Phase III clinical studies

As the program moved forward to Phase III clinical studies an evaluation of the pros and cons of each approach was carried out to assist with route selection for long-term implementation (Table 9.10). 

Phase II studies encompass a detailed assessment of the compound s safety and efficacy in a larger patient population (a few-to-several hundreds of patients). It is important that any formulation selected for these studies must be based on sound biopharmaceutical and pharmaceutical technology principles. Phase III clinical studies, also referred to as pivotal studies, involve several thousands of patients in multiple clinical centers, which are often in multiple countries. The aim of these studies is to demonstrate long-term efficacy and safety of the drug. Since these studies are vital in the approval of the drug, the dosage form plays a very critical role. 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Pre-clinical trials (as well as phase I and II clinical trials) utilizing CNTF yielded promising results, but the neurotrophic factor then failed phase III clinical trials on the basis of insufficient efficacy. However, myotrophin (IGF-1, produced by Cephalon Inc.) has proved more successful. A 266 patient phase III clinical study found that IGF-1 administration to ALS sufferers resulted in reduced severity of symptoms, and slower disease progression, although this or no related product has yet been approved for medical use. The potential world market for an ALS therapeutic agent approaches 1 billion. 

Phase III clinical studies completed NDA submitted February 2006 Company Toyama, Schering-Plough M.W. 426.41 (parent)... 

Combination chemotherapy is the treatment standard for patients with diffuse non-Hodgkin s lymphoma. The anthracycline-containing regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been considered the best treatment in terms of initial therapy. Recently, randomized phase III clinical studies have shown that the combination of CHOP with the anti-CD20 monoclonal antibody rituximab results in improved response rates, disease-free survival, and overall survival compared with CHOP chemotherapy alone. 

Two Phase III clinical studies of orally administered capecitabine in over 1,200 patients with untreated metastatic colorectal cancer demonstrated at least equal efficacy and improved tolerability versus the Mayo Clinic regimen of intravenous 5-fluorouracil/leucovorin administration. The overall response rate for patients taking capecitabine orally was 21%, versus 14% for the intravenous 5-FU/leucovorin regimen. A median 53-month follow-up revealed a three-year disease-free survival rate of 66% for capecitabine versus 63% for 5-FU/leucovorin patients. International Phase II trials also demonstrated therapeutic benefits of capecitabine monotherapy for women with metastatic breast cancer that was either resistant to both paclitaxel and anthracycline therapy. Orally administered at the twice-daily 1,250 mg/m2 regimen (cycles of two weeks of therapy followed by a week of rest), the tumor response rate was in the range of 20-25%. In addition, combination of capecitabine with a taxane yielded a unique survival benefit compared to the previous standard of taxane monotherapy for anthracycline-resistant breast cancer.13,14... 

Most recently, Panacos announced that bevirimat tablet formulation dosed twice daily achieved target plasma levels. After 14 days of bevirimat treatment given twice daily at doses of 200 mg or 300 mg (using the 50 mg tablet), 100% of 32 treatment-naive and treatment-experienced patients in this study had bevirimat plasma concentrations well above the previously identified minimum target of 20 pg/niL. Phase III clinical studies of bevirimat are currently being planned. 

Petersein, 1., Spinazzi, A., Giovagnoni, A., et al. (2000) Focal liver lesions evaluation of the efficacy of gadobenate dimeglumine in MR imaging - A multicenter phase III clinical study. Radiology, 215, 727-736. 

Although FTY720 failed to improve efficacy for preventing renal allograft rejection in Phase III clinical studies (174), a different purpose has been found for its potential use. Phase III clinical trials are underway to examine the use of FTY720 for... 

It was customary for Phase III studies that study centres were chosen on marketing grounds as well as from the scientific aspect. Because many similar products were developed and launched, hospitals decided to list in their formularies only those drugs in whose development they had participated. A vital issue for sponsoring companies is that their product be listed in the formularies of major hospitals, such as university hospitals or main regional hospitals. Therefore, the Phase III clinical study sites tend to... 

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