 50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter unless exempt under §56.104 or §56.105. The Commissioner may extend this 60-day period if necessary, either to review and act on proposed protocols or upon indication from the licensed manufacturer that the studies will commence at a specified reasonable time. If no such commitment is made, or adequate and appropriate studies are not undertaken, the biologics license or licenses shall be revoked. (2) A progress report shall be filed on the studies by January 1 and July 1 until completion. If the progress report is inadequate or if the Commissioner concludes that the studies are not being pursued promptly and diligently, or if interim results indicate the product is not a medical necessity, the biologics license or licenses shall be revoked. (3) Promptly upon completion of the studies undertaken on the product, the Commissioner will review all available data and will either retain or revoke the biologics license or licenses involved. In making this review the Commissioner may again consult the advisory review panel which prepared the report on the product, or other advisory committees, professional organizations, or experts. The Commissioner shall take such action by notice published in the (4) Labeling and promotional material for those biological products requiring additional studies shall bear a box statement in the following format: Based on a review by the (insert name of appropriate advisory review panel) and other information, the Food and Drug Administration has directed that further investigation be conducted before this product is conclusively determined to be effective for labeled indication(s). (5) A written informed consent shall be obtained from participants in any additional studies required under paragraph (f)(1) of this section, explaining the nature of the product and the investigation. The explanation shall consist of such disclosure and be made so that intelligent and informed consent be given and that a clear opportunity to refuse is presented. (g) Court appeal. The final order(s) published pursuant to paragraph (e) of this section constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at the Commissioner's discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication. (h) [Reserved] (i) Institutional review and informed consent. Information and data submitted under this section after July 27, 1981, shall include statements regarding each clinical investigation involving human subjects, that it was conducted in compliance with the requirements for informed consent under part 50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter, unless exempt under §56.104 or §56.105. [47 FR 44071, Oct. 5, 1982, as amended at 64 FR 56452, Oct. 20, 1999] (a) Required assessment. Except as provided in paragraphs (b), (c), and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. Where the course of the disease and the effects of the product are similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled effectiveness studies in adults, usually supplemented with other information in pediatric patients, such as pharmacokinetic studies. In addition, studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another. Assessments required under this section for a product that represents a meaningful therapeutic benefit over existing treatments must be carried out using appropriate formulations for the age group(s) for which the assessment is required. (b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section until after licensing of the product for use in adults. Deferral may be granted if, among other reasons, the product is ready for approval in adults before studies in pediatric patients are complete, pediatric studies should be delayed until additional safety or effectiveness data have been collected. If an applicant requests deferred submission, the request must provide an adequate justification for delaying pediatric studies, a description of the planned or ongoing studies, and evidence that the studies are being or will be conducted with due diligence and at the earliest possible time. (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—(1) General. FDA may grant a full or partial waiver of the requirements of paragraph (a) of this section on its own initiative or at the request of an applicant. A request for a waiver must provide an adequate justification. (2) Full waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section if the applicant certifies that: (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. An applicant may request a waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that: (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. FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling. (5) Definition of “meaningful therapeutic benefit”. For purposes of this section, a product will be considered to offer a meaningful therapeutic benefit over existing therapies if FDA estimates that: (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. This section does not apply to any product for an indication or indications for which orphan designation has been granted under part 316, subpart C, of this chapter. [63 FR 66671, Dec. 2, 1998] 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 of this chapter): (a) Summary. A brief summary stating whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population to support appropriate labeling for the pediatric population have been initiated. Where possible, an estimate of patient exposure to the drug product, with special reference to the pediatric population (neonates, infants, children, and adolescents) shall be provided, including dosage form. (b) Clinical data. Analysis of available safety and efficacy data in the pediatric population and changes proposed in the labeling based on this information. An assessment of data needed to ensure appropriate labeling for the pediatric population shall be included. (c) Status reports. A statement on the current status of any postmarketing studies in the pediatric population performed by, or on behalf of, the applicant. The statement shall include whether postmarketing clinical studies in pediatric populations were required or agreed to, and, if so, the status of these studies shall be reported to FDA in annual progress reports of postmarketing studies under §601.70 rather than under this section. [65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70 FR 14984, Mar. 24, 2005] (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 [65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005]
Title 21: Food and Drugs
PART 601—LICENSING
Subpart C—Biologics Licensing
§ 601.12 Changes to an approved application.
§ 601.14 Regulatory submissions in electronic format.
§ 601.15 Foreign establishments and products: samples for each importation.
§ 601.20 Biologics licenses; issuance and conditions.
§ 601.21 Products under development.
§ 601.22 Products in short supply; initial manufacturing at other than licensed location.
§ 601.25 Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.
§ 601.26 Reclassification procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.
§ 601.27 Pediatric studies.
§ 601.28 Annual reports of postmarketing pediatric studies.
§ 601.29 Guidance documents.
