Regulatory Considerations in Patient Reported Outcomes: Sponsor Perspective on the Past, Present, and Future State

1. EORTC: QUALITY OF LIFE IN
CANCER CLINICAL TRIALS
MAY 16 & 17 2019
BRUSSELS, BELGIUM
Regulatory Considerations in
Patient Reported Outcomes:
Past, Present, and Future State

2. BIO: ALICYN CAMPBELL
Alicyn Campbell is the Founder of Patient Relevant Evidence which provides strategic
advising for patient-centric evidence generation. Alicyn has over 12 years of
experience developing and implementing patient relevant endpoint strategies across
all areas of oncology from the sponsor perspective.
For 7 years Alicyn led Roche/Genentech’s oncology Patient-Centered Outcomes
Research group and was responsible for novel FDA PRO labeling claims for
both Hycela and Hemlibra.
Alicyn has participated in numerous FDA workshops, academic forums, pre-
competitive collaborations and industry groups, including former Vice President
Biden’s Cancer Moonshot Initiative.
Disclosures: Member of the Carevive Systems Inc. Scientific Advisory Board
Research Partner: Clinical Outcomes Solutions
COPYRIGHT 2019 PATIENT RELEVANT EVIDENCE LLC – NO SLIDES MAY BE
REDISTRIBUTED OR REPUBLISHED WITHOUT WRITTEN PERMISSION
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3. CONTACT INFO
PRE is headquartered in northern California, and has research partners around the
globe.
PHONE: +1 415 275 1229
EMAIL: alicyn@patientrelevantevidence.com
COPYRIGHT 2019 PATIENT RELEVANT EVIDENCE LLC – NO SLIDES MAY BE
REDISTRIBUTED OR REPUBLISHED WITHOUT WRITTEN PERMISSION
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4. WHY WE ARE HERE
Dr. Janet Woodcock, CDER, FDA:
"It turns out that what is really bothering the patient and what is really bothering the
doctor can be radically different things; patients are true experts in their disease”;
“It's clear you have to start with an understanding of the impact of the disease on the
people who have it, and what they value most in terms of alleviation before you set up a
measurement and go forward with truly patient-focused drug development."
The term ‘clinical benefit’ was introduced by FDA to describe and better assess
patient-focused outcomes; this is defined as “the impact of treatment on how a
patient feels, functions or survives”
Ref: PDUFA V Clinical Outcome Assessments Public Workshop, April 1, 2015

5. WHERE WE WERE
Poorly defined endpoints
­ E.g. “to compare quality of life between treatment A and treatment B”
Not starting out with a clear hypothesis, well defined tool(s) to measure the desired construct
­ E.g. “to explore the difference in QOL between treatment A and treatment B”
Not measuring aspects of disease and treatment most relevant to patients
Post-hoc, tertiary analyses
­ E.g. choosing the method that best fits the results rather than pre-defining the research question(s)
Variable analytic methods applied to the same tool across researchers
­ Providing different results & conclusions
Different thresholds for meaningful change applied across the same tool, lacking empirical
evidence to support
Missing data adjustments, or no adjustments, lacking sensitivity analyses in both cases
All of of these combined = reduced credibility of PRO results

6. PRESENT STATE
Alignment on core concepts of interest from regulators and patients
­ E.g. Disease Symptoms, Physical Functioning, IADLs, Treatment Burden
Alignment on well defined tools
­ E.g. EORTC, PRO-CTCAE, BPI, MDASI, PROMIS and others.
Well thought out and well defined endpoints
­ E.g. “Compare the mean change from baseline in EORTC QLQ-C30 Physical Functioning score at week
24 between patients on Treatment A vs. Treatment B in the ITT population”
Alpha spend, inclusion in the hierarchy if labeling intent
Reduced patient burden
­ Removal of non-core concepts and assessing only those concepts most relevant to patients with the
underlying disease
Clearer thresholds & definitions of meaningful change
­ Inclusion and application of anchor based methods; CDF curves to complement

7. FUTURE: APPROVALS
Systematic application of the estimand framework (ICH E9 (R1))*
Clear endpoint definitions, determined a priori
­ We’re getting there, but we’re still not there yet
Alignment between sponsors and regulators balancing rigor and feasibility
­ E.g. analgesic logs in a global environment
­ “Content validity”
Better communication between regulators and sponsors up-front, Pre-Ph3 start
­ Less: “ PRO evidence will be a review issue” then “No.”
­ More: clear, actionable feedback to allow teams to de-risk labeling concerns by generating any required
empirical evidence while the trial is ongoing
Clearer expectations of filing requests at Pre-Ph3 Meetings
­ Pre-alignment on what Information Requests (IR) may arise at the start of Phase 3 to enable resource planning for
sponsor timeline
Clearer alignment between payers and regulators on requirements for clinical evidence
*https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/E9-R1EWG_Step2_Guideline_2017_0616.pdf

8. FUTURE: COMPARATIVE
TOLERABILITY
Definition: ‘The tolerability of a medical product is the degree to which symptomatic and
non-symptomatic adverse events associated with the product’s administration affect the
ability or desire of the patient to adhere to the dose or intensity of therapy. A complete
understanding of tolerability should include direct measurement from the patient on how
they are feeling and functioning while on treatment.’
Friend of Cancer Research white paper: https://www.focr.org/sites/default/files/
Comparative%20Tolerability%20Whitepaper_FINAL.pdf

9. FUTURE: TRIAL DESIGN AND
EXECUTION
Increase in use of new study designs
­ E.g. accelerated approval off Ph1 expansion
­ Single arm
­ Multi-therapy basket trials
Movement towards decentralized clinical trials
­ BYOD, one device for all data collection
Systematic patient input into trial design and feasibility
­ Engaged, triangular communication model Patient
Investigator
SponsorRegulator

10. FUTURE: USE OF ITEM
BANKS / ITEM LIBRARIES
Reducing patient burden by assessing most relevant concepts
Increased reliance on systems that enable flexible inclusion of salient measurement
concepts:
­ E.g. EORTC, PRO-CTCAE, MDASI, PROMIS
Need to publish and disseminate empirical evidence on validity, sensitivity, specificity
of these item banks / item libraries
­ Ensure endpoints constructed using these measurement systems will be accepted by key
stakeholders

11. FUTURE: REAL WORLD
EVIDENCE
Increase in novel treatments such as cell and gene therapies where limited empirical evidence
is available at approval
­ FDA & reimbursement authorities (e.g. Medicare US) are increasingly requiring longitudinal RWE to
demonstrate long term safety & product value
In rare disease, where patients are scarce, PRO as part of routine care can provide valuable
information on the patient experience
­ Inform endpoint development
­ Serve as real world controls
­ Document real world product value for payers
Refine clinician and patient understanding of perceived barriers via empirical evidence
­ Real world understanding of treatment burden, performance status and tolerability of regimens
­ Treated-related symptom assessment incorporated into clinical practice
Systematic inclusion of PROs in real-world evidence platforms, part of routine patient care

12. QUESTIONS & DISCUSSION