This review covers a number of the many design and analytic issues associated with clinical trials that incorporate patient reported outcomes as primary or secondary endpoints. We use a clinical trial designed to evaluate a new therapy for the prevention of migraines to illustrate how endpoints are defined by the objectives of the study, the methods for handling longitudinal assessments with multiple scales or outcomes, and the methods of analysis in the presence of missing data.
Get full access to this article
View all access options for this article.
References
1.
Wilson IB , Cleary PD.Linking clinical variables with health-related quality of life - a conceptual model of patient outcomes . Journal of the American Medical Association1995; 273: 59-65 .
2.
Guyatt G , Feeny D , Patrick D.Issues in quality-of-life measurement in clinical trials . Controlled Clinical Trials1991; 12 (4S): 81S-90S .
3.
Goldhirsch A , Gelber RD , Simes RJ , Glasziou P , Coates AS.Costs and benefits of adjuvant therapy in breast cancer: a quality adjusted survival analysis . Journal of Clinical Oncology1989; 7: 36-44 .
McNeil BJ , Weichselbaum R , Pauker SG.Tradeoffs between quality and quantity of life in laryngeal cancer . New England Journal of Medicine1981; 305: 982-987 .
6.
Torrance GW , Thomas WH , Sackett DL.A utility maximizing model for evaluation of health care programs . Health Services Research1971; 7: 118-133 .
7.
Feeny D , Furlong W , Barr RD , Torrance GW , Rosenbaum P , Weitzman S.A comprehensive multi-attribute system for classifying the health status of survivors of childhood cancer . Journal of Clinical Oncology1992; 10: 923-928 .
8.
Weeks J.Quality-of-life assessment: performance status upstaged ? Journal of Clinical Oncology1992; 10: 1827-1829 .
9.
The EuroQoL Group . EuroQoL: a new facility for the measurement of health-related quality of life . Health Policy1990; 16: 199-208 .
10.
Slevin ML , Plant H , Lynch D , Wilson P , Gregory WM , Armes PJ , Downer SM.Who should measure quality of life, the doctor or the patient ? British Journal of Cancer1988; 57: 109-112 .
11.
Loprinzi CL , Laurie JA , Wieand S , Krook JE , Novotny PJ , Kugler JW , Bartel J , Law M , Bateman M , Klatt NE.Prospective evaluation of prognostic variables from patient-completed questionnaires . Journal of Clinical Oncology1994; 12: 601-607 .
12.
Coates A , Gebski V , Signorini D , Murray P , McNeil D , Byrne M , Forbes JF.Prognostic value of quality-of-life scores during chemotherapy for advance breast cancer . Journal of Clinical Oncology1992; 10: 1833-1838 .
13.
Wiklund I , Dimenas E , Wahl M.Factor of importance when evaluating quality of life in clinical trials . Controlled Clinical Trials1990; 11: 169-179 .
14.
Headache Classification Committee of the International Headache Society . Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain . Cephalalgia1988; 8 (Suppl 7): 1-96 .
15.
Osterhaus JT , Townsend RJ , Gandek B , Ware JEJ.Measuring the functional status and well-being of patients with migraine headache . Headache1994; 34: 337-343 .
16.
Solomon GD , Litaker DG.The impact of drug therapy on quality of life in headache and migraine . Pharmacoeconomics1997; 11: 334-342 .
17.
Solomon GD.Evolution of the measurement of quality of life in migraine . Neurology1997; 48 (Suppl 3): S1-S15 .
18.
Mannix LK , Solomon GD.Quality of life in migraine . Clinical Neuroscience1998; 5: 38-42 .
19.
Martin BC , Pathak DS , Kwong WJ , Batenhorst AS , Sharfman M.Assessment of responsiveness of the Migraine Specific Quality of Life Questionnaire (Version 2.1) . Presented at Drug Information Association Sixth Annual Symposium of Contributed Papers on Quality of Life Evaluation, Hilton Head, March 29, 1999.
20.
Martin BC , Pathak DS , Sharfman MI , Adelman JU , Taylor F , Kwong WJ , Jhingran P.Validity and reliability of the Migraine Specific Quality of Life Questionnaire. (MSQ Version 2.1) . Headache2000; 40: 204-215 .
21.
Ware JE , Snow KK , Kosinski M , Gandek B.SF-36 health survey: manual and interpretation guide. Boston, MA: Health Assessment Lab, New England Medical Center Health Institute , 1993.
22.
Fairclough DL.Summary measures and statistics for comparison of quality of life in a clinical trial of cancer therapy . Statistics in Medicine1997; 16: 1197-1209 .
23.
Senn S , Stevens L , Chaturvedi N.Repeated measures in clinical trials: simple strategies for analysis using summary measures . Statistics in Medicine2000; 19: 861-877 .
24.
Ware J , Kosinski M , Keller DS.SF-36 Physical and mental component summary scales: a user’s manual. Boston, MA: The Health Institute, New England Medical Center , 1994.
25.
Ware J , Kosinski M , Bayliss MS , McHorney CA , Rogers WH , Raczek A.Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study . Medical Care1995; 33: AS264-AS264 .
26.
Simon GE , Reviciki D , Grothaus L , Vonkorff M.SF-Summary Scores are physical and mental health truly distinct . Medical Care1998; 36: 567-572 .
27.
Holm S.A simple sequentially rejective multiple test procedure . Scandinavian Journal of Statistics1979; 33: 321-336 .
Westfall PH , Young SS.Resampling based multiple testing: examples and methods for p-value adjustments. NewYork, NY: John Wiley and Sons, Inc. , 1993.
30.
Marcus R , Pertz E , Gabrial KR.On closed testing procedures with special reference to ordered analysis of variance . Biometrika1976; 63: 655-660 .
31.
O’Brien PC.Procedures for comparing samples with multiple endpoints . Biometrics1984; 40: 1079-1087 .
32.
Pocock SJ , Geller NL , Tsiatis AA.The analysis of multiple endpoints in clinical trials . Biometrics1987; 43: 487-498 .
33.
Zhang J , Quan H , Ng J , Stepanavage ME.Some statistical methods for multiple endpoints in clinical trials . Controlled Clinical Trials1997; 18: 204-221 .
34.
Fetting JH , Gray R , Fairclough DL , Smith TJ , Margolin KA , Citron ML , Grove-Conrad M , Cella D , Pandya K , Robert N , Henderson IC , Osborne CK , Abeloff MD.Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study . Journal of Clinical Oncology1998; 16 (7): 2382-2391 .
35.
Fairclough DL , Fetting JH , Cella D , Wonson W , Moinpour CM.Quality of life and quality adjusted survival for breast cancer patients receiving adjuvant therapy . Quality of Life Research1999; 8: 723-731 .
36.
Efron B , Feldman D.Compliance as an explanatory variable in clinical trials . Journal of the American Statistical Association1991; 86: 9-17 .
37.
Shih WJ , Quan J.Testing for treatment differences with dropouts present in clinical trials - a composite approach . Statistics in Medicine1997; 16: 1225-1239 .
38.
Rubin DB.More powerful randomization-based p-values in double-blind trials with non-compliance . Statistics in Medicine1998; 17: 371-385 .
39.
Angrist JD , Imbens GW , Rubin DB.Identification of causal effects using instrumental variables . Journal of the American Statistical Association1996; 91: 444-455 .
40.
Newhouse JP , McClellan M.Econometrics in outcomes research: the use of instrumental variables . Annual Review of Public Health1998; 19: 17-34 .
41.
Little RJA.Modeling the dropout mechanism in repeated-measures studies . Journal of the American Statistical Association1995; 90: 1112-1121 .
42.
Fairclough DL , Peterson HF , Chang V.Why are missing quality of life data a problem in clinical trials of cancer therapy ? Statistics in Medicine1998; 17: 667-677 .
43.
Fairclough DL , Gagnon DD , Zagari MJ , Marschner N , Dicato M.Evaluation of quality of life in a clinical trial with nonrandom dropout: the effect of epoetin alfa in anemic cancer patients . Quality of Life Research2003; 12: 1013-1027 .
44.
Fairclough DL , Peterson HF , Cella D , Bonomi P.Comparison of several model-based methods for analysing incomplete quality of life data in cancer clinical trials . Statistics in Medicine1998; 17 (5-7): 781-796 .
45.
Zwinderman AH.Statistical analysis of longitudinal quality of life data with missing measurements . Quality of Life Research1992; 1: 219-224 .
46.
Little RJA.A test of missing completely at random for multivariate data with missing values . Journal of the American Statistical Association1988; 83: 1198-1202 .
47.
Diggle PJ.Testing for random dropouts in repeated measurement data . Biometrics1989; 45: 1255-1258 .
48.
Engelman L.BMDP 8D: Correlations with missing data. In: Dixon WJ , ed. BMDP statistical software, Berkeley: University of California Press , 1990, pp 711-720.
49.
Ridout MS.Testing for random dropouts in repeated measurement data . Biometrics1991; 47: 1617-1621 .
50.
Park T , Davis CS.A test of the missing data mechanism for repeated categorical data . Biometrics1993; 49: 631-638 .
51.
Laird NM.Missing data in longitudinal studies . Statistics in Medicine1988; 7: 305-315 .
52.
Jennrich RI , Schluchter MD.Unbalanced repeated-measures models with structured covariance matrices . Biometrics1986; 42: 805-820 .
53.
Dixon WJ ed. BMDP statistical software manual, Vol 2. Berkeley: University of California Press , 1990.
54.
The MIXED Procedure . SAS Technical Report P-229 SAS=STAT Software: Changes and Enhancements, Chap 16. Cary, NC: SAS Institute Inc. , 1992, pp 289-366.
55.
Fairclough DL.Quality of life in cancer clinical trials: now that we have the data, what do we do ? Journal of Applied Statistical Science1996; 4 (4): 253-269 .
56.
Wu MC , Bailey KR.Analyzing changes in the presence of informative right censoring caused by death and withdrawal . Statistics in Medicine1988; 7: 337-346 .
57.
Mori M , Woodworth GG , Woolson RF.Application of empirical Bayes inference to estimation of rate of change in the presence of informative right censoring . Statistics in Medicine1992; 11: 621-631 .
58.
Troxel AB , Harrington DP , Lipsitz SR.Analysis of longitudinal data with nonignorable non-monotone missing values . Applied Statistics1998; 47: 425-438 .
59.
Smith DM , Robertson B , Diggle PJ.Object-oriented software for the analysis of longitudinal data in S. Technical Report MA96=192. Department of Mathematics and Statistics, University of Lancaster, LA1 4YfF United Kingdom .
60.
Little RJA.A class of pattern-mixture models for normal incomplete data . Biometrika1994; 81, 471-483 .
61.
Curren D. Analysis of incomplete longitudinal quality of life data, Doctoral dissertation. Linburgs Universitair Centrum, June 2000.
62.
Diggle PJ , Kenward MG.Informative dropout in longitudinal data analysis (with discussion) . Applied Statistics1994; 43: 49-93 .
63.
Wu MC , Carroll RJ.Estimation and comparison of changes in the presence of informative right censoring by modeling the censoring process . Biometrics1988; 44: 175-188 .
64.
Schluchter MD.Methods for the analysis of informatively censored longitudinal data . Statistics in Medicine1992; 11: 1861-1870 .
65.
DeGruttola V , Tu XM.Modeling progression of CD4-lymphocyte count and its relationship to survival time . Biometrics1994; 50: 1003-1014 .
66.
Ribaudo HJ , Thompson SG , Allen-Mersh TG.A joint analysis of quality of life and survival using a random effects selection model . Statistics in Medicine2000; 19: 3237-3250 .
67.
Heyting A , Tolboom JTBM , Essers JGA.Statistical handling of dropouts in longitudinal clinical trials . Statistics in Medicine1992; 11: 2043-2061 .
68.
Gould AL.A new approach to the analysis of clinical drug trials with withdrawals . Biometrics1980; 36: 721-727 .
69.
Lavori PW , Dawson R , Shera D.A multiple imputation strategy for clinical trials with truncation of patient data . Statistics in Medicine1995; 14: 1913-1925 .
70.
Rubin DB.Multiple imputation for nonresponse in surveys. New York: Wiley , 1987.
71.
Rubin DB , Schenker N.Multiple imputation in health-care data bases: an overview and some applications . Statistics in Medicine1991; 10: 585-598 .
72.
Schafer JL.Analysis of incomplete multivariate data. New York: Chapman and Hall , 1997.
73.
Crawford SL , Tennstedt SL , McKinlay JB.A comparison of analytic methods for non-random missingness of outcome data . Journal of Clinical Epidemiology1995; 48: 209-219 .
