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Comparison of statistical methods for combining event rates from clinical trials
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Abstracts is blood pressure change between baseline and 6 months. There are three clinical centers in the study, a nutritional and behavioral core, and a coordinating center. The study consists of a 3 x 3 factorial design wherein participants are randomly allocated to nine drug-diet treatment groups. Drugs include placebo, diuretic, and beta-blocker. Diets are normal, weight loss, and low sodium/high potassium. The basic strategy, is to address clinical questions of interest by comparing mean BP changes of selected drug-ciiet combinations. This presentation includes the experimental design of the study, sample-size considerations, statistical analysis, and the organizational structure of the study.
The U.S.-Finland Lung Cancer Prevention Trial: A Report on Study Design and Recruitment Olli H e i n o n e n , B r e n d a K. E d w a r d s , D e m e t r i u s A l b a n e s , J a r m o V i r t a m o , J a a s o n H a a p a k o s k i , P h i l i p R. Taylor, A n n e H a r t m a n , Jussi H u t t u n e n , a n d P e t e r Greenwald
National Public Health Institute, Helsinki, Finland and the National Cancer Institute, Bethesda, Maryland (20) The efficacy of two micronutrients in reducing incidence of lung cancer and lowering mortality among male smokers 50-69 years of age is being evaluated in a randomized double-blind clinical trial conducted in southern Finland. Design considerations, including sample size estimation, are presented for the 2 x 2 factorial study utilizing beta-carotene and alpha-tocopheral as the intervention agents. Initial selection of potentially eligible subjects was based on responses to seven segments of a population-based postal survey with coverage of approximately 200,000 males in the age-reference target group. Results are reported on the full-scale recruitment process, which began in April 1985 and continues through June 1987 with the objective of randomizing 20,000 subjects.
Comparison of Statistical Methods for Combining Event Rates from Clinical T r i a l s Jesse A. Berlin, N a n M. Laird, H e n r y S. Sacks, a n d T h o m a s C. C h a l m e r s
Harvard School of Public Health, Boston, Massachusetts Mt. Sinai School of Medicine, New York, New York (21) Two statistical methods for handling event rates were compared, both treating each study as a stratum. The Peto-modified Mantel-Haenszel test (Peto) estimates combined odds ratios assuming homogeneity across strata, plus a test for heterogeneity. The Der Simonian and Laird Modified Cochran Method (D&L) obtains weighted averages (by size and heterogeneity) of risk differences without assuming homogeneity (a random effects model). Fifteen meta-analyses in eight reports have been done by both methods: beta-blockers, IV streptokinase and lidocaine for A.M.I., nicotine chewing gum, prevention of stroke and of bleeding in susceptible patients, and 1-day treatment of urinary tract infection. The pooled estimates were divided by their standard errors to produce a Z stat. Paired T test of Zs (Peto-D & L) was +0.314 (T = 1.5 P = 0.15). The P value for the test of heterogeneity and size of difference between Z scores are highly correlated (r = 0.91). In conclusion, the more heterogeneity the more D&L tends to be conservative and Peto sensitive. In absence of heterogeneity the tests are similar but still differ conceptually.
Problems in Design, Execution, and Analysis of Cancer Clinical Trials (CCTs) Determined During FDA Review G r e g o r y Burke
Food and Drug Administration, Rockville, Maryland (22) Problems in interpretation of cancer clinical trials from the perspective of an FDA reviewer include study designs such as positive control, combination therapy, and crossover studies. The execution of cancer clinical trials has often led to inconclusive results because of flaws in the determination of survival data, response rate, and duration, failure to adhere to the protocol for both treatment and the assessment of response and toxicities, and errors in record keeping. The analysis of cancer clinical trials has been hampered by imprecise statistical planning, changes made in the overall objectives after the study has been performed, and by the lack of clear endpoints regarding quality of life assessment. The FDA encourages early communication between sponsors and the reviewing team so that these types of deficiencies can be identified before the initiation of large phase Ill cancer clinical trials.
Abstracts is blood pressure change between baseline and 6 months. There are three clinical centers in the study, a nutritional and behavioral core, and a coordinating center. The study consists of a 3 x 3 factorial design wherein participants are randomly allocated to nine drug-diet treatment groups. Drugs include placebo, diuretic, and beta-blocker. Diets are normal, weight loss, and low sodium/high potassium. The basic strategy, is to address clinical questions of interest by comparing mean BP changes of selected drug-ciiet combinations. This presentation includes the experimental design of the study, sample-size considerations, statistical analysis, and the organizational structure of the study.
The U.S.-Finland Lung Cancer Prevention Trial: A Report on Study Design and Recruitment Olli H e i n o n e n , B r e n d a K. E d w a r d s , D e m e t r i u s A l b a n e s , J a r m o V i r t a m o , J a a s o n H a a p a k o s k i , P h i l i p R. Taylor, A n n e H a r t m a n , Jussi H u t t u n e n , a n d P e t e r Greenwald
National Public Health Institute, Helsinki, Finland and the National Cancer Institute, Bethesda, Maryland (20) The efficacy of two micronutrients in reducing incidence of lung cancer and lowering mortality among male smokers 50-69 years of age is being evaluated in a randomized double-blind clinical trial conducted in southern Finland. Design considerations, including sample size estimation, are presented for the 2 x 2 factorial study utilizing beta-carotene and alpha-tocopheral as the intervention agents. Initial selection of potentially eligible subjects was based on responses to seven segments of a population-based postal survey with coverage of approximately 200,000 males in the age-reference target group. Results are reported on the full-scale recruitment process, which began in April 1985 and continues through June 1987 with the objective of randomizing 20,000 subjects.
Comparison of Statistical Methods for Combining Event Rates from Clinical T r i a l s Jesse A. Berlin, N a n M. Laird, H e n r y S. Sacks, a n d T h o m a s C. C h a l m e r s
Harvard School of Public Health, Boston, Massachusetts Mt. Sinai School of Medicine, New York, New York (21) Two statistical methods for handling event rates were compared, both treating each study as a stratum. The Peto-modified Mantel-Haenszel test (Peto) estimates combined odds ratios assuming homogeneity across strata, plus a test for heterogeneity. The Der Simonian and Laird Modified Cochran Method (D&L) obtains weighted averages (by size and heterogeneity) of risk differences without assuming homogeneity (a random effects model). Fifteen meta-analyses in eight reports have been done by both methods: beta-blockers, IV streptokinase and lidocaine for A.M.I., nicotine chewing gum, prevention of stroke and of bleeding in susceptible patients, and 1-day treatment of urinary tract infection. The pooled estimates were divided by their standard errors to produce a Z stat. Paired T test of Zs (Peto-D & L) was +0.314 (T = 1.5 P = 0.15). The P value for the test of heterogeneity and size of difference between Z scores are highly correlated (r = 0.91). In conclusion, the more heterogeneity the more D&L tends to be conservative and Peto sensitive. In absence of heterogeneity the tests are similar but still differ conceptually.
Problems in Design, Execution, and Analysis of Cancer Clinical Trials (CCTs) Determined During FDA Review G r e g o r y Burke
Food and Drug Administration, Rockville, Maryland (22) Problems in interpretation of cancer clinical trials from the perspective of an FDA reviewer include study designs such as positive control, combination therapy, and crossover studies. The execution of cancer clinical trials has often led to inconclusive results because of flaws in the determination of survival data, response rate, and duration, failure to adhere to the protocol for both treatment and the assessment of response and toxicities, and errors in record keeping. The analysis of cancer clinical trials has been hampered by imprecise statistical planning, changes made in the overall objectives after the study has been performed, and by the lack of clear endpoints regarding quality of life assessment. The FDA encourages early communication between sponsors and the reviewing team so that these types of deficiencies can be identified before the initiation of large phase Ill cancer clinical trials.