Understanding FDA Labeling Regulations

All labels and other written, printed or graphic matter upon any article or any of its containers or wrappers, or accompanying such article. FDA holds that labeling encompasses:

• Any written, printed or graphic material
• Containing drug information
• Disseminated by or on behalf of the manufacturer of that drug
• For use by healthcare professionals

Overview of FDA’s Role in Labeling Oversight

Requirements for promotional labeling

• Claims must be consistent with prescribing information
• No false or misleading statements or omissions
• Materials must fairly balance benefits and risks
• Substantiation
• Labeling accompanied by prescribing information; ads must include “brief summary”

The Significance of Compliance with FDA Labeling Requirements

The Compliance Challenge

• Appropriate business rationale
• FDA issues
• ACCME issues
• AMA Guidelines on Gifts to Physicians
• Fraud and abuse
• Best price
• Product liability
• Lanham Act

Key Terminology in FDA Labeling Regulations

FDA’s labeling resources for human prescription drugs are primarily directed to industry staff who develop human prescription drug labeling. Human prescription drug labeling  contains a summary of the essential scientific information needed for the safe and effective use of the drug; and includes the Prescribing Information, FDA-approved patient labeling (Medication Guides, Patient Package Inserts, and/or Instructions for Use), and/or carton and container labeling. 

FDA-approved Prescribing Information (PI), also known as United States Prescribing Information (USPI), reflects FDA’s finding regarding the safety and effectiveness of the human prescription drug under the labeled conditions of use.  The PI is written for the healthcare professional and must:

1. Contain a summary of the essential scientific information needed for the safe and effective use of the human prescription drug,
2. Be informative and accurate and neither promotional in tone nor false or misleading, and
3. Be updated when new information becomes available that causes labeling to become inaccurate, false, or misleading.

The Instructions for Use (IFU) is patient labeling that can be part of FDA-approved prescription drug labeling for a biologics license application (BLA), a new drug application (NDA), or an abbreviated new drug application (ANDA). The IFU is developed by applicants for patients (or their caregivers) who use prescription drugs that have complicated or detailed patient-use instructions. The IFU provides detailed, action-oriented, step-by-step written and visual instructions for the patient on how to use the drug including instructions on preparation, administration, handling, storage, and disposal.  The IFU is developed by the applicant, reviewed and approved by FDA, and provided to patients (or their caregivers) when the drug is dispensed.  Some IFUs are not approved by the FDA.  IFU resources include:

Instructions for Use — Patient Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry:

General Content Recommendations

The IFU guides the patient on how to safely and effectively use a prescription drug product and commonly includes instructions on preparation, administration, handling, storage, and disposal. The primary purpose of an IFU is to provide detailed, step-by-step written instructions, including visuals if appropriate, in a patient-friendly manner, as visuals can complement written instructions.

1. Consistency with the FDA-Approved Prescribing Information
2. Language and Readability
3. Headings

Specific Content Recommendations

FDA recommends that the following information, if applicable, appear in the order listed to ensure consistency and to help patients become familiar with the type and location of information in the IFU.

• Title
• Product Title
• Purpose Statement
• Visual of Drug Product

Important Information You Need to Know Before Injecting MYDRUG FDA recommends that the IFU include this heading when patients should take specific actions to prepare, administer, store, and/or dispose of the drug product to prevent or reduce potentially serious outcomes that might occur if the specific action is not followed. FDA recommends that information under this heading highlight important instructions and information to alert patients about the appropriate uses, techniques, and routes of administration that, if not followed, could result in injury or impair efficacy. If confusion could occur about the route of administration based on the dosage form, such as capsules for inhalation that may be mistaken for oral capsules, FDA recommends that the first statement in this section explain how the drug product should be administered. For example:

• For oral use only (take by mouth)
• For subcutaneous injection only (inject directly under the skin)
• For topical use only (apply on top of skin)

FORMAT:

The following formatting recommendations are intended to make the IFU easier for patients to read and to help them use prescription drug products safely and effectively.

Typeface Styling Recommendations

1. Font and Font Size

FDA recommends using a sans-serif font for all text in the IFU because sans serif is easier to read than a serif type font (American Foundation for the Blind 2020). Recommended sans-serif fonts include, but are not limited to, Verdana and Arial. FDA recommends against the use of any reverse type (such as white or neutral color type on a darker color background), lightface, shading, highlighting, condensed type, or narrow fonts. These techniques can make reading more difficult for patients.

Recommendations on font size are intended for easier readability. Overall, FDA recommends that the font size be no smaller than 10 points (1 point equals 0.0138 inches) for any section of the IFU, except that FDA recommends the following sections or terminology appear in font no smaller than 8 points:

• For products marketed under an NDA or ANDA, the name and place of business of the manufacturer, packer, and/or distributor.
• For products marketed under a BLA, the name, address, and license number of the manufacturer (and, if included, the distributor).
• The verbatim statement: This Instructions for Use has been approved by the U.S. Food and Drug Administration.
• The month and year of initial FDA approval or revision of the IFU.

2. Letter Case

FDA recommends that the title INSTRUCTIONS FOR USE appear in all uppercase letters. FDA also recommends that the letter case of the proprietary name or nonproprietary name used in the body of the IFU (excluding the IFU product title) match its appearance in the PI. All other headings in the IFU are recommended to appear in title case. FDA suggests avoiding the use of words or phrases with all uppercase letters in the body of the IFU. The abundant use of uppercased text is difficult to read and may detract from the prominence of terms that should appear in uppercase text in the IFU.

3. Bold, Italicized, or Underlined Text

FDA recommends that the following information appear in bold type: INSTRUCTIONS FOR USE; product title (including drug name(s), pronunciation spelling, dosage form, and route of administration, and (when applicable) the controlled substance symbol); headings; step numbers; and figure titles. Bolded headings can help patients find information quickly and easily However, FDA suggests that bolding, italicizing, and underlining in the body of the IFU be used sparingly and be limited to important phrases or concepts (for example, important information for patients to know before using the drug product, such as For oral use only).

4. Page Layout and Design Recommendations

Step-by-Step Instructions

FDA recommends that instructions be sequentially numbered, with each step heading appearing in bold type and noted as Step 1, Step 2, etc. FDA also recommends using continuous numbering throughout the document. For example, FDA suggests avoiding more than one instance of Step 1.

The Agency recommends that action-oriented instruction appear before any supporting information particular to performing a step. The Agency also suggests that supporting information appear in bulleted text on a separate line immediately following the corresponding step.

For example:

Step 4. Check the liquid by looking through the viewing window

• The liquid should be yellow and should have no lumps or particles.
• You may see air bubbles. This is normal. If a patient needs to skip a specific step or set of steps that are not necessary for each dose, FDA recommends that the IFU refer the patient to the next appropriate step. If a patient needs to repeat a step or steps, FDA recommends that, if appropriate, the IFU refer the patient back to the listed step or steps (for example, “Repeat Steps 10 to 13 a second time, then continue to Step 14”).

For example:

Step 6. Close your eye for one minute and gently press at the corner of that eye nearest your nose.

Step 7. If you have been instructed by your health care provider to use drops in both eyes, repeat Steps 3 to 6 in the other eye. If not, continue to Step 8.

Visuals for Step-by-Step Instructions

Visuals help patients comprehend instructions. Visuals can be useful for action tasks and informational text that help a patient understand and safely prepare, administer, store, or dispose of the drug product. FDA recommends that visuals be easy to understand; be of adequate size to allow patients to see the focal point; and demonstrate one concept, single idea, or point of information. Photographs can be compelling because they show the most accurate visual representation of a product. However, in some instances, the use of line drawings and sketch illustrations may be most helpful to simplify complexities and highlight key components or avoid distracting details.

FDA recommends that visuals be placed immediately adjacent to the related instructional step. The Agency also recommends that visuals be labeled alphabetically in bold type (such as Figure A, Figure B, etc.). Steps with corresponding figures are recommended to reference the appropriate figure or figures at the end of the step.

Spacing

FDA recommends that the IFU maintain a sufficient balance of text, visuals, and white space. White space can be used carefully to keep the document from appearing cramped, overwhelming, or too spread out (for example, at a minimum, FDA recommends adding a single line before each heading). For ease of reading, FDA suggests using white space or blocks of text to separate concepts and to indicate change. Additionally, consider increasing the amount of white space around important text and visuals for emphasis.

Color

FDA recommends that the IFU be presented in black type on a white background to facilitate readability. This combination maximizes contrast and legibility and also facilitates uniform reprinting of the document. Colored text and visuals may be useful as long as all text and visuals maintain clarity and remain legible when the IFU is printed in black and white or in grayscale.