Clinical trials inclusion effect

The results of clinical trials conducted under an IND have traditionally been regarded as confidential business information that FDA was prohibited from releasing to the public under the Freedom of Information Act and that the publication of which was determined solely by the drug sponsor. The Food and Drug Administration Modernization Act of 1997 established a clinical trial data bank for drugs for serious or life-threatening disease and required the inclusion of information on all effectiveness trials for these drugs. As a result of widespread concern about the lack of public availability of information about all clinical trials and their results, individual companies and the Pharmaceutical Research and Manufacturers of America have... 

From currently available data, one adult patient (1/170) challenged with oats was reported to have a severe adverse reaction to oats. Approximately 6% of adults and 9% of children withdrew from clinical trials due to reported adverse effects from the inclusion of oats in their diet. This evidence, along with the indication from some in vitro studies of an immunological response to avenin in the absence of clinical manifestations of celiac disease and the limitations of the database (previously discussed), supports a cautionary approach for the introduction of oats into a gluten-free diet until the prevalence of oats intolerance among people with celiac disease is well established (Dickey, 2008 Garsed and Scott, 2007). 

Historically, embryo-fetal development studies were mandatory to support inclusion of women of childbearing potential (WOCBP) in clinical trials. More recently, it has become admissible under appropriate circumstances to include WOCBP in early clinical trials before performing the embryo-fetal toxicity studies, provided that effective contraception is used. In Japan and Europe, data from adequately designed preliminary embryo-fetal toxicity studies, with as few as six females per group, may be used to support the inclusion of WOCBP in short-term clinical trials (18). The predictivity of such preliminary mammalian studies has not been established (see below), but it could be argued that they may be less predictive than alternative methods such as FETAX. We therefore expect FETAX to play an evermore important role in pharmaceutical development in the future. 

As with studies of many other herbs and nutritional supplements, interpretation of clinical trials of valerian is hampered by small sample sizes, suboptimal study design, lack of specified inclusion and exclusion criteria, and unknown composition of valerian extract (Plushner, 2000). Furthermore, none of the trials have included children or teenagers. Nevertheless, several studies have showed a mild hypnotic action in persons with insomnia and in normal sleepers, as well as a mild sedative effect (Leathwood and Chauffard, 1983, 1985 Balderer and Borbely, 1985). One report has described an anxiolytic effect (Kohnen and Oswald, 1988). There are suggestions that valerian may have beneficial effects on sleep latency, frequency of waking, nighttime motor activity, and overall sleep quality. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

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. 

So that the aforementioned teratogenic effects can be avoided, pregnant women should, in general, be excluded from clinical trials in which the drug is not intended for use in pregnancy. Before the inclusion of pregnant women in clinical trials, all the reproductive toxicity studies (15,16) and the standard bat-... 

It should be noted that a recent, evidence-based, systematic review of published randomized clinical trials of therapy for toxoplasmic retinochoroiditis fitund only three studies that met the authors criteria for inclusion, two of which were carried out more than 35 years ago. Based on this evaluation the authors concluded that there was a lack of evidence to support routine antibiotic treatment for ocular toxoplasmosis, finding no evidence for a beneficial effect on the duration and severity of signs of the disease process. However, the preponderance of evidence supports the concept that appropriate antibiotic therapy is a community standard of care, which is bolstered by guidelines for treatment in many published sources, plus the responses of those practitioners recently surveyed about their preferred patterns of management of the condition. 

Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer 2001 91(12) 2246-57. 

The interpretation of these sporadic cases is controversial, although some have argued that the reported cardiovascular adverse effects occur more often with sildenafil than with other pharmacological treatments of erectile dysfunction. It is at present unclear whether there is an increased risk with sildenafil. For example, in placebo-controlled trials there have been no differences in the incidences of myocardial infarction, angina, or coronary artery disorders between sildenafil and placebo (9). Exclusion criteria in clinical trials may have prevented the inclusion of patients who are at increased risk of adverse events. On the other hand, sexual activity itself increases cardiac workload and the risk of myocardial infarction. Patients with cardiovascular disease should be cautious in their use of sildenafil. 

Placebos have been found to have effects similar to the active medication being compared.Many investigators have attempted to quantify the placebo response. Scales such as the placebo effect scale (PES) and the side effect scale (SES) have been used to identify patients likely to exhibit placebo effects. These scales determine possible predictors of placebo response such as demographic variables, illness characteristics, and diagnostic and symptom variables to identify patients at increased benefit or risk of demonstrating a placebo response.The need for routine use of such scales prior to inclusion in clinical trials and implications of identifying those most susceptible to placebo response require further study. 

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