This document discusses patient-reported outcome (PRO) measures and developing PRO instruments. It covers: - Common diseases where PROs are used like Parkinson's and rheumatoid arthritis - Applications of PROs in clinical trials, medical practice, and economic evaluations - Developing a conceptual framework, ensuring content validity, and evaluating reliability - Modifying existing PRO instruments or developing new ones for specific populations like children

1. FDA, CBER, CDER, CBRH

3. • Introduction
• Definition
• Diseases where PRO measures are used
• Applications of PRO instrument
• Development of PRO instrument
• Evaluation of PRO instrument
 End point model
 Choice of PRO instrument
 Conceptual framework of A PRO instrument
 Content validity
 Reliability, content & construct validity & ability to detect change
 Instrument modification
 PRO instrument for specific population

4. General Methods Used for Outcome Analysis

5. • Patient Reported Outcome measures are reports
of status of patient’s health condition
• P RO data collected directly from questionnaires
completed by the patient themselves or via
interviews by a clinician or anyone else
» Outcome is measured in Absolute terms
e.g. severity of a symptom, sign or state of disease, or as a
change from a previous measure

10. • Parkinson’s disease
• Rheumatoid Arthritis
• Patients undergone Renal Transplantation etc..
• PRO measures often represent the effect of
disease (e.g., heart failure or asthma) on
health and functioning from the patient
perspective.

11. …
• Used in clinical trials
• Medical practice
Drug selection & comparison
DUE
Intervention efficacy, pharmacist evaluation
• Economic evaluations : cost utility studies
• Clinical experience programs

14. • PRO instrument
 PRO instrument is a questionnaire reported voluntarily
 It captures PRO data used to measure treatment benefit or risk in
medical product clinical trials
• The adequacy of any PRO Instrument depends on whether its
characteristics
Conceptual framework
Content validity and
Other measurement properties are satisfactory.
• The FDA will review documentation of PRO instrument

15. • Concepts being measured
• Number of items & domains
• 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

16. • The acceptance of a proposed instrument
• Defines the concepts measured
– description of the relationships between items, domain (sub
concepts), and concepts measured and the scores produced by a PRO
instrument.
Concepts Measured
Intended population

18. • Adequacy of the item generation process
• What to measure may be obvious given the condition being
treated.
– For ex: treatment on pain
• When it is not obvious, instrument developers initially can
hypothesize a conceptual framework based on literature reviews
and expert opinion.
• Subsequently, patient interviews and qualitative cognitive
interviewing ensures understanding and completeness of the
concepts contained in the items.

19. • Development history available and accessible publicly.
• Documentation of content validity (i.e., Evidence that the instrument
measures what it is intended to measure), including open-ended patient
input from the appropriate population.
• Well established instrument’s measurement properties
• Engage the FDA in a discussion about PRO instrument before confirmatory
clinical trial protocols are finalized.
• Provide useful early input
– Labeling goals,
– A hypothesized PRO instrument conceptual framework, and
– The relationship of the PRO endpoints to other clinical trial endpoints

20. • Multi domain concept(Complex) vs. simple concept
• Multi domain claim cannot be substantiated by instruments that do
not adequately measure the individual component domain
concepts adequately
• General concepts often are not supported, because the instrument
may not distinguish adverse side effects of treatment that affect
the general concept
• 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.

21. • Like wise framework of PRO instrument will evolve and be
confirmed over the course of instrument development
• When used in a clinical trial, again to be confirmed by the
observed relationships among items and domains.
• Documentation reveals development process
• The exact words used to represent the concepts measured by
domain or total scores should be derived using patient input
to ensure the scores are valid.
– Pain/analgesia, bone pain/arthralgia

24. • Outline hypothesized concepts and potential claims
• Determine intended Population
• Determine intended application
• Perform literature/expert review
• Develop hypothesized Conceptual framework
• Place PRO’s within preliminary endpoint model
• Document preliminary instrument development

26. • Obtain patient input
• Generate new items
• Select recall period, response options and format
• Select mode/method of administration
• Conduct patient cognitive interview
• Pilot test draft instrument
• Document content validity

29. • Confirm conceptual framework with scoring rule
• Assess score reliability,
• Construct validity,
• Ability to direct change.
• Finalize instrument content, formats, scoring, procedures and
training materials
• Document the questionnaire development

31. • Prepare protocol and statistical analysis plan
• Collect and analyze data
• Evaluate treatment response using cumulative distribution
• Document interpretation of treatment benefit in relation to
claim.

34. • 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.

36. • 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
– End point model
– PRO instrument and its contents
– Conceptual frame work

37. • Content validity is the extent to which the instrument
measures the concept of interest.
• The items and domains of an instrument are appropriate
& specific to the population, condition, and treatment to
be studied.
• Documentation of patient input, cognitive interviewing
of patient in item generation contribute to content
validity.
• Evaluate instrument adequacy to measure the concept
represented by the labeling claim.
• Existing /new PRO instrument , adequacy of the
instrument’s content validity to be checked

38. • 1.Item Generation
• 2. Data Collection Method & Instrument Administration Mode
• 3. Recall Period
• 4. Response Options
• 5. Instrument Format, Instructions, and Training
• 6. Patient Understanding
• 7. Scoring of Items and Domains
• 8. Respondent and Administrator Burden

39. • Items can be generated from patient input, literature
reviews, or interviews with patients, clinicians, family
members, researchers, or other sources.
• Review of documentation until saturation has been reached.
• Item wording, Item coverage, Clarity and Readability.
• Content validity should be checked at every time
• The sample size depends on the completeness of the
information

42. • The choice of recall period that is most suitable depends on the
instrument’s purpose, Disease or condition’s characteristics,
duration, frequency.
• 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 make use of a diary for data collection).
• Response is likely to be influenced by the patient’s state at the
time of recall.

43. Item response options generally are considered appropriate whether:
• Wording used in responses is clear and appropriate
e.g., pain/analgesia; myalgia/arthralgia
• Appropriate for the intended population, purpose, intended use.
e.g., patients with visual impairment may find a VAS difficult to complete.
• Responses offer a clear distinction between choices
e.g., intense and severe
• The number of response options
e.g., using qualitative research, initial instrument testing, or existing
literature.
• Responses for items avoid potential ceiling or floor effects
• Responses do not bias the direction of responses (Response bias)

45. • consistent format
• Results may vary acc. To instructions ad
training
• Sponsors should consider all PRO instrument
instructions to avoid missing data or clarify
responses.

47. • Sponsor should check after preparation of the draft
• This examination should include documentation of
concepts ,
response options , response scales
recall period
instrument’s readability
• Actions taken to delete or modify items
• Evidence from the patient cognitive interview

49. • Numerical scores
• Scoring algorithm
• Combining domain scores into single general
score
• Use of statistical techniques

53. Physical, emotional, or cognitive strain on patients generally
decreases the quality and completeness of PRO data.
Factors that can contribute includes the following:
• Length of questionnaire or interview & Inadequate time
• Formatting , Font size too small to read easily
• New instructions for each item and typical style
• Requirement that patients consult records to complete responses
• Privacy of the setting
• Questions that patients are unwilling to answer
• Need for physical help in responding (e.g., turning pages, holding a
pen, assistance with a telephone or computer keyboard)

54. 1. Reliability
Because clinical trials measure change over time, the adequacy of a PRO
depends on its reliability or ability to yield consistent, reproducible
estimates of true treatment effect.
 test-retest reliability, Internal consistency, Inter-interviewer reproducibility
2. Validity
 Construct validity, Content validity
3. Ability to Detect Change

57. When a PRO instrument is modified, sponsors generally should provide
evidence to confirm the new instrument’s adequacy.
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
• 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

58. 1. Children and Adolescents
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
2. Patients Cognitively Impaired or Unable to Communicate
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.
3. Culture or Language Subgroups
We will review the process used to translate and culturally adapt
the instrument for populations that will use them in the trial.

59. Now Start preparing a PRO

60. Patient
response
Tender
Joints
Swollen
Joints
A. Physical
Function
B. Mobility
Fatigue
Pain
Intensity
Sleep
Problems
2.Emotion
al Well-
Being
1.Social
Function/
Activities
QOL

61. • http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryIn
formation/Guidances/default.htm.
• http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInf
ormation/Guidances/dfault.htm (CDER),
• http://www.fda.gov/BiologicsBloodVaccines/GuidanceCompli
anceRegulatoryInformation/default.htm (CBER) and
• http://www.fda.gov/MedicalDevices/DeviceRegulationandGui
dance/GuidanceDocuments/default.htm (CDRH)
• Fitzpatrick R, Davey C, Buxton MJ, and Jones DR. Evaluating
patient-based outcome measures for use in clinical trials.
Health Technology Assessment 1998;2:14.