1. health and fitness
2. disease
3. cancer

Patient Reported Outcomes in Ovarian Cancer Clinical Trials Missed Opportunities and Lessons Learned
Michael Friedlander1, Rebecca Mercieca-Bebber2,3 and Madeleine King2,3
1.Director of Research ANZGOG NHMRC Clinical Trials Centre Sydney Australia
2.Psycho-oncology Co-operative Research Group (PoCoG), School of Psychology, University of Sydney, Australia
3.Central Clinical School, Sydney Medical School, University of Sydney, Australia
Outline of discussion
• Clinical Trial Endpoints- RECIST-Limitations of PFS /OS
• Why include PRO’s in clinical trials
• Criteria to select the appropriate PRO
• Patterns of Reporting on HRQOL in trials
• Missed opportunities- how we can do better
• Summary checklist for trial design
Traditional Trial Outcomes
Primary Outcomes
• Progression Free Survival
• Overall Survival
Secondary Outcomes
• HRQOL- patient reported
• Toxicity- NCI- CTCAE criteria- clinician reported
Trial Endpoints- PFS
• Disease progression criteria - developed for use in phase 2
clinical trials that used response as an endpoint i.e. WHO RECIST
• Arbitrary definitions - standardise reporting
• Intended to describe what happened to tumours during therapy
• Does not necessarily infer a meaningful benefit for the patient
• Crept into use as an important primary endpoint in Phase 3 trials
RECIST 1.1
Baseline sum
30
8 weeks
12 weeks
20 weeks
20
mm
22
mm
25
mm
PR
33% Decrease
PD- 20% increase
in sum of diameters
from lowest value
PROGRESSION-OFF STUDY
Unclear whether these arbitrary changes in size, infer benefit to the
patient or whether the degree of “clinical benefit” correlates with the
percentage reduction in tumour volume.
Compounded by measurement error
Progression Free Survival
• The goal of treatment in most patients with advanced
cancer is improved quality and quantity of survival
• Uncertainty whether
- RECIST progression equates to Symptom progression
- Prolongation in PFS equates to improved QoL
Measure what really matters and make this the primary
endpoint rather than measure what’s easily measureable ⱡ
ⱡ Booth and Eisenhauer PFS - meaningful or simply measureable JCO 2012;30:1030
Control
Treatment
14 weeks increase
In median PFS
What does PFS mean to a patient
Is this question adequately addressed in trials where PFS is the Primary Endpoint?
Study has to demonstrate that delaying PFS is important for patients*better quality of life for longer / * a delay in disease symptoms / *delay
in second line treatment AND *the toxicity/price paid is acceptable
How can we use PRO’s to add value to clinical trials ?
What instrument/s to use?
• PRO’s provide the means to reliably quantify subjective
information provided by patients in response to specific
questions using validated instruments.
• There are many instruments to choose from.
• There is no “right” PRO measure in any absolute sense
• The “best” questionnaire/instrument is the one that best
matches the specific aims and objectives of the study.
PRO’s in clinical trials
• Often compromised by poor design, implementation and analysis
• General guidance available on how to include PRO’s in clinical trials
(e.g. FDA PRO Guidance 2009) and how to report (CONSORT-PRO
Calvert JAMA 2013 ).
• Close dialogue with QOL/PRO experts during the design and
planning phase of the clinical trial- to advise on:
 Instruments, assessment schedule, guidance and training for site
staff (to minimise missing data)
 Statistical analysis plan based on the PRESPECIFIED hypotheses
and sample size calculations, and predetermined thresholds
(“minimum important difference, MID”).
Recommendations targeted to clinical
Investigators and focused on design
elements relevant to clinical
and health policy decision making
CENTER FOR MEDICAL TECHNOLOGY POLICY
1.SELECTION OF MEASURES
2.IMPLEMENTATION METHODS
3.DATA ANALYSIS AND REPORTING
PROs to support drug approval
FDA document
FDA – PRO –protocol details
• Each PRO endpoint is stated as a clinical trial objective
• Reasons for Selection of Instrument/s
• Procedures for training patients and clinical investigators should be well
described in protocol
• Detailed elaboration of data analysis in SAP- will endpoint be analysed as
a continuous variable/dichotomous variable or some graded response
• Pre-specified procedures to deal with missing data- include sensitivity
analyses with different methods for missing data imputation
How well are we doing ?
Success Online
Systematic review of quality of reporting HRQOL
in clinical trials 2000-2008 - cancer trials (n=381)
Brundage et al 2011
Proportion
of trials
complying
with good
65%
56%
practice
55%
guidance
25%
17%
Discussion
of findings
Reason for
Outcome
measure
HRQOL hypothesis
stated
Information
about
Missing data
HRQOL sample
size calculation
Quality of Life and Symptom Control in RCT in
Advanced Cancer (n= 112)
•
•
•
•
•
•
•
A Priori Hypotheses regarding QoL/Symptom Control - 19%
Definition of a palliative endpoint- 22%
Definition of a palliative response - 24%
Missing data described - 16%
Reporting proportion of patients with a palliative response - 21%
Reporting duration of a palliative response -13%
Discussion of the limitations of the QoL results - 21%
Joly et al Annals of Oncology 2007
1ST Line Trials
Examples of Ovarian Cancer Trials
2nd Line Platinum Sensitive
3rd Line
Platinum Resistant
Maintenance Trials
ICON 7
PFS at 42 months was 22.4 months without
bevacizumab versus 24.1 months with
bevacizumab (P=0.04 by log-rank test)
In HIGH RISK patients - the benefit was
greater with bevacizumab PFS- at 42
months of 14.5 months vs. 18.1 months
with bevacizumab- respective median
overall survival of 28.8 and 36.6 months
Bevacizumab every 3 weeks
maintenance X 6-stopped at 12m
ICON 7
The PRO hypothesis for ICON7 was global QoL- based on EORTC-QLQC-30 at week 54
They found a small but significant decline in Qol in the bevacizumab arm (69.7 vs 76.1 - 6 points- the differences
were in role functioning; financial worries; attitudes to disease or treatment; hormonal symptoms and rash)
Editorial Lancet Oncology
ICON 7 QOL –what was missing
• Did not look at any QoL endpoints in the high risk group as not pre-specified
– given the big difference in PFS in this group would have expected a
difference if it had been looked for
• QoL data was not collected after progression – important if one of the aims
is to delay the time to second line therapy which is usually commenced when
patients are symptomatic – what happens to QoL when start chemotherapy
• Include qualitative sub-studies- including patient preferences/trade offs
Editorial accompanying ICON 7 QoL
The final sentence in the editorial encompasses the issues well:
“Women with ovarian cancer will ultimately bear the burden of
interpretation of such trials and should be asked to assess inherent
trade-offs implicated in a new treatment”
PRO endpoints/hypotheses
Maintenance studies - where PFS is primary outcome
• What value do patients place on progression free survival/time without
detectable disease on a scan /blood test?
• Is this different after 1st line therapy vs. after Recurrence
• What does PFS mean if no OS difference?
• What value do patients place on delaying time to second line chemotherapy?
• Include patient reported adverse events- not just aggregated but time course
• Can we measure Quality Adjusted PFS
Under reporting of Adverse Effects by Clinicians
Di Maio et al
1000 patients in breast and NSCLC trials
482 Patients Platinum Sensitive
Quote from manuscript………
platinum-sensitive recurrent ovarian cancer, more than
65% of the patients received 4 lines of subsequent
therapy
after randomized study treatment, and the crossover
rate was approximately 40%.26,27 Unlike PFS, OS and
OCEANS
• Significant increase in response rate: 78% vs. 57%
• PFS: 12.4 vs 8.4 months
• Bevacizumab has not been approved for this indication ?
• Could PRO endpoints have strengthened the trial findings ?
• What PRO endpoints would be important?
• Would this have made a difference and led to a regulatory
submission
Colombo et al
830 Patients
No PRO / HRQOL Endpoints
LARGEST STUDY OF 3RD LINE TREATMENT- 460 Platinum Resistant/Refractory OC
13.5 vs 8.5m
4.3 vs 2.7
RR 10.9 vs 4.3 %
Most patients had 4th line treatment (1-8 lines after PD
PFS in patients receiving olaparib
vs. pegylated liposomal doxorubicin (PLD)
Single sentence on PRO outcomes
in final paragraph of results:
“There were no significant differences in
improvement or worsening rates between the
olaparib treatment groups and the PLD group
for the FACT-O Symptom Index and Trial
Outcome Index scores. However, a higher
improvement rate was noted for olaparib 400
mg compared with PLD for the total FACT-O
score (odds ratio, 7.23; 95% CI, 1.09 to 143.3;
P = .039”
Greater attention to PRO hypotheses and endpoints
could have possibly changed the way AZ/authorities
interpreted the olaparib program
Kaye S B et al. JCO 2012;30:372-379
©2012 by American Society of Clinical Oncology
Aurelia- Bevacizumab in platinum resistant ovarian cancer
PFS and OS
PFS 3.4 vs. 6.7 months
OS 13.3 vs. 16.6 months
Checklist for phase 3 clinical trials- PRO outcomes
• Have you measured aspects of patients lives that patients consider
important?
• What is the PRO hypothesis?
• Will a PRO measure contribute to the study conclusions?
• Have PRO endpoints been incorporated in protocol development?
• Have you selected the right instrument?
▫ i.e. does it measure the specific PRO domain/s in PRO hypothesis/es
+ reliable/valid/responsive to clinically important change?
•
•
•
•
Is the study adequately powered for the QOL endpoint?
Do you have a SAP in place?
Mechanisms in place to reduce missing data?
Meets CONSORT-PRO extension guidelines?
*Next generation trials are now smarter
*Carefully consider how best to incorporate PRO endpoints
*From the very start
Educate clinicians, research nurses and patients about importance
of PRO’s to the trial endpoints