Phase III development

Pharmacogenetics and Pharmacogenomics in Late Clinical Development (Phase III Trials)... 

Table A2 The most important programs in late-stage development (Phase III and Awaiting Approval). FDA Clinical Trials, Oct. 2000...

FIGURE 9.2 Histograms showing the number of new drag entities entering phase I clinical development (blue bars), and concomitantly the number entering phase III development as a function of year. Adapted from [2]. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Antagonists of TLR-4 have been developed to prevent an excessive reaction to infection in the body. TAK-242 and Eritoran are both in phase III trials to help combat... 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

Obviously, the greater the number of subjects studied, the larger the cost. Nevertheless, having too few subjects may lead to inconclusive results, requiring that the study be repeated. Another important consideration is the availability of qualified participants. If the inclusion and exclusion criteria are very restrictive, the cost of recruiting subjects may exceed that of the actual testing. In pharmaceutical development trials, it is not unusual to see recruitment budgets of US 500- 1000 per randomized subject. Thus, for a Phase III development study with several hundred participants, often more than US 500 000 in cost is allotted to efforts to identify qualified subjects who are interested in participation. 

The data and information about an individual drug developed through Phase I, II, and III studies are extremely important to the medical community. For many drugs Phase I, II, and III data may be all, or nearly all, that is available about the clinical use of the drug at the time the product is marketed. During the time the product is in Phase I, Phase II, and Phase III, some of the compound s product and clinical data may be presented at professional meetings, published in preliminary reports, or otherwise made available to the scientific and business communities. However, it is not uncommon for a drug to be approved by FDA without the presence of its clinical research in the published biomedical literature. 

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