Clinical development, phases

Several specialized reviews on detection of QT liability in the clinical development phase have already been published and the reader is referred to these publications [63]. Guidelines of the International Society for Holter and Noninvasive Electrocardiology (IS H N E) for electrocardiographic evaluation of drug-related QT prolongation are also available [161]. The main issues related to measurement of the QT interval in clinical studies are summarized in Table 3.4. An important aspect is the calculation of sample size usually 40-60 subjects per treatment arm are required, implying high cost [162-164]. 

Phase II clinical development — Phase II involves a greater number of patients (usually 100 to 300) than phase I clinical studies. At this stage more emphasis is placed on activity, dosing, and efficacy than in phase I, and thus, only patients are used for phase II studies and beyond. Sometimes, reevaluation... 

Pharmacogenetics and Pharmacogenomics in Early Clinical Development (Phase I/II Trials)... 

The first epithilone, a highly potent microtubule stabilizer, in advanced clinical development (Phase II) is ZK-EPO (ZK-219447), while fludelone is still in preclinical trials (cf. Chapter 4). 

Burris HA, 3rd, Hurwitz HI, Dees EC et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW5720I6), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. JCfiri Oncol2005 23 5305-5313. Zaks T, Akkari A, Briley L et al. Role of pharmacogenetic studies in early clinical development Phase I studies with lapatinib. JCfiW Oncol 2006 24 3029. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

The noradrenaline and dopamine reuptake inhibitor bupropion (GlaxoSmithKline) is currently in clinical development (phase II) for neuropathic pain. 

A qualitative process approach to accelerated development emphasizes the elimination of drug candidates from the pipeline. This approach targets the advanced evaluation of specific pharmaceutical properties. The reward is not necessarily intuitive introduce a qualitative process change earlier in the drug development pipeline, resulting in the proactive identification of promising lead compounds and the utilization of fewer resources during the costly clinical development phases. This approach is driven by kinetic ... 

The monofunctional tryptase inhibitor APC-366 (Axys Pharmaceuticals) reduces the acute airway response and histamine release to allergen in a pig model of allergen-induced asthma [19]. APC-366 is also effective in a sheep model of allergen-induced asthma but was only poorly effective in asthma patients (proof-of-principle) [8], The compound was in clinical development phase II for asthma (inhalative). Although highly selective for tryptase over plasmin and plasma kal-likrein, APC-366 was not selective against thrombin and trypsin [13], Another monofunctional tryptase inhibitor is bis(5-amidino-2-benzimidazol-yl)methane (BABIM) which has been shown to be effective in the sheep. Further development of the compound was, however, discontinued, maybe because of the lack of selectivity over trypsin [13, 16, 17] (Figure 3.2.2). 

Table 12.1 DNA-based therapeutics currently in advanced stages of clinical development (phase 3 and beyond) (Patil et al. 2005)... 

Two guidelines notified in 1992 brought more detailed guidance on the purpose, methodology and assessment of the three clinical development phases ... 

For which phases shall a CMO be used The manufacturing capacity which is needed to support clinical trials differs from the commercial-scale production. During the clinical development phases smaller amounts of the product will be needed. 

Clinical development (phases lib and III) Pharmaceutical development Biostatistics and data management Global project teams... 

The major target indications of biopharmaceuticals currently undergoing clinical trials include cancer, cardiovascular, and infectious diseases, the major killers within the developed world. Although in excess of 30 nucleic acid-based drugs are currently being evaluated for gene therapy, vaccines, and other applications, the majority remain in the early stages of clinical development (phase I/II) [11]. 

In the early clinical development phases, human subjects, who will usually be healthy, will be confined for varying periods of time while single or multiple doses of the product are administered and safety data are recorded. These subjects receive little in the way of benefit, except monetary compensation. When a reasonably safe and reasonably effective dose or dose range has been identified, the safety and efficacy of the product will be determined by studying patients with the indicated symptoms, condition or disease. Some of these patients will, of necessity, receive no treatment or treatment with inactive substances (placebo). 

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