Outcome evaluation clinical trials

Only two randomized, controlled trials have been completed, and neither provides anything like compelling data (Table 2.6). Chouinard and Albright (1997) conducted a unique evaluation of a subset of patients from a previously conducted clinical trial. Subjects were categorized and profiled at baseline and end point according to clinical severity, and a group of psychiatric nurses were asked to rate various aspects of likely outcome and quality of life to each profile (mild, moderate or severe symptoms). Health state utilities were then calculated risperidone was found to provide more than double the number of quality-adjusted life years compared with haloperidol. Csernansky and Okamoto (1999) conducted a rather more conventional trial, but included no economic analyses. However, they did find that the use of risperidone substantially reduced relapse rates compared with haloperidol—an outcome likely to have a positive impact on cost-effectiveness. 

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). 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

Collaborative Working Group on Clinical Trial Evaluations. (1998). Measuring outcome in schizophrenia differences among the atypical antipsychotics. 

Clinical evaluation entailed administration to 45 MPS I patients in a randomized, placebo-controlled clinical trial. The primary efficacy outcomes assessed were forced vital capacity and distance walked in 6 min, both of which were statistically higher relative to placebo after 26 weeks of treatment. The most serious adverse reaction noted was that of a severe anaphylactic reaction in one patient. The most common adverse effects reported were respiratory tract infection, rash and injection-site reactions. The product is manufactured by BioMarin Inc. and is distributed by Genzyme Corporation. 

Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HAP, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87 3609-3617... 

Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. J Am Med Assoc 282 637-645... 

Additionally it has been observed that raloxifene reduces the risk of breast cancer by 58-66%, without producing an increased risk of endometrial cancer in postmenopausal women (Cummings et al. 1999 Jordan et al. 1998). The Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial is particularly eloquent in this regard (Cummings et al. 1999). A total of7704 postmenopausal women (average age 66.5 years) with osteoporosis and without history of breast or endometrial cancer were included. The trial, which was randomized and double-blind, used two doses of raloxifene (60 or 120mg/d) or placebo to as-... 

Clinical trials generate vast quantities of data, most of which are processed by the sponsor. Assessments should be kept to the minimum that is compatible with the safety and comfort of the subject. Highest priority needs to be given to assessment and recording of primary endpoints, as these will determine the main outcome of the study. The power calculation for sample size should be based on the primary critical endpoint. Quite frequently, trials have two or more evaluable endpoints. It must be stated clearly in the protocol whether the secondary endpoints are to be statistically evaluated, in which case power statements will need to be given, or are simply... 

The next few years will witness a greater partnership between industry, regulatory authorities and universities. Attempts to harmonise the conduct of clinical trials between these three agencies is a positive move. Hopefully, the outcome will be the minimum necessary number of clinical trials, each of which will be designed well enough to make a contribution both to the evaluation of a particular drug development and eventually to the therapeutic armamentarium available for the patient s benefit. 

Statistics is concerned with the treatment of numerical data where there is an associated uncertainty or chance. Many situations contain some element of chance, e.g. the outcome from throwing a die or the response of a patient to a drug. Even though it may be impossible to predict a particular outcome with certainty, its probability can often be quantified. Knowledge of statistical principles is essential in designing clinical trials and in the interpretation and evaluation of the results. PROBABILITY... 

In economic evaluations, there is a need to make assumptions about the variables in the analysis. For instance, assumptions that are made commonly include the incidence of adverse effects, the drug s efficacy (in clinical trials) and effectiveness (use in actual practice), and the costs of drugs or other direct medical costs. It is important to keep in mind that assumptions are simply predictions about what a researcher thinks might happen as a result of a program or intervention. To account for the variety of outcomes that may arise in any intervention, researchers should use a technique known as... 

The clinical utility of this approach will depend on the results of these initial clinical trials evaluating l7(3-estradiol and the outcomes of current DESs in higher-risk patients, Speculations about the clinical results are that an improved healing and re-endothelialization, although not completely abolishing neointima formation, will allow a controlled... 

Aliskiren is presently being evaluated in the ASPIRE HIGHER clinical trial program in more than 35,000 patients in 14 trials to study the effect of renin inhibition on outcomes in patients with conditions such as heart failure and diabetes as well as on organ protection benefit in a variety of disease states.25 To date, three of the short-term trials with organ protection endpoints have reported findings. In patients with type 2 diabetese, kidney disease, and high blood pressure, the AVOID (Aliskiren in the Evaluation of Proteinuria in Diabetes) study has demonstrated that aliskiren provides additional kidney protection when added to the maximum dose of the ARB losartan.26 In... 

Based on experimental and clinical data, cerebral hypothermia appears to be a potent therapeutic approach to treating brain trauma. However, recent results from the Multicenter National Brain Injury Study Hypothermia (NABIS H) clinical trial appear to be disappointing, and more refinement of the clinical application of hypothermia is required (73). Additional clinical trials are now required to evaluate systematically the beneficial effects of clinical hypothermia in different populations of brain-injured patients. In addition, experimental data regarding the beneficial effects of combination therapy are required to evaluate whether hypothermia plus pharmacotherapy may provide a better outcome. Forexample, mildpostischemichypothermia(33-39°C) combined with the antiinflammatory cytokine IL-10 has recently been reported to produce long-term protection of the C Al hippocampus after transient global ischemia (74). Hypothermia or IL-10 treatment alone did not protect chronically. In contrast, Kline etal. (75) showed that acute systemic administration of IL-10 suppressed the beneficial effects of... 

Assuming such preclinical studies did show such beneficial effects to combination treatment, how would a clinical trial of such combination treatment be designed Because hypothermia is not an easily blinded treatment, special care will be needed to ensure the avoidance of bias. This might include use of separate blinded evaluators of neurological outcome unrelated to the patients care. Inclusion criteria for the trial should also ensure that patients are neither too severely disabled, nor too mild affected neurologically, to avoid ceiling and floor effects. 

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