Download The FDA PRO Guidance

PRO Guidance: Theory and Practice
Ari Gnanasakthy
Head, Patient Reported Outcomes
Novartis Pharmaceuticals
15 Oct 2013
Clinical Outcome Assessments (COAs)
 Patient Reported Outcome (PRO)
• A measurement based on a report that comes directly from the patient
(i.e., study subject) about the status of particular aspects of or events
related to a patient’s health condition.
 Clinician Reported Outcome (ClinRO)
• An assessment that is determined by an observer with some
recognized professional training that is relevant to the measurement
being made.
 Observer Reported Outcome (ObsRO)
• An assessment that is determined by an observer who does not have
a background of professional training that is relevant to the
measurement being made, i.e., a non-clinician observer such as a
teacher or caregiver.
| PRO Guidance - Theory and Practice / 18 Oct 2013
Patient-reported outcomes allow a
holistic view of treatment effects
Assessing disease activity and treatment outcomes
Physiological
Biomarkers
Lab values & tests
Functional tests
Blood tests
Biopsies
Tolerance tests
Vital signs
Clinician
Signs
Patient
Caregiver
History experience History experience
Physical examination Symptoms
Visual inspection
Activity tolerance
Palpation
Cognitive function
Auscultation
Physical function
Clinical impression Psych distress
Rx satisfaction
Symptoms
Activity limitations
Cognitive function
Physical function
Psych distress
Burden
“Subjectivity”
| PRO Guidance - Theory and Practice / 18 Oct 2013
3
What Is a Patient-Reported Outcome?
 A PRO is a measurement of any aspect of a patient’s
health status that comes directly from the patient
• Without the interpretation of the physician or anyone else
 PRO Elements
• Function
• Feeling
 PRO concept
• Simple (e.g., bone pain)
• Complex (e.g., treatment satisfaction/preference)
4
| PRO Guidance - Theory and Practice / 18 Oct 2013
Guidance for the Industry (2009)
• Draft PRO Guidance: published
December 2006
• Final FDA PRO Guidance:
published December 2009
• Guidance developed by the
SEALD group within the Office of
New Drugs (OND) at FDA
• SEALD serves as an advisory
group to all reviewing divisions
| PRO Guidance - Theory and Practice / 18 Oct 2013
Purpose of the PRO Guidance
 To emphasize that FDA recognizes the importance of the
patient perspective where appropriate
 To explain how FDA evaluates PRO instruments for their
usefulness in measuring & characterizing treatment benefit
as perceived by the patient.
 To explain how FDA reviews evidence that a PRO
instrument measures the concept represented in the study
objectives and intended to support claims.
| PRO Guidance - Theory and Practice / 18 Oct 2013
Linking PRO Concepts to Claims
Desired
Claim
Product X
relieves
symptoms,
improves physical
activity, without
upsetting
stomach
PRO
Concept
PRO
Instruments
Symptom
Relief
Symptom
Diary
Physical
Activity
Upset
Stomach
8 | Presentation Title | Presenter Name | Date | Subject | Business Use Only
Physical
Activity
measure
GI-symptom
measure
Some specifics from the guidance . . .
 PRO instruments will be evaluated in the context of stated labeling
goals.
 Instrument development must be based on patient input
 A recall period that captures the patient’s current state is preferred
 Content validity is paramount and must be documented
 Instrument adequacy for one purpose does not guarantee its adequacy
for another purpose
 In order to support claims, criteria for statistical analysis and
interpretation of PRO results, including clear specification for a
“positive” study conclusion should be clearly stated in the study protocol
and statistical analysis plan
 Statistical adjustments for multiple endpoints and a plan for dealing with
missing PRO data are required
| PRO Guidance - Theory and Practice / 18 Oct 2013
Emphasis of the guidance is on five aspects
 The link between the endpoints and the proposed study
claims (specific to the protocol)
 The conceptual framework – a clear description or diagram
of the relationship among concepts, domains and items
(specific to the instrument)
 Documentation of validity and measurement properties
• Content validity / Reliability / Construct validity / Responsiveness
 Definition of a responder
 Documentation of instrument modification
Burke, LE., Kennedy DL, Miskala, PH., et. el., The use of PRO measures in the evaluation of the medical products for
regulatory approval. Clinical Pharmacology and Therapeutics June 2008
| PRO Guidance - Theory and Practice / 18 Oct 2013
COA instrument Development and Application:
Framework in Final PRO Guidance 2009 for PROs essential works
for all Clinical Outcome Assessments
i.
Identify Concepts
•
•
•
•
•
Identify claims
Identify relationships among all endpoints
Identify concepts relevant to patients
Determine intended population
Develop expected relationships among items &
concepts/domains
ii. Create Instrument
v. Modify Instrument
•
•
Change concepts
measured, populations
studied, research
application, response
options, recall period, or
method of administration
Translate & culturally
adapt to other languages
•
•
Claim
•
•
iv. Collect, Analyze, &
Interpret Data
•
•
•
•
•
•
•
Generate items
Choose administration
method, recall period &
response scales
Draft instructions
Format instrument
Draft procedures for
scoring & administration
Pilot test draft instrument
Refine instrument &
procedures
iii. Assess Measurement Properties
Prepare protocol & statistical
analysis plan
Identify responder definition
Evaluate cumulative distribution
curve
Present interpretation of treatment
benefit
•
•
•
•
•
11
Assess score reliability, validity, & ability to detect
change
Evaluate administrative & respondent burden
Add, delete, or revise items
Confirm conceptual framework
Finalize instrument formats, scoring, procedures &
training materials
Endpoint Model
14
Endpoint Model
• Clear statement as to the role a PRO endpoint is intended
to play in the clinical trial (e.g. primary, co-primary,
secondary, exploratory)
• A diagram or description of the hierarchy of hypothesized
relationships among all endpoints in a clinical trial and how
the PRO endpoints relate to the others
• Explains the demands to be placed on the PRO instrument
in order to attain the evidence to meet study objectives
15
Endpoint Model Example I
Concepts
Indication:
Treatment
of cancer X
Endpoints
Primary:
Survival (Progression Free)
Supportive Concepts:
Other
treatment
benefit
Secondary/Exploratory:
Pain palliation
Serologic markers
HRQOL
17
Endpoint Model Example 2
Concepts
Indication:
Treatment of pain
due to cancer X
Endpoints
Primary:
Pain palliation
Supportive Concepts:
Other treatment
benefit
Secondary/Exploratory:
HRQOL
Survival
18
Conceptual Framework
19
Conceptual Framework
of a PRO Instrument
• A diagram of instrument items that explains how
each item contributes to specific concepts
represented and how each score is generated
• Provides a clear description of the relationship
among concepts, domains, and items
20
Lack of Conceptual Framework
Example
Pain severity
Sitting
Pain frequency
Walking
Swelling
Standing
Overall Score
21
Conceptual Framework
Item 1
Item 2
Item 3
Domain
Concept
A
Item 4
Item 5
Item 6
Overall
Concept
Domain
Domain
Concept
B
22
Conceptual Framework: Example
Items
Domains
Pain severity
Pain frequency
Pain
Sitting
Walking
Standing
Physical
functioning
Swelling
Swelling
23
Total
Score
Enough of theory
“In theory, there is no difference between
theory and practice. But in practice, there is.”
Yogi Berra
“How empty is theory in the presence of fact!”
Mark Twain, A Connecticut Yankee in King Arthur's Court
| PRO Guidance - Theory and Practice / 18 Oct 2013
25
| PRO Guidance - Theory and Practice / 18 Oct 2013
What types of PRO labels claims have been granted by the
FDA since the release of the guidance (Jan 06 – Dec10)?
Type of claim
All products with PRO label claims (n=28)
(n)
(%)
Symptoms
24
85.7%
Functioning
7
25.0%
HRQOL
2
7.1%
Patient global rating
3
10.7%
Other
2
7.1%
Total # of claims
38
26 | PRO Guidance - Theory and Practice / 18 Oct 2013
Most Frequently Reported Reasons for Denial
of Claim
DeMuro C, Clark M, Mordin M, Fehnel S, Copley-Merriman C, Gnanasakthy A. Reasons for rejection of patient-reported
outcome label claims: a compilation based on a review of patient-reported outcome use among new molecular entities
and biologic license applications, 2006-2010. Value Health 15, 443-448 (2012).
27 | PRO Guidance - Theory and Practice / 18 Oct 2013
Reasons for rejection of PRO Label
1. Fit for purpose – content validity, validation evidence in target
population, lack of evidence of translation/cross cultural validation
2. Interpretation – issues of potential bias (open label design, etc.),
recall period, clinical meaningfulness, missingness, poor compliance
3. Statistical considerations – no adjustment for multiplicity,
inappropriate or missing SAP
4. Concepts – lack of link between concept and claim, failing to
measure full constellation of symptoms
5. Administration considerations – lack of documentation for use of
measure, copy of measure not provided to agency
6. No treatment benefit – measures did not support treatment benefit
28 | PRO Guidance - Theory and Practice / 18 Oct 2013
Evidence suggests . . .
 Since the release of the Draft PRO Guidance, many PRO
claims continue to be approved by FDA reviewing divisions
 The FDA favors PRO label claims for 1st order impacts
 Certain FDA reviewing divisions (e.g. DAARP, DPAP)
appear to be more comfortable allowing claims using
specific PRO measures (usually as primary endpoints)
 Reviewing divisions do not always follow the
recommendation by SEALD
 Reviewing divisions may or may not be adhering to the
current standards when assessing PRO data for a claim
| PRO Guidance - Theory and Practice / 18 Oct 2013
Expectations and consequences
 Delays in product development
 The PRO Guidance may have become a hurdle to
innovation
| PRO Guidance - Theory and Practice / 18 Oct 2013
But . . . It’s not all about the labels
• PRO data are often requested by advisory boards and
reimbursement authorities to evaluate drugs in a holistic
manner
• Patient reported outcomes enables holistic evaluation of
new medications
• Even after product launch PROs can help us to understand
• patients’ satisfaction with treatment
• factors that may affect adherence, and
• other patient centric outcome data to support market access.
| PRO Guidance - Theory and Practice / 18 Oct 2013
The case of Avastin in metastatic breast cancer
| PRO Guidance - Theory and Practice / 18 Oct 2013
Jakafi™ Case Study
 “It was a secondary endpoint, but in our mind this is why
we gave the application full approval. One could quibble
about the importance of reduction in spleen size, but with
reduction in all the symptoms,” full approval was
warranted, Pazdur said.
• Quote from Richard Pazdur, director of FDA’s Office of Hematology Oncology Products, BioCentury, December 5,
2011
Need for PRO data is more than ever
 The industry can no longer rely on traditional
pharmaceutical sales models alone
 An article demonstrating the benefits of a drug treatment
based on data from a well developed PRO scale is likely to
have a far reaching impact through patient-based websites
 These are precisely the kind of data that patient advocacy
groups feel they need in order to lobby payers and
politicians in order to gain access to newer, often more
expensive medical products
| PRO Guidance - Theory and Practice / 18 Oct 2013
35 | Presentation Title | Presenter Name | Date | Subject | Business Use Only