Phase III studies

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. 

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

Thiboutot D, Thieroff-Ekerdt R, Graupe K (2003) Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea results from 2 vehicle-controlled, randomized, phase III studies. J Am Acad Dermatol 48 836-845... 

The GP Ilb-IIIa complex inhibitor Tirofiban has been used as an adjunct to thrombolysis in a number of small case series reports." A small transcranial Doppler (TCD) study suggests that it reduces microembolization from unstable carotid plaque." In an open pilot smdy, Tirohban administered within 9 hours after stroke onset blocked the conversion of ischemic penumbra to mature infarction." A phase III study (SETIS) has started recruiting patients to investigate its efficacy versus aspirin within the 6-hour window. 

TODD s, WHITEHEAD A, STALLARD N, WHITEHEAD, J (2001), Interim analyses and sequential designs in phase III studies , Br J Clin Pharmacol, 51, 394-9. 

Neijt IP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carbo-platin in advanced ovarian cancer. J Clin Oncol 2000 18 3084-3092. 

Fig. 4. Structure of UK-427,857 (maraviroc), a CCR5-specific antagonist from Pfizer currently in phase III studies for HIV treatment. The original hit from the high-throughput screening, compound UK107,543, is also shown.

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

During phase III the analytical laboratory performs systematic methods validation and continues with product characterization. A suitable formulation or a formulation candidate is in place and testing for stability continues. Production evaluates the consistency of the manufacturing process, which should be at a scale capable of delivering commercial quantities. Advanced studies are continued or initiated to evaluate chronic toxicology and reproductive side effects in animal models. Parallel to phase III studies, preparations are made for the submission of the BLA. 

Vogelzang, N.J. et al.. Phase III study of pemetrexed in combination with cisplatm versus cis-platin alone in patients with malignant pleural mesothelioma, /. Clin. Oncol, 21, 2636-2644, 2003. 

Bonner, J.A. et al., Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck a phase III study of high dose radiation therapy with or without cetuximab, Proc. Am. Soc. Clin. Oncol., 22, 489S, Abstr. 5507, 2004. McLaughlin, R et al., Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma half of patients respond to a four-dose treatment program, /. Clin. Oncol., 16, 2825-2833, 1998. 

Cordon, A.N. et al.. Recurrent epithelial ovarian carcinoma a randomized phase III study of pegylated liposomal doxorubicin versus topotecan, /. Clin. Oncol., 19, 3312-3322,2001. 

Exhibit 6.6 Phase III Study A Study of Lopinavir/Ritonavir Tablets Comparing Once-Daily Versus Twice-Daily Dosing in Antiretroviral-Experienced, HIV-1 Infected Subjects... 

The two Phase II trials were Protocol 005 (N = 2391) and Protocol 007 (A = 551). The Phase III studies were FUTURE I (Protocol 013, A = 5442) and FUTURE II (Protocol 015, N = 12,157). Altogether, 20,541 women from 16 to 26 years of age were enrolled. Subjects were given Gardasil without prescreening for the presence of HPV infection. 

In 1999, TA-CD was tested on human subjects. Volunteers were injected with the cocaine vaccine once a week for four weeks and, according to researchers, antibody responses lasted almost three months without any adverse affects. In October of 2003, Xenova began testing TA-CD in a randomized, placebo-controlled clinical trial involving 132 human subjects. They expect to complete this study in 2005 and move into Phase III studies. ... 

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