Asian Journal of Pharmacodynamics and Pharmacokinetics ...

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260Asian Journal ofPharmacodynamics andPharmacokineticsISSN 1608-2281Full text is available at www.hktcm.com and www.issx.orgCSSX-CPSTranslational research in drug discovery, research and developmentChang-Xiao LiuState Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute ofPharmaceutical Research, Tianjin 300193, ChinaAbstractIn this review, according to limited information, author focuses application oftranslational research to drug discovery and development. Translational research is theunderlying basis for Translational Medicine 'the process which leads from evidence basedmedicine to sustainable solutions for public health problems. Scientists and scholars whoare able to focus their efforts to link basic scientific discoveries with the arena of clinicalinvestigation, and translating the results of clinical trials into changes in clinical practice,informed by evidence from the social and political sciences. For drug discovery anddevelopment, translational research can be divided into three phases. Phase oneTranslational Research is the research process that explores needs, develops potentialtreatments in basic laboratory research, and tests safety and efficacy, principally inrandomized clinical trials. Phase two Translational Research examines how findings fromclinical science, shown to be efficacious and safe treatments established in phase onetranslational research, function when they are applied in routine practice. Phase threeTranslational Research adds the necessary information to convert treatments andprevention strategies, shown to be effective and cost-effective in Phase two TranslationalResearch, into sustainable solutions. Current innovative drug research and developmentof the theory, methods, and key technology are the rapid emergence in China. To improvethe strength and the overall level, the establishment of China's independent innovationsystem is very important. Therefore, we face major challenges in innovative drug researchin China to reach close to the country's overall level to improve the drug innovation.Key words Biomarker; bioinformatics, discovery; development; drug; pharmacodynamics;pharmacokinetics; target;; translational medicine; translational researchArticle history Received August 15, 2010; Accepted October 30, 2010Publication data Pages: 7; Tables: 3; Figures:7; References: 34; Paper ID: AJPP-16082281-2010-04-247-14*Corresponding author Corresponding author Professor Chang-Xiao Liu, Research Center for New DrugEvaluation, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. E-mail:liuchangxiao@vip163.comIntroductionIn 1978, Abernathy and Utterback [1] describethe technology life-cycle as an evolution fromproduct innovation over dominant design toprocess innovation in three phases: (a) the fluidphase, where extensive experimentation withproduct design occurs; (b) the transitional phase,where process innovation prevails over productinnovation and (c) the specific phase, whereproduct and process innovation decrease andemphasis is set on cost reduction. The three phasesmay be a early concept on translational research.With establishing Journal of Translational247

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260translational medicine strategy focus on diseasebiomarker, patient selection, pharmacodynamicresponses (efficacy and safety) target validation,compound-target interaction). Successfuldeployment of biomarkers research, validation andimplementation is adopted and embraced as keystrategy to improved the drug discovery anddevelopment towards new medical entities. [6]On March 2004, Food and DrugAdministration (FDA) published the FDA’s WhitePaper: Challenge and Opportunity on the CriticalPath to New Medical Products. And then, CriticalPath Opportunities Report (March 2006), CriticalPath Opportunities List (March 2006), and CriticalPath Opportunities for Generic Drugs (May, 2007)were published by FDA. Here, we introduce therelated information to understand thechallenge andopportunity on the Critical Path to new medicalproducts. [7-10]The medical product development process isno longer able to keep pace with basic scientificinnovation. Only a concerted effort to apply thenew biomedical science to medical productdevelopment will succeed in modernizing thecritical path. If biomedical science is to deliver onits promise, scientific creativity and effort mustalso focus on improving the medical productdevelopment process itself, with the explicit goal ofrobust development pathways that are efficient andpredictable and result in products that are safe,effective, and available to patients. We mustmodernize the critical development path that leadsfrom scientific discovery to the patient. Fig 3shows an idealized “critical path” that encompassesthe drug, biological product, and medical devicedevelopment processes. An ideas coming out ofbasic scientific research enter into evaluationprocess. In drug development the “discovery”process seeds to select or create a molecule withspecific desired biological activities. The criticalpath begins when candidate products are selectedfor development.In response to the widening gap between basicbiomedical knowledge and clinical application,governments and the academic community haveundertaken a range of initiatives. After decades ofinvestment in basic biomedical research, the focusis widening to include translational research —multidisciplinary scientific efforts directed at"accelerating therapy development" FDA isplanning an initiative that will identify andprioritize (1) the most pressing developmentproblems and (2) the areas that provide the greatestopportunities for rapid improvement and publichealth benefits. This will be done for all threedimensions along the critical path — safetyassessment, evaluation of medical utility, andproduct industrialization. It is critical that we enlistall relevant stakeholders in this effort. We willwork together to identify the most importantchallenges by creating a Critical Path OpportunityList (Fig 3). Translational research is very important incritical path research from basic to clinical studies ofnew drugs (Fig 4).Fig 3. Critical path research and translational researchDevelopers must manage the interplaybetween each dimension from the earliest phases ofdevelopment. For example, the first dimension —ensuring product safety — is crucial to considerwhen designing a drug molecule, choosingproduction cell lines or reference strains for250

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260biological production, or selecting biomaterials foran implanted medical device. The traditional toolsused to assess product safety — animal toxicologyand outcomes from human studies — have changedlittle over many decades and have largely notbenefited from recent gains in scientific knowledge.The inability to better assess and predict productsafety leads to failures during clinical developmentand, occasionally, after marketing.The second dimension, demonstrating themedical utility of a new product — showing that itwill actually benefit people — is the source ofinnumerable failures late in product development.Better tools are needed to identify successfulproducts and eliminate impending failures moreefficiently and earlier in the development process.This will protect subjects, improve return on R&Dinvestment, and bring needed treatments to patientssooner.The final dimension on the critical path can bedescribed as the industrialization process —turning a laboratory concept into a consistent andwell-characterized medical product that can bemass produced. The challenges involved insuccessful industrialization are complex, thoughhighly underrated in the scientific community.Problems in physical design, characterization,manufacturing scale up and quality controlroutinely derail or delay development programsand keep needed treatments from patients. Theseproblems are often rate-limiting for newtechnologies, which are frequently more complexthan traditional products and lack standardassessment tools. [11,12]Translational research is a paradigm forresearch alternative to the dichotomy of basicresearch and applied research. It is often applied inthe domain of translational medicine but has moregeneral applicability as a distinct research approach.Basic research is more speculative and takes a longtime – often measured in decades – to be applied inany practical context. Basic research often leads tobreakthroughs or paradigm shifts in practice(Table1).Table 1. Translational research from basic to clinic researchTarget discovery → Lead discovery → Lead optimization → Development → Marketgenomics bioanalysis PK/PD studies Safety/effectBioinformatics Pre-clinical studies Clinical studies Re-evaluationTargets, assay, compounds,experiments, etc.Toxicology, ADME, drug formulation,animal models, etc.Clinical studies, bioanalysis, chemical, projectflow, re-evaluation in clinic, etcApplied research on the other hand ischaracterised as being capable of having an impactin practice within a relatively short time-frame, butwould often represent an incremental improvementto current processes rather than delivering radicalbreakthroughs. The concept of translationalresearch has received very strong focus in thebiomedical community over the last few years, as anew way of thinking about and conducting lifesciences research to accelerate healthcare outcomes.Global Pharmaceutical companies have beenpouring billions of dollars into life sciences basicresearch and are realizing the return on investmentis not living up to expectations, and TranslationalResearch is often seen as the key missingcomponent.Forward translation and reversetranslationOn the basis of different starting points, thetranslation research can be divided into two typesof research models, forward translation and reversetranslation (Fig 4).251

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260Fig 4. Forward translation and reverse translationForward translation based on basic research isto use bioinformatics, genomics in clinical practice,to develop biomarkers and molecular imagingtechniques for later stages (including humanstudies) early in process. Reverse translation basedon clinic research is to bring measurements formthe clinic into earlier stages of basic research, withfaster measurements in human by micro-dosingtesting and validating the biochemistry in targetand biomarker discovery.Biomarker techniques in translationalresearchBiomarkers serve as the fundamental buildingblocks of modern translational research strategies,and are widely implemented in current drugdevelopment. Biomarker techniques range fromsimple biofluid biochemical endpoints to morecomplex assessments, including imaging. Althoughbiomarker usage is common throughout drugdevelopment, applications may vary depending onwhether a drug candidate is in early- or late-stagetesting. In early clinical drug development,biomarkers capable of providing proof ofmechanism are considered critical tools in themanagement of attrition during phase II clinicaltrials. For CNS drugs, the ability to unequivocallydemonstrate pharmacologically driven biologicalactivity in the brain, as a result of the interaction ofa drug with its intended target, ensures thatproof-of-concept trials are designed in a mannerthat adequately tests the clinical efficacyhypothesis and that patients are not being exposedto inactive drugs. This review focuses on recentadvances in proof-of-pharmacology biomarkers,with an emphasis on biochemical measures andsimple circuit platforms used to demonstrate targetengagement in central compartments. [13] Since thediscovery of protein phosphorylation by E. Krebsand E. Fisher in the 1950s, protein kinases havebeen recognised as major players in cell signalling.Their implication in disease has been extensivelyvalidated in cancer, diabetes, cardiovasculardisease and central nervous system pathologies. Inthe pharmaceutical industry, despite initialscepticism on the potential selectivity of adenosinetri-phosphate (ATP) competitor kinase inhibitors,knowledge of the human genome andthree-dimensional structure of protein kinases hasrevealed structural and phylogenetic elementsallowing differentiation amongst kinases.Consequently, we can distinguish today classes ofkinases according to the selectivity profile ofinhibitors in clinical development and drugs in themarket. The abundance of available structural datafor kinases and inhibitors allows us now to identifykey interactions. However, new biding modes areidentified leading to increase selectivity ofparticular compounds. Facing this mount ofknowledge and experience on screening for smallmolecule inhibitors, industry faces severalchallenges: first, the choice of a kinase as target;secondly, how to obtain molecules with desiredselectivity, potency and pharmacokinetics allowingit to be active in patients and thirdly, developingassays for assessing target hitting and patientselection in the clinic. These challenges are keyaspects in an increasingly competitive field and anextremely active research area. [14]A priority translational research objective incancer medicine is the discovery of noveltherapeutic targets for solid tumours. Ideally,252

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260co-discovery of predictive biomarkers occurs inparallel to facilitate clinical development of agentsand ultimately personalise clinical use. However,the identification of clinically useful predictivebiomarkers for solid tumors has proven challengingwith many initially promising biomarkers failing totranslate into clinically useful applications. Inparticular, the 'failure' of a predictive biomarker hasoften only become apparent at a relatively latestage in investigation. Recently, the field hasrecognized the need to develop a robust clinicalbiomarker development methodology to facilitatethe process. This review discusses the recentprogress in this area focusing on the key stages inthe biomarker development process: discovery,validation, qualification and implementation.Concentrating on predictive biomarkers forselecting systemic therapies for individual patientsin the clinic, the advances and progress in each ofthese stages in biomarker development are outlinedand the key remaining challenges are discussed.Specific examples are discussed to illustrate thechallenges identified and how they have beenaddressed. Overall, we find that significantprogress has been made towards a formalizedbiomarker developmental process. This holdsconsiderable promise for facilitating the translationof predictive biomarkers from discovery to clinicalimplementation. Further enhancements couldeventually be found through alignment withregulatory processes. [15]The urokinase receptor (u-PAR) is one of themost critical molecules in migration, invasion,intravasation, and metastasis and is also a keyregulator between tumor cell proliferation anddormancy. It is overexpressed in most human solidcancer types, which has led to increasingtranslational and clinical research on this molecule.The current review discusses in particular the invivo, translational, and putative clinical relevanceof u-PAR in the context of this latest development.It outlines how u-PAR is already being used andmight increasingly be applied as a diagnostic tool,for example, in distinguishing benign frommalignant neoplasms, as a molecular marker forpredicting clinical response to chemotherapy ornovel targeted therapy, and finally as a promisingtool for the development of novel cancertherapeutics. [16]Drug predictions in translationalresearch: BiomarkersTranslational medicine is the integratedapplication of innovative pharmacology tools,biomarkers, clinical methods, clinical technologiesand study designs to improve diseaseunderstanding, confidence in human drug targetsand increase confidence in drug candidates,understand the therapeutic index in humans,enhance cost-effective decision making inexploratory development and increase phase IIsuccess. Translational research is one of the mostimportant activities of translational medicine as itsupports predictions about probable drug activitiesacross species and is especially important whencompounds with unprecedented drug targets arebrought to humans for the first time. Translationalresearch has the potential to deliver many practicalbenefits for patients and justify the extensiveinvestments placed by the private and public sectorin biomedical research. Translational researchencompasses a complexity of scientific, financial,ethical, regulatory, legislative and practical hurdlesthat need to be addressed at several levels to makethe process efficient. Several have resisted the ideaof supporting translational research because of itshigh costs and the fear that it may re-direct fundsfrom other biomedical disciplines. Resistance alsocomes from those more familiar with traditionalclinical research methods. The translationalresearch should be seen as enabled by ongoingefforts in basic and clinical research and notcompeting with them. Translational researchprovides the knowledge necessary to drawimportant conclusions from clinical testingregarding disease and the viability of novel drugmechanisms. [17] There is a need to have predictivebiomarkers to test novel experimental medicines infunctional gastrointestinal disorders (FGID). Thehuman pharmacodynamic models and biomarkersin functional dyspepsia (part I) and visceral pain(part II) are reviewed, including the generalchallenges of these two disorders (part I). Part IIwill also discuss the importance of drugpharmacokinetics and potential ofpharmacogenomics, including the influence of253

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260CYP metabolism and potential drug interactions.The great heterogeneity of mechanisms potentiallyresponsible for dyspeptic symptoms adds asignificant complexity to this FGID. Strategies areneeded to identify subgroups most likely to benefitfrom a specific pharmacological action targeted toone or more mechanisms. Thus, while there aresignificant challenges in drug development forfunctional dyspepsia, there is still an important rolefor pharmacodynamic studies. It remains to bedemonstrated that identifying subgroups enhancesthe response to the pharmacological drug effect.This is feasible as the end points and performanceof each test of gastric emptying, accommodationand sensitivity are well characterized. Of these,gastric emptying appears best validated at present,though responsiveness to this biomarker has not yetbeen translated into positive phase III trials.Eligibility criteria are proposed for selection ofpatients for functional dyspepsia trials. [18]There is a need to have predictive biomarkersto test novel experimental medicines in functionalgastrointestinal disorders. The humanpharmacodynamic models and biomarkerspertaining to two important conditions arereviewed in a two-part article: functional dyspepsia(part I) and visceral pain (part II). With visceralpain models, the large coefficient of variation insensation end points in human studies precludesdefinitive conclusions such as go/no go decisionsor dose selection for phase IIb or III studies, unlessvery large numbers of patients are evaluated inphase IIA pharmacodynamic studies. This renderssuch pharmacological studies ambitious, orunachievable in a timely fashion. Moreover, theresults of tests and clinical trials should beinterpreted with greater knowledge of the drugpharmacokinetics, including the influence of CYPmetabolism and potential drug interactions. Thus, itis important to identify valid biomarkers of visceralpain for the assessment of treatment response inpharmacodynamic studies. In this second part of atwo-part article, we shall discuss the specialchallenges in developing medications for visceralpain and the general importance of includingpharmacokinetic and pharmacogenomic studies indrug development programmes. [19]Metabolomics, an omic science in systemsbiology, is the global quantitative assessment ofendogenous metabolites within a biological system.Either individually or grouped as a metabolomicprofile, detection of metabolites is carried out incells, tissues, or biofluids by either nuclearmagnetic resonance spectroscopy or massspectrometry. There is potential for themetabolome to have a multitude of uses inoncology, including the early detection anddiagnosis of cancer and as both a predictive and PDmarker of drug effect. Despite this, there is lack ofknowledge in the oncology community regardingmetabonomics and confusion about itsmethodologic processes, technical challenges, andclinical applications. Metabolomics, when used asa translational research tool, can provide a linkbetween the laboratory and clinic, particularlybecause metabolic and molecular imagingtechnologies, such as positron emissiontomography and magnetic resonance spectroscopicimaging, enable the discrimination of metabolicmarkers non-invasively in vivo. Here, we reviewthe current and potential applications ofmetabolnomics, focusing on its use as a biomarkerfor cancer diagnosis, prognosis, and therapeuticevaluation. [20]Pharmacokinetic-pharmacodynamic(PK-PD) modeling in translational drugresearchPharmacokinetic-Pharmacodynamic (PK-PD)modeling helps to better understand drug efficacyand safety and has, therefore, become a powerfultool in the learning-confirming cycles ofdrug-development. In translational drug research,mechanism-based PK-PD modeling has beenrecognized as a tool for bringing forward earlyinsights in drug efficacy and safety into the clinicaldevelopment. These models differ from descriptivePK-PD models in that they quantitativelycharacterize specific processes in the causal chainbetween drug administration and effect. Thisincludes target site distribution, binding andactivation, pharmacodynamic interactions,transduction and homeostatic feedbackmechanisms. Compared to descriptive modelsmechanism-based PK-PD models that utilizereceptor theory concepts for characterization of254

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260target binding and target activation processes haveimproved properties for extrapolation andprediction. In this respect, receptor theoryconstitutes the basis for (1) prediction of in vivodrug concentration-effect relationships and (2)characterization of target association-dissociationkinetics as determinants of hysteresis in the timecourse of the drug effect. This approachintrinsically distinguishes drug- and system specificparameters explicitly, allowing accurateextrapolation from in vitro to in vivo and acrossspecies. This review provides an overview ofrecent developments in incorporating receptortheory in PK-PD modeling with a specific focus onthe identifiability of these models. [21] The use ofPK-PD modeling in translational drug research is apromising approach that provides betterunderstanding of drug efficacy and safety. It isapplied to predict efficacy and safety in humansusing in vitro bioassay and/or in vivo animal data.Current research in PK-PD modeling focuses onthe development of mechanism-based models withimproved extrapolation and prediction properties.A key element in mechanism-based PK-PDmodeling is the explicit distinction betweenparameters for describing (1) drug-specificproperties and (2) biological system-specificproperties (Fig 5).Fig 5. Drug-disease-system translational researchContemporary models in the field of PK-PDmodeling often incorporate the fundamentalprinciples of capacity limitation and operation ofturnover processes to describe the time course ofpharmacological effects in mechanistic terms. Thispermits the identification of drug- andsystem-specific factors that govern drug responses.There is considerable interest in utilizingmechanism-based PK-PD models in translationalpharmacology, whereby in silico, in vitro, andpreclinical data may be effectively coupled withrelevant models to streamline the discovery anddevelopment of new therapeutic agents. Thetranslational PK-PD models form the subject of thisreview. [22] Mechanism-based PK-PD modelscontain specific expressions for the characterizationof processes on the causal path between drugexposure and drug response. The different termsrepresent: target-site distribution, target bindingand activation and transduction. Ultimately,mechanism-based PK-PD models will alsocharacterize the interaction of the drug effect withdisease processes and disease progression. Theprinciples of mechanism-based PK-PD modelingare described and illustrated by recentapplications. [23] The renewed interest in drugdiscovery and development in academia providesan opportunity to rethink the hiearchary of studieswith the hope of improving the staid approachesthat have been criticized for lacking innovation.One area that has received limited attentionconcerns the use of PK and PD studies in thedrug-development process. Using anticancer drugdevelopment as a focus on PK/PD studies is255

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260conducted and offer new strategies that might Drug Delivery in Clinical Trialsinvestigation. [26] in the global regulatory environment. [27]bridge the gap between preclinical and clinical andTranslational researchtrials. [24]The three categories are Drug DeliveryAn important feature of mechanism-based Technology, System and Device, BiologicalPK/PD models is the identification of drug- and Molecules Platform or Technology, and Drugsystem-specific factors that determine the intensity Metabolism, Pharmacokinetic/Pharmacodynamicand time-course of pharmacological effects. Thisprovides an opportunity to integrate informationobtained from in vitro bioassays and preclinicalpharmacological studies in animals to anticipate theclinical and adverse responses to drugs in humans.The fact that contemporary PK/PD modelingcontinues to evolve and seeks to emulate systems(PK/PD) Interactions (Table 2). The first categorycovers all the drug delivery devices and systems,including biopolymers, drug carriers as well aspro-drug platforms. Each specific terminology isentered in the “search term” field. The rationale forthe choice of these broad and overlappingdescriptors/search terms is to maximize searchlevel properties should provide enhanced results for subsequent analyses. The secondcapabilities to scale-up PD data. Critical steps in category highlights biological moleculardrug discovery and development, such as lead approaches, including recombinant proteins,compound and first in human dose selection, may antibody derivatives, peptides and oligonucleotidebecome more efficient with the implementation and platforms including siRNA and aptamerfurther refinement of translational PK/PD technologies. The thresh category of drugmodeling. [25] Translational pharmacology is the metabolism and PK/PD interaction strategiescollaboration between researchers and clinicians to pertains to metabolic drug–drug interactiondiscover more effective medical therapies and toidentify new drugs for various diseases. Themediated enhancement or reduction in overall drugexposure. The special focus that entirely or in part,promise of genetic-based prescriptions and deals with clinical trials pertinent to drug deliverytherapeutic plans as a useful strategy to improveclinical outcomes of a medical therapy maytechnologies or issues associated with specific drugdelivery systems (including strategies related tobecome credible and warrants further metabolism, transport and drug–drug interactions)Table 2. Categorical Organization of Descriptors Found in www.clinicaltrials.govDrug delivery technology system anddeviceBiological moleculaesplatform/technologyDrug metabolism and PK/PDinteractionDevice, Drug delivery system, Dosageform, Formulation comparison,Transdermal, Aerosol inhalation, Route,Sustained release, Liposome, Nanomicroparticles,prodrugs, Colloid, etcAntibody, Biological and vaccine,Peptide, Recombinant proteins,Antibody conjugates, Antisennse,Oligonucleotide, siRNA, AptamerDrug metabolism inhibitorDrug transport modulatorDrug intereactionsActive metabolitesThe recommended approach to developmentof drug delivery is an integrated evaluation ofdrug’s ADME properties and efficacy in thecontext of overall safety profiles. Therefore, it issurprising that a low percentage of these trialsaddress either long-term or short-term safetyendpoints. Maintaining the most up-to-dateinformation and in-depth look at the trends inclinical development through review of thepublication and database will serve regulatory andpharmaceutical industry scientists well who relyheavily on expert opinions in the area ofpharmaceutical drug delivery. [27]Phase 0 studies in translational researchThe current phase I/II/III model forchemotherapeutic development can be traced backto the mid 1960s. [28] However, the complexities ofoptimally assessing molecularly targeted agents,associated costs, and clinical failure rates of over90% have resulted in a re-evaluation of thisparadigm. [29] Such trials can potentially establish256

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260whether the investigational drug affects its allegedtarget in the desired manner; provide humanpharmacokinetic (PK) and pharmacodynamic (PD)data to inform further agent development; validatebiomarker assays for target modulation effects;allow selection of the most promising candidatefrom a set of analogues; and evaluate humanbiodistribution, binding, and target effects usinghighly sensitive imaging technologies (Table 3) [30] .Table 3. Three Examples of Phase 0 Studies Supported by the Exploratory IND Studies Guidance DocumentThree ExamplesPhase 0 Studies Supported by the Exploratory INDPharmacokinetics or imagingPharmacologicallydosesPharmacodynamicstudiesrelevantendpointEvaluate human biodistribution and target binding characteristics usingsensitive imaging techniques or microdoses (1/100th of thepharmacologically active dose up to a maximum of 100 microgram or 30nanomoles for protein products). Preclinical toxicology studies shoulddemonstrate that a dose 100 times the proposed human dose does notinduce adverse effectsEvaluate human PD and/or PK (e.g., bioavailability) of two or more analogs toselect a lead agent. Preclinical toxicology studies must establish the noobserved adverse effect level (NOAEL) in a rodent 2-week toxicologystudy; the clinical starting dose is generally 1/50th of this dose.Evaluate whether the new molecular entity modulates its intended target.Supporting preclinical toxicology studies are generally short-termmodified toxicity or safety studies in two species.The Phase 0 concept is a new strategy withpotential value for drug evaluation, especially inoncology. However, the FDA review process forexploratory INDs is relatively untested, and there islimited published experience with Phase 0 trials todate. Many questions remain about drug suitabilityfor Phase 0 evaluation, choosing an appropriatestarting dose, the extent of preclinical toxicologystudies required, as well as incentives forconducting a Phase 0 trial. [31]The concept and efficiency of conductingPhase 0 trials is not widely accepted by thepharmaceutical industry because some ofcompanies have not knowledge about Phase 0 trialsor they doubt whether Phase 0 clinical trials wouldreally save greatly investment, shortendevelopment timeline and increase probability ofsuccessful drug development. [32]The opportunity to make clinical developmentdecisions based on observed target modulation orlack thereof depends on the extent of the preclinicalevaluation (Fig 6).Fig 6. Go/No Go clinical development decisions based on PK and PD assessment in Phase 0 trials.It requires development of validated PK andPD assays and the demonstration of an associationbetween desired target modulation at achievableplasma levels of the drug and antitumour activity inpreclinical models. Accordingly, there can be threetypes of Phase 0 trial outcomes: (1) If target plasmalevels are achieved and target modulation isobserved (PK+, PD+), further agent development iswarranted; (2) If target plasma levels are notachieved and the expected PD effect is notobserved (PK-, PD-), further development is notwarranted; and (3) If target plasma levels are257

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260achieved but target modulation is not observed(PK+, PD-), continued development will depend onthe strength of the preclinical evaluation and typeof assay used. [33]Challenges in translational researchWith the rapid development of life sciences,translational medical sciences have a newsignificance recent years. Translational medicalscience aims to eliminate the barriers betweenclinical, pharmaceutical drug breakthroughs andbasic research, to shorten the distance from benchto bed side, and to facilitate rapid patient benefitsfrom medical sciences. Growing barriers betweenclinical and basic research, along with the ever theincreasing complexities involved in conductingclinical research, are making it more difficult totranslate new knowledge to the clinic – and backagain to the bench. The challenges are limitingprofessional interest in the field and hampering theclinical research enterprise at a time when it shouldbe expanding. By enabling physicians andpharmacologists to leverage systems biologytechnologies, translational research can enableearly detection of cancer and other diseases,increase efficiency in drug development, improvedrug efficacy and enable personalized medicine.The possibilities of using biomarkers to predict,detect, and monitor disease make personalizedmedicine tangible. Only when clinicians,researchers and the various operational staff canwork together effectively, will the movement ofscientific discoveries accelerate into the clinic andclinical findings more rapidly fuel researchdirections.The translational research requires researchersand clinicians to have ready access to two criticaltypes of information, clinical information,including data contained in hospital systems andmedical records, pathology reports and diagnosticlabs, clinical trials systems and study participantquestionnaires; and biomolecular information,including genomics, proteomics, medical imagingand other high-throughput molecular and cellularresearch data (Fig 7). Translational researchrequires that information and data flow fromhospitals, clinics and participants of studies in anorganized and structured format to biorepositoriesand research-based facilities and laboratories. Thesheer volume of data, combined with the need toshare data across domains, demands an integratedand holistic approach to IT systems for informatics.Fig 7. Bedside-bench-bedside processesUniversities are traditionally associated withbasic research while polytechnics and technologyinstitutes are typically associated with appliedresearch. This separation is more than just cultural,as the physical separation across these differentinstitutions makes it difficult to establish themultidisciplinary and multi-skilled teams that arenecessary to be successful in translational research.This represents just one of the particular challengesin conducting translational research successfully.Other challenges arise in the traditional incentiveswhich reward individual principal investigatorsover the types of multi-disciplinary teams that arenecessary for translational research. Also, journal258

Liu CX. Asian Journal of Pharmacodynamics and Pharmacokinetics 2010; 10(4):247-260publication norms often require tight control ofexperimental conditions, and these are difficult toachieve in real-world contexts.An attempt to bridge these research activitieshas been undertaken particularly in the medicaldomain where the term translational medicine hasbeen applied to a research approach that seeks tomove “from bench to bedside” or from laboratoryexperiments through clinical trials to actualpoint-of-care patient applications. The mode ofresearch can be applied more generally outside themedical domain where researchers seek to shortenthe time-frame and conflate the basic-appliedcontinuum to ‘translate’ fundamental researchresults into practical applications. It is of necessitya much more iterative style of research with lowand permeable barriers and a great deal ofinteraction between academic research and industrypractice. Practitioners help shape the researchagenda in supplying what may be intractableproblems to which applied research approacheswill only offer incremental improvements.Collaboration, data sharing, data integrationand standards are integral. Furthermore, the scale,scope and multi-disciplinary approach thattranslational research dictates means a new level ofoperations management capabilities within andacross studies, biorepositories and laboratories.Meeting the increased operational requirements oflarger studies, with ever increasing specimencounts, larger and more complex systems biologydata sets, and government regulations, precipitatesan informatics approach that enables the integrationof both operational capabilities and clinical andbiomolecular data. Most informatics systems in usetoday are inadequate in terms of handling the tasksof complicated operations and contextually in datamanagement and analysis.Current innovative drug research anddevelopment of the theory, methods, and keytechnology are the rapid emergence in China. Toimprove the strength and the overall level, theestablishment of China's independent innovationsystem is very important. Therefore, we face majorchallenges in innovative drug research in China toreach close to the country's overall level to improvethe drug innovation. In the "critical path research",the implementation of the translational medicine ortranslational research will not only affect thepharmaceutical enterprises of the developmentprocess of new pharmaceutical products, but alsoimpact on the mechanism of innovative drugresearch. In particular to improve the efficiency ofthe importance of research and development,grasping the three elements is very importance inrelationship between the translational research andnew drug research and development. [34] Forscientific support systems of the critical pathresearch, the scientific support system, includingtechnical standards, research tools, registrationpolicies and registration of scientific criteria will beuseful to promote the realization of the invention.Analysis of the causes of drug elimination, you canconvert that research is the key chain, the existinganimal disease models and methods of safetyevaluation studies by the use of access toinformation to patents, to the treatment of disease,there is still a considerable distance.AcknowledgementsThis review was supported by National Basicresearch Plan (973 Plan) Foundation of China(Grant no.2010CB735602, 2010CB735600).References1. Abernathy, W.J. and Utterback, J.M. Patterns of industrialinnovation. Technol Rev 1978; 80, 40–47.2. Ginexi EM, Hilton TF. What's next for translationresearch? Eval Health Prof 200629(3):334-47.3. http://www.cancer.gov/trwg/TRWG-definition-and-TR-continuum4. http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp5. Suzuki Y, Yeung AC, Ikeno F. The pre-clinical animalmodel in the translational research of interventionalcardiology. JACC Cardiovasc Interv 2009; 2(5):373-83.6. Day M, Rutkowski JL, Feuerstein GZ. Translationalmedicine--a paradigm shift in modern drug discovery anddevelopment: the role of biomarkers. Adv Exp Med Biol2009; 655:1-12.7. FDA. Challenge and Opportunity on the Critical Path toNew Medicinal Products (March 2004),http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf8. FDA. Critical Path Opportunities Report (March 2006),http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_ report.pdf.9. FDA, Critical Path Opportunities List (March 2006),http://www.fda.gov/oc/initiatives/259

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