Download Guidance on PRO Endpoints and Label Regulations

Guidance on PRO Endpoints
and Label Regulations
Debra Silberg, MD PhD
Senior Director, Clinical Medicine
Shire
Our purpose
We enable people with life-altering conditions to lead better lives.
Disclaimer
• Debra Silberg is an employee and shareholder of Shire
Pharmaceuticals.
• The views and opinions expressed in the following
PowerPoint slides are those of the individual presenter
and should not be attributed to Shire, its directors, or
officers.
• These PowerPoint slides are the intellectual property of
the individual presenter and are protected under the
copyright laws of the United States of America and other
countries. Used by permission.
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
2
Endpoints Must Show Treatment Benefit
The impact of a treatment on how a patient “survives, feels, or
functions”
• Same as the “clinical benefit”
• Can be measured directly or indirectly
• Survives
• Feels
• A patient’s physical sensations related to health
• A patient’s perceived mental state related to health
• Functions
• A patient’s ability to perform an activity (e.g., walking 25 feet)
• Not specific organ function or physiological processes (e.g. liver
metabolism)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
3
Outcomes Assessments for Measuring Treatment
Benefit in Clinical Trials
• Clinical Outcome Assessments (COAs)
There are four types of COA measures:
•
•
•
•
Patient-reported outcome (PRO) measures
Clinician-reported outcome (ClinRO) measures
Observer-reported outcome (ObsRO) measures
Performance outcome (PerfO) measures
• Biomarkers
•Results not influenced by humans; relies on a
standardized, automated process (i.e. Blood pressure)
• Survival
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
4
Patient-Reported Outcome (PRO)
• 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.
• Only PRO assessments can measure symptoms and
patient experiences with a condition
• Examples:
• Self-report of daily number of incontinence episodes
• Self-report of pain intensity on a 0 to 10 numerical rating
scale (NRS)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
5
Observer-Reported Outcome (ObsRO)
• An assessment that is determined by an observer who
does not necessarily have a relevant background of
professional training
• Often used when the patient is unable to self-report (e.g.,
infants, young children, severely cognitively
incapacitated persons)
• Used to capture observable concepts only (e.g., signs or
behaviors—NOT symptoms)
• Not PROXY
• Examples include:
• Parent report of infant behavior (e.g., crying)
• Caregiver report of patient task performance (e.g.,
ability to dress oneself without assistance)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
6
Clinician-Reported Outcome (ClinRO)
• An assessment made by an observer with some
recognized professional training that is relevant to the
measure being taken
• May include an evaluation and interpretation of the
patient's condition based on clinical judgment.
• Examples include:
• Subjective impression following physical examination
• Physical performance measures
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
7
Performance outcome (PerfO) measures
• A PerfO is a measurement based on a task(s) performed
by a patient according to instructions that is administered
by a health care professional.
• Performance outcomes require patient cooperation and
motivation.
• Examples include:
• measures of gait speed (e.g., timed 25 foot walk test),
• memory recall (e.g., match names to faces after 10 minutes)
• cognitive testing (e.g., digit symbol substitution test - matches
symbols with their corresponding digit )
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
8
FDA Guidance
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
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
9
To be as brave as the people we help.
10
Column 1
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
11
Column 2
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
12
Column 3
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
13
To be as brave as the people we help.
14
Spoke 1
I. Identify Context of Use (COU) and Concept of Interest
(COI)
• 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
• Position COA within a preliminary endpoint model
• Document COU and COI
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
15
Context of Use
1. What is your Clinical Outcome Assessment
intended to be used for
• What claims do you want to make
2. What disease are you interested in – do you have
a definition of your disease?
3. What severity are you studying?
4. Is there a specific characteristic that you are
interested in?
• Drug mechanism of action
• Symptom complex that is dominant
• Particular feature of the disease
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
16
Draft Conceptual Framework (example from seasonal allergies*)
SASA-PRO (Seasonal Allergy Symptom Assessment-PRO)
Item 1 (sneezing)
Item 2 (coughing)
Domain 1
Airway
Item 3 (runny nose)
Domain 2
Nose
Item 4 (watery eyes)
Item 5 (itchy eyes)
Domain 3
Eyes
General Concept
Symptoms of
Seasonal Allergies
* This is not a real instrument, it is just an example
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
17
Develop an Endpoint Model
Concept
Indication
Treatment of
Seasonal Allergies
Supportive Concepts
Adjuvant therapies
Endpoints
Primary
Symptom Score
using the 5 item SASA-PRO*
(Seasonal Allergy Symptom
Assessment-PRO)
Secondary
Antihistamine use
Possible Claims: 50% reduction in symptom score and 80%
less antihistamine use
To be as brave as the people we help.
* This is not a real instrument, it is just an
© 2014 Shire Development LLC. All rights reserved
18
Spoke 2
II. Draft Instrument and Evaluate Content Validity
• Obtain patient or other reporter input
• Generate new items
• Select recall period, response options and format
• Select mode/method of administration/data collection
• Conduct cognitive interviewing
• Pilot test draft instrument
• Finalize instrument content, format and scoring rule
• Document content validity
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
19
Signs and Symptoms - Endpoint Evaluation
• Qualitative Work with Patients and/or Caregivers
• Elicit the key symptoms and signs by patient (or caregiver)
interviews, probe patients on what the literature and HCPs said
• Individual or focus groups – obtain new items
• Interview until saturation is reached – no new items/concepts
are elicited during the interviews
• Support findings from patients with further discussions with
health care providers
• Iterative process as you continue development
• Validity – The instrument measures what it is intended to
measure
• Content Validity
• Evidence that the instrument measures the concept of
interest
• ToQualitative
evidence that the items and domains are
be as brave as the people we help.
appropriate
© 2014 Shire Development LLC. All rights reserved
20
Spoke 3
III. Cross-sectional Evaluation of Other Measurement
Properties
• Assess score reliability (test-retest or inter-rater) and
construct validity
• Establish administration procedures & training materials
• Document measure development
• Prepare user manual
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
21
Attributes of PROs
• Reliability
• Ability to yield consistent, reproducible estimates of the true
treatment effect
• Shows stability of scores overtime when no change is expected
• Construct Validity
• Extent that the items and domains of the instrument measure the
construct/concept that they were intended to measure
• Responsiveness – Ability to detect change
• The PRO instrument can identify difference in scores over time
in individuals or groups who have changed with respect to the
measurement concept
To be as brave as the people we help.
Definitions from the FDA guidance document
© 2014 Shire Development LLC. All rights reserved
22
Spoke 4
IV. Longitudinal Evaluation of Measurement Properties/
Interpretation Methods
• Assess ability to detect change and construct validity
• Identify responder definition(s)
• Provide guidelines for interpretation of treatment benefit
and relationship to claim
• Document all results
• Update user manual
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
23
Quantitative Phase
• Test the instrument in a setting in which change can be
observed
• Observational or Clinical Trial
• Determine a Responder Definition or a Statistical Means of
Measurement
• Clinically meaningful change – minimally important difference (MID)
• Composite vs. single symptom endpoint
• Endpoint Evaluation
• use anchors such as global health score to establish what would
be considered a meaningful effect
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
24
Deciding on Endpoints – What is your Claim?
“Begin with the end in mind”
• Must know the claim that you want to make regarding
the therapy early in clinical development
• Utilize the TPP (Target Product Profile) guidance from
the FDA to assist in clinical development
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
25
FDA-TPP Guidance Document
Guidance for Industry and Review Staff
Target Product Profile — A Strategic
Development Process Tool
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
26
TPP – from the guidance
• “The TPP provides a statement of the overall intent of
the drug development program, and gives information
about the drug at a particular time in development”
• “Use of a TPP can facilitate the efficiency of sponsorFDA interactions and communications. A TPP helps
focus a sponsor’s drug development team and FDA
review staff on the drug development goals in terms of
drug labeling.”
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
27
Case Study– Pediatric COA for Ulcerative Colitis
Developing a PRO and ObsRO
• Ulcerative Colitis is a chronic inflammatory disease of
the colon (pediatric and adult)
• Signs and Symptoms include: abdominal pain, blood in
stool, frequent bowel movements, stool urgency and
tiredness
• Considerations: who is evaluating the disease state?
• What age child can answer a questionnaire?
• An observer can only report what they see, but not how a
patient feels
• What input should the physician have?
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
28
Current instrument and why a new one was needed
PUCAI (pediatric UC activity index) – Most commonly used in a
clinically setting and has been used for clinical trials
Items:
• Abdominal pain
• Rectal bleeding
• Stool consistency
• Number of stools per 24 hrs
• Nocturnal stools
• Activity level
•
•
Physicians ask the questions and records answers
Reflects a daily average of the last 2 days (unless conditions are
changing rapidly, then the most recent 24 hours)
•
Issues:
• The status of a patient’s health condition should come directly from the
patient without interpretation by a clinician (FDA PRO guidance)
• Recall of information over multiple days
• Limited number of days considered
To be as brave as the people we help.
Turner et.al. Gastroenterology 2007 133:423
© 2014 Shire Development LLC. All rights reserved
29
Endpoint Model for Pediatric Ulcerative Colitis (UC)
Concept
Indication 1
Improvement in signs and symptoms
among children and adolescence
with mild to moderate UC
Indication 2
Endpoints
Primary
*DUCS total sign and
symptom score (PRO and
ObsRO)
Stability of signs and symptoms
among children and adolescence
with UC in remission
Supportive Concept
Improvement of the mucosal
appearance of the colon
Secondary
Endoscopic appearance of
the colon
*DUCS=Daily Ulcerative Colitis Scale
for Children and Caregivers
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
30
Process for Developing DUCS*
•
Concept Elicitation
• Literature Review
• Interviews with patients with UC in active and remission stage (8-17 y.o.)
and parents/caregivers
• Reached information saturation (i.e., the criterion that no new information
is presented in the last patient interview)
•
Supportive information and confirm consistency for 5-7 y.o.
• Healthcare professional interviews
• Patient/parent on-line blogs
•
•
Establishment of the Conceptual Framework for patients and
parents/caregivers
Create the questions for the eDiary
•
Cognitive Debriefing
•
•
Determine that the items will be uniformly interpreted among patients and
parents/caregivers
Assess the content validity (i.e., clarity, relevance, and comprehensiveness of the
diaries.)
To be as brave as the people we help.
*Developed with Oxford Outcomes – An ICON plc company
© 2014 Shire Development LLC. All rights reserved
31
Conceptual Framework for PRO for DUCS (8-17 y.o.)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
32
Conceptual Framework for ObsRO – DUCS (5-10 y.o.)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
33
Example of the DUCS for the patient (PRO)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
34
Example of DUCS for the Parent/Caregiver (ObsRO)
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
35
Next Steps for DUCS
• Quantitative Stage done during Clinical Trial
• Psychometric evaluation
• The validity and reliability of the DUCS measures
• Test with anchors (current health and global change)
• Determine a responder definition
• score change experienced by a patient over a time period, that
reflects a meaningful improvement from the patient perspective
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
36
Successful Labeling Based on Symptoms
Reported in a PRO using the FDA guidance from 2009
• Clinical trial for Myelofibrosis :
• Pre-specified Secondary endpoint: the proportion of patients
with a reduction in the total symptom score of 50% or more from
baseline to week 24, as assessed with the modified
Myelofibrosis Symptom Assessment Form (MFSAF)
• Clinical trial for Varicose Veins:
•
Primary efficacy endpoint: improvement in patient symptoms,
as measured by the change from baseline to Week 8 in the 7day average electronic daily diary VVSymQ® score. The
VVSymQ® score is a patient-reported outcome measure based
on daily patient assessment of the varicose vein symptoms
determined to be most important to patients: heaviness,
achiness, swelling, throbbing, and itching.
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
37
Pitfalls in Study Design that Affect Label
• Keep endpoints as primary or key secondary
• Example from the medical reviewer: “Dyspnea Domain: While
CRQ was defined as a secondary endpoint for other international
sites, in the US this endpoint was designated as an “other
endpoint”. There Is no regulatory precedent for a claim based on
this questionnaire”
• Numerical improvement, not clinically important:
• The results showed numeric improvements, however the
differences did not exceed the minimal clinical important
difference that is reported in the literature.
• Instrument not “validated” to use for regulatory purposes
• Multiplicity and hierarchical testing
• To account for multiplicity, a step-down testing procedure based
upon statistical significance for the previous tests in the
hierarchy was used. If the symptomatic endpoints were after
other efficacy measures that did not meet statistical significance,
even if the symptoms showed significance they can not be used
in the label.
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
38
Useful Reference
• Clinical Outcome Assessment Qualification Program
• Qualification of COAs from the FDA
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DrugDevelopmentToolsQualificationProgram/ucm28407
7.htm
To be as brave as the people we help.
© 2014 Shire Development LLC. All rights reserved
39