Controlled clinical trial limitations

Randomized, controlled clinical trials reduce bias and variability by a process of selection, randomization and standardization of treatment, and often take place under artificial conditions isolated from those of routine clinical practice (Freemande et al, 1993 Simon et al, 1995b). Yet it is the uncontrolled interactions of a dmg technology with patients, health-care workers and the system of health care that ultimately lead to much of the variability in outcomes and expenditures in clinical practice. Thus the value of RCTs in evaluating cost-effectiveness in clinical practice maybe limited (Reeder, 1995 Simon et al, 1995b Hotopf et al, 1996). 

The first 24-hour dose may be individualized for each patient however, in controlled clinical trials, mean daily doses greater than 2100 mg were associated with an increased risk of hypotension. The initial infusion rate should not exceed 30 mg/min. Based on the experience from clinical studies, a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient s age, renal function, or left ventricular function. There has been limited experience in patients receiving amiodarone IV for more than 3 weeks. 

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

In an early study, Insel et al. [1983b] compared the efficacy of CMI with that of clorgiline, a monoamine oxidase-A inhibitor, in a controlled crossover study of patients with OCD. Although CMl was effective, patients on clorgiline did not improve at all. Vallejo et al. [1992] conducted a controlled clinical trial of the efficacy of CMl and phenelzine in 30 patients with OCD. The authors reported improvement in both groups however, the lack of a placebo control and the small size of the study groups limit the applicability of these findings. Further studies on the therapeutic role of monoamine oxidase inhibitors in OCD, especially in OCD with comorbid panic disorder, are warranted. 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

The randomized controlled clinical trial is the method of choice for the objective and quantitative demonstration of the efficacy and tolerability of a new medicine. None the less, such studies have limitations in discovering possible adverse events that may occur, in particular those that are rare or develop after prolonged use, in combination with other drugs, or perhaps due to unidentified risk factors. Clinical trials are inherently limited in duration and number of patients, and, significantly, patients are selected prior to inclusion. In other words, the conditions of a trial are artificial compared with the real-life use after the introduction of a medicine (p. 229). 

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. 

As the FDA has made clear, a reasoned analysis discloses that the controlled clinical trials used in the FDA process have grave limitations in regard to the detection of adverse drug effects. The FDA came to this conclusion without discussing some of the more subtle issues I have raised in this chapter. 

Combination antimicrobial therapy is commonplace in equine practice. However, combination therapy has never been demonstrated to be superior to single drug therapy in controlled clinical trials. The use of multiple antimicrobial agents should be limited to certain situations. 

A variety of therapeutic agents have been tried in patients with NES but there have not been any randomised double-blind controlled clinical trials. From the limited data available it appears that serotonin reuptake inhibiting antidepressants SSRI are the most promising. A 12-week open-label trial of sertraline in seventeen patients (12 women, 5 men) showed, a significant reduction in the mean number of nocturnal awakenings, the number of ingestions and in the amount of food consumed after the evening... 

A hope for the future would be to limit the massive burden of premarketing testing of new drugs, which threatens the continuation of research in the pharmaceutical industry, and to establish methods of investigation in the postmarketing phase that would provide the necessary safeguards. It should be remembered that the cost of a patient in a controlled clinical trial may be 10-20 times greater than that of the same patient in an observational study. There is certainly a difference in the type... 

Despite the high incidence of malnutrition pre-OLT, data supporting a mortality benefit from pre-OLT nutrition support are relatively lacking. Studies thus far have been limited by small sample size, so it is uncertain whether nutritional interventions in these patients truly convey a survival benefit long term. Larger controlled clinical trials are needed. 

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