Clinical studies/trials publishing

The standard deviation for change in SBP can be harder to determine. One way is to examine previously published data on similar outcomes (maybe other drugs in the same class). If few data are available from this source, consulting with experts in this research domain may be helpful. Another possibility is to conduct a small pilot study. In the later phases of a clinical development program, data from earlier studies may be informative. This often means that for confirmatory clinical drug trials there will be results from earlier trials, so information is readily available. From these two items, the standardized effect size can be calculated as the ratio CRD/SD. 

In the future the FDA may develop guidance for preclinical toxicology studies but one has not been published at this time. The guidance recommending design of clinical studies can be used to model animal studies to support the various clinical trials. 

The agency also provided us with a meta-analysis that showed that the estimated efficacy of antidepressants in children was minimal and likely to have been overestimated, because published studies have much more favorable results than unpublished studies. Thus, both clinical experience and published trials are likely to lead to inflated estimates of the efficacy of these drugs. 

Initial results for the STARAD study were published early in 2006, providing useful insights for the clinician (Rush et ah, 2006 Trivedi, Fava, et ah, 2006 Trivedi, Rush, et ah, 2006). The Level I patients were all treated with the antidepressant citalopram, and only about 30% of the patients reached remission (that is, their symptoms essentially disappeared). However, about half of the patients experienced a response (a less demanding outcome measure that is commonly used in clinical drug trials and that reflects the rate of patients who experienced at least a 50% reduction in the severity of symptoms). These results are congruent with efficacy trials and with clinical experience. The results from Level I also showed that, in general, responders to treatment have a higher education, have fewer medical problems or psychiatric comorbidities, and are currently employed white women. 

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. 

Phase I clinical studies with DMP 543 (181), up to a single dose of 55 mg, demonstrated that it was well tolerated and had an improved mean elimination half-life of 30-57 h (linopirdine was 0.4-3.2 h) (549). To date, preclinical studies describing cognitive enhancement with these compounds have not been published. The development of DMP 543, after reaching phase II clinical trials as a potential therapy for the treatment of Alzheimer s disease, has now been discontinued (DuPont Pharm, 2000 Annual Report). 

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