Lecture 6: Patient Reported Outcomes

what consequences do we measure

Clinical Outcomes + PROs + Preferences

whcih frameworks are used in PRO?

Clinical and humanistic

Measurable change in health status, disease, survival, or adverse events that reflect what happens to patients clinically

measurable change

nformation reported directly by patients, without interpretation by clinicians or others.

• Pain, Fatigue, Symptoms, Physical functioning, Health-related quality of life

Patient Centered Outcomes

How patients value and trade off different treatment benefits, risks, and attributes.

patient preferences

• Natural history

• Biomarkers

• D&I recruitment

• Event rates

epidemiology of disease

• Post-licensure commitments

• Product safety

• Produce effectiveness

safety and effectiveness

• COA endpoint development, validation, and interpretation, including PROs

• regulatory interactions and reimbursement needs

endpoint strategy

• RWE for regulatory decisions

• external regulatory RWE guidance, policy, and environment

• methodology development

• work with CORE to support evidence generation

RWE methods, standards, and policy

what are the key contributors for all regulatory- facing observational studies and activities?

• key contributor for all regulatory- facing observational studies and activities

Report directly from the patient (i.e., study subject) about the status of a patient's health condition without interpretation of the patient's response by a clinician or anyone else

NO observable concept

patient reported outcome (PRO)

Report from a trained health-care professional after observation of a patient’s health condition based on interpretation of the observable signs, behaviors, or other manifestations related to a disease or condition

clinician reported outcome (ClinRO)

Report of observable signs, events, or behaviors related to a patient’s health condition by someone other than the patient or a health professional (e.g., parent or caregiver)

observer reporter outcome (ObsRO)

Standardized task(s) performed by a patient that is administered and evaluated by an appropriately trained individual or is independently completed

Performance outcome (PerfO)

Which outcomes make up clinical outcome assesments?

1. patient reported

2. clinician reported

3. observer reported

4. performance

What outcome could this be?

Observable concept —> report trained by health profession needed

Clinical reported outcome + Performance outcome

What outcome is listed?

observable concept —> NO report by trained proffesional needed

patient reported (if self report feasable)

observer reported (if self report not feasable)

a measure that describes or reflects how a patient feels, functions, survives

clinical outcome assesement

True/false: Clinical Outcomes Assesment and Patient Reported Outcomes are INCREASINGLY important to many stakeholers

true

who are the stakeholders involved in COAs and PROs and what are their roles?

1. Patients (ask for and use medical products)

2. families, caregivers, loved ones (want the nest for pateients)

3. Providors (decide and prescribe treatments)

4. Regualtory Authorities (evaluate new products for approval and promotion)

5. Agencies (make reimbursement decisions that affect patients’ access to treatment)

______ provide supportive evidence to assist clinicicians, patients, and regulatory, and reimbursmenet agencies awith treatment decisions and recommendations

PROs

Clinical outcomes assesmenets are included in trials and/ or non-interventional studies to support WHAT 2 THINGS?

1. critical regulatory requirmenets

2. cricial access and reimbursement requirements

• primary or key secondary endpoints for approval, promotable claims

• inform benefit-risk assesement

• inclusion criteria

• psychometric validation for future approval/promotable claims

critical regulatory requrienments

• Patient-relevant data required in several countries

• Utilities (QALYs- quality-adjusted life years) and economic modeling

• Publications based on COA data from pivotal trials

ciritcal access and REIMBURSMENT requirements

________ __________ Highlights the Importance of the

Patient and Patient Experience Data

regulatory landscape

What are the four components?

1. collecting patient experience data

2. qualitative methodology

3. identifying fit-for-purpose COAs

4. COA endpoint strategy

PRO Endpoint are developed based on scientifically robust ______ ______ and guidance

best practice

Health Technology Assesment (HTA) agencies are interested in different aspects of PRO/patient data

“PRO data support 2 of the 4 pillars for evaluation which are used to determine benefit rating”

IQWIG/AMNOG/G-BA (Germany)

Health Technology Assesment (HTA) agencies are interested in different aspects of PRO/patient data

“Data from EQ-5D questionnaire used to calculate ‘utilities’ and QALYs which are mandatory for HTA/reimbursement submission”

NICE (UK), HAS (France), CADTH (Canada), and others

Health Technology Assesment (HTA) agencies are interested in different aspects of PRO/patient data

“Patient insights are sought early in the CADTH process and included in the HTA assessment protocol and reports”

CADTH (Canada)

Health Technology Assesment (HTA) agencies are interested in different aspects of PRO/patient data

“PRO data considered in evaluation only when endpoints are

multiplicity controlled”

HAS (france)

_____ _______ from trials to support clinician-

patient decision-making

PRO publications

How patients feel and function on your products is KEY to ______ and ______ discuss treatment options

clinicians and patients

Are PRO outcomes included on labels of products?

YES

COA Endpoint Strategy Development:

____-for-______ measures are required to support interpretation and successful use of trial data

fit for purpose

Endpoint strategy goes hand in hand with ________ and _______ goals

regulatory and reimbursement

What are the components of endpoint strategy which go hand in hand with regulatory and reimbursment goals?

1. Endpoint Concepts

2. Endpoint Measures

3. Trial endpoints

4. Meaningful change

5. Endpoint hierarchy

6. Labeling and value messages

The first three componenets of Endpoint Strategy are

1. endpoint concepts

2. endpoint measures

3. trial endpoints

which part of the three describes:

WHAT is being measured

(ex. blood pressure, cognition symptoms, work productivity, impact om daily life/ Quality of life)

endpoint concepts

The first three componenets of Endpoint Strategy are

1. endpoint concepts

2. endpoint measures

3. trial endpoints

which part of the three describes:

HOW the concept is captured?

Type of measure:

PRO, ClinRO, ObsRO, PerfO

Specific measure:

Select: if well-developed, reliable, and

validated for use in the target population

Modify: change wording of questions/

response options, use in different target

population, etc.

Develop: may need to develop a new

instrument if a valid, reliable one is not

available

Examples of specific measures:

Leicester Cough Questionnaire, EORTC QLQ-

C-30, lesion counts, Brief Pain Inventory,

ADAS-Cog

Endpoint measures

The first three componenets of Endpoint Strategy are

1. endpoint concepts

2. endpoint measures

3. trial endpoints

which part of the three describes

WHAT endpoint will be derived from the measure

(ex. mean change from baseline in totak score, % responders, time to deterioration)

trial endpoints

PRO Development, Validation, and Interpretation:

1. Appropriate for its _________ _____

   1. study design

   2. patient population

   3. therapy under study

2. _________ and _______ measures concepts that are

   1. clinically relevant

   2. important to patients

3. Can be communicated in ________ in a way that is accurate, interpretable, and not misleading (well-defined)

1. intended use

2. Validity and reliability

3. labeling

What are the steps of the rigorous scientific process to develop and validate COA Endpoints, starting with Literature Review?

1. Literature review

2. Concept elicitation

• Open-ended to hear how patients describe how they experience the disease in terms of signs/symptoms/ impacts

3. Cognitive debriefing

• Item review and revision of the draft instrument based on patient input

4. Psychometric Evaluation

• establish reliability/validity and estimate meaningful change threshold (MCT)

5. Implementation into trials

• schedule of assessments to support endpoints, mode of administration, translation, and cultural adaptation, sSAP development

6. Analysis + Interpretation

• interpretation of data using global assessments of change and/or severity

7. Label and Value Messaging

• patient/clinician/ expert input obtained at specific timepoints

What are the components of psychometric evaluation?

1. content validity

2. reliability and internal consistency

3. convergent and known groups validity

4. ability to detect change (reponsivenss)

EXAMPLE of Development and Psychometric Validation of the RSV- iiiQ

• RSV causes significant morbidity and mortality in older adults

• At the time of program initiation, there were no existing disease- specific, self-reported measures that assessed symptoms and severity of RSV infection from the perspective of adult patients with RSV

• The RSV ________ _________ and _______ Questionare (RSV-iiiQ) was developed by adapting the __________ ________ and ________ Questionanaire (FluiiQ)

RSV Infection Intensity and Impact Questionire

adapted from

Influenza Intensitty and Impact Questionairre (FluiiiQ)

Background literature, expert input, and a non-interventional qualitative study with 20 adults with confirmed RSV were conducted to inform the content and development of the RSV-iiiQ

study 1 - DEVELOPMENT of RSV-iiiQ

A non-interventional study with 111 adults with confirmed RSV was conducted to collect data from a web-based platform over two consecutive days. Participants completed the RSV-iiiQ, a Patient Global Impression of Severity/Change (PGIS/C), the Sheehan Disability Scale (SDS), the EQ-5D-5L, and a demographic questionnaire

study 2 - PSYCHOMETRIC VALIDATION of RSViiiQ

what were the following steps in order of the first study of the RSV-iiiQ which focosed on DEVELOPMENT?

1. literature review

2. expert imput

3. RSV-iiiQ (1st draft)

4. Qualitative Interviews

5. Qualitative Data Analysis

6. Conceptual Framework

7. RSV-iiiQ Final Draft

what is being shown in this table?

Psychometric Validation of the RSV-iiiQ

Conclusions: Development and psychometric validation of the RSV-iiiQ

• Findings provide preliminary evidence of the measurement structure, internal consistency, test-

retest reliability, construct validity, and responsiveness

• Study #2 substantiated the findings of the previous qualitative research performed to develop

the RSV-iiiQ in accordance with FDA PRO guidance

Collectively, do the results from both studies suggest the RSV-iiiQ could be useful for the assesment of severity of symptoms and impact of RSV infection in adults

Are any further studies needed?

YES Collectively, results from both studies suggest the RSV-iiiQ COULD be useful for the assessment of severity of symptoms and impact of RSV infection in adults

• Further studies ARE needed in the context of vaccine or treatment trial to determine the RSV iiiQ’s responsiveness to change across the full course of the infection and recovery period and develop thresholds for meaningful score changes

degree of change on a COA that is considered clinically meaningful by patients and/or clinicians

Meaningful Change Threshold (MCT):

what are some methods to define the MCT?

Often apply multiple estimates; triangulating

– Anchor-based methods

– Distribution-based methods

– Previous clinical trials

Applying the MCT

• Change within a subject – i.e., ‘responder’

• Mean change within a group

• Difference between groups – i.e., active trt vs. pbo

Anchor-Based MCT:

1. Select an _________

2. Confirm the _________ is related

• PGIC should correlate with RSV-iiiQ score change at r ≥ 0.30 (hypothetical r = 0.45 ✓)

3. Group _______ by ______ response

Much better · A little better · No change · Worse

4 Estimate the __________

Mean score change in the smallest meaningful group (“A little better”) = candidate MCT

1. anchor

2. anchor

3. patients by anchor response

4. estimate the threshold

Change patients themselves judge as “a little better” – the smallest difference that matters to them

anchor-based MCT (meaningful change threshold)

Proactively design PRO endpoint strategies to reduce _______ data, consider “patient ______” and

________

missing

burden

compliance

What are some considerations for PRO measure implementation?

1. Hierarchy of PRO endpoints

2. Schedule of activities – time points for completion

3. Assessment order of PRO measures

4. Site & participant training

5. Clearly determine compliance expectations

6. Monitor compliance; follow up with retraining

7. Translation and cultural adaptations

8. Electronic implementation

Development of PRO Endpoint Strategies require considerable

• __________________

• __________________

• __________________

• cross functional collaboration

• discussion

• planning

different types of COAs may be needed to support _____________ and adressing __________ needs

• primary/key endpoints

• stakeholder needs

COA/PRO measures need to be ‘___-for-________’ and developed & validated following rigorous scientific methods

fit for purpose

Endpoints derived from COA/PROs need to be _______-driven, with defined __________ ________ thresholds

evidence

meaningful change thresholds

An externally facing website showcasing Merck’s 25 + years history in the development of patient centered outcomes measures

Merk COA measures

What is the purpose of the Merck COA Measures Website?

• Increase the visibility and use of Merck developed COA measures

• Deepen and broaden engagement with key stakeholders

• Speed and simplify stakeholders’ ability to use Merck-developed COA measures

• Help establish Merck-developed COA measures as standard in the scientific field