Clinical phase III

OPG has been shown to reduce bone turnover in postmenopausal women. More recently, Denusomab, an anti-RANKL mAb, has been tested for its ability to increase BMD and to reduce bone turnover. Results were promising and clinical phase III studies with fracture endpoints are presently under way. 

HU-210 is (8.1) among the most potent cannabinoids known. Its enantiomer HU-211 (8.2) does not bind to the cannabinoid receptor and lacks psychotropic side effects (as long as optical purity is guaranteed). In animal models it shows analgesic and antiemetic activity. It also shows neuroprotec-tive effects after brain injury and was tested in humans as anti-traiuna agent, where it did not meet the expectations in a clinical phase III trial. 

Some 60,000 U.S. women die of ovarian and breast cancer each year. Each patient would need 2g of taxol, which means 120 kg of taxol per year. This would mean 800,000 Taxus trees per year, assuming a yield of 1500 ppm. Since six century-old trees had to be killed to treat each patient, the destruction or extinction of these trees aroused the anger of many environmentalists. To ensure the future supply of trees, the Weyerhauser company was asked to grow more than 500,000 yew plants as starter material for future production. In 1990, a large-scale clinical Phase III trial began on ovarian cancer, and the supply of taxol for these crucial clinical trials became... 

More recently fluoromethylene deoxycytidines have been rationally designed by McCarthy et al. as bio-precursors of mechanism-based inhibitors of RDPR, after phosphorylation in vivo by the deoxycytidine kinase. Among these, tezacita-bine (MDL 101731) [92] has a high anti-proliferative activity and is currently in clinical phase III evaluation for the treatment of solid tumours [92],... 

Lubiprostone is a novel agent, currently in clinical phase III for the treatment of constipation. This 16,16-difluoro-15-ketoprostaglandine potently activates intestinal Ch channels without altering Na+ and K+ ones. The difluoromethylk-etone is in equilibrium with the bicyclic hemiketal form, and the latter is predominant in the absence of water (Fig. 71) [166],... 

Marine natural products are also on trial as CNS aids (SNX-111, a peptide from mollusks, which is a nonaddictive analgesic agent 100-1,000 fold more potent than morphine, now in clinical phase III) and against pathogenic fimgi (15G256y, a macrolide from filamentous fimgi). 

Transdermal systems with electrophoretic release of the active substance are under development, e.g. ETRANS by ALZA with fentanyl for postoperative pain in clinical phase III. By virtue of the electrical field administration of the active substance is faster and on demand, e.g. similar to PCA therapy. 

Tirapazamine (SR 4233) is the lead compound to a class of bioreductive anticancer drugs that makes use of the fact that solid tumors are hypoxic (Brown 1990, 1993 Brown and Wang 1998) and clinical phase III trials are under the way (Gandara et al. 2002). With an anticancer drug that is that far advanced in clinical trials one would like to know the mechanism of its action. Obviously, this has attracted many research teams that are expert in different techniques to tackle the problem. It will be shown below that there is now a host of first-class information, but it is as yet difficult, if not impossible, to arrive at a conclusive mechanism of its action. 

Tfeible 3 Clinical phase III trials with ximelagatran... 

Level III is applied during clinical phase III and for the submission, as well as for important intermediates, and corresponds to the ICH requirements. At this stage of development, the commercial synthetic process for drug substance is established, and important process and degradation impurities have been identified and synthesized. The final formulations and dosages have also been established. 

Table 53.3 Costing categories for a clinical Phase III project...

Assuming the clinical development plan proceeds smoothly, the formal transfer of analytical methods takes place during the latter part of clinical phase III. At this point, the requirements for analytical technical transfer are outlined between R D and operations, and are suitably executed. After successfully meeting appropriate acceptance criteria, the receiving laboratory is... 

Clinical Phase Process Dev. Optimization Clinical Phase " Process Dev. Scale-up Clinical Phase III Registration Commerciali- zation... 

As a change to another CMO will take about three years (as post-approval change), it is important to select a CMO which will not only supply the material for clinical Phase III but is willing to dehver product for the initial three years of marketing requirements. Typically, that will require scale-up of the process to larger bio-reactor(s) and purification unit operations. 

Therefore, key issues of CMO/CHent contracting for clinical Phase III and launch requirements are ... 

A Biologies License Application (BLA)-enabling process is typically used for the manufacture of clinical Phase III material and the full-scale market supply after launch out of the final plant. This process... 

Sorafenib and sunitinib are both approved for the treatment of renal cell carcinoma. A clinical phase III trial studying sunitinib compared to sorafenib or placebo in treating patients with kidney cancer that has... 

MACI Genzyme (US) Porcine collagen membrane cultured with human chondrocytes Treatment of articular cartilage defects Clinical (phase III)... 

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