Guidance for Industry

Patient-Reported Outcome Measures: 

Use in Medical Product Development 

to Support Labeling Claims 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Devices and Radiological Health (CDRH) 

December 2009 

Clinical/Medical 
Guidance for Industry 

Patient-Reported Outcome Measures: 

Use in Medical Product Development 

to Support Labeling Claims 

Additional copies are available from: 

Office of Communications, Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

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Silver Spring, MD 20993-0002 

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

or 

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Food and Drug Administration 

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Tel: 800-835-4709 or 301-827-1800; E-mail: ocod@fda.hhs.gov

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm 

or 

Office of Communication, Education, and Radiation Programs 

Division of Small Manufacturers, International, and Consumer Assistance, HFZ-220 

Center for Devices and Radiological Health 

Food and Drug Administration 

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(Tel) Manufacturers Assistance: 800-638-2041 or 301-443-6597 

(Tel) International Staff: 301-827-3993 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Devices and Radiological Health (CDRH) 

December 2009 

Clinical/Medical 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. EVALUATION OF A PRO INSTRUMENT ................................................................. 3

A. Endpoint Model..............................................................................................................................3

B. Choice of PRO Instrument............................................................................................................5

C. Conceptual Framework of a PRO Instrument............................................................................7

1. Concepts Measured..........................................................................................................................7

2. Intended Population.......................................................................................................................10

D. Content Validity...........................................................................................................................12

1. Item Generation .............................................................................................................................12

2. Data Collection Method and Instrument Administration Mode ....................................................13

3. Recall Period .................................................................................................................................14

4. Response Options...........................................................................................................................14

5. Instrument Format, Instructions, and Training .............................................................................16

6. Patient Understanding...................................................................................................................16

7. Scoring of Items and Domains.......................................................................................................16

8. Respondent and Administrator Burden..........................................................................................17

E. Reliability, Other Validity, and Ability to Detect Change .......................................................18

1. Reliability.......................................................................................................................................18

2. Other Validity ................................................................................................................................19

3. Ability to Detect Change................................................................................................................20

F. Instrument Modification .............................................................................................................20

G. PRO Instruments Intended for Specific Populations ...............................................................21

1. Children and Adolescents ..............................................................................................................21

2. Patients Cognitively Impaired or Unable to Communicate...........................................................21

3. Culture or Language Subgroups....................................................................................................22

IV. CLINICAL TRIAL DESIGN......................................................................................... 22

A. General Protocol Considerations................................................................................................22

1. Blinding and Randomization..........................................................................................................22

2. Clinical Trial Quality Control .......................................................................................................23

3. Handling Missing Data..................................................................................................................23

B. Frequency of Assessments...........................................................................................................24

C. Clinical Trial Duration................................................................................................................24

D. Design Considerations for Multiple Endpoints.........................................................................24

E. Planning for Clinical Trial Interpretation Using a Responder Definition..............................24

F. Specific Concerns When Using Electronic PRO Instruments .................................................26

V. DATA ANALYSIS.......................................................................................................... 27

A. General Statistical Considerations .............................................................................................27

B. Statistical Considerations for Using Multiple Endpoints.........................................................28

i
ii

C. Statistical Considerations for Composite Endpoints ................................................................29

D. Statistical Considerations for Patient-Level Missing Data.......................................................29

1. Missing Items within Domains.......................................................................................................30

2. Missing Entire Domains or Entire Measurements.........................................................................30

E. Interpretation of Clinical Trial Results .....................................................................................30

GLOSSARY................................................................................................................................. 31

APPENDIX: INFORMATION ON A PRO INSTRUMENT REVIEWED BY THE FDA 35
Contains Nonbinding Recommendations 

Guidance for Industry1

Patient-Reported Outcome Measures: 

Use in Medical Product Development 

to Support Labeling Claims

This guidance represents the Food and Drug Administration’s (FDA’s) 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 

This guidance describes how the Food and Drug Administration (FDA) reviews and evaluates 

existing, modified, or newly created patient-reported outcome (PRO) instruments used to 

support claims in approved medical product labeling.2

 A PRO instrument (i.e., a questionnaire

plus the information and documentation that support its use) is a means to capture PRO data used 

to measure treatment benefit or risk in medical product clinical trials. This guidance does not 

address the use of PRO instruments for purposes beyond evaluation of claims made about a 

medical product in labeling. This guidance also does not address disease-specific issues. 

Guidance on clinical trial endpoints for specific diseases can be found on various FDA Web 

sites.3

By explicitly addressing the review issues identified in this guidance, sponsors can increase the 

efficiency of their discussions with the FDA during the medical product development process, 

streamline the FDA’s review of PRO instrument adequacy and resultant PRO data collected 

 

1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the 

Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH) 

at the Food and Drug Administration. 

2 Labeling, as used in this guidance, refers to the information about an FDA-approved medical product intended for 

the clinician to use in treating patients. See 21 CFR 201.56 and 201.57 for regulations pertaining to prescription 

drug (including biological drug) labeling. Section 201.56 specifically describes the need for labeling that is not false 

or misleading. See 21 CFR part 801 for medical device labeling. See 21 CFR 606.122 for blood and blood products 

for transfusion. 

3

 See the following FDA Web sites: 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (CDER), 

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm (CBER), and 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm (CDRH). 

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during a clinical trial, and provide optimal information about the patient perspective for use in 

making conclusions about treatment effect at the time of medical product approval. PRO 

instrument development is an iterative process and we recognize there is no single correct way to 

develop a PRO instrument. Different strategies and methods can be used to address FDA review 

issues. 

The Glossary defines many of the terms used in this guidance. Words or phrases found in the 

Glossary appear in bold italics at first mention. Specifically, we encourage sponsors to 

familiarize themselves with the terms conceptual framework of a PRO instrument, endpoint 

model, and content validity. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s 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 

A PRO is any report of the status of a patient’s health condition that comes directly from the 

patient, without interpretation of the patient’s response by a clinician or anyone else. The 

outcome can be measured in absolute terms (e.g., severity of a symptom, sign, or state of a 

disease) or as a change from a previous measure. In clinical trials, a PRO instrument can be used 

to measure the effect of a medical intervention on one or more concepts (i.e., the thing being 

measured, such as a symptom or group of symptoms, effects on a particular function or group of 

functions, or a group of symptoms or functions shown to measure the severity of a health 

condition). 

Generally, findings measured by a well-defined and reliable PRO instrument in appropriately 

designed investigations can be used to support a claim in medical product labeling if the claim is 

consistent with the instrument’s documented measurement capability. The amount and kind of 

evidence that should be provided to the FDA is the same as for any other labeling claim based on 

other data. Use of a PRO instrument is advised when measuring a concept best known by the 

patient or best measured from the patient perspective. A PRO instrument, like physician-based 

instruments, should be shown to measure the concept it is intended to measure, and the FDA will 

review the evidence that a particular PRO instrument measures the concept claimed. The 

concepts measured by PRO instruments that are most often used in support of labeling claims 

refer to a patient’s symptoms, signs, or an aspect of functioning directly related to disease status. 

PRO measures often represent the effect of disease (e.g., heart failure or asthma) on health and 

functioning from the patient perspective. 

Claims generally appear in either the Indications and Usage or Clinical Studies section of 

labeling, but can appear in any section. Regardless of the labeling section, PRO instrument 

evaluation principles described here apply. 

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Contains Nonbinding Recommendations 

III. EVALUATION OF A PRO INSTRUMENT 

The evaluation of a PRO instrument to support claims in medical product labeling includes the 

following considerations: 

• The population enrolled in the clinical trial 

• The clinical trial objectives and design 

• The PRO instrument’s conceptual framework 

• The PRO instrument’s measurement properties

Because the purpose of a PRO measure is to capture the patient’s experience, an instrument will 

not be a credible measure without evidence of its usefulness from the target population of 

patients. Sponsors should provide documented evidence of patient input during instrument 

development and of the instrument’s performance in the specific application in which it is used 

(i.e., population, condition). An existing instrument can support a labeling claim if it can be 

shown to reliably measure the claimed concept in the patient population enrolled in the clinical 

trial. 

A. Endpoint Model 

Sponsors should define the role a PRO endpoint is intended to play in the clinical trial (i.e., a 

primary, key secondary, or exploratory endpoint) so that the instrument development and 

performance can be reviewed in the context of the intended role, and appropriate statistical 

methods can be planned and applied. It is critical to plan these approaches in what can be called 

an endpoint model. 

Figures 1 and 2 show examples of endpoint models. In Figure 1, a PRO symptom assessment is 

a secondary endpoint with a physiologic measure as the primary endpoint intended to support an 

indication for the treatment of Disease X. In this case, the clinical trial would need to succeed on 

the physiologic endpoint before success could be attained on the secondary endpoints. In Figure 

2, a PRO symptom assessment is the primary clinical trial endpoint intended to support an 

indication for the treatment of symptoms associated with Disease Y and the physical 

performance and limitation measures would be the key secondary endpoints. PRO instrument 

adequacy depends on its role and relationships with other clinical trial endpoints as depicted in 

the endpoint model. The endpoint model explains the exact demands placed on the PRO 

instrument to attain the evidence to meet the clinical trial objectives and support the targeted 

claims corresponding to the concepts measured. 

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Contains Nonbinding Recommendations 

Figure 1. Endpoint Model: Treatment of Disease X 

Figure 2. Endpoint Model: Treatment of Symptoms Associated with Disease Y 

Concept Endpoints

Indication Primary

Treatment of symptoms Total Disease Y symptoms score 

of Disease Y (PRO assessment) 

Supportive Concepts Secondary

Other treatment benefit Physical performance 

 (PRO or non-PRO 

assessment) 

 Disease Y-related physical 

 limitations (PRO 

 assessment) 

Concept Endpoints

Indication Primary

Treatment of Disease X Physiologic effect 

 (non-PRO assessment) 

Supportive Concepts Secondary

Improvement in symptoms/ Symptoms diary 

signs of Disease X (PRO assessment) 

 Signs diary 

 (PRO assessment) 

 Physical exam 

 (non-PRO assessment) 

 Physical performance 

 (PRO or non-PRO 

 assessment) 

To help specify potential labeling claims and to facilitate communication with the FDA about the 

specific clinical trials designed to assess the planned concepts, sponsors can use a target product 

profile (TPP), which is a clinical development program summary in the context of prescribing 

information goals (i.e., targeted labeling claims).4,5 

 

4

 See the draft guidance for industry and review staff Target Product Profile — A Strategic Development 

Process Tool. When final, this guidance will represent the FDA’s current thinking on this topic. 

For the most recent version of a guidance, check the FDA Drug guidance Web page at 

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

5

 Although the TPP process is used for drug and biologic approvals, the concept of beginning with the desired 

claims and designing the clinical trials to assess these claims is similar for medical devices. 

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Contains Nonbinding Recommendations 

B. Choice of PRO Instrument 

Early in medical product development, sponsors planning to use a PRO instrument in support of 

a labeling claim are encouraged to determine whether an adequate PRO instrument exists to 

assess and measure the concepts of interest. If it does not, a new PRO instrument can be 

developed. In some situations, the new instrument can be developed by modifying an existing 

instrument. 

The adequacy of any PRO instrument, whether existing, modified, or newly developed, as a 

measure to support medical product labeling claims depends on whether its characteristics (see 

this section), conceptual framework (see section III.C.), content validity (see section III.D.), and 

other measurement properties (see section III.E.) are satisfactory. The FDA will review 

documentation of PRO instrument development and testing in conjunction with clinical trial 

results to determine whether a labeling claim is substantiated. The Appendix lists the type of 

PRO information sponsors should provide to the FDA to facilitate instrument review. 

Characteristics of PRO instruments that are reviewed by the FDA include the following: 

• Concepts being measured 

• Number of items

• Conceptual framework of the instrument 

• Medical condition for intended use 

• Population for intended use 

• Data collection method 

• Administration mode 

• Response options 

• Recall period

• Scoring 

• Weighting of items or domains

• Format 

• Respondent burden 

• Translation or cultural adaptation availability 

We encourage instrument developers to make their instruments and related development history 

available and accessible publicly. When development history is not available, sponsors generally 

should provide documentation of content validity with an application (i.e., evidence that the 

instrument measures what it is intended to measure), including open-ended patient input from the 

appropriate population. Content validity is discussed in more detail in section III.D., Content 

Validity. In addition, we anticipate empiric evidence of an instrument’s other measurement 

properties, discussed in more detail in section III.E., Reliability, Other Validity, and Ability to 

Detect Change. 

We suggest that an instrument’s measurement properties be well established before enrollment 

begins for confirmatory clinical trials. Therefore, sponsors should begin instrument development 

and evaluation early in medical product development, and engage the FDA in a discussion about 

a new or unique PRO instrument before confirmatory clinical trial protocols are finalized. 

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Contains Nonbinding Recommendations 

Requests for FDA input should be addressed to the review division responsible for the medical 

product in question. For the FDA to provide useful early input, sponsors should provide their 

labeling goals, a hypothesized PRO instrument conceptual framework, and the relationship of the 

PRO endpoints to other clinical trial endpoints in preliminary endpoint models for the planned 

confirmatory trials. 

If the measurement goal is to support a complex, multidomain concept, PRO instruments that 

measure a simple concept may not be adequate to substantiate the complex claim. For example, 

PRO-based evidence of improved symptoms alone will only support claims specific to 

improvement of the symptoms and would not support a general claim related to improvement in 

a patient’s ability to function or the patient’s psychological state. In addition, a complex, 

multidomain claim cannot be substantiated by instruments that do not adequately measure the 

individual component domain concepts adequately. 

PRO instruments can be used to measure important safety concerns if those concerns represent 

symptoms or signs that are best captured from the patient perspective. The principles for PRO 

instrument development are not different for this application. 

Claims representing general concepts often are not supported, even though the PRO instrument 

was developed to measure the general concepts, because the instrument may not distinguish 

adverse side effects of treatment that affect the general concept and that may not be known at the 

time the clinical trials are designed. If adverse effects are captured, PRO instruments should aim 

to measure the adverse consequences of treatment separately from the effectiveness of treatment. 

As with any clinical trial evaluating FDA-regulated medical products, all adverse events detected 

with a PRO instrument should be included in the clinical trial report. 

Figure 3 summarizes the iterative process used in developing a PRO instrument for use in 

clinical trials. FDA review of the developmental process documentation is discussed in more 

detail in section III.C., Conceptual Framework of a PRO Instrument, through section III.G., PRO 

Instruments Intended for Specific Populations. 

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Contains Nonbinding Recommendations 

Figure 3. Development of a PRO Instrument: An Iterative Process 

i. Hypothesize Conceptual Framework

• Outline hypothesized concepts and potential claims

• Determine intended population

• Determine intended application/characteristics (type of scores, 

mode and frequency of administration)

• Perform literature/expert review

• Develop hypothesized conceptual framework

• Place PROs within preliminary endpoint model

• Document preliminary instrument development

PRO

↕

Claim

v. Modify Instrument

• Change wording of items, 

populations, response options, recall 

period, or mode/method of 

administration/data collection

• Translate and culturally adapt to 

other languages

• Evaluate modifications as 

appropriate

• Document all changes

ii. Adjust Conceptual 

Framework and Draft 

Instrument • Obtain patient input 

• Generate new items

• Select recall period, response 

options and format

• Select mode/method of 

administration/data collection

• Conduct patient cognitive 

interviewing

• Pilot test draft instrument

• Document content validity

iii. Confirm Conceptual Framework and 

Assess Other Measurement Properties • Confirm conceptual framework with scoring rule

• Assess score reliability, construct validity, and ability to 

detect change 

• Finalize instrument content, formats, scoring, procedures 

and training materials

• Document measurement development

iv. Collect, Analyze, and 

Interpret Data • Prepare protocol and statistical analysis plan 

(final endpoint model and responder 

definition)

• Collect and analyze data 

• Evaluate treatment response using 

cumulative distribution and responder 

definition 

• Document interpretation of treatment benefit 

in relation to claim

C. Conceptual Framework of a PRO Instrument 

The adequacy of a proposed instrument to support a claim depends on the conceptual framework 

of the PRO instrument. The conceptual framework explicitly defines the concepts measured by 

the instrument in a diagram that presents a description of the relationships between items, 

domain (subconcepts), and concepts measured and the scores produced by a PRO instrument. 

1. Concepts Measured 

One fundamental consideration in the review of a PRO instrument is the adequacy of the item 

generation process to support the final conceptual framework of the instrument. In some cases, 

the question of what to measure may be obvious given the condition being treated. For example, 

to assess the effect of treatment on pain, patients from the target population are queried about 

pain severity using a single-item PRO instrument. Generally, when it is not obvious, instrument 

developers initially can hypothesize a conceptual framework to support the measurement of the 

concept of interest drafting the domains and items to be measured based on literature reviews 

and expert opinion. Subsequently, patient interviews, focus groups, and qualitative cognitive 

interviewing ensures understanding and completeness of the concepts contained in the items. 

(See section III.D.1., Item Generation.) 

The conceptual framework of a PRO instrument will evolve and be confirmed over the course of 

instrument development as a sponsor gathers empiric evidence to support item grouping and 

scores. When used in a clinical trial, the PRO instrument’s conceptual framework should again 

be confirmed by the observed relationships among items and domains. 

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Contains Nonbinding Recommendations 

Documentation of the instrument development process should reveal the means by which the 

items and domains were identified. The exact words used to represent the concepts measured by 

domain or total scores should be derived using patient input to ensure the conclusions drawn 

using instrument scores are valid. 

For measures of general concepts, we intend to review how individual items are thought to be 

associated with each other, how items are associated with each domain, and how domains are 

associated with each other and the general concept of interest based on the conceptual framework 

of the PRO instrument. The diagram in Figure 4 depicts a generic example of a conceptual 

framework of a PRO instrument where Domain 1, Domain 2, and General Concept each 

represent related but separate concepts. Items in this diagram are aggregated into domains. The 

final framework is derived and confirmed by measurement property testing. 

Figure 4. Diagram of the Conceptual Framework of a PRO Instrument

Item 1 

Item 2 

Item 3 

Item 4 

Item 5 

Item 6 

Domain 

1 

General 

Concept 

Domain

2

The conceptual framework of a PRO instrument may be straightforward if a single item is a 

reliable and valid measure of the concept of interest (e.g., pain intensity). If the concept of 

interest is general (e.g., physical function), a single-item PRO instrument does not provide a 

useful understanding of the treatment’s effect because a stand-alone single item does not capture 

the domains of the general concept. For this reason, single-item questions about general 

concepts that include multiple items or domains rarely provide sufficient evidence to support 

claims about that general concept. For example, in clinical trials of functional disorders defined 

by clusters of specific symptoms and signs, a PRO instrument consisting of a single-item global 

question usually would be inadequate as an endpoint to support labeling claims and would be 

uninformative about the effects on each specific symptom and sign. Instead, the effect of 

treatment on each of the appropriate symptoms and signs should be adequately measured. 

The conceptual framework for PRO instruments intended to measure a general concept will be 

complex because identifying all of the appropriate domains and items of the general concept can 

be difficult. Multidomain PRO instruments can be used to support claims about a general 

concept if the PRO instrument has been developed to measure the important and relevant 

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Contains Nonbinding Recommendations 

domains of the general concept contained in the claim. However, the complex nature of 

multidomain PRO instruments often raises significant questions about how to interpret and report 

results in a way that is not misleading. For example, if improvement in a score for a general 

concept (e.g., symptoms associated with a certain condition) is driven by a single responsive 

item (e.g., pain intensity improvement) whereas other important items (e.g., other symptoms) did 

not show a response, a general claim about the general concept (e.g., improvements in symptoms 

associated with the condition) cannot be supported. However, that single responsive item or 

domain may support a claim specific to that item or domain. 

We intend to examine the final version of an instrument in light of its development history, 

including documentation of the complete list of items generated and the reasons for deleting or 

modifying items, as illustrated in Table 1. We will determine from empiric evidence provided 

whether the PRO instrument’s final conceptual framework (e.g., the hypothesized relationships 

among items, domains, and concepts measured) is confirmed in the appropriate study population 

and is consistent with the endpoint model of the planned clinical trials. 

Table 1. Common Reasons for Changing Items during PRO Instrument Development 

Item Property Reason for Change or Deletion 

Clarity or relevance • Reported as not relevant by a large segment of the target population 

• Generates an unacceptably large amount of missing data points 

• Generates many questions or requests for clarification from patients as they 

complete the PRO instrument 

• Patients interpret items and responses in a way that is inconsistent with the 

PRO instrument’s conceptual framework 

Response range • A high percent of patients respond at the floor (response scale’s worst end) 

or ceiling (response scale’s optimal end) 

• Patients note that none of the response choices applies to them 

• Distribution of item responses is highly skewed 

Variability • All patients give the same answer (i.e., no variance) 

• Most patients choose only one response choice 

• Differences among patients are not detected when important differences are 

known

Reproducibility • Unstable scores over time when there is no logical reason for variation from 

one assessment to the next 

Inter-item correlation • Item highly correlated (redundant) with other items in the same concept of 

interest 

Ability to detect change • Item is not sensitive (i.e., does not change when there is a known change in 

the concepts of interest) 

Item discrimination • Item is highly correlated with measures of concepts other than the one it is 

intended to measure 

• Item does not show variability in relation to some known population 

characteristics (i.e., severity level, classification of condition, or other known 

characteristic) 

Redundancy • Item duplicates information collected with other items that have equal or 

better measurement properties 

Recall period • The population, disease state, or application of the instrument can affect the 

appropriateness of the recall period 

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Contains Nonbinding Recommendations 

10

2. Intended Population 

Using documentation of the process described in Figure 3 and of the measurement properties as 

described in Table 2, we plan to compare the patient population studied in the PRO instrument 

development process to the population enrolled in the clinical trial to determine whether the 

instrument is applicable for that population. See the Appendix for a description of the types of 

information sponsors should provide for FDA discussion and review of PRO instruments. 

Specific measurement considerations posed by pediatric, cognitively impaired, or seriously ill 

patients are discussed in section III.G., PRO Instruments Intended for Specific Populations. 
Contains Nonbinding Recommendations 

Table 2. Measurement Properties Considered in the Review of PRO Instruments Used in Clinical Trials 

Measurement 

Property 

Type What Is Assessed? FDA Review C

Test-retest or intrainterviewer reliability (for interviewer-administered PROs only) 

Stability of scores over time when no change is expected in the concept of interest 

• Intraclass correlation coeff

• Time period of assessment 

Internal consistency • Extent to which items comprising a scale 

measure the same concept 

• Intercorrelation of items that contribute 

to a score 

• Internal consistency 

• Cronbach’s alpha for summ

• Item-total correlations 

Reliability 

Inter-interviewer reliability (for interviewer-administered PROs only) 

Agreement among responses when the PRO is administered by two or more different interviewers 

• Interclass correlation coeff

Content validity Evidence that the instrument measures the 

concept of interest including evidence from qualitative studies that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use. Testing other measurement properties will not replace or rectify problems with content validity. 

• Derivation of all items 

• Qualitative interview sched

• Interview or focus group tr

• Items derived from the tran

• Composition of patients us

• Cognitive interview transcr

understanding 

Validity 

Construct validity Evidence that relationships among items, 

domains, and concepts conform to a priorihypotheses concerning logical relationships that should exist with measures of related concepts or scores produced in similar or diverse patient groups 

• Strength of correlation test

(discriminant and converge

• Degree to which the PRO i

among groups hypothesize(known groups validity) 

Ability to detect change 

Evidence that a PRO instrument can identify differences in scores over time in individuals or groups (similar to those in the clinical trials) who have changed with respect to the measurement concept 

• Within person change over 

• Effect size statistic 

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D. Content Validity 

Content validity is the extent to which the instrument measures the concept of interest. Content 

validity is supported by evidence from qualitative studies that the items and domains of an 

instrument are appropriate and comprehensive relative to its intended measurement concept, 

population, and use. Content validity is specific to the population, condition, and treatment to be 

studied. For PRO instruments, items, domains, and general scores reflect what is important to 

patients and comprehensive with respect to patient concerns relevant to the concept being 

assessed. Documentation of patient input in item generation as well as evaluation of patient 

understanding through cognitive interviewing can contribute to evidence of content validity. 

Evidence of other types of validity (e.g., construct validity) or reliability (e.g., consistent scores) 

will not overcome problems with content validity because we evaluate instrument adequacy to 

measure the concept represented by the labeling claim. It is important to establish content 

validity before other measurement properties are evaluated. 

When evaluating the utility of an existing instrument or developing a new PRO instrument, 

sponsors are encouraged to support the adequacy of the instrument’s content validity by 

documenting the following development processes and instrument attributes. 

1. Item Generation 

Item generation should include input from the target patient population to establish the items that 

reflect the concept of interest and contribute to its evaluation. The population will help generate 

item wording, evaluate the completeness of item coverage, and perform initial assessment of 

clarity and readability. PRO instrument items can be generated from literature reviews, 

transcripts from focus groups, or interviews with patients, clinicians, family members, 

researchers, or other sources. We may review whether appropriate individuals and sources were 

used and how information gleaned from those sources was used in the PRO instrument 

development process. We will also review whether open-ended patient interviews provide a full 

understanding of the patient’s perspective of the concept of interest. 

Item generation generally incorporates the input of a wide range of patients with the condition of 

interest to represent variations in severity and in population characteristics such as age, sex, 

ethnicity, and language groups in accordance with the anticipated clinical trial design. 

Without adequate documentation of patient input, a PRO instrument’s content validity is likely to 

be questioned. We will review documentation to determine that the items cover all aspects of the 

concept important to patients, and that saturation has been reached. Saturation is reached at the 

point when no new relevant or important information emerges and collecting additional data will 

not likely add to the understanding of how patients perceive the concept of interest and the items 

in the questionnaire. 

Documentation provided to the FDA to support content validity should include all item 

generation techniques used, including any theoretical approach; the populations studied; source 

of items; selection, editing, and reduction of items; cognitive interview summaries or transcripts; 

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pilot testing; importance ratings; and quantitative techniques for item evaluation. Table 1 lists 

common reasons for changing items. 

If items are not generated in all language groups included in the clinical trials, the 

appropriateness of the content should be addressed in cognitive interviewing in each language 

group tested. An item tracking matrix may be helpful to document the changes or deletions in 

items and the reasons for those changes. 

With existing instruments, it cannot be assumed that the instrument has content validity if 

patients were not involved in instrument development. New qualitative work similar to that 

conducted when developing a new instrument can provide documentation of content validity for 

existing instruments if patient interviews or focus groups are conducted using open-ended 

methods to elicit patient input. Such qualitative testing of existing instruments is particularly 

important if a review of the instrument content gives cause for concern. For example, if 

symptoms known to be common to the population to be studied in the clinical trial are missing 

from a measure meant to capture important symptoms in that population, we will question the 

instrument’s content validity. We cannot provide recommendations for the number or size of the 

individual patient interviews or focus groups for establishing content validity. The sample size 

depends on the completeness of the information obtained from analysis of the transcripts. 

Generally, the number of patients is not as critical as interview quality and patient diversity 

included in the sample in relation to intended clinical trial population characteristics. 

Items that ask patients to respond hypothetically may cause patients to respond on the basis of 

their desired condition rather than on their actual condition and therefore are not recommended 

for clinical trials. For example, in assessing the concept ability to perform daily activities, it is 

more appropriate to ask whether or not the patient performed specific activities (and if so, with 

how much difficulty) than whether or not the patient perceived that he or she can perform daily 

activities, because patients may report they are able to perform a task even when they never do 

the task. 

When using multi-item instruments, it is important that all items be relevant to most of the 

patients in the clinical trial. Using the example in the previous paragraph, it would be severely 

disadvantageous to use a measure with items that include activities most of the clinical trial 

patients would not perform. Doing so would yield a bias toward the null, or a tendency to show 

no effect of treatment, even if the treatment were effective. In such cases, a negative response 

(or indication of little to no activity) is not useful. Use of not applicable response options creates 

problems with scoring. Skip patterns may create difficulties in administration. 

2. Data Collection Method and Instrument Administration Mode 

Sponsors should consider the data collection method and all procedures and protocols associated 

with the instrument administration mode, including instructions to interviewers, instructions for 

self-administration, or instructions for supervising self-administration. We will review data 

quality control procedures specific to the data collection method or instrument administration 

mode along with case report forms or screen shots of electronic PRO instruments. 

Administration modes can include self-administration, interview, or a combination of both. Data 

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collection methods can include paper-based, computer-assisted, and telephone-based 

assessments. We intend to review the comparability of data obtained when using multiple data 

collection methods or administration modes within a single clinical trial to determine whether the 

treatment effect varies by method or mode. If a patient diary or some other form of unsupervised 

data entry is used, we plan to review the clinical trial protocol to determine what steps are taken 

to ensure that patients make entries according to the clinical trial design and not, for example, 

just before a clinic visit when their reports will be collected. 

3. Recall Period 

Sponsors should also evaluate the rationale and the appropriateness of the recall period for a 

PRO instrument. To this end, it is important to consider patient ability to validly recall the 

information requested. The choice of recall period that is most suitable depends on the 

instrument’s purpose and intended use; the variability, duration, frequency, and intensity of the 

concept measured; the disease or condition’s characteristics; and the tested treatment. When 

evaluating PRO-based claims, we intend to review the clinical trial protocol to determine what 

steps were taken to ensure that patients understood the instrument recall period. In many cases, 

what is of real interest is not the integrated effect over a short time period (e.g., 2-week period), 

but the effect at regular intervals (e.g., 2, 4, and 6 weeks), similar to how measurements might be 

made every 2 weeks in a blood pressure trial. In that case, patients can be asked to report on 

recent status. Note also that any problems created by differential recall are likely to add noise 

and obscure treatment effects. 

PRO instruments that call for patients to rely on memory, especially if they must recall over a 

long period of time, compare their current state with an earlier period, or average their response 

over a period of time, are likely to undermine content validity. Response is likely to be 

influenced by the patient’s state at the time of recall. For these reasons, items with short recall 

periods or items that ask patients to describe their current or recent state are usually preferable. 

If detailed recall of experience over a period of time is necessary, we recommend the instrument 

use appropriate methods and techniques for enhancing the validity and reliability of 

retrospectively reported data (e.g., ask patients to respond based on their worst (or best) 

experience over the recall period or make use of a diary for data collection). 

4. Response Options 

It is also important to consider whether the response options for each item are consistent with its 

purpose and intended use. Table 3 describes some of the various types of item response options 

that are typically seen in PRO instruments. 

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Table 3. Response Option Types 

Type Description 

Visual analog 

scale (VAS) 

A line of fixed length (usually 100 mm) with words that anchor the scale at the extreme ends 

and no words describing intermediate positions. Patients are instructed to indicate the place 

on the line corresponding to their perceived state. The mark’s position is measured as the 

score. 

Anchored or 

categorized 

VAS 

A VAS that has the addition of one or more intermediate marks positioned along the line with 

reference terms assigned to each mark to help patients identify the locations between the 

scale’s ends (e.g., half-way). 

Likert scale An ordered set of discrete terms or statements from which patients are asked to choose the 

response that best describes their state or experience. 

Rating scale A set of numerical categories from which patients are asked to choose the category that best 

describes their state or experience. The ends of rating scales are anchored with words but the 

categories are numbered rather than labeled with words. 

Recording of 

events as they 

occur 

Specific events are recorded as they occur using an event log that can be included in a patient 

diary or other reporting system (e.g., interactive voice response system). 

Pictorial scale A set of pictures applied to any of the other response option types. Pictorial scales are often 

used in pediatric questionnaires but also have been used for patients with cognitive 

impairments and for patients who are otherwise unable to speak or write. 

Checklist Checklists provide a simple choice between a limited set of options, such as Yes, No, and 

Don’t know. Some checklists ask patients to place a mark in a space if the statement in the 

item is true. Checklists are reviewed for completeness and nonredundancy. 

Item response options generally are considered appropriate when: 

• Wording used in responses is clear and appropriate (e.g., anchoring a scale using the term 

normal assumes that patients understand what is normal for the general population). 

• The item response options are appropriate for the intended population. For example, 

patients with visual impairment may find a VAS difficult to complete. 

• Responses offer a clear distinction between choices (e.g., patients may not distinguish 

between intense and severe if both are offered as response choices to describe their pain). 

• Instructions to patients for completing items and selecting responses for the items are 

adequate. 

• The number of response options is justified empirically (e.g., using qualitative research, 

initial instrument testing, or existing literature). 

• Responses for an item are appropriately ordered and represent similar intervals. 

• Responses for items avoid potential ceiling or floor effects (e.g., it may be necessary to 

introduce more responses to capture worsening or improvement so that fewer patients 

respond at the response continuum top or bottom). 

• Responses do not bias the direction of responses (e.g., bias exists if possible responses 

are weighted toward the severity spectrum’s mild end with two severity options for mild

and only one each for moderate and severe). 

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5. Instrument Format, Instructions, and Training 

Results obtained using a PRO instrument can vary according to the instructions given to patients 

or the training given to the interviewer or persons supervising PRO data collection during a 

clinical trial. Sponsors should consider all PRO instrument instructions and procedures 

contained in publications and user manuals provided by developers, including procedures for 

reviewing completed questionnaires and procedures used to avoid missing data or clarify 

responses. 

It is important that the PRO instrument format used in the clinical trial be consistent with the 

format that is used during the instrument development process. Format refers to the exact 

questionnaire, diary, or interview script appearance used to collect the PRO data. Format is 

specific to the administration mode and the data collection method. We plan to review the 

specific format used in the clinical trial including the order and numbering of items, the 

presentation of response options in single response or grid formats, the grouping of items, 

patterns for skipping questions, and all instructions to interviewers or patients. 

We recommend that the user manual provided by a developer during the PRO instrument 

development process specify how to incorporate the instrument into a clinical trial in a way that 

minimizes administrator burden, patient burden, missing data, and poor data quality. The user 

manual should explain to investigators and interviewers critical principles of PRO 

administration. 

6. Patient Understanding 

When the initial and subsequent drafts of an instrument are prepared, sponsors are encouraged to 

examine all items and procedures in a pilot test of whether patients understand the items and 

instructions included in the PRO instrument. This examination should include documentation 

that the concepts represented in the PRO instrument’s conceptual framework are confirmed, that 

the response options and recall period are appropriately comprehended, and that the instrument’s 

readability is adequate for the intended population. The FDA’s evaluation of these procedures is 

likely to include a review of a cognitive interviewing report containing the script used in patient 

cognitive interviews, the interview transcripts, the readability test used (if applicable), the 

usability testing process description (if applicable), the cognitive interviews analysis, and the 

actions taken to delete or modify items, response scales, or patient instructions in response to the 

cognitive interview or pilot test results. Evidence from the patient cognitive interview studies 

(i.e., the interview schedule, transcript, and listing of all concepts elicited by a single item) can 

be used to determine when a concept is adequately captured. Repeating cognitive interviews can 

help confirm content validity. 

7. Scoring of Items and Domains 

For each item, numerical scores generally should be assigned to each answer category based on 

the most appropriate scale of measurement for the item (e.g., nominal, ordinal, interval, or ratio 

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scales). We will review the distribution of item responses to ensure that the response choices 

represent appropriate intervals. 

A scoring algorithm creates a single score from multiple items. We will review the evidence that 

the summary score is appropriate. Equally weighted scores for each item are appropriate when 

the responses to the items are independent. If two items are dependent, their collected 

information is less than two independent items and they are over-weighted when they are treated 

as two equally weighted items. Over-weighting also may be a concern when the number of 

response options or the values associated with response options varies by item. The same 

weighting concerns apply with added complexity when combining domain scores into a single 

general score. Using qualitative research or defined statistical techniques, sponsors should 

justify the method chosen to combine items to create a score or to combine domain scores to 

create a general score. 

When empirically determined patient preference ratings are used to weight items or domains, we 

intend to review the composition of samples and the process used to determine the preference 

weights. Because preference weights are often developed for use in resource allocation (e.g., as 

in cost-effectiveness analysis that may use predetermined community weights), it is tempting to 

use those same weights in the clinical trial setting to demonstrate treatment benefit. However, 

this practice is discouraged unless the preference weights’ relationship to the intended clinical 

trial population is known and found adequate and appropriate. 

Total scores combining multiple domains should be supported by evidence that the total score 

represents a single albeit complex concept. As described earlier in section III.C., Conceptual 

Framework of a PRO Instrument, the instrument’s final conceptual framework documents the 

concept represented by each score. If a score is intended to support a targeted claim, the concept 

measured will match the targeted claim language. Generally, we discourage claims expressed in 

terms of domain or instrument titles because they often do not represent the concept measured. 

8. Respondent and Administrator Burden 

Undue physical, emotional, or cognitive strain on patients generally decreases the quality and 

completeness of PRO data. Factors that can contribute to respondent burden include the 

following: 

• Length of questionnaire or interview 

• Formatting 

• Font size too small to read easily 

• New instructions for each item 

• Requirement that patients consult records to complete responses 

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• Privacy of the setting in which the PRO is completed (e.g., not providing a private space 

for patients to complete questionnaires containing sensitive information about their 

sexual performance or substance abuse history) 

• Inadequate time to complete questionnaires or interviews 

• Literacy level too high for population 

• Questions that patients are unwilling to answer 

• Perception by patients that the interviewer wants or expects a particular response 

• Need for physical help in responding (e.g., turning pages, holding a pen, assistance with a 

telephone or computer keyboard) 

The degree of respondent burden that is tolerable for instruments in clinical trials depends on the 

frequency and timing of PRO assessments in a protocol and on patient cognition, illness severity, 

or treatment toxicity. For example, if the questionnaire contains instructions to skip one or more 

questions based on response to a previous question, respondents may fail to understand what to 

do and make errors in responding or find the assessment too complicated to complete. Sponsors 

should consider missing data and the refusal rate as possible indications of inappropriate 

respondent burden or inappropriate items or response options. 

E. Reliability, Other Validity, and Ability to Detect Change 

Once the instrument’s content validity has been established, we intend to consider the following 

additional measurement properties during FDA review of a PRO instrument: reliability, construct 

validity, and ability to detect change. We plan to review the measurement properties that are 

specific to the documented PRO instrument’s conceptual framework, confirmed scoring 

algorithm, administration procedures, and questionnaire format in light of the clinical trial’s 

objectives, design, enrolled population, and statistical analysis plan (SAP). We also plan to 

review whether the population and medical conditions included in any sample used to develop or 

test a PRO instrument are appropriate for the planned clinical trials. 

In addition, an adequate study to evaluate any specific measurement property of a PRO 

instrument should be designed to test a prespecified hypothesis. For example, if the study 

compares a new PRO measure to an existing measure of the same concept administered during 

the same interview or within a short time of each other to establish construct validity, the study 

should be designed to test the hypothesized level of correlation and the results should be 

discussed in light of that hypothesis. 

1. Reliability 

Because clinical trials measure change over time, the adequacy of a PRO instrument for use in a 

clinical trial depends on its reliability or ability to yield consistent, reproducible estimates of true 

treatment effect. 

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We will review documentation of tests to determine if reproducibility (e.g., test-retest reliability) 

has been demonstrated. Test-retest is most informative when the time interval chosen between 

the test and retest is long enough in stable patients to minimize memory effects. The time 

interval chosen depends on the variability of the state or experience being evaluated and on the 

potential for change in the condition or population over time that reflects actual change in the 

condition rather than variability in stable patients. Test-retest reliability can be tested over a 

variety of periods to satisfy different study protocols or even in different intervals between visits 

in the same protocol. We acknowledge that for remitting and relapsing or episodic diseases, testretest reliability may be difficult or impossible to establish. 

Internal consistency reliability tests (e.g., Cronbach’s alpha) to determine agreement among 

responses to different questions, in the absence of test-retest reliability, may not constitute 

sufficient evidence of reliability for clinical trial purposes. However, as is true for other 

imperfections in testing, in general, flaws in reliability tend to increase the beta (Type II) error, 

and instruments demonstrating poor reliability are unlikely to give a false positive result. 

When PRO instruments are interviewer-administered, we will review inter-interviewer 

reproducibility. Inter-interviewer reproducibility depends on instrument administration 

standardization and interviewer training on this standard. 

2. Other Validity 

In addition to content validity (discussed in section III.D., Content Validity), we will evaluate 

evidence of construct validity, and if appropriate, criterion validity. 

Construct validity is determined by evidence that relationships among items, domains, and 

concepts conform to a priori hypotheses concerning logical relationships that should exist with 

other measures or characteristics of patients and patient groups. 

We will review the construct validity of an instrument to determine whether the documented 

relationships between results gathered using the instrument and results gathered using other 

measures are consistent with pre-existing hypotheses concerning those relationships (i.e., 

discriminant and convergent validity). We will also review evidence that the instrument can 

differentiate between clinically distinct groups (i.e., known groups validity). 

As stated earlier, single-item questions about general concepts are not useful to support claims; 

however, they can be useful to help assess the construct validity of multi-item measures of the 

same concept and to determine whether important items or domains of a general concept are 

missing. For example, when results using single-item general questions do not correlate with 

results using a multi-item questionnaire of the same general concept, this may be evidence that 

the questionnaire is not capturing all the important domains of the general concept. 

Criterion validity is the extent to which the scores of a PRO instrument are related to a known 

gold standard measure of the same concept. In rare cases, we will also review the criterion 

validity of an instrument if a criterion measure is purported for the PRO concept assessed (e.g., 

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comparing a new sleep scale to a clinical measure of polysomnography). However, for most 

PROs, criterion validity testing is not possible because the nature of the concept to be measured 

does not allow for a criterion measure to exist. This is true for any symptom measure where the 

symptom is known only to the patient. If a criterion measure is used, sponsors should provide 

rationale and support for that criterion. We will review the extent to which the PRO measure is 

correlated with the criterion measure as well as the sensitivity, specificity, and predictive value 

of the criterion measure. 

3. Ability to Detect Change 

We will review an instrument’s ability to detect change using data that compare change in PRO 

scores to change in other similar measures that indicate that the patient’s state has changed with 

respect to the concept of interest. A review of the ability to detect change includes evidence that 

the instrument is equally sensitive to gains and losses in the measurement concept and to change 

at all points within the entire range expected for the clinical trial population. 

When patient experience of a concept is predicted to change, the values for the PRO instrument 

measuring that concept should change. If there is clear evidence that patient experience relative 

to the concept has changed, but the PRO scores do not change, then either the ability to detect 

change is inadequate or the PRO instrument’s validity should be questioned. If there is evidence 

that PRO scores are affected by changes that are not specific to the concept of interest, the PRO 

instrument’s validity may be questioned. 

The ability of an instrument to detect change influences the sample size for evaluating the 

effectiveness of treatment. The extent to which the PRO instrument’s ability to detect change 

varies by important patient subgroups (e.g., sex, race, or age) can affect clinical trial results. If 

important subgroup differences in ability to detect change are known, these documented 

differences can be taken into account in assessing results. In general, an inability to detect 

change tends to support the null hypothesis of no treatment effect. 

F. Instrument Modification 

The adequacy of an instrument’s development and testing is specific to its intended application 

in terms of population, condition, and other aspects of the measurement context for which the 

instrument was developed. When a PRO instrument is modified, sponsors generally should 

provide evidence to confirm the new instrument’s adequacy. That is not to say that every small 

change in application or format necessitates extensive studies to document the final version’s 

measurement properties. Additional qualitative work may be adequate depending on the type of 

modification made. Examples of changes that can alter the way that patients respond to the same 

set of questions include: 

• Changing an instrument from paper to electronic format 

• Changing the timing of or procedures for PRO instrument administration within the clinic 

visit 

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• Changing the application to a different setting, population, or condition 

• Changing the order of items, item wording, response options, or recall period or deleting 

portions of a questionnaire 

• Changing the instructions or the placement of instructions within the PRO instrument 

A small nonrandomized study may be adequate to compare the distribution of responses between 

versions of a questionnaire with different formats (e.g., changing a response scale from vertical 

to horizontal). If the PRO instrument will be used in a significantly different patient population 

(e.g., a different disease or age group), we may recommend using qualitative studies to confirm 

content validity in the new population. A small randomized study to ascertain the measurement 

properties in the new population may minimize the risk that the instrument will not perform 

adequately. 

G. PRO Instruments Intended for Specific Populations 

As previously mentioned, if multiple versions of an instrument will be used in a clinical trial, 

documentation should exist that the content validity and other measurement properties of those 

versions are similar to each other. Measurement of PRO concepts in children and adolescents, in 

patients who have cognitive impairment or are unable to communicate because of serious illness, 

and across culture or language groups introduces challenges in addition to those already 

mentioned. These challenges are discussed below. 

1. Children and Adolescents 

In general, the review issues related to the development process for pediatric PRO instruments 

are similar to the issues detailed for adults. Additional review issues for PRO instruments 

applied in children and adolescents include age-related vocabulary, language comprehension, 

comprehension of the health concept measured, and duration of recall. Instrument development 

within fairly narrow age groupings is important to account for developmental differences and to 

determine the lower age limit at which children can understand the questions and provide reliable 

and valid responses that can be compared across age categories. We discourage proxy-reported 

outcome measures for this population (i.e., reports by someone who is not the patient responding 

as if that person were the patient). For patients who cannot respond for themselves (e.g., infant 

patients), we encourage observer reports that include only those events or behaviors that can be 

observed. For example, observers cannot validly report an infant’s pain intensity but can report 

infant behavior thought to be caused by pain. 

2. Patients Cognitively Impaired or Unable to Communicate 

We discourage proxy-reported outcome measures for this population. For patients who cannot 

respond for themselves (e.g., cognitively impaired), we encourage observer reports that include 

only those events or behaviors that can be observed. 

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3. Culture or Language Subgroups 

Because many development programs are multinational, application of PRO instruments to 

multiple cultures or languages is common in clinical trials. Regardless of whether the instrument 

was developed concurrently in multiple cultures or languages or whether a fully developed 

instrument was adapted or translated to new cultures or languages, we recommend that sponsors 

provide evidence that the content validity and other measurement properties are adequately 

similar between all versions used in the clinical trial. We will review the process used to 

translate and culturally adapt the instrument for populations that will use them in the trial. 

IV. CLINICAL TRIAL DESIGN 

The same clinical trial design principles that apply to other endpoint measures also apply to 

PROs. Therefore, this section is not a comprehensive overview of those principles but rather 

focuses primarily on issues unique to PRO endpoints. 

A. General Protocol Considerations 

If the PRO measurement goal is to support labeling claims, PRO concept measurement should be 

stated as a specific clinical trial objective or hypothesis. It is important that the case report form 

in the protocol include the exact format and version of the specific PRO instrument to be 

administered. If an electronic version of the instrument will be used, the protocol can include 

screen shots or other similar instrument representations. In the process of considering the new 

drug application (NDA)/biologics license application (BLA)/medical device premarket approval 

(PMA) or NDA/BLA/PMA supplement, we intend to compare both the planned and actual PRO 

instrument used and its analysis. 

1. Blinding and Randomization 

Open-label clinical trials, where patients and investigators are aware of assigned therapy, are 

rarely adequate to support labeling claims based on PRO instruments. Patients who know they 

are in an active treatment group may overestimate benefit whereas patients who know they are 

not receiving active treatment may underreport any improvement actually experienced. For the 

same reasons, to prevent influencing patient perceptions, PRO instruments administered during a 

clinic visit should be administered before other clinical assessments or procedures. 

In blinded clinical trials, patients should be blinded to treatment assignment throughout the trial. 

If the treatment has obvious effects, such as adverse events, the clinical trial may be at risk for 

unintentional unblinding. In these situations, sponsors can use PRO instrument administration 

techniques that may minimize the effects of possible unblinding, such as using response options 

that ask for current status, not giving patients access to previous responses, and using instruments 

that include many items about the same concept. 

Suspicion of inadvertent unblinding can be a problematic review consideration for the FDA 

when assessing PRO endpoints. Therefore, when PRO instruments are included in a clinical 

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trial, we encourage sponsors to include a single item during or at the end of the trial to ask 

patients to identify the clinical trial arm in which they believe they participated. 

The effect of intentional unblinding is important to consider in the interpretation of clinical trial 

results. There are certain situations, such as in the evaluation of some medical devices or 

administration of identifiable treatment regimens, where blinding is not feasible and other 

situations where there is no reasonable control group (and therefore no randomization). When a 

PRO instrument appears useful in assessing patient benefit in those situations, we encourage 

sponsors to confer with the appropriate review division. 

2. Clinical Trial Quality Control 

The quality of a clinical trial can be optimized at the design stage by specifying in the protocol 

procedures to minimize inconsistencies in trial conduct. We recommend a standardized order by 

which PRO and other clinical assessments are administered. Other examples of standardized 

instructions and processes that can appear in the protocol include: 

• Training and instructions to patients for self-administered PRO instruments 

• Interviewer training and interview format for PRO instruments administered in an 

interview format 

• Instructions for the clinical investigators regarding patient supervision, timing and order 

of questionnaire administration during or outside the office visit, processes and rules for 

questionnaire review for completeness, and documentation of how and when data are 

filed, stored, and transmitted to or from the clinical trial site 

• Plans for confirmation of the instrument’s measurement properties using clinical trial 

data 

3. Handling Missing Data 

Sometimes patients fail to report for visits, fail to complete questionnaires, or withdraw from a 

clinical trial before its planned completion. The resulting missing data can introduce bias and 

interfere with the ability to compare effects in the test group with the control group because only 

a subset of the initial randomized population contributes, and these patient groups may no longer 

be comparable. Missing data is a major challenge to the success and interpretation of any 

clinical trial. The clinical trial protocol should describe how missing data will be handled in the 

analysis. 

The protocol can increase the likelihood that a clinical trial will still be informative by 

establishing backup plans for gathering all treatment-related reasons for patients failing to report 

at scheduled times or withdrawing from a treatment or the clinical trial and by trying to minimize 

patient dropouts before trial completion. Patients should remain in the clinical trial, even if they 

have discontinued treatment, and should continue to provide PRO data. The protocol should also 

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establish a process by which PRO measurement is obtained before or shortly after patient 

withdrawal from treatment should early withdrawal be unpreventable. 

B. Frequency of Assessments 

The frequency of PRO assessment should correspond with the specific research questions being 

addressed, length of recall asked by the instrument’s response options, demonstrated instrument 

measurement properties, the disease or condition’s natural history, the treatment’s nature, and 

planned data analysis. Some diseases, conditions, or clinical trial designs may necessitate more 

than one baseline assessment and several PRO assessments during treatment. 

C. Clinical Trial Duration 

The duration of PRO assessment depends on the PRO research questions being posed. It is 

important to consider whether the clinical trial’s duration is of adequate length to support the 

proposed claim and assess a durable outcome in the disease or condition being studied. 

Generally, duration of follow-up with a PRO assessment should be the same as for other 

measures of effectiveness. However, the clinical trial duration appropriate for the PRO-related 

objective may not be the same duration as for other endpoints. 

D. Design Considerations for Multiple Endpoints 

A single hierarchy of endpoints as diagrammed in an endpoint model (see Figures 1 and 2 in 

section III.A., Endpoint Model) is determined by the trial’s stated objectives and the clinical 

relevance and importance of each specific measure independently and in relationship to each 

other. We consider any endpoints that are not part of the prespecified hierarchy of primary and 

key secondary endpoints to be exploratory. Endpoints included for economic evaluation that are 

not intended for labeling claims should be designated as such, and will be regarded as 

exploratory. A PRO measurement can be the clinical trial’s primary endpoint measure, a coprimary endpoint measure in conjunction with another PRO measure, other clinical endpoints or 

physician-rated measurements, or a secondary endpoint measure whose analysis is considered 

according to a hierarchical sequence. It is critical that the clinical trial protocol define the 

endpoint measures and the criteria for the statistical analysis and interpretation of results, 

including a specification of the conditions for a positive clinical trial conclusion, because 

determination of these criteria and conditions after data are unblinded will not be credible. 

Sponsors should avoid separate consideration of PRO endpoints from the clinical trial’s primary 

objectives in terms of clinical trial design or data analysis. Sponsors also should avoid cherry 

picking or post hoc selective picking of PRO endpoint results for inclusion in proposed labeling. 

E. Planning for Clinical Trial Interpretation Using a Responder Definition 

Regardless of whether the primary endpoint for the clinical trial is based on individual responses 

to treatment or the group response, it is usually useful to display individual responses, often 

using an a priori responder definition (i.e., the individual patient PRO score change over a 

predetermined time period that should be interpreted as a treatment benefit). The responder 

definition is determined empirically and may vary by target population or other clinical trial 

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design characteristics. Therefore, we will evaluate an instrument’s responder definition in the 

context of each specific clinical trial. 

The empiric evidence for any responder definition is derived using anchor-based methods. 

Anchor-based methods explore the associations between the targeted concept of the PRO 

instrument and the concept measured by the anchors. To be useful, the anchors chosen should be 

easier to interpret than the PRO measure itself. For example, the number of incontinence 

episodes collected in incontinence diaries has been used to determine a responder definition for 

PRO instruments assessing the annoyance of incontinence. A 50 percent reduction in 

incontinence episodes might be proposed as the anchor for defining a responder on the PRO 

instrument. Confirmation of this anchor approach in early clinical trials can provide the basis for 

the proposed responder definition in the confirmatory trials. 

Another anchor-based approach to defining responders makes use of patient ratings of change 

administered at different periods of time or upon exit from a clinical trial. These numerical 

ratings range from worse to the same and better. The difference in the PRO score for persons 

who rate their condition the same and better or worse can be used to define responders to 

treatment. Patient ratings of change are less useful as anchors when patients are not blinded to 

treatment assignment. 

Another set of approaches to defining a responder are distribution-based methods that use, for 

example, the between-person standard deviation or the standard error of measurement to define a 

meaningful change on a scale. Distribution-based methods can be used to categorize these 

changes as small, moderate, and large and often can be combined with anchor-based estimates to 

provide confidence in the responder definition. Distribution-based methods for determining 

clinical significance of particular score changes should be considered as supportive and are not 

appropriate as the sole basis for determining a responder definition. 

Alternatively, it is possible to present the entire distribution of responses for treatment and 

control group, avoiding the need to pick a responder criterion. Whether the individual responses 

are meaningful represents a judgment, but that problem is present with almost all endpoints 

except survival. Such cumulative distribution displays show a continuous plot of the percent 

change from baseline on the X-axis and the percent of patients experiencing that change on the 

Y-axis. This display type may be preferable to attempting to provide categorical definitions of 

responders. A variety of responder definitions can be identified along the cumulative 

distribution of response curve. 

Guidance on interpretation considerations for a clinical trial’s SAP is found in section V.E., 

Interpretation of Clinical Trial Results. 

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F. Specific Concerns When Using Electronic PRO Instruments 

When PRO instruments are used, sponsors must ensure that FDA regulatory requirements are 

met for sponsor and investigator record keeping, maintenance, and access.6

 These 

responsibilities are independent of the method used to record clinical trial data and, therefore, 

apply to all types of PRO data including electronic PRO data. Sponsors are responsible for 

providing investigators with all information to conduct the investigation properly, for monitoring 

the investigation, for ensuring that the investigation is conducted in accordance with the 

investigational plan, and for permitting the FDA to access, copy, and verify records and reports 

relating to the investigation. 

The principal record keeping requirements for clinical investigators include the preparation and 

maintenance of adequate and accurate case histories (including the case report forms and 

supporting data), record retention, and provision for the FDA to access, copy, and verify records 

(i.e., source data verification). The investigator’s responsibility to control, access, and maintain 

source documentation can be satisfied easily when paper PRO instruments are used, because the 

patient usually returns the diary to the investigator who either retains the original or a certified 

copy as part of the case history. The use of electronic PRO instruments, however, may pose a 

problem if direct control over source data is maintained by the sponsor or the contract research 

organization and not by the clinical investigator. We consider the investigator to have met his or 

her responsibility when the investigator retains the ability to control and provide access to the 

records that serve as the electronic source documentation for the purpose of an FDA inspection. 

The clinical trial protocol, or a separate document, should specify how the electronic PRO source 

data will be maintained and how the investigator will meet the regulatory requirements. 

In addition, the FDA has previously provided guidance to address the use of computerized 

systems to create, modify, maintain, archive, retrieve, or transmit clinical data to the FDA and to 

clarify the requirements and application of 21 CFR part 11.7,8

 Because electronic PRO data 

(including data gathered by personal digital assistants or phone-based interactive voice recording 

systems) are part of the case history, electronic PRO data should be consistent with the data 

standards described in that guidance. Sponsors should plan to establish appropriate system and 

security controls, as well as cyber-security and system maintenance plans that address how to 

ensure data integrity during network attacks and software updates. 

Sponsors also should avoid the following: 

• Direct PRO data transmission from the PRO data collection device to the sponsor, 

clinical investigator, or other third party without an electronic audit trail that documents 

all changes to the data after it leaves the PRO data collection device. 

 

6

 For the principal record keeping requirements for clinical investigators and sponsors developing drugs and 

biologics, see 21 CFR 312.50, 312.58, 312.62, and 312.68. For medical devices, see 21 CFR 812.140 and 812.145. 

7

 See the guidance for industry Computerized Systems Used in Clinical Investigations

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

8

 See the guidance for industry Part 11, Electronic Records; Electronic Signatures — Scope and Application

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

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• Source document control by the sponsor exclusively. 

• Clinical investigator inability to maintain and confirm electronic PRO data accuracy. 

The data maintained by the clinical investigator should include an audit trail to capture 

any changes made to the electronic PRO data at any point in time after it leaves the 

patient’s electronic device. 

• The existence of only one database without backup (i.e., risk of data corruption or loss 

during the trial with no way to reconstitute or verify the data). 

• Ability of any entity other than the investigator (and/or site staff designated by the 

investigator) to modify the source data. 

• Loss of adverse event data.

• Premature or unplanned access to unblinded data. 

• Inability of an FDA investigator to inspect, verify, and copy the data at the clinical site 

during an inspection. 

• An insecure system where records are easily altered. 

• Direct PRO data transmission of important safety information to sponsors, clinical 

research organizations, and/or third parties, without ensuring the timely transmission of 

the data to the clinical investigator responsible for the patients. 

V. DATA ANALYSIS 

Incorporating PRO instruments as clinical trial endpoint measures introduces challenges in the 

analysis of clinical trial data. The most important of these challenges are discussed in the 

following sections. 

A. General Statistical Considerations 

The statistical analysis considerations for PRO endpoints are not unlike statistical considerations 

for any other endpoint used in medical product development.9

 Every protocol should describe 

the principal data analysis features in the statistical section with a detailed elaboration of the 

analysis in an SAP. We intend to determine the adequacy of clinical trial data to support claims 

in light of the prespecified method for endpoint analysis. We usually view unplanned or post 

hoc statistical analyses conducted after unblinding as exploratory and, therefore, unable to serve 

as the basis of a labeling claim of effectiveness. 

 

9

 See the ICH guidance for industry E9 Statistical Principles for Clinical Trials

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

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B. Statistical Considerations for Using Multiple Endpoints 

PROs in a clinical trial, like non-PRO clinical endpoints, can be primary or secondary endpoints. 

Primary endpoints are those endpoints on which the main benefit of a clinical trial’s test 

treatment is judged rigorously. Primary endpoints are used to determine the clinical trial sample 

size and are the endpoints that will be tested statistically. They are clinically meaningful but 

may not be the most important endpoint because choice of clinical trial endpoints is a complex 

evolution of expected effect size, expected number of events, and other factors. 

There are often multiple endpoints that would be of clinical interest. Analysis of multiple 

endpoints, where an effect on any of the endpoints will be considered evidence of effectiveness, 

can inflate the probability of false positive findings known as the Type I error rate, an inflation 

that can be controlled by a prospectively planned multiplicity adjustment. It is common to 

analyze secondary endpoints only after success on a primary endpoint. This can be done using a 

sequential analysis, testing additional endpoints in a defined sequence each at the usual alpha = 

0.05 level of statistical significance. The analyses cease when a failure occurs. It is important 

that the clinical trial protocol specify all primary and secondary endpoints. The SAP should 

describe the planned primary analysis in detail noting whether the endpoint will be analyzed as a 

continuous variable (mean scores), dichotomous variable (success or failure), or some graded 

response; the primary and secondary endpoints; adjustments for multiplicity to control the 

overall Type I error rate; and the specific statistical methods planned. Sponsors should provide 

the FDA with the clinical trial’s SAP for review. 

Cases arise in clinical trials where a clinically meaningful treatment benefit depends on having 

two or more primary endpoints achieving statistical significance at a specified alpha level (e.g., 

alpha = 0.05). For example, a clinical trial may identify two endpoints with a decision rule that 

each should show that the treatment is better than control. Such a decision rule does not require 

multiplicity adjustment because the maximum Type I error rate (alpha) is actually reduced. 

However, this type of decision rule will increase the Type II error. Therefore, we recommend 

sizing the trial carefully for this situation. 

There is no single best statistical procedure for multiplicity adjustment because the choice of 

procedure depends upon the clinical trial’s objectives, the most important endpoints, the decision 

rule for declaring treatment benefit, and other considerations. Some of the statistical procedures 

that can be useful for a more efficient analysis approach include methods that prespecify a 

sequence or order of testing or a hierarchy of comparisons that should first be satisfied before 

others are considered for testing as described above. These methods can be less conservative 

than the conventional nonhierarchical type methods, such as Bonferroni, the step-down or stepup tests, and prospective alpha allocations schemes, which ignore the hierarchy of comparisons 

or their families. These conventional type methods should be used when a restriction on the 

order of testing is not warranted. 

A multidomain PRO measure may successfully support a labeling claim based on one or a subset 

of the domains measured if an a priori analysis plan prespecifies the domains that will be 

targeted as endpoints and the method of analysis that will adjust for the multiplicity of tests for 

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the specific claim. The use of domain subsets as clinical trial endpoints presupposes that the 

PRO instrument was adequately developed and validated to measure the subset of domains 

independently from the other domains. 

C. Statistical Considerations for Composite Endpoints 

For a PRO instrument with multiple domains, combining the scores to calculate a general score 

creates a composite endpoint. Composite endpoints have a few advantages (e.g., they can reduce 

multiplicity problems), but their use for confirmatory clinical trials for specific claims of 

treatment benefit poses many difficulties and challenges. 

Rules for interpretation of composite endpoints depend on substantial experience with the 

measure in the clinical trial setting. Therefore, development of a composite endpoint at the time 

the confirmatory clinical trial protocol is written depends on special considerations and 

substantial empirical evidence of the following: the components are of similar importance to 

patients, the more important and less important components are equally likely to occur with 

similar frequency, and the components are likely to have roughly similar treatment effects. 

Therefore, we discourage the use of a composite endpoint for confirmatory clinical trials when 

large variations are predicted to exist between its components. 

Multiplicity problems arise when the multiple individual components of a composite endpoint 

are intended as possible claims. In general, individual components of a composite endpoint will 

not be adequate to support a labeling claim for the components unless the components are 

prespecified in the protocol as separate endpoints and all prespecified components are reported in 

labeling as suggested in current guidance.10 The components of a composite endpoint will be 

shown in labeling to convey what drove a favorable result. Sequential testing approaches can be 

used to test the components of a composite. The components are tested only when there is a 

statistically significant treatment benefit for the composite. 

D. Statistical Considerations for Patient-Level Missing Data 

When the amount of missing data becomes large, clinical trial results can be inconclusive. As 

described in section IV., Clinical Trial Design, we encourage prespecified procedures in the 

clinical trial protocol to avoid missing data. We also encourage prespecified procedures for 

obtaining data on each patient at the time of early withdrawal from the clinical trial. If a 

measurement is taken at the time of withdrawal, this information can be handled according to 

rules established in the SAP. In clinical trials of terminal illness, it is critical to plan ahead for 

how missing data because of death will be handled. Missing data may occur because of the 

treatment received or the underlying disease and can introduce bias in the analysis of treatment 

differences and conclusions about treatment effect. 

 

10 See the guidance for industry Clinical Studies Section of Labeling for Human 

Prescription Drug and Biological Products — Content and Format

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

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30

Even with the best planning, data may be missing at the end of the clinical trial. The SAP should 

address plans for how the statistical analyses will handle missing data when evaluating treatment 

benefit and when considering patient success or patient response. 

1. Missing Items within Domains 

At a specific patient visit, a domain measurement may be missing some, but not all, items. One 

approach to handling this type of missing data is to define rules that specify the number of items 

that can be missing and still consider the domain as adequately measured. Rules for handling 

missing data should be specific to each PRO instrument and usually should be determined during 

the instrument development process. The SAP should specify all rules for handling missing data. 

For example, the SAP can specify the proportion of items that can be missing before a domain is 

treated as missing. 

2. Missing Entire Domains or Entire Measurements 

We will consider a variety of statistical strategies to deal with missing data because of a patient’s 

early termination before planned completion of a trial. No single method is generally considered 

as preferred. All of these strategies are imperfect, as they involve strong or weak assumptions 

about what caused data to be missing, assumptions that usually cannot be verified from the data. 

Methods of missing data imputation should take the patient population, disease progression, and 

respondent burden into account. How to impute the missing data for a PRO endpoint and any 

related supportive endpoints should be addressed in the protocol and the SAP. In addition, the 

sensitivity analyses in analyzing the PRO endpoints should be proposed in the protocol and the 

SAP to assess the robustness of statistical estimation for endpoints with the missing data 

imputed. We recommend that in the protocol the sponsor propose two or more sensitivity 

analyses with different methods for missing data imputation. 

E. Interpretation of Clinical Trial Results 

Because statistical significance can sometimes be achieved for small changes in PRO measures 

that may not be clinically meaningful (i.e., do not indicate treatment benefit), we encourage 

sponsors to avoid proposing labeling claims based on statistical significance alone. 

To demonstrate treatment benefit, we find it informative to examine the cumulative distribution 

function (CDF) of responses between treatment groups to characterize the treatment effect and 

examine the possibility that the mean improvement reflects different responses in patient subsets. 

To interpret the CDF, sponsors can apply the responder definition along the CDF curve at each 

level of response (see section IV.E., Planning for Clinical Trial Interpretation Using a Responder 

Definition). 

Interpretation of PRO endpoints follows similar considerations as for all other endpoint types 

used to evaluate treatment benefit of a medical product. 
Contains Nonbinding Recommendations 

GLOSSARY 

Ability to detect change — Evidence that a PRO instrument can identify differences in scores 

over time in individuals or groups who have changed with respect to the measurement concept. 

Claim — A statement of treatment benefit. A claim can appear in any section of a medical 

product’s FDA-approved labeling or in advertising and promotional labeling of prescription 

drugs and devices. 

Cognitive interviewing — A qualitative research tool used to determine whether concepts and 

items are understood by patients in the same way that instrument developers intend. Cognitive 

interviews involve incorporating follow-up questions in a field test interview to gain a better 

understanding of how patients interpret questions asked of them. In this method, respondents are 

often asked to think aloud and describe their thought processes as they answer the instrument 

questions. 

Concept — The specific measurement goal (i.e., the thing that is to be measured by a PRO 

instrument). In clinical trials, a PRO instrument can be used to measure the effect of a medical 

intervention on one or more concepts. PRO concepts represent aspects of how patients function 

or feel related to a health condition or its treatment. 

Conceptual framework of a PRO instrument — An explicit description or diagram of the 

relationships between the questionnaire or items in a PRO instrument and the concepts measured. 

The conceptual framework of a PRO instrument evolves over the course of instrument 

development as empiric evidence is gathered to support item grouping and scores. We review 

the alignment of the final conceptual framework with the clinical trial’s objectives, design, and 

analysis plan. 

Construct validity — Evidence that relationships among items, domains, and concepts conform 

to a priori hypotheses concerning logical relationships that should exist with other measures or 

characteristics of patients and patient groups. 

Content validity — Evidence from qualitative research demonstrating that the instrument 

measures the concept of interest including evidence that the items and domains of an instrument 

are appropriate and comprehensive relative to its intended measurement concept, population, and 

use. Testing other measurement properties will not replace or rectify problems with content 

validity. 

Criterion validity — The extent to which the scores of a PRO instrument are related to a known 

gold standard measure of the same concept. For most PROs, criterion validity cannot be 

measured because there is no gold standard. 

Domain — A subconcept represented by a score of an instrument that measures a larger concept 

comprised of multiple domains. For example, psychological function is the larger concept 

containing the domains subdivided into items describing emotional function and cognitive 

function. 

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Endpoint — The measurement that will be statistically compared among treatment groups to 

assess the effect of treatment and that corresponds with the clinical trial’s objectives, design, and 

data analysis. For example, a treatment may be tested to decrease the intensity of symptom Z. 

In this case, the endpoint is the change from baseline to time T in a score that represents the 

concept of symptom Z intensity. 

Endpoint model — A diagram of the hierarchy of relationships among all endpoints, both PRO 

and non-PRO, that corresponds to the clinical trial’s objectives, design, and data analysis plan. 

Health-related quality of life (HRQL) — HRQL is a multidomain concept that represents the 

patient’s general perception of the effect of illness and treatment on physical, psychological, and 

social aspects of life. Claiming a statistical and meaningful improvement in HRQL implies: (1) 

that all HRQL domains that are important to interpreting change in how the clinical trial’s 

population feels or functions as a result of the targeted disease and its treatment were measured; 

(2) that a general improvement was demonstrated; and (3) that no decrement was demonstrated 

in any domain. 

Instrument — A means to capture data (i.e., a questionnaire) plus all the information and 

documentation that supports its use. Generally, that includes clearly defined methods and 

instructions for administration or responding, a standard format for data collection, and welldocumented methods for scoring, analysis, and interpretation of results in the target patient 

population. 

Item — An individual question, statement, or task (and its standardized response options) that is 

evaluated by the patient to address a particular concept. 

Item tracking matrix — A record of the development (e.g., additions, deletions, modifications, 

and the reasons for the changes) of items used in an instrument. 

Measurement properties — All the attributes relevant to the application of a PRO instrument 

including the content validity, construct validity, reliability, and ability to detect change. These 

attributes are specific to the measurement application and cannot be assumed to be relevant to all 

measurement situations, purposes, populations, or settings in which the instrument is used. 

Patient-reported outcome (PRO) — A measurement based on a report that comes directly from 

the patient (i.e., study subject) about the status of a patient’s health condition without amendment 

or interpretation of the patient’s response by a clinician or anyone else. A PRO can be measured 

by self-report or by interview provided that the interviewer records only the patient’s response. 

Proxy-reported outcome — A measurement based on a report by someone other than the patient 

reporting as if he or she is the patient. A proxy-reported outcome is not a PRO. A proxy report 

also is different from an observer report where the observer (e.g., clinician or caregiver), in 

addition to reporting his or her observation, may interpret or give an opinion based on the 

observation. We discourage use of proxy-reported outcome measures particularly for symptoms 

that can be known only by the patient. 

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Quality of life — A general concept that implies an evaluation of the effect of all aspects of life 

on general well-being. Because this term implies the evaluation of nonhealth-related aspects of 

life, and because the term generally is accepted to mean what the patient thinks it is, it is too 

general and undefined to be considered appropriate for a medical product claim. 

Questionnaire — A set of questions or items shown to a respondent to get answers for research 

purposes. Types of questionnaires include diaries and event logs. 

Recall period — The period of time patients are asked to consider in responding to a PRO item 

or question. Recall can be momentary (real time) or retrospective of varying lengths. 

Reliability — The ability of a PRO instrument to yield consistent, reproducible estimates of true 

treatment effect. 

Responder definition — A score change in a measure, experienced by an individual patient over 

a predetermined time period that has been demonstrated in the target population to have a 

significant treatment benefit. 

Saturation — When interviewing patients, the point when no new relevant or important 

information emerges and collecting additional data will not add to the understanding of how 

patients perceive the concept of interest and the items in a questionnaire. 

Scale — The system of numbers or verbal anchors by which a value or score is derived for an 

item. Examples include VAS, Likert scales, and rating scales. 

Score — A number derived from a patient’s response to items in a questionnaire. A score is 

computed based on a prespecified, validated scoring algorithm and is subsequently used in 

statistical analyses of clinical trial results. Scores can be computed for individual items, 

domains, or concepts, or as a summary of items, domains, or concepts. 

Sign — Any objective evidence of a disease, health condition, or treatment-related effect. Signs 

are usually observed and interpreted by the clinician but may be noticed and reported by the 

patient. 

Symptom — Any subjective evidence of a disease, health condition, or treatment-related effect 

that can be noticed and known only by the patient. 

Target product profile (TPP) — A clinical development program summary in the context of 

labeling goals where specific types of evidence (e.g., clinical trials or other sources of data) are 

linked to the targeted labeling claims or concepts. 

Treatment benefit — The effect of treatment on how a patient survives, feels, or functions. 

Treatment benefit can be demonstrated by either an effectiveness or safety advantage. For 

example, the treatment effect may be measured as an improvement or delay in the development 

of symptoms or as a reduction or delay in treatment-related toxicity. Measures that do not 

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34

directly capture the treatment effect on how a patient survives, feels, or functions are surrogate 

measures of treatment benefit. 

Usability testing — A formal evaluation with documentation of respondents’ abilities to use the 

instrument, as well as comprehend, retain, and accurately follow instructions. 
Contains Nonbinding Recommendations 

APPENDIX: INFORMATION ON A PRO INSTRUMENT 

REVIEWED BY THE FDA

The following topics represent areas that should be addressed in PRO documents provided to the 

FDA for review. The extent of background information provided in each section will vary 

depending upon the PRO instrument used. Some sections may be less relevant for a particular 

PRO instrument application than others, or may be less complete for discussions in early stages 

of medical product development. Refer to the content of this guidance for additional information 

concerning the types of evidence needed in each of the following areas. 

If the PRO information is provided electronically, it should be placed in section 5.3.5.3 of the 

electronic common technical document.11

I. Instrument (review cannot begin without a copy of the proposed instrument): 

A. Exact version of the instrument proposed or used in the clinical trial (protocol) under 

review and all instructions for use. Include screen shots or interviewer scripts, if 

relevant. 

B. Prior versions, if relevant. 

C. Instructions for use: An instrument user manual can be provided as Appendix A and 

referenced here. 

1. Administration timing, method (e.g., paper or pencil, electronic), and mode (e.g., 

self-, clinician-, or interviewer-administered) 

2. The scoring algorithm 

3. Training method and materials used for questionnaire administration 

a. Patient training — summarize here and include a copy of all materials in 

Appendix A1 

b. Investigator training — summarize here and include a copy of all materials in 

Appendix A2 

c. Other training — summarize here and include a copy of all materials in Appendix 

A3 

II. Targeted Claims or Target Product Profile (TPP)12

Include language describing all specific targeted labeling claims related to all clinical trial 

endpoint measures, both PRO and non-PRO, and specific to: 

 

11 See the ICH guidance for industry M2 eCTD: Electronic Common Technical Document Specification

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

12 See the draft guidance for industry and review staff Target Product Profile — A Strategic Development 

Process Tool. When final, this guidance will represent the FDA’s current thinking on this topic. 

For the most recent version of a guidance, check the FDA Drug guidance Web page at 

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

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Contains Nonbinding Recommendations 

• Disease or condition with stage, severity, or category, if relevant 

• Intended population (e.g., age group, sex, other demographics) 

• Data analysis plan 

III. Endpoint Model

A. Relationships (known and hypothesized) among all clinical trial endpoints, both PRO and 

non-PRO. These endpoints can include physiologic/lab/physical, caregiver, or clinicianreported measures in addition to PROs. 

B. Hierarchy of all PRO and non-PRO endpoints intended to support claims corresponding 

with the planned data analyses. 

IV. The PRO Instrument’s Conceptual Framework

Diagram of hypothesized (proposed) or final PRO instrument conceptual framework showing 

relationship of items to domains and domains to total score. Ensure that the PRO 

instrument’s conceptual framework corresponds to the clinical trial endpoints described in 

the clinical trial protocol and proposed as labeling claims. 

V. Content Validity Documentation

Evidence that instrument captures all of the most clinically important concepts and items, and 

that items are complete, relevant (appropriate), and understandable to the patient. This 

evidence applies to both existing and newly created instruments and is specific to the planned 

clinical trial population and indication. Documentation includes: 

A. Literature review and documentation of expert input 

B. Qualitative study protocols, interview guides, and summary of results for: 

1. Focus group testing (include transcripts in Appendix C1) 

2. Open-ended patient interviews (include transcripts in Appendix C2) 

3. Cognitive interviews (include transcripts in Appendix C3) 

C. Origin and derivation of items with chronology of events for item generation, 

modification, and finalization 

Item tracking matrix for versions tested with patients showing items retained and items 

deleted providing evidence of saturation. Summarize here and include complete 

materials under Appendix B. 

D. Qualitative study summary that supports content validity for: 

1. Item content 

2. Response options 

3. Recall period 

4. Scoring 

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Contains Nonbinding Recommendations 

E. Summary of qualitative studies demonstrating how item pool was generated, reduced, 

and finalized. Specify type of study (i.e., focus group, patient interview, or cognitive 

interview) and characteristics of study population. Include full transcripts and datasets in 

Appendix C. 

VI. Assessment of Other Measurement Properties

Assuming content validity is established in the intended population and application, evidence 

that the instrument is reliable, valid, and able to detect change. The same version of the 

instrument to be used in the clinical trial should be used to assess measurement properties. 

A. Protocols for instrument testing 

B. Summary of testing results for each domain or summary score proposed as support for 

claims: 

1. Reliability (internal; test-retest) 

2. Construct validity (convergent, discriminant, known-groups) 

3. Ability to detect change 

VII. Interpretation of Scores

A. Summary of the logic and methods used to interpret the clinical meaningfulness of 

clinical trial results 

B. Responder definition (i.e., definition of meaningful within-person change specific to the 

clinical trial population) 

VIII. Language Translation and Cultural Adaptation

A. Process used to translate and culturally adapt the instrument for populations that will use 

them in the trial 

B. Description of patient testing, language- or culture-specific concerns, and rationale for 

decisions made to create new versions. 

C. Copies of translated or adapted versions 

D. Evidence that content validity and other measurement properties are comparable between 

the original and new instruments 

IX. Data Collection Method

A. Process used to develop data collection methods (e.g., electronic, paper) intended for use 

in the clinical trial 

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If electronic data collection is used to assess PRO endpoints, evidence that procedures for 

maintenance, transmission, and storage of electronic source documents comply with 

regulatory requirements. 

B. Evidence that content validity and other measurement properties are comparable among 

all data collection methods 

C. User manual for each additional data collection method 

X. Modifications

Any change in the original instrument (e.g., wording of items, response options, recall 

period, use in a new population or indication) 

A. Rationale for and process used to modify the instrument 

B. Copy of original and new instruments 

C. Evidence that content validity and other measurement properties are comparable between 

the original and modified instruments (including use in a new indication or population) 

XI. PRO-Specific Plans Related to Clinical Trial Design and Data Analysis

A. Clinical trial protocol. Ensure in the protocol that: 

• Each PRO endpoint is stated as a specific clinical trial objective and multiplicity 

concerns are addressed 

• The clinical trial will be adequately blinded 

• Procedures for training are well-described for: 

− Patients 

− Interviewers 

− Clinical investigators 

• Plans for instrument administration are consistent with instrument’s user manual 

• Plans for PRO instrument scoring are consistent with those used during instrument 

development 

• Procedures include assessment of PRO endpoint before or shortly after a patient 

withdraws from the clinical trial 

• Frequency and timing of PRO assessments are appropriate given patient population, 

clinical trial design and objectives, and demonstrated PRO measurement properties 

• Clinical trial duration is adequate to support PRO objectives 

• Plans are included for handling missing data 

• Plans are included for a cumulative distribution function comparison among treatment 

groups 

• Data collection, data storage, and data handling and transmission of procedures, 

including electronic PROs, are specified 

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Contains Nonbinding Recommendations 

39

B. Statistical analysis plan (SAP). Ensure the SAP includes: 

• Plans for multiplicity adjustment 

• Plans for handling missing data at both the instrument and patient level 

• Description of how between-group differences will be portrayed (e.g., cumulative 

distribution function) 

XII. Key References

List and attach all relevant published and unpublished documents 

Appendix A — User Manual 

A1: Patient training 

A2: Investigator training 

 A3: Other training 

Appendix B — Item Tracking Matrix 

Appendix C — Transcripts 

C1: Focus groups 

C2: Open-ended patient interviews 

C3: Cognitive interviews