Label Comprehension Study: FDA Requirements, Design, and Scoring

A label comprehension study is an FDA-regulated test that measures whether ordinary consumers can read a nonprescription drug label and understand it well enough to use the product safely without a doctor’s guidance. The agency expects primary safety messages to reach a comprehension rate of 90 percent or higher among study participants, and for messages with especially serious clinical consequences the target should be even higher.¹ Whether a drug moves from behind the pharmacy counter to a retail shelf depends, in large part, on how real people perform in that controlled setting.

When the FDA Requires One

The most common trigger is a prescription-to-OTC switch. If a manufacturer wants to sell a previously prescription-only drug without a doctor visit, the FDA needs evidence that consumers can handle the product on their own. The agency’s guidance points to several other situations that call for a study: approval of a new nonprescription drug, addition of new indications or a new target population for an existing OTC product, and introduction of a new strength.²

The regulatory teeth come from 21 CFR 314.125, which lets the FDA refuse to approve any new drug application when the proposed labeling doesn’t comply with Part 201.³ Part 201 sets out the format and content standards for OTC drug labeling, including the Drug Facts panel, minimum font sizes, and required headings.⁴ A comprehension study is how a manufacturer proves those standards actually work in practice. If the label fails to communicate warnings or dosing effectively, the product stays prescription-only.

Designing the Study

The Label Mockup

The first step is producing a realistic mockup of the Drug Facts label that follows the formatting rules in 21 CFR 201.66, including the required headings in their prescribed order, minimum type sizes, and line spacing.⁴ The mockup must match the proposed production version exactly. Testing a cleaner or more spacious label than the one that will ship defeats the point.

Who Participates

The study population needs to mirror the general U.S. adult population in age, education, and background, with particular attention to people who read at lower grade levels. The FDA estimates the average American reads at an eighth-grade level and recommends OTC labels be written at a fourth- to fifth-grade reading level, no higher than eighth grade.² Protocols must recruit enough participants with fourth- through eighth-grade reading skills to analyze that subgroup separately. If only college graduates can understand the label, it isn’t ready for the general public.

Questions and Grading Rubric

Every question maps directly to a specific communication objective on the label. If the Warnings section tells people with kidney disease not to use the drug, the questionnaire needs a question testing whether participants grasp that restriction. The objectives and the coding criteria for correct and incorrect answers must be defined before any data is collected.² Locking the rubric in advance prevents anyone from redefining “correct” after seeing disappointing results.

Questions can be open-ended, where the participant explains the answer in their own words, or closed-ended multiple choice. Open-ended items are harder to grade but reveal more about genuine understanding. Closed-ended items produce cleaner data but risk inflated scores from lucky guesses. Most protocols use both.

Running the Study

The study takes place in a controlled setting, either a testing facility or a secure digital platform designed to simulate a shopping experience. Participants review the label mockup as they would in a store. An interviewer then walks through the questionnaire, recording responses without offering hints or steering the conversation. Neutrality is the whole point: the data has to reflect what the participant understood alone.

Interviewers also note how participants interact with the label, including whether they naturally find the Warnings section or skip it. After each session a coordinator logs the responses, and a second staff member verifies those entries against the participant’s actual statements. Once interviews are complete, records go to central processing. Participant identifiers are stripped for privacy while demographic data is kept so results can be broken down by age, education, and literacy. The manufacturer documents the testing environment and administration procedures to create an audit trail the FDA can review.

Scoring Results

Analysis turns on primary and secondary communication objectives. Primary objectives cover the most safety-critical information: who should avoid the drug, when to stop taking it, maximum dosage, and similar questions where a wrong answer could cause real harm. The FDA sets a target comprehension rate of 90 percent or greater for these primary endpoints, and higher for the most serious messages.¹

Every response is graded against the pre-defined rubric. For open-ended questions, the coding procedures spelled out in the protocol determine whether a paraphrased answer counts as correct.² Partially correct answers sit in a gray area, and the rubric must say in advance whether they pass or fail. Using two independent evaluators keeps grading consistent.

The final report aggregates success rates for each communication objective, with a separate breakdown for the low-literacy subgroup, and goes into the new drug application supporting the OTC switch. If the numbers fall short, manufacturers typically revise the label’s wording, layout, or both, and run the study again. There is no formal limit on retesting, but each round costs time and money.

How It Differs From Self-Selection and Actual Use Studies

A label comprehension study asks whether people understand what the label says. A self-selection study asks something narrower and more personal: whether people can apply that information to their own situation and correctly decide if the drug is appropriate for them.⁵ Understanding that a drug is not for people with liver disease is comprehension. Knowing you have liver disease and choosing not to buy it is self-selection.

The FDA recommends completing the comprehension study first, using the results to optimize the label, and then running the self-selection study.⁵ There is no point testing whether consumers make correct personal decisions based on a label they can’t understand. Applicants seeking an OTC switch must show that consumers can use the drug safely and effectively without professional supervision, and these studies form the evidentiary backbone of that showing.⁶ A separate actual use study goes further still, looking at whether consumers use the product correctly at home, not just whether they answer correctly in a testing room.

What the ACNU Rule Changes

A final rule published in late 2024, with an effective date in 2025, created the Additional Condition for Nonprescription Use, or ACNU, framework.⁷ An ACNU applies when the FDA determines that labeling alone isn’t enough to ensure consumers can safely self-select or use a drug. In those cases the manufacturer must implement an additional step, such as a questionnaire on a website or mobile app that decides whether the drug is appropriate for a particular consumer based on their responses.

Products with an ACNU still require consumer studies, including label comprehension, self-selection, and human factors studies. The label itself must include new required elements. The outer packaging needs a prominent yellow-background statement, in boldface black type at least 12-point or 25 percent as large as the biggest words on the front panel, warning consumers not to take the drug without completing the extra screening step.⁷ The comprehension study for an ACNU product must therefore test whether consumers notice, read, and understand that additional warning.

IRB Approval and Informed Consent

Even though participants only read a label rather than take a drug, these studies are clinical investigations regulated by the FDA. That means Institutional Review Board approval is required before the first participant is enrolled.⁸ The FDA can refuse to consider data from any clinical investigation that wasn’t reviewed and approved by an IRB meeting federal standards.

The IRB evaluates whether risks to participants are minimized, whether selection is fair, and whether privacy protections are adequate. Physical risk is negligible, but recruitment gets close attention because protocols deliberately target people with limited literacy. Every participant must give informed consent before the session starts. Under 21 CFR Part 50, the consent process must explain that the activity is research, describe what will happen, disclose how records will be handled, and make clear that participation is voluntary with no penalty for declining.⁹

1
GovInfo. Guidance for Industry – Label Comprehension Studies for Nonprescription Drug Products
2
Food and Drug Administration. Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products
3
eCFR. 21 CFR 314.125 – Refusal to Approve an NDA
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eCFR. 21 CFR 201.66 – Format and Content Requirements for Over-the-Counter Drug Product Labeling
5
Food and Drug Administration. Self-Selection Studies for Nonprescription Drug Products
6
U.S. Food and Drug Administration. Prescription-to-Nonprescription (Rx-to-OTC) Switches
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Federal Register. Nonprescription Drug Product With an Additional Condition for Nonprescription Use
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eCFR. 21 CFR Part 56 – Institutional Review Boards
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eCFR. 21 CFR Part 50 Subpart B – Informed Consent of Human Subjects