Introduction on Drug Research and Development (R & D) Process in the USA1“Rock” Diagram of Drug Development ProcessTargetsScrrens SAR Discovery Pre-clinical Clinical Marketing I II III Toxicology Pharmaco- kinetics Selection NDA IND 2,000 cpds 20 6 3 2 1 1 year 1 1 2 3 50 Mill 50 100 200 400 800 2Drug Development Process(1). Discovery Stage(2). Pre-clinical Stage(3). Clinical Stage(4). Marketing Stage3Major Steps in Discovery StageTarget generation and selectionCompound LibraryCombinatorial chemistryLibrary chemistryNatural productsDevelopmentMethod set-upMethod validationTechnique assesmentAutomationOptimizationHigh throughput screensLead confirmation and chemistryIn vivo functional testsAssay development and validationPreliminary PK investigationSAR4Target Generation and SelectionScreening Target based on hypothesis Target associatedwith disease Target as mechanism of disease Target causing disease Copying others (Fluoxetine and olanzapine stories) Schizophrenia AlzheimerParkinson Genetics (DA in Pfc) (Ab-42) (DA in Striatum) (Disease genes) Market Analysis5Structure of Olanzapine and Other Anti-psychotics6Structure of Fluoxetine and Other Anti-depressants7Developments of Anti-depressants(I). Monoamine related drugs (A). Monoamine uptake inhibitors(1). Selective 5-HT uptake inhibitors (SSRIs)AstraZimeldine (Withdrawn in 83)LillyFluoxetine (Prozac)PfizerSertraline (Zoloft)GSKParoxetine (Paxil)Forest/LundbergCitalopram (Celexa)(2). Selective NE uptake inhibitors (SNRI)Reboxetine(3). Selective DA uptake inhibitorsNomifensine(4). Dual 5-HT/NE uptake inhibitorsDuloxetine (Cymbalta)(5). Dual DA/NE uptake inhibitorsBupropion(6). Non-selective reuptake inhibitors:Tricyclic (TCAs): imipramine, desipramine, etc. (B). Auto-receptor inhibitors to achieve rapid onset of actions(1). 5-HT1A antagonistsPindolol(2). a2-adrenoceptor antagonistsNapamezole (C). Neurotransmitter releaserFenfluramine (D). Monoamine oxidase inhibitors (MAOI)Resagerine (E). Specific receptors agents(1). 5-HT receptorsBuspirone (5-HT1A partial agonist)(2). NE receptor agentModafinil (a1-adrenoceptor agonist) (F). Combinations of SSRI with other mechanisms(II). Non-monoamine related drugs(1). NK-1 antagonistsAprpitant (MK-869, L-754030, stopped)(2). PDE4 inhibitorsMEM 1414 (preclinical)(3). CRF1 antagonistsMany compounds(4). Other mechanismsSt Johns Wort 8Problems with Current Anti-depressantsLimitations in efficacyEfficacy between currently antidepressants and TCAsTCAsAnti-cholinergic side effectsCV side effects and orthostatic hypotensionSSRIsNausea, headache, insomnia, agitation and sexual dysfunction, etc.Delayed onset of actionsMAOsHypertensive crisis Weight gainWeight gain could be a sign of improvement in depressive symptomsTCAs and MAOs are likely to cause weight gain than SSRIsParoxetine may be more likely to cause weight gain (3.6% in 6 months)9Combinations of SSRIs and 5-HT1A Antagonists5-HTSSRIT5-HT5-HTP5-HT1ATRYP(-) WAY(-)(-)Hypothesis:Combination of SSRI and 5-HT1A antagonist may overcome the delayed onset of anti-depressant action of SSRIs10Multiple Possibilities for the Development of New Anti-depressants5-HTSSRI5-HT3NapamezoleDANETEG5-HT ATPcAMP5-HT?5-HTP5-HT1ATRYP(-) WAY5-HT1B5-HT1DAnti-depressant Actions(-)(-) 1 1 2 2 Bupropion(-)(+)NEDA(+)(-)(-)(-)11Animal Models for Depression StudiesLearned helplessness (increase escape behavior)Forced swim/behavioral despair (increase the latency)Tail suspension test (increase the latency)Chick isolation (increase the latency)Olfactory bulbectomy (increase learning and memory)Differential reinforcement of low rates of response (DRL)5-HTP induced head twitch (increase response)Aggression behaviors (attenuate aggression)Amphetamine self-administration (reduce response)Activity wheel stress (reduce response) 12Drug Development Process(1). Discovery Stage(2). Pre-clinical Stage(3). Clinical Stage(4). Marketing Stage13Major Steps in Pre-clinical StageGeneral pharmacological studies Effects on various systems for safety evaluationComprehensive PK studies Absorption, distribution, metabolism and excretion (ADME) Formulation developmentFurther improve PK profiles of the final candidatesScale-up and stabilityPrepare large quantity of the compounds for safety studiesAcute and chronic animal toxicological studies14Pre-clinical Safety and Toxicological Studies(A). Safety Pharmacology Studies(1) General pharmacology on major systems(2) CNS safety(3) CV safetyhERG, APD, anaethetized dog, dog telemetric study (4) GI motility(5). GeneticCytogenicity, Ames, mutagenic, etc.(B). Toxicology Studies(1). Study durationAcute 1 day1 wk4 wksChronic 12 wks6 mons12 mons 2 years (2) Animal speciesRatMouseDog Monkey(3) Doses2 4 doses(4) Administration routeUsually oral, but sometimes ip, iv(5) GoalsTo determine NOAEL, motility, clinical pathology, histopathology, etc.15Drug Development Process(1). Discovery Stage(2). Pre-clinical Stage(3). Clinical Stage(4). Marketing Stage16Major Steps in Clinical StagePhase I studies in health volunteers Focus on drug safety and dosing range in humansPre-IND meting with the authoritiesIND (Investigational New Drug) filingPhase II studies in selective patient population Phase IIa: Proof-of-Concept studiesPhase IIb: dose findingEnd of Phase II meeting with the authoritiesPhase III studies in large patient population 2 adequate and well-controlled positive trials Need about $50 100 millions and 2 - 4 yearsNew Drug Application (NDA) filing17Process of Clinical Trials(1). Preparation for clinical studies(2). Conduct of clinical studies(3). Completion of clinical studies18Things to Do to Start Clinical TrialsDevelop CDPConsult the FDA and medical expertsDevelop protocolDevelop Case Report Form (CRF)Select and initiate sitesFile IRB and other regulatory documentsSelect CROsHold investigator meeting and site trainingPrepare drug supplyDevelop timeline and budget19Things to Do to Conduct Clinical TrialsVisit sites to validate data recordingMonitor patient enrollmentAnalyze baseline dataMonitor safety and other issues during the trialsReview patient profileInterim analysis to validate power calculationExecute site and patient paymentsPrepare data transfer from labs to sponsorPrepare database and statistic analysis plan20Things to Do to Complete Clinical TrialsReview all patient profiles and issue queriesTransfer out-site data to in-house databaseClear and lock databaseAnalyze data and produce tables and listingsPrepare study reportCommunicate results with various functional areasClose sites and labsComplete all paymentsRetrive un-used study medication(s)Complete working relationship with the CROs21Clinical Development Plan (CDP)(1). Background Medical NeedRationale for Development Preclinical data summaryEfficacy, Pharmacokinetics and Toxicology Data Formulation Development Doses, Routes, and SchedulesRegulatory Review Input from External Advisors(2).Target Product Profile (TPP)(3).Clinical Development Strategy Approach to Characterization and Optimization of TherapyApproach to Defining Efficacy and SafetyApproach to Non-registration Trials and Commercialization (4).Potential Challenges 22Target Product Profile (TPP)Indications and UsagePopulationDose & AdministrationEfficacySafetyContraindications and Precautions Clinical PharmacologyOutcomes ResearchCost of Goods23Main Components of Investigators Brochure (IB)SummaryIntroduction Research rationale and therapeutic indicationsGeneral evaluation approach, etc.Physical and chemical properties and formulationNon-clinical studiesNon-clinical PharmacologyPK and metabolism in animalsToxicologyEffects in HumansPK and metabolism in humansSafety and efficacyMarketing experienceGuidance for the investigators24Protocol of Clinical Trials(1). BackgroundIntroduction about the disease and unmet medical needsOverview of pre-clinical data of study drugRational for the development(2). Study Objectives and Endpoints(3). Study Design (4). Patient Selection(5). Schedule of Events(6). Enrollment Procedures(7). Treatments(8). AssessmentsEfficacy AssessmentsSafety AssessmentsPharmacokinetic Assessment(9). Statistical Methods(10). Quality Control(11). Data Handling and Record Keeping(12). Others including ethics, references, appendices, etc.25Scales for Clinical EvaluationDepressionHamilton Depression Rating Scale (HAMS)Montgomery-Asberg Depression Rating Scale (MADRS)Beck Depression Inventory (BDI) SchizophreniaBrief Psychiatric Rating Scale (BPRS)Positive and Negative Syndrome Scale (PANSSScale for the Assessment of Negative Symptoms (SANS) Stroke NIH Stroke Scale for severityGlasgow Scale for disabilityBarthel Index for functional evaluation Parkinsons diseaseUnified Parkinsons Disease Rating Scale (UPDRS)Parkinson Dyskinesia Scale (PDS)Hoehu and Yahr Scale GeneralClinical Global Impression (CGI)Quality of Life Scale (QLS)Medical Outcome Study 36-item Short Form Health Survey (SF-36)26Rough Estimate of Mean Sample Size N = k (Z 1- + Z 1- )2 / (Effective size) 2N: ITT patient number per group (total number should be larger to cover dropouts)Effective size = (mean difference between drug and placebo group) / Pooled SDPooled SD = square root of (SD12 + SD22) SD = SEM times square root of Nk: enrollment factor (ratio of treatment groupsk = 4 (for 2 groups) for an enrollment ratio of 1:1 (1/ 0.5) + (1/0.5) k = 4.5 (for 2 groups) for an enrollment ratio of 2:1 (1/ 0.666) + (1/0.333) : power factor obtained from the Z tableIf powered at 80%, a factor of 1 0.8 = 0.2 will be used for Z table 0.8416If powered at 90%, a factor of 1 0.9 = 0.1 will be used for Z table 1.28155 : P factor obtained from the P table Z = 0.05 for one dose or no multiple comparison 1.96, for 2-sided = 0.025 for multiple comparison of 2 doses 2.24, for 2-sided = 0.017 for multiple comparison of 3 doses27Donepezil (Aricept) Studies for Alzheimers Disease*Study 1Study 2AD diagnosisNINCDS-ADRDA, DSM III-R NINCDS-ADRDA, DSM III-R AD severityMild-moderate (MMSE 10-26)Mild-moderate (MMSE 10-26)PatientsRandomized: 473Randomized: 468TreatmentPBOPBOAricept: 5 mg/dayAricept: 5 mg/dayAricept: 10 mg/day Aricept: 10 mg/dayDuration30 wks (washout 6 wks) 15 wks (washout 3 wks)Primary efficacy-1 ADAS-cog (cognitive)ADAS-cog (cognitive)At wk24: diff vs PBOAt wk12: diff vs PBO5 mg: 2.8, P0.055 mg: 2.7, P0.0510 mg: 3.1, P0.0510 mg: 3.0, P0.05 Primary efficacy-2 CIBIS-Plus (global)CIBIS-Plus (global)At wk24: diff vs PBOAt wk12: diff vs PBO 5 mg: 0.35, P0.055 mg: 0.36, P0.0510 mg: 0.39, P0.0510 mg: 0.38, P0.05(*From Aricept Approved Labeling Text)28Interactions with the FDA(1). Pre-INDSafety study design (doses, duration, assessments, etc.)(2). IND filingAnswer to the possible FDA questions about the INDIND number for clinical enter(3). Pre-phase IIFDA input on phase II protocol ($1 millions to prepare for it(8). Label What exactly will be included in the package insert(9). Post-marketCommitment to the FDA before approvalSafety issues after approvalPediatric exclusivity (two trials in kids for 6 more months)(10). OthersFDA scientific meetings FDA and CPMP guidelines for specific disease(s)29Investigational New Drug (IND) ApplicationThree IND types:Investigator INDTo be submitted by a physicianEmergency INDEmergency use of an experimental drugTreatment INDExperimental drugs for life-threatening conditions30 day waiting periodPossible FDAs questions on safetyPre-IND meeting with the FDA. Materials for the meeting include:Purpose of the meetingSpecific questionsProduct name and structureProposed indicationsDosage regimen and route of administrationOverview of the clinical development programClinical data summaryNon-clinical data summary30Main Components of an IND Application(1) IND Application form (FDA form 1571) 21 CFR 312.23(a)(1)(2) Statement of Investigator (Form FDA 1572)(3) Table of contents 21 CFR 312.23(a)(2)(4) Introduction and general plan 21 CFR 312.23(a)(3)(5) Investigators brochure (IB) 21 CFR 312.23(a)(5)(6) Protocols 21 CFR 312.23(a)(6) (Focus on safety(7) Chemistry, manufacturing and control information 21 CFR 312.23(a)(7)Drug substance Drug productPlacebo control Labels (8) Animal pharmacology and toxicology information 21 CFR 312.23(a)(8)Pharmacology and drug distribution Toxicology GLP certification Full data for each animal toxicology study(9) Previous human experience 21 CFR 312.23(a)(9)31IND Application Process32New Drug Application (NDA) Filing(A). Main Components of a NDA:(1). Application Summary(2). Final report for registration study 1(3). Final report for registration study 2(4). Integrated Summary of Efficacy (ISE)(5). Integrated Summary of Safety (ISS)(6). NDA Application Form FDA 356h(B). The goals of the NDA are to reach the following key decisions:(1). Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks(2). Whether the drugs proposed labeling (package insert) is appropriate, and what it should contain(3). Whether the methods used in manufacturing the drug and the controls used to maintain the drugs quality are adequate to preserve the drugs identity, strength, quality, and purity33NDA Review Process34Preparation for the FDA AC Meetings(1). Briefing docu: A very good summary of the key data sets(2). Speaker(s)Know about 90% of the dataOrganize the talk and prepare the slidesEndless practice for presentation and Q & A sessions(3). Advisory panelComments and suggestions for improvementAnswer to any scientific questionsOpinion on key issues from a FDA point of viewSuggestions on what you can or cannot say to the FDA (4). ConsultantsProvide trainings to the speakers Develop slide category and databaseFDA meeting format simulation (5). Company teamCareful review every single slide Provide comments to the speaker about everything(6) Q & A groupGuess all possible questions the AC members might askPrepare sets of slides to answer all questions at different levelsSort the slides and prepare the Q & A binderTraining and practice to pick up right slides in few seconds.(7). Others: Public affairs, security, drills, gifts, parties, etc.35Top 10 Issues to Remember When Preparing for FDA Meetings(1). Highlight the main points that you want the FDA agents to remember(2). Get to your points quickly and finish meetings on time(3). Give the FDA a short but good summary of your statement(4). Listen to the comments of Advisory Committees(5). Make sure you get right person from the right division in the meeting so a decision can be made at end of the meeting(6). Pay your attention to Project Managers, the messengers of the King(7). Do not ask for meetings on Fridays(8). Limit the number of person for the meeting(9). Be clear if you are going to talk about non-scientific issues(10). Make sure you know the exact location of the meeting room36General Considerations for Clinical Evaluation of DrugsInstitutional reviewPatients: Informed consentDesign:ObjectivesObservation methodNumber of patients Selection of patients Randomization of patientsControl: Placebo and/or active drugDosage consideration Patient compliancePhase I studiesSubjects: usually normal volunteersInvestigators: skilled in initial evaluation for safety and efficacyAdditional considerations: ECG data, special tests, blood drug levelPhase II and III studiesSubjects: patientsInvestigators: experts in the particular disease categoriesAdditional considerations: blood drug levels, etc)Tests for safetyWomen: Usually excluded from the earliest dose ranging studiesMale: Special consent forma if abnormalities occur in animal studChildren: Not until there has been considerable experience in adults37Good Clinical Practice (GCP) An international ethical and scientific quality standard for designing, conducting and reporting trials. The goal is to protect public rights, safety and well-being. GCP covers the following areas of clinical study:(1). Institutional review board (IRB) / independent ethics committee (IEC)(2). InvestigatorQualification and resourcesMedical cares of trial subjectsCommunication with IRB / IECCompliance with protocolRandomization proceduresInformed consentRecords and reportsSafety reportingTermination or suspension of a trialFinal report(3). SponsorQuality controlTrial design and managementInvestigator selectionPay to subjects and investigatorsNotification of regulatory authorityInformation on study products Supplying and labeling productAdverse reaction reportingMonitoring and audit(4). Clinical trial protocol(5). Investigators brochure (IB)(6). Essential documents for the conduct of a clinical trial Before: IB, protocol, informed consent form, IRB approval, investigator CV, randomization list, etc. During: visit reports, adverse events, screening log, record of retained body fluids, etc. After: product accountability, audit certificate, close-out report, clinical study report, etc.38Drug Development Process(1). Discovery Stage(2). Pre-clinical Stage(3). Clinical Stage(4). Marketing Stage39Drug Development Process Marketing StageLaunch of new productCosts $800 millions to reach peak saleFurther evaluation of long-tern safety in large patient population Post-market clinical studies Active isomerNew indicationsDifferent patient populationsCommitment to the FDA before approvalPediatric exclusivityTwo trials conducted in kids regardless the outcome of the studies to get 6 more months of patent coverageMedical outcome studies Economic impact of your drug vs comparative drugs40Clinical Drug Development ProcedureProgramStudyStudy StudyData ResultNDAStrategyPlanDesign ConductAnalysis ReportFilingDiscoveryTher area dirStatistics Clin OperationStatistics Med WritingRegulatoryIn-licensingClin PharmaClin Supply Data MgtData Mgt RegulatoryMed AffairsBusiness MgtRegulatoryData Mgt Safety SurveillanceProgramming Clin Data Std MarketingMarketing IPClin Planning Med Outcome ResOthersProject mgtClin OperationDocument MgExp MedicineQuality AssuranceFinance / AdmProject mgtPharma DlptOutsourcing (lab, ECG, recruitment, audit, data entry, randomization, etc.)41Clinical Operations Process (1)Study planning Feasibility test(2)Investigator selectionCenter screening and selection criteria(3)Contract and grants(4)Essential documentsFDA 1572 and CVs, IRB, ICF, etc.(5)Investigator meeting / coordinate training(6)Study suppliesDrugs, CRFs, etc.(7)Study conductSite monitoring, patient recruitment, etc.(8)Data flowData management, SAEs, etc.(9)Clinical trial management system (CTMS)(10) Clinical support center(11) More:Central labs, etc.42Roles of Project Management in Clinical Development(1). Develop an effective strategy for project management(2). Establish realistic timelines and project budget(3). Refine project management responsibilities(4). Develop an effective project communication plan(5). Develop a plan for project changes and risk management(6). Implement best strategies for conflict management(7). Effectively manage data reporting and adverse event reporting(8). Review guidelines for compliance a quality assurance system43Thank You Jiang-Xi Medical College, Nan-ChangProf. Wang, Chong-Wen and many othersInstitute of Materia Medica, Chinese Academy of Medical SciencesProf. Zhang, Jun-Tian and his groupKarolinska Institute, Stockholm, SwedenProf. Kjell Fuxe and his groupEli Lilly and CompanyRay Fuller David WongAnd many others44同学们同学们来学校和回家的路上要注意安全来学校和回家的路上要注意安全同学们同学们来学校和回家的路上要注意安全来学校和回家的路上要注意安全