Concurrent controls clinical trials

There are two main types of clinical trial design, parallel and cross-over. In a parallel study, subjects are assigned to one of two or more treatments, e.g. active and placebo, and proceed through the trial concurrently. In a cross-over design, subjects act as their own controls, undergoing two or more treatments in sequence (see Fig. 12.1). 

Biliary excretion As most entacapone excretion is via the bile, exercise caution when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone (see Drug Interactions). Lab test abnormalities Entacapone is an iron chelator. The impact of entacapone on the body s iron stores is unknown however, a tendency towards decreasing serum iron concentrations was noted in clinical trials. In a controlled clinical study, serum ferritin levels (as a marker of iron deficiency and subclinical anemia) were not P.764... 

Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996 14(ll) 2901-2907. 

Non-randomized concurrent clinical trials initially assign participants to a control or test group in a non-random fashion. These trials are run concurrently, but are unblinded. This introduces a danger that the control and intervention groups are not strictly comparable. 

Statistical thinking and practice is very much determined by the regulatory guidelines that are in place. Primarily it is ICH E9 Statistical Principles for Clinical Trials , published in 1998, which sets down the broad framework within which we operate. In 2001 we saw the publication of ICH ElO Choice of Control Group which contained advice on the appropriate choice of concurrent control group and in particular first introduced the concept of assay sensitivity (see Section 12.5) in active control, non-inferiority trials. 

Table 5-27 and Table 5-28 summarize the clinically relevant pharmacokinetic and pharmacodynamic properties of other novel antipsychotics ( 326). Drug interactions with these agents were not systematically evaluated because controlled clinical trials usually prohibit concurrent medications. There are also many special circumstances (e.g., patients with comorbid medical diseases, substance abuse, epilepsy, or atypical indications such as agitation associated with mental retardation or dementia) that are not usually addressed in clinical research trials. Thus, much remains to be learned about significant drug interactions in these patient groups. To our knowledge, however, no consistent, serious, clinically relevant interactions have been reported. 

Serious life-threatening infections, including sepsis and pneumonia, have been reported with the use of TNF inhibitors. Patients should be evaluated for tuberculosisrisk factors and tested for latent tuberculosis infection prior to starting therapy. Concurrent use with other immunosuppressive therapy should be avoided. In clinical trials of all TNF-blocking agents more cases of lymphoma were observed compared with control patients. Patients with a prior history of prolonged phototherapy treatment should be monitored for nonmelanoma skin cancers. 

Chronic toxicity Rodent and non-rodent species. 6 months or longer. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trial. Goals of subacute and chronic tests are to show which organs are susceptible to drug toxicity. Tests as noted above for subacute. 3 dose levels plus controls. 

After promising results in experimental models of myocardial ischemia (58,59), multiple clinical trials were initiated. As in 2005, data from six clinical trials applying BM or peripheral blood-derived stem cells in patients with chronic HF and seven trials in patients with AMI were published (Tables 2 and 3). Stamm et al. injected 1.5 X 106 AC 133 + BM stem cells into the infarct borderzone of patients, who underwent concurrent CABG. However, in contrast to myoblast studies, this study examined patients treated shortly after AMI. Atotal of 12 patients were treated, and they showed increased perfusion in treated areas and improved LV dimensions and EF compared with the controls (10,60). Further, unlike patients in myoblast trials, the improvements in this trial occurred without any incidence of electrical abnormalities. Whether this represents a difference in patient population, cell type, or even cell dose, remains unknown. 

Human pharmacology and therapeutic exploratory studies define the most likely safe and effective dosage regimens for use in subsequent therapeutic confirmatory studies. These therapeutic confirmatory studies are typically run as double-blind, randomized, concurrently controlled clinical trials. 

Over the last two to three decades randomized concurrently controlled clinical trials have become established as the method which investigators must use to assess new treatments if their claims are to find widespread acceptance. The methodology underpinning these trials is firmly based in statistical theory, and the success of randomized trials perhaps constitutes the greatest achievement of statistics in the second half of the twentieth century (Preface). 

While preapproval clinical trials are crucial in drug development, even the gold standard double-blind, randomized, concurrently controlled clinical trials are limited in their ability to provide information that truly represents the safety and effectiveness of the drug once it has been widely prescribed and is being taken by many more individuals than participated in the preapproval clinical trials. 

A subsequent Phase II, multicenter, randomized, double-masked, placebo-controlled clinical trial was performed in patients undergoing phacoemulsification and intraocular lens implantation (18). Only one eye per patient was eligible for treatment and exclusion criteria included previous uveitis, concurrent anterior segment disease or intraoperative surgical complications. Patients were randomized in a 2 1 ratio into an active treatment group or a control group. Patients in the two... 

The idea behind the use of concurrent controls is so simple that it would scarcely seem to be worth discussing, yet, despite the essential simplicity of using concurrent controls, analyses of clinical trials commonly encountered in the medical literature betray the fact that tricdists often do not understand the implications of having adopted such a design. 

Obviously, by virtue of having used concurrent controls, any observed difference between treatments in a clinical trial cannot be due to differences between trials. The patients being compared, irrespective of treatment, are in the same trial. This obvious point is worth labouring because it reinforces once again that the basic logic of clinical trials is comparative and not representative. If it were representative we should require patients who were typical the difference between patients from trial to trial would then not be an issue and we would not need concurrent controls. Nevertheless, even though the patients studied are studied in the same trial, there may be important differences between them. The purpose of randomization is to deal with this within-trial source of variation. It has nothing to do with differences between trials. 

On the other hand, if we assume that the reported changes in body composition are accurate for each nial, it appears that the effect of CLA supplementation in adults was not related to body size, adiposity, or dose. The composition of the concurrent dietary intake might be one factor contributing to the variabihty in body composition outcome. Studies conducted in mice demonstrated that the quantity and type of dietary fat did not affect the CLA response in that species (11). However, the type of protein in the diet altered the fat-reducing capability of CLA in rats (36). In the clinical trials, with the exception of the San Erancisco study (32), dietary intake was not controlled, raising the possibility that CLA could be interacting with other dietary constituents that might attenuate or accentuate its effect. 

The evidence of a time factor of concurrent chemo-radiation remains a controversial issue. A randomized clinical trial in patients with limited disease small cell lung cancer (SCLC) treated with chemoradiation demonstrated a significantly higher local tumour control when OTT was reduced from 33 to 19 days (Turrisi etal. 1999). A meta-analysis of four randomized clinical trials in patients with Umited disease SCLC revealed that OTT is the most important predictive factor for outcome after chemoradiation (De Ruysscher etal. 2006). In contrast to the results of this meta-analysis. 

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