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Clinical Trials for Quality of Life Endpoints in Oncology

Jeff A. Sloan, Ph.D. Mayo Clinic, Rochester, MN, USA. Clinical Trials for Quality of Life Endpoints in Oncology. Oncology Education Session Rochester, November 1, 2005. QOL challenges. Reliability: if I were to use this tool under the same conditions would I get the same results?

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Clinical Trials for Quality of Life Endpoints in Oncology

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  1. Jeff A. Sloan, Ph.D. Mayo Clinic, Rochester, MN, USA Clinical Trials for Quality of Life Endpoints in Oncology Oncology Education Session Rochester, November 1, 2005

  2. QOL challenges • Reliability: if I were to use this tool under the same conditions would I get the same results? • Validity: am I measuring what I want to measure? • Missing data: imputation, design considerations • Response shift: hospice patients at 75%

  3. Take home message:there is good news • There are problems with using QOL assessments as indicators of efficacy in clinical trials. • There are scientifically sound solutions to these problems. The problems have been disseminated widely and consistently. The solutions have not.

  4. Checklist for designing, conducting and reporting HRQL - PRO in clinical trialsPatient Reported Outcomes (PRO) and Regulatory Issues : A European Guidance Document for the improved integration of health-related quality of life assessment in the drug regulatory process. Chassany O et ERIQA Working Group. Drug Information Journal 2002. • HRQL / PRO objectives • Added value of HRQL / PRO • Choice of the questionnaires • Hypotheses of HRQL / PRO changes • Study design • Basic principles of RCT fulfilled ? • Timing and frequency of assessment • Mode and site of administration... • HRQL / PRO measure • Description of the measure (items, domains…) • Evidence of validity • Evidence of cultural adaptation • Statistical analysis plan • Primary or secondary endpoint • Superiority or equivalence trial • Sample size • ITT, type I error, missing data • Reporting of results • Participation rate, data completeness • Distribution of HRQL / PRO scores • Interpreting the results • Effect size, • Minimal Clinically Important Difference • Comparison with other criteria / scores • Number needed to treat…

  5. EMEA RECOMMENDATIONS Points to consider (CPMP/EWP/562/98) on clinical investigation of medicinal products in the chronic treatment of patients with COPD, 1999 • In the major efficacy studies of symptomatic benefit the primary endpoint should reflect the clinical benefit the applicant wishes to claim in the future SPC (Summary of Product Characteristics) • It should include the FEV1as a measure of lung function and include a measure of symptomatic benefit • A significant benefit for both endpoints, should be demonstrated so that no multiplicity adjustment to significance levels is indicated • The primary symptomatic benefit endpointshould be justified by referencing published data which supports its validity; one example is the St George’s Respiratory Questionnaire • There are number of secondary endpointswhich may provide useful information. … e.g. symptom scales, … and quality of life assessment

  6. QOL: The big picture

  7. Symptoms and QOL:Is there a difference? • If you count the number of emetic episodes, you are assessing a symptom • If you ask the patient how bad their nausea is, you are assessing QOL • The measurement issues and analytical procedures are the same • Literature is converging to the term patient-reported outcomes (PRO)

  8. Developmental Timeline of Commonly Used QOL Measurement Tools

  9. What is an Appropriate QOL Instrument? • Research objective (HYPOTHESIS DRIVEN) • Specific rationale for the QOL part of the study • Relevant domains of QOL (LIST & MATCH) • Disease and patient population characteristics • Psychometric characteristics (reliability & validity) of QOL instrument • Practical considerations (e.g. respondentburden, language translations)

  10. Timing of QOL Assessment • Study objective • Characteristics and natural course of disease • Baseline and one follow-up QOL assessment are necessary • Treatment regimen • Similar timing of QOL assessment across treatment arms • Expected effects of the treatment

  11. QOL Research Themes 1. Assess QOL within clinical trials with efficiency, consistency, specificity 2. Improve QOL methodology 3. Develop intervention studies targeted at QOL endpoints

  12. QOL in NCCTG Clinical Trials • Since 1995, 84 trials with QOL component • >50 different QOL questionnaires used • >20 papers per year published with QOL • Average baseline compliance rate: 94%

  13. What underlies these QOL metrics? • “NCCTG does not experience the problems that other groups report with respect to QOL”. • “Efforts to make the inclusion of QOL components in treatment trials easy and efficient have been well received by investigators”. (Integrating cancer control research into the CCOP network: a case study of the NCCTG, NCI, 2004)

  14. QOL Team Resources • MD tumor group liaisons • Operations manual • Forms bank • Literature bank • Background templates • Web-based utilities

  15. Cancer Patient Assessment • Cancer patient assessment involves tumor growth and survival data. • We measure these scientifically and the effect of interventions on these endpoints. • Cancer also involves other things besides tumors and reduced lifespan that can be measured…..

  16. … by answering scientific questions • What is the value added of loooooong QOL assessments to treatment trials? • What is the evidence for the use of single-item QOL assessments? • How do you deal with multiple endpoints? • How do you handle missing data? • What is the clinical significance of QOL assessments?

  17. What is the value added of additional questions?

  18. Less is More • Numerous studies indicate shorter assessments are “just as good” as longer assessments • Bernhard. single item quality of life indicators in cancer clinical trials. Brit J Cancer 84(9)1156-1165, 2002 • Vickers. Contolled Clinical Trials, 24: 731 – 735, 2003 • Abdel-Khalek. Measuring anxiety. Death Studies 22(8):763-772, 1998 • Gardner. Ed Psych Measurement 58(6):898-915, 1998 • Sloan. Overall QOL. JCO 16:3662-3673, 1998 • Sloan. Clinical significance of single items relative to summated scores. Mayo Clinic Proc 77: 479-487, 2002

  19. Sloan et al, Biopharm Stat 14(1): 73-96, 2004.

  20. Single-Item or Multiple-Item PRO? Sloan et al, Mayo Clinic Proc 77: 479-487, 2002.

  21. A Comparison of Simple Single-Item Measures and the Common Toxicity Criteria in Detecting the Onset of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer R. F. Morton, J. A. Sloan, A. Grothey, D. J. Sargent, H. McLeod, E. M. Green, C. Fuchs, R. K. Ramanathan, S. K. Williamson, R. M. Goldberg ASCO 2005

  22. Background • Peripheral neuropathy (PN) is common during treatment with Oxaliplatin • Assessment of PN is historically done via the Common Toxicity Criteria (CTC) • We developed a single-item numerical analogue scale assessment to help measure PN • We compared the two measures to look at the sensitivity of the CTC in detecting the onset of PN

  23. Methods • 696 patients randomized to FOLFOX4 • PN assessed bi-weekly during treatment • NAS filled out at baseline and every 12 weeks during treatment

  24. NCCTG/Intergroup Trial N9741 IFL: Irinotecan + 5-FU/LV RANDOMI ZAT ION FOLFOX4: Oxaliplatin + 5-FU/LV IROX: Irinotecan + Oxaliplatin Goldberg et al, JCO 2004

  25. NAS Tools

  26. An Empirical Anomaly • According to CTC only 20% of patients experienced serious PN • Clinical knowledge suggested the incidence rate should be much higher (about 80%)

  27. Agreement The agreement of < 65% indicates CTC and NAS measure different aspects of PN.

  28. Dose to PN: CTC versus NAS Which Comes First? Median dose to NAS CSD of 424 mg/m2 versus 765 ( 961) mg/m2 for CTC grade 2+ (3+) event

  29. Time to PN: CTC versus NAS Which Comes First? Patients notice an increase in PN two or three months earlier via the NAS

  30. Conclusions • Grade 2+ PN is found to be a significant problem according to the NAS • Using CTC, PN is under-reported • NAS may allow for earlier detection • NAS should be used in conjunction with CTC

  31. Are the occurrence of adverse events and clinically significant changes in symptom specific and global quality of life measures predictable? Sumithra J. Mandrekar, Ph.D. Mashele M. Huschka, B.S. James R. Jett, M.D. Jeff A. Sloan, Ph.D. Mayo Clinic Rochester, MN

  32. NCCTG Lung Cancer Trials

  33. QOL Assessments • Spitzer’s Uniscale • 1 question for the global assessment of QOL • Functional Assessment of Cancer Therapy Lung (FACT-L) • 27 questions divided into 4 well-being constructs: physical, social/family, emotional, and functional • 10 questions specific to lung cancer • Lung Cancer Symptom Scale (LCSS) • 9 questions pertaining to lung cancer symptoms • Symptom Distress Scale (SDS) • 12 questions related to symptoms commonly experienced by cancer patients

  34. Determine the relationship of a single-item assessment with the multiple-item summated scales

  35. Post-Baseline QOL Spearman Rank Correlations between the Uniscale and the FACT-L, LCSS, and SDS were 0.66, 0.57, and 0.49 respectively

  36. When QOL is high: Uniscale > LCSS When QOL is low: Uniscale < LCSS  Greater variability in Uniscale Scores Correlation=0.43

  37. Determine if clinically significant declines are more readily detected by a single-item or multiple-item assessment

  38. Individual Patient Data over time; Greater variability in Uniscale Scores

  39. Clinically Significant Decline (CSD) [10-point decline on a 0-100 scale] • Uniscale more likely to detect a CSD in QOL than the multiple-item assessments (58% vs. 39%) • The overall percent agreement in detecting a CSD in QOL between Uniscale and multiple-item assessments was 59%

  40. Determine how single-item assessment and multiple-item summated scales relate to adverse events data

  41. Adverse Events (AE) • Severe adverse event is defined as a grade 3, 4, or 5, regardless of attribution • 33% experienced a severe AE post baseline • Nine AEs experienced by at least 2% of the population that can also be collected via a QOL instrument • Alopecia, Anorexia, Constipation, Diarrhea, Dyspnea, Fatigue, Nausea, Neurosensory, Vomiting • 95% experienced at least one of the nine AEs • 20% had at least one of the nine graded as severe • CSD in AE is defined as a baseline AE of grade 0, 1, or 2 that changes to a grade 3, 4, or 5 post baseline

  42. Severe AE and CSD in QOL

  43. CSD in AE and CSD in QOL

  44. CSD in AE and CSD in QOL

  45. 70% 12%

  46. 83.7% • 6 events reported via CTC • 25 CSD reported via SDS 25.3%

  47. Summary • Uniscale demonstrates greater variability than the multiple-item indices • The Uniscale is better able to detect a CSD in QOL than the multiple item assessments, and captures a CSD earlier than the multiple item assessments • Correlations and percent agreement between Uniscale and multiple-item assessments were modest

  48. Summary • There is indication that a CSD in QOL occurs earlier than CTC AE reporting • Consistent with a recent finding that single-item QOL assessments detect a patient-perceived problem in peripheral neuropathy more than six weeks earlier than CTC (Morton et al, ASCO 2005) • The multiple-item assessments are in better agreement with occurrence or CSD in AE compared to the Uniscale

  49. What is the evidence for the use of simple (single-item) LASA’s?

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