Stopping a clinical trial

Pocock (1992) has succinctly summarized most of the situations that obtain when it is considered whether to stop a clinical trial. Efficacy, like safety, can cause ethical concerns to the pharmaceutical physician when he or she suspects that patients will be exposed to alternative therapies which are suboptimal. 

Stopping a clinical trial because of an emergent safety problem, either by a medical monitor or by a safety committee, is always a unique situation. Little useful, generalizable guidance can be provided here. These are decisions that are always... 

Clinical Trial Application (CTA) has to be submitted to Health Canada seeking permission to conduct clinical trials. The submission should include information regarding drug characteristics, test data, animal studies, and clinical protocol. A clinical trial may be stopped when either it is shown to be unsafe or dramatic benefits are obtained. The approval process may be fast-tracked if a drug is shown to have substantial benefits, such as for treatment of life-threatening or severely debilitating conditions. 

This document has set down some initial thoughts from a regulatory point of view about the issues involved in allowing the design of a clinical trial to be adapted as the trial progresses. Modification of the sample size based on blinded data and stopping for overwhelming efficacy or futility are forms of adaptation that are already well accepted, but this Reflection Paper considers other possibilities that are more controversial. 

A recent case concerning an fflV vaccine, which used a replication defective adenovirus type 5 (Ad5) vector, was stopped after a clinical trial showed an increase in HIV infections postvaccination. A followup investigation by Perreau et al.,96 using ex vivo modeling with dendritic cells, showed how the formation of Ad5 immune complexes, a consequence of previous adenovirus exposure, can lead to specific CD4 and 8 T cell responses, which are targeted more toward the adenovirus than the HIV antigen, and as a consequence are less protective. 

All proposed clinical trials in Europe now have to receive an affirmative favorable opinion from a properly constituted ethics committee, before commencement. In the case of multinational, multicenter trials, only a single ethics committee opinion is needed in each MS. There is nonetheless the capability for individual sites, with additional ethics committees, to reject a clinical trial. But a negative opinion from the local ethics committees would only stop the trial at the particular site, and not affect the overall approval given from the lead ethics committee in the relevant MS. 

Abrupt cessation of a clinical trial could occur for nonclinical reasons, such as a nonclinical toxicology study finding. In such a situation, not all subjects would have completed the clinical trial—an incompletely observed study. The question arises as to what the responses of the subjects who could not complete the study would have been if the trial was not stopped abruptly. If a solution was found that provided an insight into what the study outcome would have been, the need for repeating such a study once the nonclinical problems are resolved could be obviated. 

Note, that these proportions are true in the long run. If a clinical trial is stopped after a short while and all future patients are then allocated to the treatment which has proved best so far, with no option to reverse this policy, then the randomized trial... 

This is an issue which has received much attention elsewhere but which is generally seen to be less relevant within the context of drug development. If one performs regular meta-analyses of clinical trials and then stops doing clinical trials if or when the result of the meta-analysis becomes signlflcant, then such a procedure is subject to the general bias to which (unadjusted) sequential clinical analysis of ordinary clinical trials is liable. 

Sequential trial. (A somewhat unfortunate term since nearly all patients are recruited sequentially and in this sense nearly all trials would be sequential.) A clinical trial in which the results are analysed at various intervals with the intention of stopping the trial when a conclusive result has been reached. A stopping rule is usually defined in advance. In frequentist statistics it is necessary to make an adjustment to the results of an otherwise standard analysis to take the stopping rule into account. Such an adjustment is not necessary in Bayesian statistics, although the stopping rule itself ought to be at least partly dependent on the prior distribution so that, for this reason alone, the posterior distribution will vary with the stopping rule. 

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

The effect of statins on plasma lipids and lipoproteins is rapidly seen and fully achieved after 4-6 weeks of treatment. The effect persists unchanged during continued use for several years, but after stopping the diug, LDL-cholesterol rapidly increases to pretreatment levels. Treatment with statins is therefore usually continued indefinitely and not as a short-term cure. Finally, it is generally advisable to use the statins that have documented their efficacy in clinical trials (evidence-based medicine). 

Consequently, S-1360, a triazole analogue of DKA, was the first integrase strand transfer inhibitor (INSTI) to enter clinical trials, but the development was stopped during phase Eli (Billich 2003). Subsequently, a novel series of potent INSTIs, which replaced the 1,3-diketo acid moiety by an isosteric 8-hydroxy-1,6-naphthyridine core, showed improved metabohc stabihty (Zhuang et al. 2003). The compound L-870,810 moved into clinical trials, where it provided proof of concept in antiretroviral therapy-experienced and antiretroviral therapy-naive... 

Analysis of most (perhaps 65%) pharmacokinetic data from clinical trials starts and stops with noncompartmental analysis (NCA). NCA usually includes calculating the area under the curve (AUC) of concentration versus time, or under the first-moment curve (AUMC, from a graph of concentration multiplied by time versus time). Calculation of AUC and AUMC facilitates simple calculations for some standard pharmacokinetic parameters and collapses measurements made at several sampling times into a single number representing exposure. The approach makes few assumptions, has few parameters, and allows fairly rigorous statistical description of exposure and how it is affected by dose. An exposure response model may be created. With respect to descriptive dimensions these dose-exposure and exposure-response models... 

Gebski V, McNeil D, Coates A, Forbes J. Monitoring distributional assumptions and early stopping for a prospective clinical trial using Monte Carlo simulation. StatMed 1987 Sep 6(6) 667-78. 

Using SQL, you can create very sophisticated database joins that were not easily done before SQL became part of Base SAS. Keep in mind that these data set joins can get very complex. For example, the previous scenario gets quite a bit more complicated with the introduction of missing start and stop dates, which are a common occurrence in clinical trial data. 

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