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Point and intercal estimation in clinical trials with interim analyses
Abstracts
253 However, the decision rules for the two analyses differ in general structure. Here a decision rule similar to the one proposed in the latter is employed for the problem examined in the former and some comparisons are made.
Point and Interval E s t i m a t i o n in C l i n i c a l Trials w i t h Interim Analyses G e r r i t - A n n e v a n Es, Jacobus Lubsen, a n d Roel v a n Strik Thoraxcenter, Rotterdam, The Netherlands (39) The Cooperative North-Scandinavian Enalapril Survival Study (CONSENSUS), a multicenter, double-blind, placebo-controlled trial, was terminated prematurely because a planned interim analysis of the data had shown a clear mortality reduction in the enalapril-treated group compared to placebo-treated group [rate ratio = 0.56, 95%CI = (0.41,0.77)]. It was concluded that further continuation of the trial was no longer justifiable on ethical grounds and was of limited scientific value. The purpose of performing interim analyses in clinical trials with long-term follow-up is to look whether continuation of the trial is justified. With respect to the major outcome event(s) the trial will be stopped early (1) when a minimally clinically important effect (DIF) can be assumed to exist, or (2) when the current data make it unlikely that the final results will demonstrate DIF. The performance of such a decision rule, expressed in terms of point and interval estimates of the effect measure(s), is presented for CONSENSUS. On the basis of these results and simulation studies more general guidelines are given.
Early Termination Scheme for a Trial of Prophylactic Chemotherapy in Stage 1 Testicular Teratoma Sally S t e n n i n g a n d L a u r e n c e F r e e d m a n
Medical Research Council Cancer Trials Office, Cambridge, England (40) It is now possible to identify, by pathological examination, patients at high risk of relapse following orchiectomy for stage 1 testicular teratoma. These patients have a documented relapse rate of 50% with the first 2 years. The British Medical Research Council has designed a study in which 50 such patients are to be treated by chemotherapy following orchiectomy. It is hoped to completely eliminate disease relapse by this strategy, since the chemotherapy has been found to be highly effective in manifest disease. Because the chemotherapy is toxic clinicians demand that the relapse rate following treatment should not exceed 5%; otherwise the treatment is not clinically justified. An early termination scheme is therefore required to alert the clinician to data that strongly suggest a relapse rate greater than 5%. A method based on predictive probability is presented in which the endpoint is time to relapse rather than tumor response. A range of schemes are considered and one that has favorable type I and type II error is selected. Since this method is based on an approximation, computer simulations have been carried out to check the theoretical results.
Reasons for D e f e r r a l of Protocols b y a Non-Institutional Review Board William P. M u l l o y Temple University Medical Center, Philadelphia, Pennsylvania (41) A number of research protocols were deferred in the year 1987 by a Non-Institutional Review Board. This paper studies the disposition of all protocols reviewed in a 12-month period, with attention to those deferred for action. The Board considered qualifications of the investigators, design and structure of the protocol, and the Informed Consent form. Reasons for deferral fell into three categories: (1) Most frequent was failure of the protocol design to answer questions posed by the investigator. A redesign according to published FDA guidelines allowed an acceptable resubmission to be approved. (2) The second most frequent reason was risk to the participants, who were considered inadequately protected. (3) The Board frequently required changes in the Consent Form to assure it contained all information in the protocol itself. In nearly all cases, researchers were able to rectify the errors listed above and resubmit material acceptable to the Board.
253 However, the decision rules for the two analyses differ in general structure. Here a decision rule similar to the one proposed in the latter is employed for the problem examined in the former and some comparisons are made.
Point and Interval E s t i m a t i o n in C l i n i c a l Trials w i t h Interim Analyses G e r r i t - A n n e v a n Es, Jacobus Lubsen, a n d Roel v a n Strik Thoraxcenter, Rotterdam, The Netherlands (39) The Cooperative North-Scandinavian Enalapril Survival Study (CONSENSUS), a multicenter, double-blind, placebo-controlled trial, was terminated prematurely because a planned interim analysis of the data had shown a clear mortality reduction in the enalapril-treated group compared to placebo-treated group [rate ratio = 0.56, 95%CI = (0.41,0.77)]. It was concluded that further continuation of the trial was no longer justifiable on ethical grounds and was of limited scientific value. The purpose of performing interim analyses in clinical trials with long-term follow-up is to look whether continuation of the trial is justified. With respect to the major outcome event(s) the trial will be stopped early (1) when a minimally clinically important effect (DIF) can be assumed to exist, or (2) when the current data make it unlikely that the final results will demonstrate DIF. The performance of such a decision rule, expressed in terms of point and interval estimates of the effect measure(s), is presented for CONSENSUS. On the basis of these results and simulation studies more general guidelines are given.
Early Termination Scheme for a Trial of Prophylactic Chemotherapy in Stage 1 Testicular Teratoma Sally S t e n n i n g a n d L a u r e n c e F r e e d m a n
Medical Research Council Cancer Trials Office, Cambridge, England (40) It is now possible to identify, by pathological examination, patients at high risk of relapse following orchiectomy for stage 1 testicular teratoma. These patients have a documented relapse rate of 50% with the first 2 years. The British Medical Research Council has designed a study in which 50 such patients are to be treated by chemotherapy following orchiectomy. It is hoped to completely eliminate disease relapse by this strategy, since the chemotherapy has been found to be highly effective in manifest disease. Because the chemotherapy is toxic clinicians demand that the relapse rate following treatment should not exceed 5%; otherwise the treatment is not clinically justified. An early termination scheme is therefore required to alert the clinician to data that strongly suggest a relapse rate greater than 5%. A method based on predictive probability is presented in which the endpoint is time to relapse rather than tumor response. A range of schemes are considered and one that has favorable type I and type II error is selected. Since this method is based on an approximation, computer simulations have been carried out to check the theoretical results.
Reasons for D e f e r r a l of Protocols b y a Non-Institutional Review Board William P. M u l l o y Temple University Medical Center, Philadelphia, Pennsylvania (41) A number of research protocols were deferred in the year 1987 by a Non-Institutional Review Board. This paper studies the disposition of all protocols reviewed in a 12-month period, with attention to those deferred for action. The Board considered qualifications of the investigators, design and structure of the protocol, and the Informed Consent form. Reasons for deferral fell into three categories: (1) Most frequent was failure of the protocol design to answer questions posed by the investigator. A redesign according to published FDA guidelines allowed an acceptable resubmission to be approved. (2) The second most frequent reason was risk to the participants, who were considered inadequately protected. (3) The Board frequently required changes in the Consent Form to assure it contained all information in the protocol itself. In nearly all cases, researchers were able to rectify the errors listed above and resubmit material acceptable to the Board.