US Codex
C.F.R.
Browse by date

View an earlier version

Latest
Current
Browse all versions by date
Notes

21 C.F.R. §§ 514.3–514.8

6 sections in range

§514.3. Definitions.

21 C.F.R. § 514.3

The definition and interpretation of terms contained in this section apply to those terms as used throughout subchapter E.

Adverse drug experience is any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in accordance with the approved labeling (i.e., used according to label directions or used in an extralabel manner, including but not limited to different route of administration, different species, different indications, or other than labeled dosage). Adverse drug experience includes, but is not limited to:

(1)
An adverse event occurring in animals in the course of the use of an animal drug product by a veterinarian or by a livestock producer or other animal owner or caretaker.
(2)
Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected effectiveness).
(3)
An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug.

ANADA is an abbreviated new animal drug application including all amendments and supplements.

Applicant is a person or entity who owns or holds on behalf of the owner the approval for an NADA or an ANADA, and is responsible for compliance with applicable provisions of the act and regulations.

Increased frequency of adverse drug experience is an increased rate of occurrence of a particular serious adverse drug event, expected or unexpected, after appropriate adjustment for drug exposure.

NADA is a new animal drug application including all amendments and supplements.

Nonapplicant is any person other than the applicant whose name appears on the label and who is engaged in manufacturing, packing, distribution, or labeling of the product.

Potential applicant means any person:

(1)
Intending to investigate a new animal drug under section 512(j) of the Federal Food, Drug, and Cosmetic Act (the act),
(2)
Investigating a new animal drug under section 512(j) of the act,
(3)
Intending to file a new animal drug application (NADA) or supplemental NADA under section 512(b)(1) of the act, or
(4)
Intending to file an abbreviated new animal drug application (ANADA) under section 512(b)(2) of the act.

Presubmission conference means one or more conferences between a potential applicant and FDA to reach a binding agreement establishing a submission or investigational requirement.

Presubmission conference agreement means that section of the memorandum of conference headed “Presubmission Conference Agreement” that records any agreement on the submission or investigational requirement reached by a potential applicant and FDA during the presubmission conference.

Product defect/manufacturing defect is the deviation of a distributed product from the standards specified in the approved application, or any significant chemical, physical, or other change, or deterioration in the distributed drug product, including any microbial or chemical contamination. A manufacturing defect is a product defect caused or aggravated by a manufacturing or related process. A manufacturing defect may occur from a single event or from deficiencies inherent to the manufacturing process. These defects are generally associated with product contamination, product deterioration, manufacturing error, defective packaging, damage from disaster, or labeling error. For example, a labeling error may include any incident that causes a distributed product to be mistaken for, or its labeling applied to, another product.

Serious adverse drug experience is an adverse event that is fatal, or life-threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability, or disfigurement.

Unexpected adverse drug experience is an adverse event that is not listed in the current labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an event listed on the labeling, but differs from the event because of greater severity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling referred only to elevated hepatic enzymes or hepatitis.

Notes, amendments, and revision history

Amendments

[68 FR 15365, Mar. 31, 2003, as amended at 69 FR 51170, Aug. 18, 2004]

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

Amendments

[68 FR 15365, Mar. 31, 2003, as amended at 69 FR 51170, Aug. 18, 2004]

§514.4. Substantial evidence.

21 C.F.R. § 514.4

(a)
Definition of substantial evidence. Substantial evidence means evidence consisting of one or more adequate and well-controlled studies, such as a study in a target species, study in laboratory animals, field study, bioequivalence study, or an in vitro study, on the basis of which it could fairly and reasonably be concluded by experts qualified by scientific training and experience to evaluate the effectiveness of the new animal drug involved that the new animal drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. Substantial evidence shall include such adequate and well-controlled studies that are, as a matter of sound scientific judgment, necessary to establish that a new animal drug will have its intended effect.
(b)
Characteristics of substantial evidence—
(1)
Qualifications of experts. Any study that is intended to be part of substantial evidence of the effectiveness of a new animal drug shall be conducted by experts qualified by scientific training and experience.
(2)
Intended uses and conditions of use. Substantial evidence of effectiveness of a new animal drug shall demonstrate that the new animal drug is effective for each intended use and associated conditions of use for and under which approval is sought.
(i)
Dose range labeling. Sponsors should, to the extent possible, provide for a dose range because it increases the utility of the new animal drug by providing the user flexibility in the selection of a safe and effective dose. In general, substantial evidence to support dose range labeling for a new animal drug intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at the lowest dose of the dose range suggested in the proposed labeling for that intended use. Substantial evidence to support dose range labeling for a new animal drug intended to affect the structure or function of the body of an animal generally must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at all doses within the range suggested in the proposed labeling for the intended use.
(ii)
[Reserved]
(3)
Studies—
(i)
Number. Substantial evidence of the effectiveness of a new animal drug for each intended use and associated conditions of use shall consist of a sufficient number of current adequate and well-controlled studies of sufficient quality and persuasiveness to permit qualified experts:
(A)
To determine that the parameters selected for measurement and the measured responses reliably reflect the effectiveness of the new animal drug;
(B)
To determine that the results obtained are likely to be repeatable, and that valid inferences can be drawn to the target animal population; and
(C)
To conclude that the new animal drug is effective for the intended use at the dose or dose range and associated conditions of use prescribed, recommended, or suggested in the proposed labeling.
(ii)
Types. Adequate and well-controlled studies that are intended to provide substantial evidence of the effectiveness of a new animal drug may include, but are not limited to, published studies, foreign studies, studies using models, and studies conducted by or on behalf of the sponsor. Studies using models shall be validated to establish an adequate relationship of parameters measured and effects observed in the model with one or more significant effects of treatment.
(c)
Substantial evidence for combination new animal drugs—
(1)
Definitions. The following definitions of terms apply to this section:
(i)
Combination new animal drug means a new animal drug that contains more than one active ingredient or animal drug that is applied or administered simultaneously in a single dosage form or simultaneously in or on animal feed or drinking water.
(ii)
Dosage form combination new animal drug means a combination new animal drug intended for use other than in animal feed or drinking water.
(iii)
Antibacterial— with respect to a particular target animal species means an active ingredient or animal drug: That is approved in that species for the diagnosis, cure, mitigation, treatment, or prevention of bacterial disease; or that is approved for use in that species for any other use that is attributable to its antibacterial properties. But, antibacterial does not include ionophores or arsenicals intended for use in combination in animal feed or drinking water.
(iv)
Appropriate concurrent use— exists when there is credible evidence that the conditions for which the combination new animal drug is intended can occur simultaneously.
(2)
Combination new animal drugs that contain only active ingredients or animal drugs that have previously been separately approved.
(i)
For dosage form combination new animal drugs, except for those that contain a nontopical antibacterial, that contain only active ingredients or animal drugs that have previously been separately approved for the particular uses and conditions of use for which they are intended in combination, a sponsor shall demonstrate:
(A)
By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug;
(B)
That each active ingredient or animal drug intended for at least one use that is different from all the other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and
(C)
That the active ingredients or animal drugs are physically compatible and do not have disparate dosing regimens if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible or have disparate dosing regimens.
(ii)
For combination new animal drugs intended for use in animal feed or drinking water that contain only active ingredients or animal drugs that have previously been separately approved for the particular uses and conditions of use for which they are intended in combination, the sponsor shall demonstrate:
(A)
By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug;
(B)
For such combination new animal drugs that contain more than one antibacterial ingredient or animal drug, by substantial evidence, as defined in this section, that each antibacterial makes a contribution to labeled effectiveness;
(C)
That each active ingredient or animal drug intended for at least one use that is different from all other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and
(D)
That the active ingredients or animal drugs intended for use in drinking water are physically compatible if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible.
(3)
Other combination new animal drugs. For all other combination new animal drugs, the sponsor shall demonstrate by substantial evidence, as defined in this section, that the combination new animal drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling and that each active ingredient or animal drug contributes to the effectiveness of the combination new animal drug.
Notes, amendments, and revision history

Amendments

[64 FR 40756, July 28, 1999]

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

Amendments

[64 FR 40756, July 28, 1999]

§514.5. Presubmission conferences.

21 C.F.R. § 514.5

(a)
General principle underlying the conduct of a presubmission conference. The general principle underlying the conduct of any presubmission conference is that there should be candid, full, and open communication.
(b)
Requesting a presubmission conference. A potential applicant is entitled to one or more conferences prior to the submission of an NADA, supplemental NADA, or an ANADA to reach an agreement establishing part or all of a submission or investigational requirement. A potential applicant's request for a presubmission conference must be submitted to FDA in a signed letter. The letter must include a proposed agenda that clearly outlines the scope, purpose, and objectives of the presubmission conference and must list the names and positions of the representatives who are expected to attend the presubmission conference on behalf of the applicant.
(c)
Timing. A potential applicant may request one or more presubmission conferences at any time prior to the filing of a NADA, supplemental NADA, or an ANADA. A request for a presubmission conference must be received by FDA at least 30 calendar days in advance of the requested conference date. FDA will schedule the presubmission conference at a time agreeable to both FDA and the potential applicant.
(d)
Advance information. The potential applicant must provide to FDA, at least 30 calendar days before a scheduled presubmission conference, a detailed agenda, a copy of any materials to be presented at the conference, a list of proposed indications and, if available, a copy of the proposed labeling for the product under consideration, and copies of materials evaluated or referenced relative to issues listed in the agenda for the conference. If the materials are not provided or are not sufficient to provide the basis for meaningful discussion, FDA may elect to postpone part or all of the meeting until sufficient materials are provided to FDA.
(e)
Conduct of a presubmission conference. The potential applicant and FDA may each bring consultants to the presubmission conference. The presubmission conference(s) will be directed primarily at establishing agreement between FDA and the potential applicant regarding a submission or investigational requirement. The submission or investigational requirement may include, among other things, the number, types, and general design of studies that are necessary to demonstrate the safety and effectiveness of a new animal drug for the intended uses and conditions of use prescribed, recommended, or suggested in the proposed labeling for the new animal drug.
(f)
Documentation of a presubmission conference—
(1)
Memorandum of conference—
(i)
Preparation. FDA will prepare a memorandum for each presubmission conference that will include, among other things, any background pertinent to the request for meeting; a summary of the key points of discussion; agreements; and action items and assignments of responsibility. That portion of the memorandum of conference that documents any agreements reached regarding all or part of a submission or investigational requirement will be included under the heading “Presubmission Conference Agreement.” If the presubmission conference agreement section of the memorandum is silent on an issue, including one that was discussed in the conference or addressed by materials provided for the conference, such silence does not constitute agreement between FDA and the potential applicant on the issue.
(ii)
Sending a copy to the potential applicant. FDA will send a copy of the memorandum to the potential applicant for review no later than 45 calendar days after the date of the conference
(iii)
Requests for changes or clarification. If a potential applicant requests changes to, or clarification of, the substance of the memorandum, the request must be sent to FDA within 30 calendar days from the date a copy of the memorandum is sent to the applicant. If the potential applicant requests changes or clarification, FDA will send the potential applicant a response to their request no later than 45 calendar days after the date of receipt of the request.
(iv)
Administrative record. A copy of FDA's original memorandum of conference and, as appropriate, a copy of an amended memorandum to correct or clarify the content of the original memorandum will be made part of the administrative file.
(2)
Field studies. If FDA requires more than one field study to establish by substantial evidence that the new animal drug is effective for its intended uses under the conditions of use prescribed, recommended, or suggested in the proposed labeling, FDA will provide written scientific justification for requiring more than one field study. Such justification must be provided no later than 25 calendar days after the date of the conference at which the requirement for more than one field study is established. If FDA does not believe more than one field study is required but the potential applicant voluntarily proposes to conduct more than one field study, FDA will not provide such written justification. If FDA requires one field study to be conducted at multiple locations, FDA will provide justification for requiring multiple locations verbally during the presubmission conference and in writing as part of the memorandum of conference.
(g)
Modification of presubmission conference agreements. An agreement made under a presubmission conference requested under section 512(b)(3) of the act and documented in a memorandum of conference is binding on the potential applicant and FDA and may only be modified if:
(1)
FDA and the potential applicant mutually agree to modify, in part or in whole, the agreement and such modification is documented and provided to the potential applicant as described in paragraph (f)(1) of this section; or
(2)
FDA by written order determines that a substantiated scientific requirement essential to the determination of safety or effectiveness of the new animal drug appeared after the conference.
(h)
When the terms of a presubmission conference agreement are not valid.
(1)
A presubmission conference agreement will no longer be valid if:
(i)
The potential applicant makes to FDA, before, during, or after the presubmission conference, any untrue statement of material fact; or
(ii)
The potential applicant fails to follow any material term of the agreement; and
(2)
A presubmission conference may no longer be valid if the potential applicant submits false or misleading data relating to a new animal drug to FDA.
(i)
Dispute resolution. FDA is committed to resolving differences between a potential applicant and FDA reviewing divisions with respect to requirements for the investigation of new animal drugs and for NADAs, supplemental NADAs, and ANADAs as quickly and amicably as possible through a cooperative exchange of information and views. When administrative or procedural disputes arise, a potential applicant should first attempt to resolve the matter within the appropriate review division beginning with the individual(s) most directly assigned to the review of the application or investigational exemption. If the dispute cannot be resolved after such attempts, the dispute shall be evaluated and administered in accordance with applicable regulations (21 CFR 10.75). Dispute resolution procedures may be further explained by guidance available from the Center for Veterinary Medicine.
Notes, amendments, and revision history

Amendments

[69 FR 51170, Aug. 18, 2004]

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

Amendments

[69 FR 51170, Aug. 18, 2004]

§514.6. Amended applications.

21 C.F.R. § 514.6

The applicant may submit an amendment to an application that is pending, including changes that may alter the conditions of use, the labeling, safety, effectiveness, identity, strength, quality, or purity of the drug or the adequacy of the manufacturing methods, facilities, and controls to preserve them, in which case the unamended application may be considered as withdrawn and the amended application may be considered resubmitted on the date on which the amendment is received by the Food and Drug Administration. The applicant will be notified of such date.
Notes, amendments, and revision history

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

§514.7. Withdrawal of applications without prejudice.

21 C.F.R. § 514.7

The sponsor may withdraw his pending application from consideration as a new animal drug application upon written notification to the Food and Drug Administration. Such withdrawal may be made without prejudice to a future filing. Upon resubmission, the time limitation will begin to run from the date the resubmission is received by the Food and Drug Administration. The original application will be retained by the Food and Drug Administration although it is considered withdrawn. The applicant shall be furnished a copy at cost on request.
Notes, amendments, and revision history

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

§514.8. Supplements and other changes to an approved application.

21 C.F.R. § 514.8

(a)
Definitions.
(1)
The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) apply to those terms when used in this part.
(2)
The following definitions of terms apply to this part—
(i)
Assess the effects of the change means to evaluate the effects of a manufacturing change on the identity, strength, quality, purity, and potency of a drug as these factors may relate to the safety or effectiveness of the drug.
(ii)
Drug substance means an active ingredient as defined under § 210.3(b)(7) of this chapter.
(iii)
Minor changes and stability report (MCSR) means an annual report that is submitted to the application once each year within 60 days before or after the anniversary date of the application's original approval or on a mutually agreed upon date. The report must include minor manufacturing and control changes made according to § 514.8(b)(4) or state that no changes were made; and stability data generated on commercial or production batches according to an approved stability protocol or commitment.
(iv)
Specification means the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of drugs including, for example, drug substances, Type A medicated articles, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug. For the purpose of this definition, the term “acceptance criteria” means numerical limits, ranges, or other criteria for the tests described.
(b)
Manufacturing changes to an approved application—
(1)
General provisions.
(i)
The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about it in a supplement under paragraph (b)(2) or (b)(3) of this section or by inclusion of the information in the annual report to the application under paragraph (b)(4) of this section.
(ii)
The holder of an approved application under section 512 of the act must assess the effects of the change before distributing a drug made with a manufacturing change.
(iii)
Notwithstanding the requirements of paragraphs (b)(2) and (b)(3) 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 drug, or by notification in the next annual report described in paragraph (b)(4) of this section).
(iv)
In each supplement and amendment to a supplement providing for a change under paragraph (b)(2) or (b)(3) of this section, the applicant must include a statement certifying that a field copy has been provided to the appropriate FDA district office. No field copy is required for a supplement providing for a change made to a drug manufactured outside of the United States.
(v)
A supplement or annual report described in paragraph (b)(4) of this section 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.
(2)
Changes requiring submission and approval of a supplement prior to distribution of the drug made using the change (major changes).
(i)
A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.
(ii)
These changes include, but are not limited to—
(A)
Except those described in paragraphs (b)(3) and (b)(4) of this section, changes in the qualitative or quantitative formulation of the drug, including inactive ingredients, or in the specifications provided in the approved application;
(B)
Changes requiring completion of appropriate clinical studies to demonstrate the equivalence of the drug to the drug as manufactured without the change;
(C)
Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation;
(D)
Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance;
(E)
Changes in a drug product container closure system that controls the drug delivered to the animal or changes in the type or composition of a packaging component that may affect the impurity profile of the drug product;
(F)
Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following:

(1) Changes in the virus or adventitious agent removal or inactivation method(s),

(2) Changes in the source material or cell line, and

(3) Establishment of a new master cell bank or seed;

(G)
Changes to a drug under an application that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that application.
(iii)
The applicant must obtain approval of a supplement from FDA prior to distribution of a drug made using a change under paragraph (b)(2) of this section. The supplement must be labeled “Prior Approval Supplement.” Except for submissions under paragraph (b)(2)(v) of this section, the following information must be contained in the supplement:
(A)
A completed Form FDA 356V;
(B)
A detailed description of the proposed change;
(C)
The drug(s) involved;
(D)
The manufacturing site(s) or area(s) affected;
(E)
A description of the methods used and studies performed to assess the effects of the change;
(F)
The data derived from such studies;
(G)
Appropriate documentation (for example, updated master batch records, specification sheets) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;
(H)
For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section;
(I)
For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section; and
(J)
Any other information as directed by FDA.
(iv)
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 must be plainly marked: “Prior Approval Supplement-Expedited Review Requested.”
(v)
Comparability Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug as these factors may relate to the safety or effectiveness of the drug. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of the drug produced with the manufacturing change. The supplement, if approved, may subsequently 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. A comparability protocol supplement must be labeled “Prior Approval Supplement—Comparability Protocol.”
(3)
Changes requiring submission of a supplement at least 30 days prior to distribution of the drug made using the change (moderate changes).
(i)
A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.
(ii)
These changes include, but are not limited to—
(A)
A change in the container closure system that does not affect the quality of the drug except as otherwise described in paragraphs (b)(2) and (b)(4) of this section;
(B)
Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including:

(1) An increase or decrease in production scale during finishing steps that involves different equipment, and

(2) Replacement of equipment with that of a different design that does not affect the process methodology or process operating parameters.

(C)
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.
(iii)
A supplement submitted under paragraph (b)(3)(i) or (b)(3)(vi) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is made. The supplement submitted under paragraph (b)(3)(i) must be labeled “Supplement-Changes Being Effected in 30 Days.”
(iv)
Pending approval of the supplement by FDA and except as provided in paragraph (b)(3)(vi) of this section, distribution of the drug made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement.
(v)
The applicant must not distribute the drug made using the change if within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:
(A)
The change requires approval prior to distribution of the drug in accordance with paragraph (b)(2) of this section; or
(B)
Any of the information required under paragraph (b)(3)(iv) of this section is missing. In this case, the applicant must not distribute the drug made using the change until the supplement has been amended to provide the missing information.
(vi)
The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved application may commence distribution of the drug involved upon receipt by the agency of a supplement for the change. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement. The supplement must be labeled “Supplement-Changes Being Effected.” These changes include, but are not limited to:
(A)
Addition to a specification or changes in the methods or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess; and
(B)
A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another.
(vii)
If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug(s) made with the manufacturing change.
(4)
Changes and updated stability data to be described and submitted in an annual report (minor changes).
(i)
Changes in the drug, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug must be documented by the applicant in an annual report to the application as described under paragraph (a)(2)(iii) of this section. The report must be labeled “Minor Changes and Stability Report.”
(ii)
These changes include but are not limited to—
(A)
Any change made to comply with a change to an official compendium, except a change in paragraph (b)(3)(ii)(C) of this section, that is consistent with FDA statutory and regulatory requirements;
(B)
The deletion or reduction of an ingredient intended to affect only the color of the drug product;
(C)
Replacement of equipment with that of the same design and operating principles except for those equipment changes described in paragraph (b)(3)(ii)(B)(2) of this section;
(D)
A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another;
(E)
A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;
(F)
An extension of an expiration dating period based upon full shelf-life data on production batches obtained from a protocol approved in the application;
(G)
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 drug being tested as the analytical procedure described in the approved application, or deletion of an alternative analytical procedure; and
(H)
The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.
(iii)
For changes under this category, the applicant is required to submit in the annual report—
(A)
A completed Form FDA 356V;
(B)
A statement by the holder of the approved application that the effects of the change have been assessed;
(C)
A detailed description of the change(s);
(D)
The manufacturing site(s) or area(s) involved;
(E)
The date each change was implemented;
(F)
Data from studies and tests performed to assess the effects of the change;
(G)
For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, relevant validation protocols and/or standard operating procedures;
(H)
Appropriate documentation (for example, updated master batch records, specification sheets, etc.) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;
(I)
Updated stability data generated on commercial or production batches according to an approved stability protocol or commitment; and
(J)
Any other information as directed by FDA.
(c)
Labeling and other changes to an approved application—
(1)
General provisions. The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully.
(2)
Labeling changes requiring the submission and approval of a supplement prior to distribution of the drug made using the change (major changes).
(i)
Addition of intended uses and changes to package labeling require a supplement. These changes include, but are not limited to:
(A)
Revision in labeling, such as updating information pertaining to effects, dosages, adverse reactions, contraindications, which includes information headed “adverse reactions,” “warnings,” “precautions,” and “contraindications,” except ones described in (c)(3) of this section;
(B)
Addition of an intended use;
(C)
If it is a prescription drug, any mailing or promotional piece used after the drug is placed on the market is labeling requiring a supplemental application, unless:

(1) The parts of the labeling furnishing directions, warnings, and information for use of the drug are the same in language and emphasis as labeling approved or permitted; and

(2) Any other parts of the labeling are consistent with and not contrary to such approved or permitted labeling.

(3) Prescription drug labeling not requiring an approved supplemental application is submitted in accordance with § 514.80(b)(5)(ii).

(D)
Any other changes in labeling, except ones described in paragraph (c)(3) of this section.
(ii)
The applicant must obtain approval of the supplement from FDA prior to distribution of the drug. The supplement must contain the following:
(A)
A completed Form FDA 356V;
(B)
A detailed description of the proposed change;
(C)
The drug(s) involved;
(D)
The data derived from studies in support of the change; and
(E)
Any other information as directed by FDA.
(3)
Labeling changes to be placed into effect prior to receipt of a written notice of approval of a supplemental application.
(i)
Labeling changes of the following kinds that increase the assurance of drug safety proposed in supplemental applications must be placed into effect immediately:
(A)
The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, adverse reaction, and precaution information;
(B)
The deletion from package labeling, promotional labeling, or drug advertising of false, misleading, or unsupported intended uses or claims for effectiveness; and
(C)
Any other changes as directed by FDA.
(ii)
Labeling changes (for example, design and style) that do not decrease safety of drug use proposed in supplemental applications may be placed into effect prior to written notice of approval from FDA of a supplemental application.
(iii)
A supplement submitted under paragraph (c)(3) of this section must include the following information:
(A)
A full explanation of the basis for the changes, the date on which such changes are being effected, and plainly marked on the mailing cover and on the supplement, “Supplement—Labeling Changes Being Effected”;
(B)
Two sets of printed copies of any revised labeling to be placed in use, identified with the new animal drug application number; and
(C)
A statement by the applicant that all promotional labeling and all drug advertising will promptly be revised consistent with the changes made in the labeling on or within the new animal drug package no later than upon approval of the supplemental application.
(iv)
If the supplemental application is not approved and the drug is being distributed with the proposed labeling, FDA may initiate an enforcement action because the drug is misbranded under section 502 of the act and/or adulterated under section 501 of the act. In addition, under section 512(e) of the act, FDA may, after due notice and opportunity for a hearing, issue an order withdrawing approval of the application.
(4)
Changes providing for additional distributors to be reported under Records and reports concerning experience with approved new animal drugs (§ 514.80). Supplemental applications as described under paragraph (c)(2) of this section will not be required for an additional distributor to distribute a drug that is the subject of an approved new animal drug application or abbreviated new animal drug application if the conditions described under § 514.80(b)(5)(iii) are met.
(d)
Patent information. The applicant must comply with the patent information requirements under section 512(c)(3) of the act.
(e)
Claimed exclusivity. If an applicant claims exclusivity under section 512(c)(2)(F) of the act upon approval of a supplemental application for a change in its previously approved drug, the applicant must include such a statement.
(f)
Good laboratory practice for nonclinical laboratory studies. A supplemental application that contains nonclinical laboratory studies must include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.
Notes, amendments, and revision history

Amendments

[71 FR 74782, Dec. 13, 2006]

Authority

Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381.

Source

Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted.

Amendments

[71 FR 74782, Dec. 13, 2006]