Preclinical, clinical trials

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Year is year of launch in the U.S. market unless indicated Pre-Cl = preclinical, Ph III = phase III clinical trials (status as of Feb. 1990). 

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

Toxicity Amelioration. Cancer researchers traditionally have not focused their attention on the question of toxicity amehoration. This is partiy attributed to the lack of predictive animal models for human toxicities. For example, the preclinical rat model, used as a predictor of myelosuppression, has failed to predict myelosuppression in humans in clinical trials. In addition, reduction of one toxicity may result in the emergence of another, more serious problem. Research efforts to address the problem of toxicity amelioration has progressed in several directions. The three most prominent areas are analogue synthesis, chemoprotection, and dmg targeting. 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

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. 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

Costs in R D are a mix of short-run cost, dominated by the cost of clinical trials, and long-run cost, dominated by the fixed assets and specialized expertise of discovery and preclinical organizations. Therefore, when seeking to maximize the value of output relative to input, development teams need to be concerned with external spending and the length of tasks, whereas research teams need to look at their investments in capacity and the way they use fixed capacity. 

The current accessible information from this company do not show any records on BDS activities, the most recent recorded event correspond to 2000 activities. On November 14, 2001, their report announced a restructuring process of the Company s Scientific Advisory Board, replacing members with scientists and physicians with experience in cancer, production of therapeutic proteins, preclinical development and clinical trials. That indication for a new orientation and focus to the health sector did not last enough, and soon after, the company disappeared from the SEC (and any other financial) listing. 

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