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PRO Guidance: Theory and Practice Ari Gnanasakthy Head, Patient Reported Outcomes Novartis Pharmaceuticals 15 Oct 2013.

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Presentation on theme: "PRO Guidance: Theory and Practice Ari Gnanasakthy Head, Patient Reported Outcomes Novartis Pharmaceuticals 15 Oct 2013."— Presentation transcript:

1 PRO Guidance: Theory and Practice Ari Gnanasakthy Head, Patient Reported Outcomes Novartis Pharmaceuticals 15 Oct 2013

2 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

3 Patient-reported outcomes allow a holistic view of treatment effects Caregiver History experience  Symptoms  Activity limitations  Cognitive function  Physical function  Psych distress  Burden PatientPhysiologicalClinician Biomarkers  Lab values & tests  Functional tests  Blood tests  Biopsies  Tolerance tests  Vital signs Signs  Physical examination  Visual inspection  Palpation  Auscultation  Clinical impression History experience  Symptoms  Activity tolerance  Cognitive function  Physical function  Psych distress  Rx satisfaction “Subjectivity” Assessing disease activity and treatment outcomes 3 | PRO Guidance - Theory and Practice / 18 Oct 2013

4 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) | PRO Guidance - Theory and Practice / 18 Oct

5 Conceptual Framework for Patient-Reported Outcome Measures | PRO Guidance - Theory and Practice / 18 Oct Doward L, Gnanasakthy A, Baker M. Patient reported outcomes: looking beyond the label claim. Health and Quality of Life Outcomes. 2010; 8(89):doi / BDI = Beck Depression Inventory; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EQ-5D = EuroQOL; HADS = Hospital Anxiety and Depression Scale; HAQ = Health Assessment Questionnaire; HUI = Health Utilities Index; NHP = Nottingham Health Profile; SF-36 = Short-Form 36; SIP = Sickness Impact Profile; PIQOL-AD = Parent’s Index of Quality of Life in Atopic Dermatitis; QOL = quality of life; QOLIAD = Quality of Life in Atopic Dermatitis; RAQOL = Rheumatoid Arthritis Quality of Life Questionnaire; RGHQOL = Recurrent Genital Herpes Quality of Life Questionnaire. Type of PRO measure: PRO Framework Symptoms Functioning HRQOL Needs-based QOL Utility Impairments Disability Combination impairment, disability, & some QOL QOL Combination impairment, disability, or QOL Clinical perspective Clinical/Society perspective Patient perspective Society perspective BDI, HADS, McGill Pain Questionnaire HAQ, DLQI, CDLQI HAQ, DLQI, CDLQI NHP, SF-36, SIP QOPLIAD, PIQOL-AD, RGHQOL, RAQOL EQ-5D, HUI Constructs assessed: Constructs assessed: Determines impact primarily from: Example instruments:

6 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

7 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

8 8 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Product X relieves symptoms, improves physical activity, without upsetting stomach Linking PRO Concepts to Claims Desired Claim PRO Concept Physical Activity Upset Stomach Symptom Relief Physical Activity measure Symptom Diary GI-symptom measurePROInstruments

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

10 | 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

11 11 COA instrument Development and Application: Framework in Final PRO Guidance 2009 for PROs essential works for all Clinical Outcome Assessments

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14 14 Endpoint Model

15 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

16 16 Endpoint Model Development Define target indication Define concepts which support the indication Select endpoints which support the concept of interest Establish the relationship between endpoints (Develop an endpoint model)

17 17 Endpoint Model Example I Concepts Indication: Treatment of cancer X Supportive Concepts: Other treatment benefit Endpoints Primary: Survival (Progression Free) Secondary/Exploratory: Pain palliation Serologic markers HRQOL

18 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 19 Conceptual Framework

20 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

21 21 Lack of Conceptual Framework Example Pain severity Sitting Pain frequency Walking Swelling Standing Overall Score

22 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 23 Conceptual Framework: Example Items Pain severity Pain frequency Sitting Walking Standing Swelling Domains Pain Physical functioning Swelling Total Score

24 Enough of theory | PRO Guidance - Theory and Practice / 18 Oct 2013 “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 25 | PRO Guidance - Theory and Practice / 18 Oct 2013

26 What types of PRO labels claims have been granted by the FDA since the release of the guidance (Jan 06 – Dec10)? Type of claimAll products with PRO label claims (n=28) (n) (%) Symptoms2485.7% Functioning725.0% HRQOL27.1% Patient global rating310.7% Other27.1% Total # of claims38 | PRO Guidance - Theory and Practice / 18 Oct

27 Most Frequently Reported Reasons for Denial of Claim | PRO Guidance - Theory and Practice / 18 Oct 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, Value Health 15, (2012).

28 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 | PRO Guidance - Theory and Practice / 18 Oct

29 | 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 1 st 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

30 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

31 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

32 The case of Avastin in metastatic breast cancer | PRO Guidance - Theory and Practice / 18 Oct 2013

33 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

34 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 35 | Presentation Title | Presenter Name | Date | Subject | Business Use Only


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