668 Abstracts

S131 PARALLEL RANDOMIZED AND NONRANDOMIZED CLINICAL TRIALS: WHAT CAN WE GAIN?

Sue M. Marcus University of Pennsylvania Philadelphia, Pennsylvania

In a randomized clinical trial where one treatment is more invasive (e.g., surgery versus no surgery), a large proportion of patients eligible for randomization may decline consent to be randomized. Some inves- tigators have responded to this situation by conducting, in addition to the randomized trial, a separate nonrandomized but otherwise identical trial consisting of those patients who are eligible for randomization, but instead choose their own treatment. Three such clinical trials considered are those comparing coronary artery bypass surgery versus no surgery, adenoidectomy versus no surgery, and tonsillectomy versus no surgery.

Various types of bias can arise in parallel randomized and nonrandomized trials. Patients who accept randomization may differ from those in the nonrandomized trials in ways that affect response. In addition, those in the nonrandomized trial who receive the treatment may differ from those who receive the control. Nonetheless, it has been asserted in the literature that the nonrandomized trials can add useful information. Claims from the above studies that the addition of the nonrandomized trials maximize generalizability and support and extend the inference from the randomized trials will be evaluated.

P1 THERAPEUTIC COVERAGE: A CROSSOVER COMPARISON BETWEEN TWO DRUGS OF THE SAME

CLASS IN OUTPATIENT PRACTICE

Guy Heynen Medical Department

Pfizer AG Zurich, Switzerland

Taking compliance (% of prescribed doses taken) and therapeutic coverage (% TC) were estimated in 79 outpatients suffering from hypertension or angina using an open crossover design of two times one month observation. During the first month, patients were to continue or asked to take a twice-a-day calcium antagonist (nifedipine SR, 2 x 20 mg) (NIF) and then asked to take a once-a-day calcium antagonist of the same class (amlodipine, 1 x 5 mg) (AML) for another month. During this 2 month observation period, actual times of drug intake were monitored by an electronic device (MEMS, TM, Aprex Corporation, California). Intervals of subtherapeutic drug action (ISDA) were estimated by summing up the intervals between drug intake exceeding one and a half times the half-life of each drug and % TC then computed as: 100 (Duration of treatment - ISDA)/(Duration of treatment). Mean age of the patients was 65 (range 27-82) and 70 of the 79 patients were suffering from hypertension. Observation period was equal between drugs (29 days). Taking compliance during NIF and AML treatments were 87% and 99% respectively (p < 0.001 ). Percentage TC during NIF and AML treatments were 82% and 99.6% respectively. In 25% of the patients during NIF treatment, % TC was less than 75% (mean 60% +/- 10,SD). In these patients, % TC increased to 99.7% during AML treatment (p < 0.001).

P2 INTERIM P-VALUES FOR GROUP SEQUENTIALLY MONITORED TRIALS

Kathryn Davis and Lloyd Fisher University of Washington

Seattle, Washington

Group sequential monitoring procedures such as the Pocock and O'Brien-Fleming methods are set up to accept or reject the null hypothesis at a fixed alpha level. The methods do not provide a p-value at the termination of the trial or at intedm points before a boundary is reached or accrual and follow-up end. A method of providing an interim p-value will be described. Briefly, the boundaries for most sequential monitoring procedures are nested, that is the boundary for alpha-level 1 is entirely inside the boundary for alpha-level 2 if alpha 1 is greater than alpha 2. Thus for each observed point, the alpha level for which that observation would have ended the trial at that time point can be uniquely determined. This alpha may then be used as an intedm p-value. The presentation will discuss the probability interpretation of this p-value and will give an iterative method of determining p for a given observed value for the Pocock method and for the O'Bden- Fleming method.