Patient Reported Outcomes in Ovarian Cancer Clinical Trials - Missed Opportunities and Lessons Learned Michael Friedlander 1, Rebecca Mercieca-Bebber 2,3 and Madeleine King 2,3 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 8 weeks 12 weeks 20 weeks 30 20 mm PR 33% Decrease 22 mm 25 mm 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 1.SELECTION OF MEASURES 2.IMPLEMENTATION METHODS 3.DATA ANALYSIS AND REPORTING CENTER FOR MEDICAL TECHNOLOGY POLICY
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
Success Online How well are we doing?
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 practice 65% 56% 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
Examples of Ovarian Cancer Trials 1 ST Line Trials 2 nd Line Platinum Sensitive 3 rd 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 1 st 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 3 RD 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 4 th 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