Clinical studies setting

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

In order to define the obese state ia a clinical setting, it is necessary to have a means of estimating the amount of adipose (fat) tissue relative to lean body mass. Whereas highly accurate determiaations of body composition require complex laboratory procedures, large clinical studies typically employ measures of skia-fold thickness (11) or more commonly, body mass iadex (BMl) as a quantitative measure of obesity. 

As such, an asymmetric synthesis of tarantabant had been demonstrated centered around a DKR as the key step to set both stereocenters in a single catalytic step. The synthesis proceeded in six steps and 40% yield from the ketone rac-13. This route was found to be robust and reliable and generated in excess of 70 kg of API in various campaigns from both preparative laboratories and pilot plant facilities, and provided support for the project through longer term toxicology and clinical studies [13]. 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

Development and validation of PD assays to confirm drug effect on molecular target in pre-clinical studies and clinical trials conducted under an exploratory INDA, or in a traditional Phase I/II setting... 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

A full set of studies normally includes short-term and long-term animal studies on chronic effects and potential carcinogenicity, studies on reproductive and developmental toxicity, genotoxicity, kinetics and metabolism, pharmacological properties and special studies depending on the characteristics of the substance and observation in the standard set of studies. Human clinical studies may be necessary for substances which are metabolised and may interfere with functions of the human body. 

Clinical studies Analytical Phase 1 for determination of accuracy, precision, sensitivity, and specificity Analytical and clinical Phase II for determination of usual range of results encountered in healthy subjects or comparing results in various disease states Phase III to establish the actual medical usefulness of a test in a realistic clinical setting Phases I—III completed before 510(k) clearance or PMA approval... 

The list of subjects in the pivotal studies of dose setting/efficacy clinical studies... 

The use of estimates of treatment effect based on indirect comparisons when there is a common comparator has recently been shown on many occasions to agree with the results of head-to-head clinical trials (Song et al. 2003). Clearly a more challenging situation exists where there is not a common parameter, for example, in a recent study of the relative cost effectiveness of newer drugs for treatment of epilepsy (Wilby et al. 2003). In this study, Bayesian Markov chain Monte Carlo models for multiparameter synthesis were used (Ades 2003). Here, complex models were used to analyze a set of clinical studies involving a series of clinical alternatives, including the two alternatives of interest. 

A related issue in pharmacoeconomics trials is the generalizability of the health care delivery system of the patients in the study. A pharmacoeco-nomic study conducted through health a maintenance organization using its members as subjects may observe less referrals to specialist physicians than would the same clinical study in a different practice setting. This effect may be even more pronounced in multinational clinical trials, in which health care systems, physician education, and patients expectations for treatment differ by country. 

ICH E3(1995) Structure and Content of Clinical Study Reports sets down the structure, down to the numbering of the sections and precisely what goes in each of those sections, required within the regulatory setting for reporting each study. Medical writers will work with statisticians to put these reports together. 

Clinical and epidemiological studies sharply differ on rates of ADHD seen among individuals with TS (Walkup et ah, 1998). Clinical studies vary according to setting and established referral patterns, but it is not uncommon to see reports of 50% or more of referred children with TS diagnosed with comorbid ADHD. In contrast, epidemiological studies typically indicate a much lower rate of comorbidity (Apter et al., 1993). 

---