124S Abstracts

84P THE GRAPHICAL REPRESENTATION OF THE RELATIONSHIP BETWEEN

SURVIVAL AND TIME-DEPENDENT VARIABLES: A SAS MACRO FOR REALIZATION OF THE SIMON & MAKUCH METHOD

H. Ansari, C. Biller and D. Messerer Biomewic Center for Therapeutic Studies

Munich, Germany

An univariate survival analysis and a graphical realization of the effect of time- dependent covariates (e.g., tumor response or bone marrow transplantation during a chemotherapy regimen) using the product-limit method of Kaplan & Meier is biased. A patient with "response" (response is a stochastical change of a status during the observation) must live long enough to achieve a response, whereas a patient with the event "death" in the non-responder group has never had the chance to achieve a response. A stratified Kaplan- Meier analysis can only be used for initial prognostic variables.

Simon & Makuch published a modification of the Kaplan-Meier estimator to present graphically the results of survival analysis for time-dependent variables. In the estimation of survival probability using Kaplan-Meier method the number of "at risk" patients decreases over the time. The main idea of the Simon & Makuch procedure is the change of the number of the patients "at risk" in the responder group. That means the number of patients "at risk" increases at the beginning and decreases afterwards.

We developed a SAS/IML macro for the non-parametric graphic representation according to the Simon & Makuch method, because a standard procedure in common statistical packages (e.g. SAS or BMDP) does not exist.

The effect of hematological response and bone marrow eransplantation on survival using the Simon & Malmch method will be presented in an example from the German CML- trial.

85P A COMPARISON OF INTERIM ANALYSES USING THE TRIANGLE TEST

AND THE RESTRICTED PROCEDURES/ALPHA SPENDING FUNCTION- EXPERIENCE WITH TWO CLINICAL TRIALS

Michael Thorn and John Horton Burroughs Wellcome Co.

Research Triangle Park, North Carolina

Group sequential procedures for interim analysis of large multicenter clinical trial is a well-established procedure involving mortality and other important endpoints. A variety of techniques are available to implement these procedures, each with different sensitivities to various trial outcomes. Two of these statistical procedures are the Triangle Test and the Lan = DeMets Alpha Spending Function. This later procedure is equivalent to the Restricted Procedure of Whitehead.

Simulation results comparing the Triangle Test and Restricted Procedure/Alpha Spending Function are presented for various treatment benefits. These results are directly contrasted. Advantages and disadvantages for the use of each of these procedures are explored and documented.

Two recently completed large multicenter clinical trials were stopped prematurely. One stopped early because of negative results, based on the Restricted Procedure; the only stopped due to lack of treatment efficacy based on the Lan-DeMets Alpha Spending Function.

Abstracts 1 2 5 S

These are examined as case studies comparing the trial outcomes using the Triangle Test and the Restricted Procedure/Alpha Spending Function.

86P EQUIVALENCE TESTING: "NO DIFFERENCE" IS NOT

SYNONYMOUS WITH "EQUIVALENT"

Laurence Lion, Margaret C. Haugh and Jean-Pierre Boissel Un~ de Pharmacologie ¢linique

Lyon, France

Increasingly, it is necessary to evaluate the therapeutic equivalence of two or more therapies, so that differences in terms of safety, or quality of life, for example, can then be assessed in order to differentiate the therapies. Bioequivalence is a biological concept and is important when new formulations of drugs are developed. Therapeutic equivalence is a similar concept in the clinical field where only the endpoints change since assessing the theoretical equivalence of two therapies which have very different modes of action makes little sense; the interest is in terms of pragmatic therapeutic decision making. In many cases equivalence is concluded when a nonsignificant difference is found, although it is obvious that there are many reasons for this, such as lack of sta~stical power. In reality, the hypothesis tested is not suitable for the required goal. There are two main approaches to this problem: one based on confidence intervals of the differences between the therapies and the other on p-values. The first approach enables to determine only which equivalence intervals are compatible with the observa~ons, whereas the second uses appropriate tests that attach a statistical significance to the hypothesis of equivalence defined, a pr/or/. This latter approach is often misused in decision making. These different methods were applied to d~ta from 633 patients included in OCAPI, a clinical trial in which the initial aim was to demonstrate the therapeutic equivalence of four hypertensives from different pharmacological classes. The endpoint used was the difference between the pre-inclusion diastolic blood pressure and the mean of the median from each follow-up visit, divided by the initial value, expressed as a percentage. In the event of equivalence, differences in the patients' subjective quality of life were to be assessed. Pairwise comparisons of the treatments using the 90% confidence interval for the difference, or the shorter confidence interval method of Westlake, or Hauck & Anderson method were performed. Although this latter test, in certain circumstances, is the most powerful, with our d~t, set, similar results were obtained with all three methods.

87P PRACTICAL ISSUES IN APPLYING THE RESTRICTED MEAN LIFE

Rick Chappeil University of Wisconsin-Madison

Madison, Wisconsin

It would seem redundant to tell statisticians the virtues of the sample mean. Yet, for right-censored date the natural extension of the sample mean has undesirable traits which have led to its disuse. Irwin (1949) described a restricted mean life (RML) e s l ~ t e which obviated these emits.

The basic properties of the estimated RML are summarized and contrasted with those of analogous estimates computed under common parametric assumptions. Efficiency calculations are given. The RML is shown to be useful under more general patterns of missing data such as truncation and interval censoring.

These results are applied to dAt~ from an ophthalmologic trial and a study on aging.