Pharmaceuticals clinical trials

Burley, D.M. Glynne, A. Clinical Trials. Pharmaceutical Medicine-, Burley, D.M., Binns, T.B., Eds. Edward Arnold London, 1985 18-38. 

Mallinckrodt CH, Watkin JG, Molenberghs G, Carroll RJ (2004d) Choice of the primary analysis in longitudinal clinical trials. Pharmaceutical Statistics 3 161-169. 

Hammad G (1996b) Medicines abroad—China (Part II). Pharmaceuticals in the People s Republic—clinical trials. Pharmaceut Physician 7(8) 59-68. 

Amit O, Heiberger RM, Lane PW. Graphical approaches to the analysis of safety data from clinical trials. Pharmaceutical Statistics, 7 20-35, 2008. 

Durham TA, Turner JR (2008) Introduction to statistics in pharmaceutical clinical trials. Pharmaceutical Press, London... 

Human growth hormone, used as a human pharmaceutical, is approved for only one indication in the United States, treatment of growth failure owing to hGH deficiency, a condition known as pituitary dwarfism. However, clinical trials are under way to test its efficacy in Turner s syndrome, bums, wound healing, cachexia, osteoporosis, constitutional growth delay, aging, malnutrition, and obesity. 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

All preparations of enzymes intended for parenteral use are tested for safety in lower animals under the conditions anticipated in clinical trials ie, their use must be nonpyrogenic in the USP rabbit assay (255), and must be sterile. Such toxicologic studies are usually a prerequisite for approval by the FDA for the sale of such pharmaceuticals. 

The purification of value-added pharmaceuticals in the past required multiple chromatographic steps for batch purification processes. The design and optimization of these processes were often cumbersome and the operations were fundamentally complex. Individual batch processes requires optimization between chromatographic efficiency and enantioselectivity, which results in major economic ramifications. An additional problem was the extremely short time for development of the purification process. Commercial constraints demand that the time interval between non-optimized laboratory bench purification and the first process-scale production for clinical trials are kept to a minimum. Therefore, rapid process design and optimization methods based on computer aided simulation of an SMB process will assist at this stage. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Clinical trials should be designed so as to mirtimise potential sources of bias. It is known that patients can demonstrate a positive response to treatments that they believe will benefit them, even if no pharmaceutical agent has been admrrtistered (the placebo effect ). Similarly, investigators may be biased in their observations by an expectation of particular results. To avoid such bias, blinded trial designs are used. 

Requests for permission to conduct clinical trials with pharmaceuticals in the US are termed Investigational New Drug Applications (INDs). The applications are actually a request for an exemption to supply a drug without a marketing authorisation. A cover sheet (Form 1571) must accompany the application. This cover sheet should also be used with each subsequent communication with the FDA, with each form consecutively numbered, starting at 000 for the initial submission. A copy of the form is shovm in Figure 5.6. 

Presently, several clinical trials with liposome-encapsulated agents are under way and more are planned (Zonneveld and Crommelin, 1988 Klausner, 1988). During the last 5 years, key issues related to the pharmaceutical manufacturing of liposomes such as stability, sterilization, upscaling, and reproducibility have been successfully addressed. Although it is generally believed that a proper selection of the bi-layer components can minimize the occurrence of toxic effects due to the use of natural body constituents, the issue of liposome-related toxicity is not a trivial one and should be carefully studied,... 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

Even on a relatively small subset of reused data, it is possible to license old medicines for new therapeutic applications and greatly reduce the costs of clinical development—many of these reused medicines have already passed muster for pharmacokinetic safety, so smaller-scale clinical trials are possible, saving considerable money (e.g., Arakis—soon to become Sosei). Even Sildenafil may have new indications [39]. There are huge potential reserves of information to mine in each and every large pharmaceutical company ... 

Duffal SB, Kimko HC (eds). Simulation for designing clinical trials a pharmacokinetic-pharmacodynamic modeling perspective (Drugs and the pharmaceutical sciences, Vol 127). New York Marcel Dekker, 2003... 

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