PRO Guidance: Theory and Practice

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

Caregiver

History experience

SymptomsActivity limitationsCognitive functionPhysical functionPsych distressBurden

PatientPhysiological Clinician

Biomarkers Lab values & tests Functional tests Blood tests Biopsies Tolerance tests Vital signs

Signs Physical examination Visual inspection Palpation Auscultation Clinical impression

History experience

SymptomsActivity toleranceCognitive functionPhysical functionPsych distressRx satisfaction

“Subjectivity”

Assessing disease activity and treatment outcomes

3| PRO Guidance - Theory and Practice / 18 Oct 2013

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)


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


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.


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Product X relieves symptoms, improves physical activity, without upsetting stomach

Linking PRO Concepts to Claims

Desired Desired ClaimClaim

PROPROConceptConcept

Physical Activity

UpsetStomach

SymptomRelief

Physical Activitymeasure

Symptom Diary

GI-symptom measure

PROPROInstrumentsInstruments


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


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 modificationBurke, 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

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

Claim

v. Modify Instrument• Change concepts

measured, populations studied, research application, response options, recall period, or method of administration

• Translate & culturally adapt to other languages

ii. Create Instrument• 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• 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

iv. Collect, Analyze, & Interpret Data

• Prepare protocol & statistical analysis plan

• Identify responder definition • Evaluate cumulative distribution

curve • Present interpretation of treatment

benefit11

COA instrument Development and Application: Framework in Final PRO Guidance 2009 for PROs essential works

for all Clinical Outcome Assessments

14

Endpoint Model

15

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

17

Endpoint Model Example IConcepts

Indication:

Treatment

of cancer X

Supportive Concepts:

Other

treatment

benefit

Endpoints

Primary:Survival (Progression Free)

Secondary/Exploratory:

Pain palliation

Serologic markers

HRQOL

18

Endpoint Model Example 2

Concepts

Indication:

Treatment of pain

due to cancer X

Supportive Concepts:

Other treatment

benefit

Endpoints

Primary:

Pain palliation

Secondary/Exploratory:

HRQOL

Survival

19

Conceptual Framework

20

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

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Lack of Conceptual FrameworkExample

Pain severity

Sitting

Pain frequency

Walking

Swelling

Standing

Overall Score

22

Conceptual Framework

Domain

Item 1

Item 2

Item 3

Item 4

Item 5

Item 6

Domain Concept

B

Domain Concept

A

Overall Concept

23

Conceptual Framework: ExampleItems

Pain severityPain frequency

Sitting WalkingStanding

Swelling

Domains

Pain

Physicalfunctioning

Swelling

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

25


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


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).

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



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

Expectations and consequences

Delays in product development

The PRO Guidance may have become a hurdle to innovation


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.


The case of Avastin in metastatic breast cancer


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


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