Guidance for Industry 

Label Comprehension Studies for 

Nonprescription Drug Products
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
August 2010 

OTC 

 
   
Guidance for Industry 

Label Comprehension Studies for 

Nonprescription Drug Products
  
 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
August 2010 

OTC 

 
   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   STUDY DESIGN AND CONDUCT................................................................................ 3 
 
A.   Study Objectives ............................................................................................................................3
  
1.  Primary Communication Objective .................................................................................................4
  
2.  Secondary Communication Objectives ............................................................................................ 4 
 
3.  Self-Selection Objective ...................................................................................................................4
  
B.   Study Population............................................................................................................................4
  
C.   Statistical Considerations and Data Analysis..............................................................................6
  
1.  Primary Endpoints and Success Criteria.........................................................................................6
  
2.  Sample Size Considerations.............................................................................................................6
  
3.  Data Analysis...................................................................................................................................7
  
D.   Questionnaire Design.....................................................................................................................7
  
E.   Label Versions and Format and Content Requirements............................................................9
  
F.   Study Conduct and Location ........................................................................................................9
  
G.   Data Collection, Recording, and Auditing...................................................................................9
  
IV.   FINAL STUDY REPORT................................................................................................ 9 
 
V.   INTERPRETATION OF STUDY FINDINGS ............................................................ 10 
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Label Comprehension Studies for 

Nonprescription Drug Products 

 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION 
 
The Food and Drug Administration (FDA) sometimes requires sponsors to conduct label 
comprehension studies that are designed to evaluate proposed nonprescription drug product 
labeling. This guidance is intended to provide recommendations to industry on conducting label 
comprehension studies.  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.   
 
It is important to note that label comprehension study data do not predict consumer behavior 
(e.g., how consumers actually use a drug product). Drug product use and other behaviors are 
often evaluated in an actual use study.  We recommend that the label used in an actual use study 
be tested in a label comprehension study beforehand to ensure that consumers understand the 
information on the label.    
 
This guidance covers general principles related to the conduct of label comprehension studies 
and should not be considered a substitute for an FDA review of specific protocols.  This 
guidance incorporates advice obtained from the September 25, 2006, meeting of the 
Nonprescription Drug Advisory Committee that considered issues related to analysis and 
interpretation of consumer studies conducted to support marketing of nonprescription drugs,2 and 
comments received regarding the draft guidance published on May 1, 2009. 
                                                 
1  This guidance has been prepared  by  the Division  of Nonprescription Clinical  Evaluation and  the Office of  
Biostatistics in the Center for Drug Evaluation and Research (CDER) at the Food and Drug  Administration. 
 
2 The transcript  from the September 25, 2006, Nonprescription Drug  Advisory Committee meeting is available at 
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4230t.pdf. 
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  Contains Nonbinding Recommendations 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND  
 
Under the Federal Food, Drug, and Cosmetic Act (the Act), the 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 (21 U.S.C. 353(b)(1)).  In addition, 
section 502 states that a drug product is misbranded if its labeling fails to bear adequate 
directions for use (21 U.S.C. 352(f)). 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 (21 U.S.C. 352(c)).   
 
Section 505(d) of the Act requires adequate tests by all methods reasonably applicable to show 
that a drug product is safe for use under the conditions prescribed, recommended, or suggested in  
proposed labeling (21 U.S.C. 355(d)). In addition, section 503(b)(1) of the Act requires an 
assessment of whether a drug product is safe for use without a prescription (21 U.S.C. 
353(b)(1)). Moreover, FDA regulations further require that labeling state the intended uses and 
results of the product; adequate directions for proper use; and warnings against unsafe use, side 
effects, and adverse reactions in such terms as to render them  likely to be read and understood by 
the ordinary individual, including individuals of low comprehension under customary conditions 
of purchase and use (21 CFR 330.10(a)(4)(v)).  Regulations on the format and content 
requirements for nonprescription drug product labeling are contained in 21 CFR 201.66.   
 
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.  Some of the circumstances 
under which the FDA might require a label comprehension study include:  
 
	   Before the approval of a new drug product for the nonprescription market  
 
	   When one or more new indications, a new target population, or a new strength are 

proposed for a marketed nonprescription drug product 

 
	   When a substantive labeling change has been proposed (e.g., a change in the directions, a 
new warning) for a marketed nonprescription drug product 
 
	   When drug products with new active ingredients that have a proprietary name associated 
with other active ingredients are proposed 
 
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  Contains Nonbinding Recommendations 
	   When adequate consumer labeling for the drug product requires the inclusion of a 

package insert; comprehension testing of the insert may be needed  

 
Sponsors desiring FDA advice and consultation on a protocol for a label comprehension study 
should submit the protocol to an existing investigational new drug or new drug application in the 
Division of Nonprescription Clinical Evaluation. 
 
 
III.  STUDY DESIGN AND CONDUCT 
 
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) 
 
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.   
 
A.  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.  
These major messages should be the communication objectives for the study.  Other messages on 
the label do not necessarily need to be tested. 
 
The study protocol should state the communication objectives.  A label comprehension study can 
have many communication objectives.  All the communication objectives should be identified a 
priori. The characteristics of the active ingredient and the drug product class under consideration 
should determine what is important for consumers to understand, and therefore drive the 
communication objectives. 
 
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  Contains Nonbinding Recommendations 
1.  Primary Communication Objective 
 
The primary communication objective should be the major communication message with the 
greatest clinical consequence to the consumer.  Depending on the drug product, a study can have 
more than one primary communication objective.  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.  
 
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 
 
2.  Secondary Communication Objectives 
 
Secondary communication objectives also should be specified a priori.  Not all label 
comprehension studies will have secondary communication objectives.  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). Prespecified target comprehension levels are not needed for 
secondary communication objectives.  
 
3.  Self-Selection  Objective  
 
Self-selection is the decision a consumer makes to use or not to use a drug product based on 
reading the information on the drug product label and applying knowledge of his or her personal 
medical history.  It is optimal to test for appropriate self-selection in a separate self-selection 
study or in the setting of an actual use study. However, in some circumstances it may be useful 
to test for appropriate self-selection as part of a label comprehension study.  If this is the case, 
sponsors should enrich the study with subjects who would be interested in using the drug 
product, and subjects with specific relative or absolute contraindications to use of the proposed 
drug product, to ensure that the population at greatest risk understands the label.   
 
B.  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.  Because nonprescription drug products are available for purchase without a 
learned intermediary, and since no drug product is administered in the study, exclusion factors 
should be minimal (e.g., inability to read and understand English) and should be justified in the 
study protocol. 
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  Contains Nonbinding Recommendations 
 
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.  The average reading 
level in the United States is estimated to be 8th grade.3  Standard practice is to write medical 
information at a 4th to 5th grade reading level.4,5  Therefore, attempts should be made to write 
the nonprescription label at a 4th to 5th grade reading level and no higher than an 8th grade 
reading level. 
 
To adequately test the label, the low literate subjects should consist of an equal distribution of 
consumers who have 4th to 8th grade reading skills or marginal functional health literacy skills.  
Education level is not a reliable substitute for literacy testing.  At screening, the sponsor should 
assess literacy levels of the study subjects by administering a validated instrument such as the 
Rapid Estimate of Adult Literacy in Medicine (REALM) test,6 REALM-Teen for testing 
adolescents,7 or the Test of Functional Health Literacy in Adults (TOFHLA or S-TOFHLA).8,9,10   
Investigators should receive training to properly administer the literacy test.  If the label being 
tested requires the ability to understand and interpret numbers (e.g., weight- and/or age-based 
dosing directions), it may be appropriate for sponsors to screen for functional health literacy 
using the TOFHLA or S-TOFHLA.11  
 
                                                 
3 Cotunga, N, CE Vickery, and KM Carpenter-Haefele, 2005, Evaluation  of Literacy Level of Patient  Education  
Pages in  Health-Related Journals, Journal  of Community Health, 30(3), 213-219.  
 
4 Andrus, MR and MT Roth, 2002, Health Literacy:  A Review, Pharmacotherapy, 22(3), 282-302. 
 
5 Paasche-Orlow, MK et al., 2003, Readability Standards for Informed-Consent Forms as Compared With Actual 
Readability, New England Journal of Medicine, 348:721-6. 
 
6 REALM:   Davis, TC et al., 1993, Rapid Estimate of Adult Literacy in Medicine:   A Shortened Screening 
Instrument, Family Medicine, 25:391-395. 
 
7 REALM-Teen:  Davis, TC et al., 2006, Development and Validation  of the Rapid Estimate of Adolescent Literacy 
in Medicine (REALM-Teen);  A Tool to  Screen Adolescents for Below-Grade Reading in Health Care Settings, 
Pediatrics, 118(6):e1707-1714. 
 
8 TOFHLA:  Parker, RM et al., 1995, The Test of Functional Health Literacy in Adults:  A New Instrument for 
Measuring Patients Literacy Skills, Journal of  General Internal Medicine, 10:537-541. 
 
9 Baker,  DW et  al., 1999,  Development of a Brief Test to Measure Functional Health Literacy, Patient Education and  
Counseling, 38:33-42. 
 
10 The REALM  and TOFHLA  were designed as rapid screening tools that  were validated  against the Wide Range  
Achievement Test for literacy; therefore, use of these instruments to screen literacy levels within the context of  
health is appropriate. 
 
11 TOFHLA:  Parker, RM et al., 1995, The Test of Functional Health Literacy in Adults:  A New Instrument for 
Measuring Patients Literacy Skills, Journal of  General Internal Medicine, 10:537-541. 
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  Contains Nonbinding Recommendations 
C.  Statistical Considerations and Data Analysis 
 
1.  Primary Endpoints and Success Criteria 
 
The study protocol should specify primary endpoints (primary variables), along with rationales 
for their selection. 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.  
 
Based on the specified primary endpoints, the study protocol should also specify success criteria 
(i.e., what determine success for the study) that should be related to the predefined target level of 
comprehension for the primary communication objectives.  The success criteria should be 
defined using the confidence interval approach, because it considers uncertainty in the sample 
data. For example, if the study has only one primary endpoint and is designed to ensure a 
predefined target level of comprehension, then the study can be claimed as a success only when 
the lower limit of the two-sided 95 percent (or one-sided 97.5 percent) confidence interval for the 
comprehension rate is above the predefined target level.   
 
We recommend sponsors use the two-sided 95 percent confidence interval to estimate the 
comprehension rate (or failure rate) and to define the success criteria.  This approach sets the 
type I error rate for one-sided tests (2.5 percent) at half the conventional type I error rate of 5 
percent used in two-sided tests. 
 
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 co-
primary endpoints.  If the endpoints are not co-primary endpoints, the study protocol should 
address multiplicity issues to ensure that the overall type I error rate is appropriate and the 
confidence intervals are adjusted accordingly. 
 
2.  Sample Size Considerations 
 
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.  
 
If the primary endpoints are not co-primary, then the sample size should be adjusted for the 
multiple confidence interval calculations for each of the primary endpoints.  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.  
 
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  Contains Nonbinding Recommendations 
3.  Data Analysis 
 
The principal features of the planned analysis should be defined in the protocol.  The statistical 
methods for characterization of study subjects, and the analysis of the primary and secondary 
endpoints should be specified in the protocol. Methods for constructing a two-sided confidence 
interval to estimate and define the success criteria for the comprehension rate of the primary 
endpoints (or failure rate) should be described.  Methods for handling missing data should be 
specified. A comprehensive statistical analysis plan should address all the details of the data 
analysis. 
 
D.  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.  
A detailed discussion of questionnaire development is beyond the scope of this guidance.  We  
recommend that sponsors consult experts in questionnaire design.  The following points merit 
particular consideration: 
 
	   Questions should be designed to assess the specific communication objectives. 
 
	   Simple vocabulary and pretested questions should be used.  Pretesting the questionnaire 
with a sample of respondents to ascertain that the questionnaire is eliciting the intended 
information should be routine practice.  
 
	   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.  For 
example:  Jennifers son is 8 years old and weighs 52 pounds.  According to the label, 
how many teaspoons of Drug X should Jennifer give him?    
 
	   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.  Scenario-based 
questions are often used to assess the ability to make correct decisions based on 
information on the label.  For example:  Sally is pregnant and would like to take Drug X.  
According to the label, is it okay or not okay for Sally to take Drug X?  Answers to the 
closed-ended question (e.g., okay or not okay) should be validated with answers to an 
open-ended probing question; otherwise subjects have a 50 percent chance of being 
correct by chance alone. For example:  John has diabetes and would like to take Drug X.  
Is it okay or not okay?  Why did you say that?   
 
	   Biasing questions, such as leading questions, should be avoided.  An example of a 
leading question is:  Joe stopped taking Drug X and went to see his doctor because he 
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  Contains Nonbinding Recommendations 
developed a rash. Is this okay or not okay?  An example of a nonleading question is:  Joe 
developed a rash after he started taking Drug X.  What should Joe do?    
 
	   Questions that may cause framing or mindset bias should be avoided.  An example of this 
type of bias is providing the response category of talk to a doctor for multiple-choice 
questions. If the correct answer to the question is talk to a doctor, a multiple-choice 
question with a response category of talk to a doctor may be leading.  When a subject 
does not know an answer, he or she may choose talk to a doctor rather than I dont know 
because it seems like the right thing to do.  This type of bias is often referred to as social 
desirability. In this situation, a multiple-choice question is not recommended.  
 
 	  Questions should not contain information that educates and influences a subjects ability 
to answer subsequent questions. 
 
 	  Response choices in multiple-choice questions should be mutually exclusive and 
independent and contain only one correct answer.  A limited use of multiple-choice 
questions is recommended.  Questions that require subjects to generate meaning or 
content on their own (rather than simply selecting an existing answer option) provide 
more reliable data to assess a subjects ability to comprehend written material.  
 
 	  When listing response categories for multiple-choice questions, the category I dont know  
should be included as one of the response categories to give subjects permission to admit 
that they do not know so they avoid guessing.  The reasons for incorrect answers can also 
be assessed.  
 
 	  If a label comprehension study includes testing the subjects ability to appropriately self-
select, questions that are used to validate the self-selection decision should be asked at 
the end of the study. Prompting subjects to think about their medical history before they 
make a self-selection decision or are tested on label comprehension can bias the study.   
 
 	  Questions intended to measure the behavioral intent of the subject should not be used.  
Testing behavior is outside the scope of a label comprehension study.  An actual use 
study should be conducted if information about how subjects would behave under 
nonprescription conditions is needed. 
 
 	  If subjects answer questions incorrectly, verbatim responses should be collected using 
open-ended probing questions to assess why they answered a question incorrectly.  It is 
important to collect this information to determine what changes to the label are needed to 
improve comprehension.     
 
 	  Other types of questions that have not been described that do not introduce bias may be 
appropriate. 
 
The following two general approaches to administering the questionnaire can be considered:  (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, 
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using an interviewer may lead to interviewer bias particularly if the interviewer leads the subject 
to elicit a response. Interviewers involved in the study should be adequately trained, and have 
standard protocols and/or scripts to adhere to, especially regarding questions that subjects might 
ask. Sponsors should consider inherent bias that can occur with any data collection method.  
Therefore, they should provide their rationale as to why they chose a particular method and 
should address any potential bias. 
 
E.  Label Versions and Format and Content Requirements 
 
The standardized nonprescription Drug Facts Label format and content requirements should be 
used (see 21 CFR 201.66(e) and (f)).  If a sponsor chooses to deviate from the Drug Facts Label, 
a rationale should be provided and testing should be conducted comparing the deviation with the 
Drug Facts Label. 
 
F.  Study Conduct and Location 
 
Advertisements for the study should not contain information about the proposed drug product.  
Interested subjects should be provided only with information on how and where to participate in 
the study. The study site can be in a mall or in other places frequented by consumers.  The study 
setting should be comfortable and well lit for reading.  Subjects should be told before the study 
starts that they can refer to the label during questioning.  Questions can begin with the statement 
according to the label; however, subjects should not be overly prompted to look at the label 
during questioning. 
 
Subjects should receive sufficient instruction on the format and conduct of the study and the 
expected length of time it will take to participate.  Well-trained study site investigators should 
carry out procedures according to the protocol.  Investigators should adhere to scripted responses 
to subject queries. 
 
G.  Data Collection, Recording, and Auditing 
 
Verbatim responses to all questions should be recorded.  The procedure for coding, categorizing, 
and analyzing verbatim responses to open-ended questions should be specified a priori in the 
protocol. Correct and incorrect answers to closed-ended questions also should be prespecified.  
Post-hoc coding for open-ended questions should be documented.    
 
Methods for verification of complete and accurate recording of study data should be described in 
the protocol (i.e., subjects responses, data entry, missing data, and data coding).  
 
 
IV.  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. 
 
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The study report should describe the nature of the recruitment effort and the response rate (i.e., 
the proportion of screened subjects who were actually enrolled in the study).  Potential subjects 
who were excluded should be characterized by the reasons for exclusion.  Enrolled subjects 
should be characterized as to relevant demographic factors and whether or not they completed 
the entire study. Reasons why subjects failed to complete the study should be provided in the 
study report. 
 
The presentation of the study results should include both the overall comprehension rates and 
comprehension rates in appropriate subgroups (e.g., low literacy, normal literacy).  
 
 
V.  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.   
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