Label Comprehension Studies for Nonprescription Drug Products

The Food and Drug Administration (FDA) sometimes requires sponsors to conduct label comprehension studies that are designed to evaluate proposed nonprescription drug product labeling. A label comprehension study assesses the extent to which consumers understand the information on nonprescription drug product labeling and then apply this information when making drug product use decisions in a hypothetical situation. Data derived from a label comprehension study can identify areas on the label that would benefit from clearer or simpler presentation of important consumer information.

Why should this be of interest to labelers of homeopathic drug products? Label comprehension studies have a role to play when little is known about consumer understanding in a therapeutic category transitioning for self use. Homeopathic drug products are often, but not always, labeled with language consistent with the over-the-counter (OTC) drug review, including indications, warnings and directions. In cases when label language does not match approved language exactly or when transitioning from existing label language in general, comprehension studies may be of value to labelers and consumers.

Label comprehension study data do not predict consumer behavior in terms of drug product use. Drug product use and other behaviors are often evaluated in studies on actual use. Label comprehension studies if indicated, and actual use studies are powerful product design tools capable of delivering products that are more consumer friendly.

FDA has the authority to require sponsors to conduct label comprehension studies. Section 503(b)(1) of the Act requires an assessment of whether a drug product is safe for use without the professional supervision of a practitioner licensed by law to administer such drug product. In addition, section 502 (f) states that a drug product is misbranded if its labeling fails to bear adequate directions for use. Furthermore, a drug product is misbranded if any word, statement, or other information required by, or under authority of, the Act to appear on the label or labeling is not “in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use” 502(c).

The development of a nonprescription label is an iterative process that may depend upon testing and re-testing as the label evolves. Label comprehension studies should assess whether literate and low-literate individuals can understand a drug product label. Label comprehension studies are open-label, uncontrolled trials. Qualitative research and pilot testing should be conducted comparing different versions of the label prototypes before the larger label comprehension study is conducted. This enables refinement of the study questionnaire and the label before the label is tested in a larger study.

Label Comprehension Study Design Elements
When designing and conducting a label comprehension study, it is important to:

• State the purpose of the study
• Identify the communication objectives (the important concepts that need to be understood by the consumer)
• Enroll a demographically diverse population with varying levels of literacy
• Specify a study design that meets study objectives and calculate the appropriate sample size
• Construct a questionnaire that targets the communication objectives
• Use test labeling as close as possible to the final drug product label
• Minimize factors that may contribute to a biased study (e.g., sampling, recruitment strategies, leading questions, interviews that bias the responses in a particular direction)

Study Objectives
The goal of a label comprehension study should be to test consumer comprehension of the major communication messages that detail the safe and effective use of a nonprescription drug product.

The primary communication objective should be the major communication message with the greatest clinical consequence to the consumer. Depending upon the drug product, the primary communication objective can address:

• Consumer understanding of the indication
• Consumer understanding of dose and dosing interval
• Consumer understanding of specific contraindications, warnings, and drug interactions
• Consumer understanding of when to stop using the drug product

A target level of comprehension for each primary communication objective should be determined a priori. The target level of comprehension should reflect the clinical significance of the primary communication objective.

Secondary communication objectives also should be specified a priori. Secondary communication objectives often address areas less critical to the safe and appropriate use of the drug product, such as general health information (e.g., when using this product, continue a healthy diet and exercise). Pre-specified target comprehension levels are not needed for secondary communication objectives.

Study Population
The study should include all subjects who can potentially use the drug product, regardless of age, sex, underlying medical conditions, and use of concomitant medications. The study should test label comprehension in a general population whether or not individuals express interest in using the drug product. Exclusion factors should be minimal (e.g., inability to read and understand English) and should be justified in the study protocol.

Label comprehension studies should also include an adequate number of subjects who have low literacy skills to examine the comprehension of the label in this subgroup. The proportion of low-literacy subjects in the study sample should be representative of the proportion of adults in the United States with basic literacy skills based on available national data. Standard practice is to write medical information at a 4th to 5th grade reading level.

Statistical Considerations and Data Analysis
The study protocol should specify primary endpoints. Primary endpoints should directly relate to the primary communication objectives. Primary endpoints should be the endpoints capable of capturing the most relevant and convincing data on consumer comprehension of the critical label elements.

The success criteria should be defined using the confidence interval approach, because it considers uncertainty in the sample data. A two-sided 95 percent confidence interval to estimate the comprehension rate (or failure rate) and to define the success criteria is recommended. Typically, label comprehension studies have multiple primary endpoints and should demonstrate success for all the primary endpoints. In this case, the primary endpoints are referred to as co­primary endpoints.

The number of subjects in a label comprehension study should be large enough to provide a reliable answer to the primary communication objectives. Sizing of such a study should be based on the success criteria. This generally involves the predefined target level for the comprehension rate, the assumed comprehension rate for the study population, the type I error rate, and the type II error rate (or the study power).

The type I error rate should be set at 2.5 percent. The type II error rate can be in the range of 10 percent to 20 percent. The target comprehension rates can vary depending upon the medical significance of the communication objectives. The number of subjects in a label comprehension study should be large enough to evaluate the primary endpoints for important subgroups, such as the low-literate subgroup.

Questionnaire Design
The questionnaire design should reflect the communication objectives of the study and optimize the validity and interpretability of the information collected. Wording, question structure, and question sequences may significantly affect the validity and interpretability of the data collected. The following points merit particular consideration:

• Questions should be designed to assess the specific communication objectives.
• Simple vocabulary and pretested questions should be used.
• Questions should be direct, specific, and unambiguous. Each question should address a single item or issue.
• Questions should test whether subjects can apply the information on the label.
• Different types of questions, such as open-ended, closed-ended, and multiple choice questions can be used.
• Scenario questions that are based on hypothetical situations can be used.
  • Biased questions, such as leading questions, should be avoided.
• Questions that may cause framing or mindset bias should be avoided.
• Questions should not contain information that educates and influences a subject.
• Response choices in multiple-choice questions should be mutually exclusive and independent and contain only one correct answer.
• When listing responses for multiple-choice questions, the choice of “I don’t know” should be included as a response.

The questionnaire may be administered via: (1) self-administration; and/or (2) asking the questions using a trained interviewer. Using a trained interviewer may lessen the chance that low-literate subjects will incorrectly respond because they cannot comprehend the written question when, in fact, they comprehend the label. However, using an interviewer may lead to interviewer bias, particularly if the interviewer leads the subject to elicit a response.

Final Study Report
The final study report should describe the study design, conduct, and interpretation of the study results in detail. The demographic characteristics of the study subjects, including literacy level, should be presented in the study report.

Interpretation of Study Findings
The acceptable comprehension level of a communication objective should be based on meeting the success criteria established a priori. The interpretation of these quantitative data also should be supported by the verbatim responses where applicable. There may be times when the quantitative information reflects correct comprehension but the verbatim responses do not and vice versa. Thus, an analysis of both quantitative and qualitative data types should be provided to support and interpret the study findings.

Marketers and labelers of homeopathic drug products may consider the principles of label comprehension when developing or modifying labels for OTC drug products. Label comprehension studies if indicated, and actual use studies are powerful product design tools capable of delivering products that are more consumer friendly.

Readers are encouraged to read FDA’s guidance on this topic at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm143834.pdf