Labeling: Required Content, Format and Changes
Labeling is far broader than the label on the bottle. It is the document that defines what a product is approved to do, and changing a single sentence of it can require prior approval or else can be made the day it is filed.
The rule in short
Labeling under 21 U.S.C. 321(m) includes all written, printed or graphic matter on an article, its containers or wrappers, or accompanying it. A product is misbranded under 21 U.S.C. 352 where its labeling is false or misleading in any particular. Prescription labeling follows 21 CFR 201.56 and 201.57, over-the-counter labeling follows 201.66, and changes are made through the supplement categories in 21 CFR 314.70.
Labeling is the operative document in drug and device regulation. It states what the product is for, who should not receive it, what can go wrong and what to do about it. Almost every enforcement theory in this field is ultimately a labeling theory: either the labeling is wrong, or the product is being sold for something the labeling does not say.
What counts as labeling
The statutory definition is deliberately wide. Labeling means all labels and other written, printed or graphic matter upon any article or any of its containers or wrappers, or accompanying such article. The word accompanying does the work, because it reaches material that is physically separate from the product but functionally connected to it.
Two related bodies of rules sit alongside it. Promotional labeling covers material such as brochures, detail pieces and file cards distributed by or on behalf of a firm, and it is measured against the approved labeling. Advertising is regulated separately, with requirements for fair balance between effectiveness and risk information and for the presentation of a summary of the risk information. The same claim can therefore be evaluated under more than one heading depending on where it appeared.
A product is misbranded where its labeling is false or misleading in any particular. Misleading is judged not only by what is stated but by the failure to reveal material facts, including consequences that may result from use under the conditions prescribed or under customary conditions. A product is also misbranded where it lacks adequate directions for use, a requirement that prescription drugs satisfy through a specific exemption conditioned on carrying the prescribing information.
The prescribing information and its order
Prescription drug labeling follows a prescribed structure. It opens with highlights of the prescribing information, a summary limited in length and designed to be read quickly, followed by a table of contents and then the full prescribing information. Where a boxed warning applies, it appears first.
The full prescribing information runs in a fixed numbered order: indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, adverse reactions, drug interactions, use in specific populations, drug abuse and dependence, overdosage, description, clinical pharmacology, nonclinical toxicology, clinical studies, references, how supplied with storage and handling, and patient counseling information. Sections that do not apply are omitted rather than renumbered, so the numbering itself tells a reader what is present.
Each section has content rules. Contraindications are limited to situations in which the drug should not be used because the risk clearly outweighs any benefit. Warnings and precautions describe clinically significant adverse reactions and other hazards, and a hazard is added when there is reasonable evidence of a causal association, which does not require proof of causation.
The supplement system is not neutral between safety and marketing. Certain changes that strengthen the safety message, such as adding or strengthening a contraindication, warning, precaution or adverse reaction, or adding an instruction intended to increase safe use, may be distributed when the supplement is submitted. Changes that expand what a product claims to do generally require approval before distribution. The asymmetry is intentional, and reading a supplement category correctly is what keeps a labeling revision from becoming a marketing violation.
Over-the-counter and device labeling
Over-the-counter drug labeling uses a standardized panel with required headings in a required order: active ingredient, purpose, uses, warnings, directions, other information, inactive ingredients, and a questions or comments contact. Type size, contrast and spacing are prescribed, because the format exists so that a consumer can compare two packages on a shelf.
The boxed warning deserves separate mention because it is the strongest instrument in the format. It is reserved for adverse reactions so serious in proportion to the potential benefit that they should be considered in assessing the risks and benefits of using the drug, and for serious risks that can be avoided or reduced by appropriate use. It appears at the top of the labeling and is summarized in the highlights, and its presence carries consequences for advertising and for what promotional material may say.
Device labeling is governed by its own part. Prescription devices are exempt from the adequate directions requirement on conditions including that the device be sold only on the order of a licensed practitioner and that its labeling bear the required caution statement and information for use by practitioners. Device labeling also carries unique device identification requirements, which support the traceability the field otherwise lacks. Which requirements attach depends on the product's class, described in device classification and the three classes.
| Change category | Examples | When distribution may begin | Risk if miscategorized |
|---|---|---|---|
| Prior approval supplement | New indication, new dosing regimen, expanded population | Only after approval | Distribution of an unapproved change |
| Changes being effected in thirty days | Certain manufacturing and container changes | After the stated period, unless the agency objects | Premature distribution |
| Changes being effected immediately | Strengthening a warning, contraindication or adverse reaction | On submission of the supplement | Delay in communicating a known risk |
| Annual reportable change | Minor editorial and administrative changes | Immediately, reported in the periodic report | Underreporting a substantive change |
| Agency-required safety labeling change | New safety information the agency determines must appear | On the schedule the agency sets | Enforcement for failure to comply |
How a label is changed and who can force it
Changes to an approved product are made through supplements, and the category determines whether the change may be distributed before the agency acts. The applicant chooses the category and bears the consequences of choosing wrong, which is why the classification of a change is documented rather than assumed.
The agency is not confined to reacting. Where it becomes aware of new safety information that should be included in labeling, it can require the holder to make a safety labeling change and can initiate the process if the holder does not. Risk evaluation and mitigation strategies operate alongside labeling for products where labeling alone is judged insufficient, adding elements such as communication plans or restrictions on distribution.
The relationship between labeling and everything else is direct. The labeling approved in the process described in the new drug application and its review cycle defines the lawful claim set, and communications outside it raise the issues addressed in off-label communication and what may be said. Safety information arriving through the channels described in adverse event and malfunction reporting is the usual source of a labeling change, and where the problem is with product already distributed rather than with the words, the response is the one set out in recalls, corrections and removals.
Points to carry away
- Labeling includes material accompanying a product, not only what is printed on it.
- Labeling false or misleading in any particular renders a product misbranded.
- Prescription drug labeling follows a prescribed sequence of numbered sections.
- Over-the-counter labeling uses the standardized drug facts panel.
- Some safety-strengthening changes may be distributed when the supplement is filed.
- The agency can require a safety labeling change based on new safety information.
Questions readers ask
Is a website part of a product's labeling?
It can be. The statutory term reaches matter accompanying an article, and that phrase has been read to cover material that explains or supplements the product even where it travels separately. Promotional material is also regulated as advertising under separate provisions, and the two categories overlap. The practical consequence is that a company cannot place claims on a website that would be unlawful on the insert and treat the location as a defense. What is said, to whom, and about what use is what matters, not the medium.
What is a medication guide and when is one required?
It is patient labeling in a prescribed format, required for certain products where the agency determines that patient labeling could help prevent serious adverse effects, where the product has serious risks relative to benefits that could affect a patient's decision to use it, or where adherence to directions is essential to effectiveness. Where required, the guide must be distributed with the product to patients, and the distribution obligation runs through the supply chain to the dispenser. It may also form part of a risk evaluation and mitigation strategy imposed on a product.
Do generic and reference labeling have to match exactly?
Substantially, with defined exceptions. An abbreviated application must show labeling that is the same as the reference product's, permitting differences such as those attributable to a different manufacturer, different expiration dating, different formulation of inactive ingredients, or an indication or other aspect protected by patent or exclusivity. Where the reference labeling changes, generic labeling is expected to follow. The mechanics of who may initiate a change to which labeling, and when, have been contested and remain a source of litigation.
Sources
- Cornell Legal Information Institute — 21 U.S.C. 321, DefinitionsSubsection (m) defines labeling to include matter accompanying an article.
- Cornell Legal Information Institute — 21 U.S.C. 352, Misbranded Drugs and DevicesThe misbranding grounds, including false or misleading labeling and inadequate directions.
- eCFR — 21 CFR 201.56, Requirements on Content and Format of Labeling for Human Prescription Drug and Biological ProductsGeneral format requirements and the ordered list of required sections.
- eCFR — 21 CFR 201.57, Specific Requirements on Content and Format of LabelingWhat each section of the prescribing information must contain.
- eCFR — 21 CFR 201.66, Format and Content Requirements for Over-the-Counter Drug Product LabelingThe drug facts panel, its headings and their required order.
- eCFR — 21 CFR 314.70, Supplements and Other Changes to an Approved NDAPrior approval supplements, changes being effected supplements and annual reportable changes.
- eCFR — 21 CFR 801.109, Prescription DevicesThe labeling exemption and the conditions attaching to prescription device labeling.
Liberty Law Library is a publication, not a law firm. This article states general rules and cites its sources; it is not advice about any particular case, and the law differs by state and changes over time.
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