Preclinical and Clinical Trials

The approval of a new drug requires preclinical and chnical studies and takes an average of 10 years to complete. The preclinical and chnical trials have to prove the safety and efficacy of every new medicine. 

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. 

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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. 

Due to the increasing amounts of pDNA required for preclinical and clinical trials, production of pDNA needs to be performed on a large scale. These production processes must fulfill FDA regulatory requirements and be economical feasible. A typical production process is schematically presented in Fig. 11. 

The annual R D expenditure for biopharmaceuticals is around US 19-20 billion. There are estimated to be 2500 biopharmaceuticals in the discovery phase, 900 in preclinical trials, and 1600 in clinical trials. This represents 44% of all drugs in the development phase and 27% of all drugs in both preclinical and clinical trials. The most common target is cancer and monoclonal antibodies and vaccines have the largest amount of R D activities. 

Newman DJ, Cragg GM. (2004) Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Curr Med Chem, 11 1693-1713. 

Newman DJ, Cragg GM (2004) Advanced Preclinical and Clinical Trials of Natural Products and Related Compounds from Marine Sources. Curr Med Chem 11 1693... 

The results of the preclinical and clinical trials and all manufacturing, chemistry, quality control, and test methods data are submitted to FDA in the form of a new drug application (NDA) or a biologies license application (BLA) for marketing approval. 

Explain the differences between (a) preclinical and clinical trials and (b) Phase I and Phase II trials. 

The same process that will be used for commercial-scale production should be adopted to produce the material used in the preclinical and clinical trials. Significant differences in the production process used to obtain this material can invalidate the clinical trial results for the commercial product, unless the comparability is demonstrated by identity, purity, stability, and potency tests (ICH, 1998b). 

The drug development program is divided into preclinical development, clinical development, and post-approval surveillance. Several preclinical and clinical trials are conducted during this program. In the following the phases of the clinical drug development process are described with a special focus on the data available for modeling and simulation and some objectives are exemplarily listed for the respective phases. 

All available results available from preclinical and clinical trials... 

Products for a rare disease or condition may be too small to recover their development and registration cost from sales. If this situation is expected, the developer may ask the FDA for written recommendations for the required preclinical and clinical trials. In addition, the manufacturer and sponsor can ask for an official designation as "orphan drug" (also for biological products). Orphan drugs are entitled to tax reductions and a 7 year monopoly on their use for the designated indication. 

Preclinical and clinical trial data and data from phase IV studies have shown that levofloxacin, moxifloxacin, and gatifloxacin cause prolongation of the QT interval, but that the potential for torsade de pointes is rare and is influenced by several independent variables (for example concurrent administration of class la and III antidysrhyth-mic agents) (25). There is a moderate increase in the QT interval associated with sparfloxacin, averaging 3%, and the few serious adverse cardiovascular events that have been reported during postmarketing surveillance all occurred in patients with underlying heart disease (26). 

First MR. An update on new immunosuppressive drugs undergoing preclinical and clinical trials potential applications in organ transplantation. Am J Kidney Dis 1997 29(2) 303-17. Birck R, Warnatz K, Lorenz HM, Choi M, Haubitz M, Grunke M, Peter HH, Kalden JR, Gobel U, Drexler JM, Hotta O, Nowack R, Van Der Woude FJ. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol 2003 14(2) 440-7. 

First MR. An update on new immunosuppressive drugs undergoing preclinical and clinical trials potential applications in organ transplantation. Am J Kidney Dis 1997 29(2) 303-17. 

Preclinical and clinical trial data and data from phase IV studies have suggested that levofloxacin causes prolongation of the QT interval (10). There were cardiovascular problems in 1 in 15 million prescriptions compared with 1-3% of patients taking sparfloxacin, who had QTc prolongation to over 500 ms. Poljmorphous ventricular tachycardia with a normal QT interval has been associated with oral levofloxacin in the absence of other causes (6,9,11,12). 

Feldman AM, Kadokami T, Higuichi Y, Ramani R, McTiernan CF. The role of anticytokine therapy in heart failure recent lessons from preclinical and clinical trials Med Clin N Am 2003 87 419-24. 

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