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A comparative study of non-randomized and randomized controls
abstracts
661
Al12 AN ANALYSIS STRATEGY FOR MULTI-DOSE COMBINATION DRUG CLINICAL TRIALS James Phillips, Gary Koch, and Victoria Cairns Quintiles, Inc. Research Triangle Park, North Carolina Combination drugs frequently are developed to treat more than one symptom of a disease process or to enhance efficacy. Regulatory requirements in the United States demand that the sponsor of such a product demonstrate the superior efficacy of the combination relative to each of its components and additionally, the safety of the combination for the indicated patient population. An empirical set of procedures is presented for consideration in the design and analysis of such a clinical tdal. The procedures are based on the concepts of response surface methodology (RSM) and adapted to address the statistical issues involved. In particular, the phase of drug development determines the appropriate emphasis. RSM procedures can be applied to predict dosage combinations that are expected to produce optimal responses. A confirmatory tdal generally requires hypothesis testing procedures to compare treatment groups directly. RSM procedures also may be used in this situation although regression modeling has not been traditionally applied in a confirmatory setting. The procedures discussed include sample size estimation for the different treatment combinations. A strategy is presented using RSM procedures for the results of a study with a 3 x 4 factorial design comparing different doses of an ACE inhibitor combined with different doses of a diuretic in the treatment of hypertension.
Al13 A COMPARATIVE STUDY OF NON-RANDOMIZED AND RANDOMIZED CONTROLS L.C. Ward, British Stomach Cancer Group and West Midlands Regional Cancer Registry ,~University of Birmingham Birmingham, England Prospectively randomized controlled clinical trials (RCTs) are the preferred method of evaluating new cancer treatments. Nonrandomized controls (NRCs) have been advocated where there are difficulties in randomizing sufficient cases (Gehan, 1974). It is suggested that NRCs can produce a reliable comparison if carefully matched for selection criteria and major prognostic factors (Gehan, 1978), however there are serious methodological problems with this approach (Byar, 1974). A study has been performed to evaluate the use of NRCs derived from cancer registration data. A concurrent NRC arm to a controlled, prospectively randomized trial was obtained by reviewing data at the WM Registry. The effect of entry criteria on patient numbers and survival will be described. During 1976-80, 249 cases aged between 15-74, were randomized to a trial comparing adjuvant chemotherapy or a placebo following resection for operable adenocaroinoma of the stomach. The study found no difference in survival between placebo and treatment (Allum, 1989). During this period a further 1,261 cases meeting the broad criteria were treated in the Region. Further objective eligibility criteria included prior malignancy, SNOP classification, and stage, while fitness, consent and surgical intent were highly subjective. Criteria were ranked by the accuracy of the retrospective documentation, and were then successively applied to model the effect of failure to control for a criterion. Survival of trial versus NRCs was compared at each step. Trial cases showed an initial survival advantage over NRCs (p = 0.05). This advantage increased as all objective criteria were applied (p : 0.0001) but was removed when the cdterion of fitness was added (p = 0.1). Applying all cdteda reduced the number eligible for study by 53% to 217 (31%) tdal versus 493 NRCs (p = 0.2). The wide range of possible conclusions on the role of treatment can only be resolved by reference to the randomized control arm. This supports Pocock's (Pocock, 1983) statement that it is impossible to be certain that the comparison made is fair if NRCs are used. The need for randomized tdals is confirmed.
A114 GUIDELINES FOR SIMULTANEOUS PARTICIPATION IN TWO OR MORE RANDOMIZED TRIALS R.J. Slmes University of Sydney New South Wales, Australia In pragmatic large-scale randomized clinical trials such as the planned GUSTO and ISIS-IV trials in acute myocardial infarction, reservations have been expressed that patient participation in more than one trial may jeopardize the first tdal through reduced compliance or subadditive effects, or invalidate conclusions. Yet
661
Al12 AN ANALYSIS STRATEGY FOR MULTI-DOSE COMBINATION DRUG CLINICAL TRIALS James Phillips, Gary Koch, and Victoria Cairns Quintiles, Inc. Research Triangle Park, North Carolina Combination drugs frequently are developed to treat more than one symptom of a disease process or to enhance efficacy. Regulatory requirements in the United States demand that the sponsor of such a product demonstrate the superior efficacy of the combination relative to each of its components and additionally, the safety of the combination for the indicated patient population. An empirical set of procedures is presented for consideration in the design and analysis of such a clinical tdal. The procedures are based on the concepts of response surface methodology (RSM) and adapted to address the statistical issues involved. In particular, the phase of drug development determines the appropriate emphasis. RSM procedures can be applied to predict dosage combinations that are expected to produce optimal responses. A confirmatory tdal generally requires hypothesis testing procedures to compare treatment groups directly. RSM procedures also may be used in this situation although regression modeling has not been traditionally applied in a confirmatory setting. The procedures discussed include sample size estimation for the different treatment combinations. A strategy is presented using RSM procedures for the results of a study with a 3 x 4 factorial design comparing different doses of an ACE inhibitor combined with different doses of a diuretic in the treatment of hypertension.
Al13 A COMPARATIVE STUDY OF NON-RANDOMIZED AND RANDOMIZED CONTROLS L.C. Ward, British Stomach Cancer Group and West Midlands Regional Cancer Registry ,~University of Birmingham Birmingham, England Prospectively randomized controlled clinical trials (RCTs) are the preferred method of evaluating new cancer treatments. Nonrandomized controls (NRCs) have been advocated where there are difficulties in randomizing sufficient cases (Gehan, 1974). It is suggested that NRCs can produce a reliable comparison if carefully matched for selection criteria and major prognostic factors (Gehan, 1978), however there are serious methodological problems with this approach (Byar, 1974). A study has been performed to evaluate the use of NRCs derived from cancer registration data. A concurrent NRC arm to a controlled, prospectively randomized trial was obtained by reviewing data at the WM Registry. The effect of entry criteria on patient numbers and survival will be described. During 1976-80, 249 cases aged between 15-74, were randomized to a trial comparing adjuvant chemotherapy or a placebo following resection for operable adenocaroinoma of the stomach. The study found no difference in survival between placebo and treatment (Allum, 1989). During this period a further 1,261 cases meeting the broad criteria were treated in the Region. Further objective eligibility criteria included prior malignancy, SNOP classification, and stage, while fitness, consent and surgical intent were highly subjective. Criteria were ranked by the accuracy of the retrospective documentation, and were then successively applied to model the effect of failure to control for a criterion. Survival of trial versus NRCs was compared at each step. Trial cases showed an initial survival advantage over NRCs (p = 0.05). This advantage increased as all objective criteria were applied (p : 0.0001) but was removed when the cdterion of fitness was added (p = 0.1). Applying all cdteda reduced the number eligible for study by 53% to 217 (31%) tdal versus 493 NRCs (p = 0.2). The wide range of possible conclusions on the role of treatment can only be resolved by reference to the randomized control arm. This supports Pocock's (Pocock, 1983) statement that it is impossible to be certain that the comparison made is fair if NRCs are used. The need for randomized tdals is confirmed.
A114 GUIDELINES FOR SIMULTANEOUS PARTICIPATION IN TWO OR MORE RANDOMIZED TRIALS R.J. Slmes University of Sydney New South Wales, Australia In pragmatic large-scale randomized clinical trials such as the planned GUSTO and ISIS-IV trials in acute myocardial infarction, reservations have been expressed that patient participation in more than one trial may jeopardize the first tdal through reduced compliance or subadditive effects, or invalidate conclusions. Yet