CVM Releases Proposed Rule on Labeling Requirements for Approved or Conditionally Approved New Animal Drugs

CVM Releases Proposed Rule on Labeling Requirements for Approved or Conditionally Approved New Animal Drugs

March 13, 2024, Covington Alert

Many years in the making, the U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) published yesterday a proposed rule that would for the first time create a comprehensive set of regulations for new animal drug labels and labeling (collectively, labeling).[1]The proposed regulations would apply to the labeling of approved and conditionally approved prescription and over-the-counter (OTC) new animal drugs, as well as new animal drugs for use in animal feeds. If finalized, the rule would provide sponsors with predictable requirements for the content and format of labeling for new animal drugs, and it would codify FDA's longstanding practices with respect to the review of labeling submitted as part of a new animal drug application (NADA), certain abbreviated new animal drug applications (ANADAs) that reference a new animal drug for which the NADA has been withdrawn, or a new animal drug application for conditional approval (CNADA).

I. Background

FDA first issued regulations establishing requirements for prescription drug animal labels in 1955.[2]In 1975, FDA redesignated those requirements as 21 CFR § 201.105.[3]Existing regulations are scattered across Parts 201, 500, 501, 510, 514, and 516 of Chapter 21 of the Code of Federal Regulations.

The current fragmentation of labeling requirements has created confusion and unpredictability for sponsors of new animal drugs. For example, animal drug labeling often consists of multiple components, including the label, one or more package inserts, and labeling for secondary containers, multiple unit cartons, shipping, and/or display cartons. Though existing regulations outline some requirements for the content of prescription new animal drug labeling, they do not provide direction on the format or order of information with respect to specific labeling components. Moreover, existing regulations are silent as to the general content and format requirements of labeling for OTC new animal drugs and new animal drugs administered in animal feed.

FDA's proposed regulations seek to remedy these issues by identifying the specific labeling components that would be required and permitted for each approved or conditionally approved new animal drug, the information needed for each component, and the order in which information would appear. Prescription animal drugs not subject to an approved or conditionally approved application or index listing would be excluded from the regulations. Consistent and standardized content and format of new animal drug labeling may make it easier for end users (veterinarians, animal owners, or persons treating the animals) to access, read, and use the information to make informed decisions quickly, while promoting safe use of the drug.

II. Current Regulatory Framework

A. Prescription (Rx) New Animal Drug Labeling

Under current FDA regulations at 21 C.F.R. 201.105, labeling for prescription new animal drugs should bear adequate information for use, including: indications, effects, dosages, routes, methods, and frequency and duration of administration; any relevant warnings, hazards, contraindications, side effects, and precautions under which veterinarians can use the drug safely and for the intended purposes; and ingredient information. Certain prescription animal drug labeling must also bear the date of its latest revision. Applicants may request an exemption from the requirement for including adequate information for use on the drug's dispensing package for which directions, hazards, warnings, and use information are commonly known to licensed veterinarians.

Because they are intended for use under the supervision or on the direction of a veterinarian, many prescription animal drugs are currently exempt from the requirement to bear adequate directions for use in their labeling. Products exempt from this requirement must still include in their labeling a standard statement restricting use to on the order of a licensed veterinarian, dosage information, route of administration if it is not oral, the drug's established name and the quantity or proportion of each active ingredient, the names of inactive ingredients if the drug is not for oral use (with some exemptions), and an identifying lot or control number.

Manufacturers are permitted to streamline this information to a reasonable extent for the labeling affixed to the product if their container is too small or the information will not fit on the label, provided the information is included in other approved labeling.

B. OTC New Animal Drug Labeling

The Federal Food, Drug, and Cosmetic Act (FDCA) requires that all OTC drugs must bear adequate directions for use in their labeling. Current regulations (21 C.F.R. § 201.5) also specify that "adequate directions for use" are those "under which a layman can use a drug safely and for the purposes for which it is intended."

C. Labeling for New Animal Drugs for Use in Animal Feeds

With limited exceptions applicable to veterinary feed directive (VFD) drugs,[4]the FDCA and FDA's regulations do not currently include specific requirements concerning the contents and formatting of labeling for new animal drugs intended for use in the manufacture of medicated feeds. FDA's current regulations do, however, require sponsors of applications for approval or conditional approval of a "Type A medicated article," which is a concentrated form of the drug intended solely for use in the manufacture of another Type A medicated article, a Type B medicated feed,[5]or a Type C medicated feed[6]to submit certain labeling information with the application, including:

(a) Specimens of labeling to be used for such new animal drug with adequate directions for the manufacture and use of finished feeds for all conditions for which the new animal drug is intended, recommended, or suggested in any of the labeling, including advertising, sponsored by the applicant.

(b) Representative labeling proposed to be used for Type B and Type C medicated feeds containing the new animal drug.[7]

FDA currently works with sponsors to ensure the approved labeling for the Type A medicated article and the representative labeling for Type B and Type C medicated feeds include the information FDA deems appropriate during the approval process. FDA also refers to the representative labeling for Type B and Type C medicated feeds as "Blue Bird labels."

III. Proposed Rule

A. Prescription (Rx) New Animal Drug Labeling

The proposed rule would require labeling for approved and conditionally approved prescription new animal drugs to conform to an application approved under sections 512 or 517 of the FDCA, respectively, and provides content and format requirements for all components of the drug's labeling. Certain labeling sections could be omitted if they do not apply (e.g., prescription new animal drugs approved for use in non-food-producing animals would not require the labeling subsection entitled either "Withdrawal Periods and Residue Warnings" or "Withdrawal Periods").

Labeling would be required to be informative and accurate, and appear consistent with new formatting requirements specified in the proposed rule. The new formatting specifications would include requirements for the placement, size, and prominence of the drug's established name relative to its proprietary name. The proposed rule also includes general requirements that the letters used in labeling do not touch, and the text is easy to read and adheres to minimum height or size requirements, as well as more specific requirements that the text appear in English and running text, section headings, and subsection headings be in black type on a white background. The regulations would also mandate that background graphics and designs not interfere with the legibility of the text.

The proposed rule specifies the content and format requirements for all components of labeling, including "package inserts" (defined as "a labeling component which contains full prescribing information and is included with the immediate or secondary container, or attached to the label"), secondary container labeling, (labeling that "surrounds the immediate container," which must contain the "full prescribing information" if the product labeling includes no package insert), and the "label" (the labeling component that "appears on the immediate container that comes in contact with the drug"). If FDA determines that the product lacks sufficient space to comply with the proposed "label" requirements, the proposed rule further provides for a "small label."

Full Prescribing Information

The proposed rule defines "full prescribing information" as "all information necessary for the safe and effective use of approved or conditionally approved new animal drugs," and the proposed regulations use that term for new animal drugs.

The full prescribing information for approved and conditionally approved prescription new animal drugs must include the following sections in order: drug product identification; a prescription statement; a conditional approval statement, if appropriate; boxed warnings; extralabel use prohibition statement; product description; indications for use; dosage and administration; contraindications; warnings and precautions, including withdrawal periods and residue warnings or withdrawal periods (if applicable), user safety warnings, animal safety warnings and precautions, environmental warnings, and other warnings; adverse reactions; contact information; information for animal owner; clinical pharmacology; microbiology; target animal safety; effectiveness; net contents; how supplied; storage, handling, and disposal; NADA/ANADA approval statement; name and place of business; lot number and expiration date; and revision date.

Certain proposed requirements for some sections are particularly noteworthy. The "drug product identification" section would be required to include the proprietary name of the finished drug product and its established name, and the name and strength of the drug's active ingredients. If the established name excludes the route of administration and dosage form, that should also be included. Conditionally approved prescription new animal drugs would be required to include a conspicuous and prominent statement indicating that the product is conditionally approved along with its application number, as required under FDCA section 571. A prescription new animal drug which includes a boxed warning in its label would also be required to disclose the boxed warning in the "boxed warning" section of its full prescribing information.

For approved new animal drugs that are prohibited from extralabel use under 21 C.F.R. § 530.41, the proposed rule would require the drug's full prescribing information to include an "extralabel use prohibition statement" that begins with the phrase: "Federal law prohibits the extralabel use of this drug…" and concludes with a description of the prohibition as specified in § 530.41.

Finally, the "description" would include the drug product's proprietary name and established name, and all identifying characteristics of the dosage form, such as: color, shape, coating, scoring, and imprinting. All approved and available strengths or concentrations of the drug to which full prescribing information applies would need to be identified in this section.

Small Labels

The proposed rule would also establish "Small labels" that would include abbreviated labeling requirements if FDA determines that an immediate container, such as a blister pack, pre-filled syringe, or small vial, is so small that only a minimal amount of information can be included on its label. FDA's determination about the sufficiency of space on the container would take place during the review of the new animal drug and its labeling, and would include considerations like readability and legibility of the information.

Secondary Containers

For an approved or conditionally approved prescription new animal drug that includes a package insert, the proposed rule also provides for content and format requirements for the product's secondary labeling. The proposed rule specifies the content and format for secondary labeling in various configurations, including one with only a front panel and one side or back panel, and another with a front panel and multiple side and/or back panels. In all configurations, the active ingredient and inactive ingredient information must appear on the same panel.

The following information must appear on the front panel in this order: drug product identification, prescription statement, conditional approval statement, boxed warnings, indications for use, extralabel prohibition statement, net contents, and the NADA/ANADA approval statement. On the side or back panel must appear in this order: full prescribing information statement; dosage and administration; contraindications; warnings and precautions; active ingredients; inactive ingredients; storage, handling, and disposal; name and place of business; lot number and expiration date; and revision date.

Shipping Labeling

The proposed rule would also establish content and format requirements for the shipping labeling of approved or conditionally approved prescription new animal drugs. Shipping labeling must identify the new animal drug, the manufacturer, and drug storage and handling information. The proposed rule includes content and format requirements that would also apply to other containers, such as display cartons and multiple unit (multi-unit) cartons, which may be packaged in shipping cartons and contain immediate containers or secondary containers that sponsors may use to sell or display an approved or conditionally approved prescription new animal drug.

B. OTC New Animal Drug Labeling

Similar to the proposed requirements for prescription new animal drugs, the proposed rule specifies the content and format requirements for all labeling components of OTC new animal drugs, including "package inserts," "secondary container labeling," and the "label," defined parallel to the requirements for prescription new animal drugs. If FDA determines that the product lacks sufficient space to comply with the proposed "label" requirements, the proposed rule further provides for a "small label." As with prescription new animal drugs, "small labels" for OTC new animal drug products would include abbreviated labeling requirements.

Importantly, all approved or conditionally approved OTC new animal drugs would be required to maintain a labeling component that includes "full product information." Similar to "full prescribing information" for prescription new animal drugs, full product information for OTC new animal drugs includes "all information necessary for the safe and effective use of the product." Under the proposed rule, a package insert must include full product information but, if the manufacturer does not include such a package insert, then full product information must be included on the secondary container label. If there is no package insert or secondary container, then the full product information must appear on the label.

The "full product information" would be the same as the "full prescribing information" for prescription new animal drugs, with some exceptions. The requirements for OTC new animal drugs do not include sections for a prescription statement, boxed warning, indications for use, dosage and administration, contraindications, adverse reactions, contact information, information for animal owner, clinical pharmacology, microbiology, target animal safety, or effectiveness. "Uses" and "extralabel use statement" would be added sections in the full product information for OTC new animal drugs.

The proposed rule also does not require a "description" section for OTC new animal drugs due to space limitations, so the manufacturer of a "sterile" OTC new animal drug product must identify the product as "sterile" in the drug product identification section of the OTC label, rather than in the "description" section as would be required for prescription new animal drugs. OTC new animal drugs would also be permitted to bear the "withdrawal periods and residue warnings" on a side or back panel if there is insufficient room on the front panel. OTC new animal drug labeling may also include a statement reminding the user to read the full product information instead of including the full product information statement. Additionally, FDA may decide to exclude the directions from the back or side panel because of insufficient space. Finally, OTC labels must bear the product expiration date on the immediate container or refer to the location of the expiration date in the "lot number and expiration date" section of the label.

The same requirements that apply to the shipping labeling of approved and conditionally approved prescription new animal drugs would also apply to OTC new animal drug labeling.

C. Labeling for New Animal Drugs for Use in Animal Feeds

The proposed rule includes content and format requirements for all labeling components for approved or conditionally approved new animal drugs for use in feeds, including VFD drugs. This includes labeling requirements for Type A medicated articles and representative labeling for Type B and Type C medicated feeds.

The proposed rule would require the following sections or statements to be presented on a Type A medicated article label for an approved or conditionally approved new animal drug:

• Type A medicated article identification. This section of the label must include the proprietary name and established name of the Type A medicated article, and the phrase "Type A medicated article" or "Type A liquid medicated article," as applicable, if not included as part of the established name.
• VFD cautionary statement. For VFD new animal drugs, the label must include the following cautionary statement in accordance with 21 C.F.R. § 558.6(a)(6): "Caution: Federal law restricts medicated feed containing this veterinary feed directive (VFD) drug to use by or on the order of a licensed veterinarian."
• "For further manufacturing only." The label must include the statement, "For further manufacturing only," to indicate that the Type A medicated article can only be used to manufacture another Type A medicated article or a medicated feed.
• Conditional approval statement. For conditionally approved new animal drugs, the label must include a conditional approval statement as described above for prescription new animal drugs.
• "Indications for Use." This section must bear the heading "Indications for Use," followed by the approved or conditionally approved indication(s) and target animal(s).
• Extralabel use statement. The label must include a statement concerning the extralabel use of the drug.
• "Active Ingredient" or "Active Ingredients." This section must bear the heading "Active Ingredient" or "Active Ingredients," followed by the established name and concentration of each active ingredient.
• "Inactive Ingredients." When inactive ingredients are disclosed on the label, they must be listed in the "Inactive Ingredients" section in decreasing order of predominance, by weight or concentration.
• "Directions." This section must bear the heading "Directions," followed by the directions for use of the Type A medicated article. The "Directions" section of the label would include three subsections:
  • "Approved Concentration(s) of Active Ingredient in Type C Medicated Feeds."
  • "Mixing Directions."
  • "Feeding Directions."
• "Warnings." This section must bear the heading "Warnings," and identify all applicable warnings.
• "Additional Recommendations." For Type A medical articles having precautions, the label must include a section bearing the heading "Additional Recommendations," followed by all precautions. For VFD new animal drugs, this section would include precautions directed to veterinarians as well as the layperson.
• "Other Effects You May Notice." For new animal drugs that have effects on target animal(s) that are not considered contraindications, target animal safety warnings, adverse reactions, or post-approval adverse drug experiences, and if FDA determines that these effects must be described on labeling, the proposed rule would require this section of the Type A medicated article label to have the heading "Other Effects You May Notice," followed by a description of the effects.
• "Net Weight." This section of the label must have the heading "Net Weight," followed by the net weight of the Type A medicated article in the immediate container.
• "Storage, Handling, and Disposal." This section must bear the heading "Storage, Handling, and Disposal" and include storage information for the Type A medicated article, as well as any required handling and disposal information. This section would be the same as described in proposed § 201.405(a)(20) for full prescribing information for Rx new animal drugs.
• "Questions/Comments?" This section must have the heading "Questions/Comments?," followed by the sponsor's contact information for feed manufacturers or other users of the Type A medicated article to facilitate requesting additional information or to report suspected adverse drug experiences. The sponsor's contact information would be the name of the manufacturer, packer, or distributor, whichever is identified in the "Name and place of business" section of the Type A medicated article label.
• NADA/ANADA approval statement. For approved or generic Type A medicated articles, the label must include an "NADA approval statement" or "ANADA approval statement," respectively.
• Name and place of business. This section of the label must identify the name and place of business of the manufacturer, packer, or distributor.
• "Lot Number and Expiration Date." This section must have the heading "Lot Number and Expiration Date," followed by the identifying lot or control number of the Type A medicated article within the immediate container.
• "Revision Date." This section of the label must have the heading "Revision Date," followed by the date of the most recent revision of the Type A medicated article label, listing the month followed by the year.

The proposed rule would also establish content and format requirements for representative Type B and Type C medicated feed labeling, and require representative Type B medicated feed labeling to include the sections listed below. Many of these sections would include similar information as the Type A medicated article label and, for brevity's sake, that information is not included below.

• Description of the Type B medicated feed. This section must describe the Type B medicated feed and serve as a placeholder for the proprietary name the feed manufacturer would add to the label of the final Type B medicated feed.
• Established name of the Type B medicated feed. This section must include the established name of the Type B medicated feed, including the active moiety or active ingredient of each new animal drug, followed by either "Type B medicated feed" or "Type B liquid medicated feed," as applicable.
• VFD cautionary statement.
• "Do Not Feed Undiluted." This statement must appear on the representative Type B medicated feed label.
• Conditional approval statement (if applicable).
• "Indications for Use."
• Extralabel use statement.
• "Active Ingredient" or "Active Ingredients."
• "Guaranteed Analysis." This section must bear the heading "Guaranteed Analysis," followed by the nutritional content guarantees of the Type B medicated feed.
• "Ingredients." This section must bear the heading "Ingredients," and list the feed ingredients by their common or usual names in descending order of predominance by weight. Spices, flavorings, colorings, and chemical preservatives, if used, must be declared in the ingredient statement.
• "Mixing Directions." This section must bear the heading "Mixing Directions," followed by approved mixing directions for the manufacture of a Type C medicated feed(s) or another Type B medicated feed(s), as applicable.
• "Warnings."
• "Additional Recommendations."
• "Other Effects You May Notice."
• Name and place of business. This section must contain the name and place of business of the manufacturer, packer, or distributor of the final Type B medicated feed on the final printed Type B medicated feed label.
• "Net Weight."
• "Storage, Handling, and Disposal."
• "Questions/Comments?"
• "Lot, Batch, or Control Number."
• "Expiration Date."
• "Revision Date."

The proposed rule would establish similar requirements for representative Type C medicated feed labeling, including the following:

• Description of the Type C medicated feed.
• Established name of the Type C medicated feed.
• VFD cautionary statement.
• Conditional approval statement (if applicable).
• "Indications for Use."
• Extralabel use statement.
• "Active Ingredient" or "Active Ingredients."
• "Guaranteed Analysis."
• "Ingredients."
• "Feeding Directions."
• "Warnings."
• "Additional Recommendations."
• "Other Effects You May Notice."
• Name and place of business.
• "Net Weight."
• "Storage, Handling, and Disposal."
• "Questions/Comments?"
• "Lot, Batch, or Control Number."
• "Expiration Date."
• "Revision Date."

IV. Compliance Dates

If finalized, new animal drug sponsors would need to comply with the regulations on a staggered schedule over the course of six years. The compliance schedule, which is based on application number, requires approved NADAs with higher application numbers to achieve compliance earliest.

In the case of the representative labeling for medicated feed containing approved drug combinations, because the combination will necessarily be approved after the approval of the individual drugs, the proposed rule would likely result in the requirement that the conforming labeling for the combination approval would need to be submitted before the conforming labeling for the individual Type A medicated articles. To obviate this problem, the proposed regulation would require the confirming labeling for combination new animal drugs to be submitted within 180 days following the approval of all conforming labeling for the individual new animal drugs used in the combination.

V. Exemptions and Other Considerations

The proposed rule would establish a process by which sponsors could request, and FDA could grant, exemptions from labeling requirements on a case-by-case basis. The proposed rule further delegates the authority to grant such requests to the CVM Director or her designee.

CVM is also consolidating into the Section 201.400 rules existing regulations applicable to specific animal drugs. The current regulation for corticosteroids is § 510.410, which will become § 201.413(a). Section 500.25, which addresses approved and conditionally approved anthelminthics, will be incorporated into § 201.413(b)(1). Labeling requirements for indexed OTC anthelminthics will be moved from § 500.25 to § 516.155.

Finally, § 201.413(c) would require that all new animal drugs approved or conditionally approved for horses include a statement in the "Other Warnings" labeling subsection advising against use of the drug in horses intended for human consumption.

* * *

CVM is accepting comments on the proposed rule until June 10, 2024 through www.regulations.gov (Docket No. FDA-2023-N-5160).

If you have any questions concerning the material discussed in this client alert, please contact the members of our Animal Food and Drug practice.

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