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Preclinical Drug Development Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 67 No. 6 pp. 579ñ586, 2010 ISSN 0001-6837 Polish Pharmaceutical Society MINI REVIEW PRECLINICAL DRUG DEVELOPMENT TERESA BRODNIEWICZ1 and GRZEGORZ GRYNKIEWICZ2* 1MTZ Clinical Research, PawiÒskiego 5, 02-106 Warszawa, Poland 2Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warszawa, Poland Abstract: Life sciences provide reasonably sound prognosis for a number and nature of therapeutic targets on which drug design could be based, and search for new chemical entities ñ future new drugs, is now more than ever based on scientific principles. Nevertheless, current very long and incredibly costly drug discovery and development process is very inefficient, with attrition rate spanning from many thousands of new chemical structures, through a handful of validated drug leads, to single successful new drug launches, achieved in aver- age after 13 years, with compounded cost estimates from hundreds of thousands to over one billion US dollars. Since radical pharmaceutical innovation is critically needed, number of new research projects concerning this area is steeply rising outside of big pharma industry ñ both in academic environment and in small private com- panies. Their prospective success will critically depend on project management, which requires combined knowledge of scientific, technical and legal matters, comprising regulations concerning admission of new drug candidates to be subjects of clinical studies. This paper attempts to explain basic rules and requirements of drug development within preclinical study period, in case of new chemical entities of natural or synthetic origin, which belong to low molecular weight category. Keywords: drug design discovery and development, new molecular entities, biological activity testing, phar- macokinetics, quality management, common technical document, preclinical phase Development of new drugs is perceived as a personally, as project managers, researchers or very complex process, which can be described reviewers and experts. Following European integra- from many different points of view; science and tion, local scientists finally stand a chance to design business story behind a new drug launch do not and submit ambitious research projects in advanced necessary match. Brisk scientific discovery can medicinal chemistry, prospectively realized within end up in clinical study failure or even withdrawal international cooperation. It is obvious that such after launch ñ over 90% drug leads do not make it development puts considerable load of responsibili- to the market. ty on the entire environment of researchers within Therefore, general view of the contemporary life sciences. In particular, chemists, pharmacists pharmaceutical industry is, despite of its some spec- and biochemists should strive for more effective tacular successes, that of certain dissatisfaction ñ communication with drug discovery and develop- globally, more is spent on drug discovery and devel- ment (DDD) area, which requires some specific opment every year and less is delivered, in terms of knowledge. We intend to recapitulate essentials of radical innovation (1ñ3), which remains in sharp DDD process as practiced under current legal contrast to incredible progress achieved in basic sci- requirements, with some focus on quality assurance ence research and phenomenal involvement of tech- systems and safety. In particular, an evolution of a nical potential, spanning from new information drug candidate will be explained in terms of knowl- technology to sophisticated robotics. Leaving aside edge accumulation and technical documentation fil- overwhelming economical R&D problems of big ling. In order to simplify this complex task, we will pharma industry with knowledge management and be concerned only with so called ìsmall moleculesî generating much needed innovation, we would like (basically synthetics, roughly below 1000 daltons), to discuss this part of drug research and develop- as opposed to ìbiologicalsî of either natural or ment, which our readers are likely to come across biotechnological origin (4). * Corresponding author: e-mail: [email protected] 578 Preclinical Drug Development 579 Origin of new structures for DDD tiscale dynamic modeling of physiology takes over, the general idea of starting DDD process with bio- Although application of foreign substances logical descriptors screened against structural repre- (xenobiotics) in case of illness had been practiced sentations will stay in force (5, 6). Although since the time immemorial, modern pharmacy, oper- genomics as a single line of research did not fulfilled ating with defined chemical entities of reasonable its promise to deliver identified medicinal targets, chemical purity, is just a little more than a century there are many more ìomicî approaches, which sig- old. During that time there were two principal nificantly increase our knowledge how physiologi- sources of medicinal substances: a) natural products, cal processes are related and governed on a cellular obtained chiefly from plants or microbial sources, and organismal levels. The second big step in any and b) chemical synthesis, which basically took over DDD project or program is development of an activ- in the second part of the period. Currently, historical ity assay, in which new compounds can be tested, to view of an individual scientist discovering new eliminate inactive ones. Typically, for a given target drugs in his individual, modest laboratory, gave way two types of tests are made available: high through- to entirely different picture ñ that of a large organi- put, based on interaction with target proteins or zation, in which sophisticated logistics combines an selected cell lines, which allow to check effort of cohorts of various specialists into a pipeline affinity/activity of large libraries of compounds very of DDD, involving dozens of laboratories focusing quickly (within hours), and low throughput, run on on particular tasks within narrow technical special- tissues, organs or animals, in which preselected ties. At the same time a new source of pharmaco- compounds are investigated in more detailed proce- logically active substances emerged ñ biotechnolo- dures, for weeks or months. This system reflects gy, using biochemical methods on technical scale, incredible inefficiency of traditional way of pharma- providing secondary metabolites and recombinant ceutical industry screening, characterized by very proteins by mastering natural metabolic pathways high drop-out rate, amounting to many thousand and generating new ones. Biologicals and biosimilar failures per one successful drug candidate. Once products became a large branch of pharmaceutical proper target is defined and bioassays are estab- industry with its own specificity. It is generally lished and validated, medicinal chemistry enters the agreed, that the first step of the DDD process consist field, with a mission to provide a new chemical enti- of target identification and validation. While tradi- ty, which can interact with the target on the systemic tionally a disease or pathology was considered a tar- level in a drug-like manner. Moreover, prospective get, today molecular level of perception is new drug candidate must demonstrate: specificity employed, and identification of a faulty biochemical (defined mechanism of action), potency (high affin- process and a macromolecule responsible is regard- ity for selected target), selectivity over other possi- ed obligatory. Typical targets are receptors, ble biological targets, and above all ñ safety for enzymes, elements within gene expression systems patients, which is to be demonstrated at the end of or particular events of intracellular signaling cas- DDD process, in carefully designed clinical trials, cades. Such reductionism is not entirely satisfactory, starting from early preclinicals (Fig. 1). but even if systems biology approach, with its mul- Additionally, the new drug candidate should also Figure 1. Drug development diagram 580 TERESA BRODNIEWICZ and GRZEGORZ GRYNKIEWICZ fulfill some non medical criteria: 1) intellectual question: how to arrange for preclinical verification property rights for the active molecule should be of selected new chemical entity is by no means sim- clearly defined and well protected; 2) the compound ple, as prospective therapeutical indications gener- should be available in reasonably priced and techni- ate great variety of pathology models, activity tests cally feasible process, easy to scale up and control, and other procedures. In general, the nonclinical affording consistently the active substance (API, team, is responsible for regulatory affairs strategy historically referred to as Bulk Drug Substances formulation, anticipating questions to be posed by [BDS]) of high chemical purity and desired physico- authorities examining future registration applica- chemical properties (7). These rather restrictive tion. Secondly, safety assessments are to be under- requirements concerning the new drug itself and the taken and manufacture of clinical supplies (both: way in which it is developed, are a matter of phar- API and pharmaceutical preparation) have to be maceutical law as well as numerous guidelines secured. All these activities should be coordinated issued by agencies regulating main markets of phar- and planned to minimize time to the first application maceutical products. Both: the law and the guide- to humans, without compromising safety. As all lines are currently a subject of
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