DRUG DISCOVERY & CLINICAL EVALUATION OF NEW DRUGS PRESENTED BY: HEENA PARVEEN, M.PHARMACOLOGY, ASST.PROFESSOR.DRUG DISCOVERY & CLINICAL EVALUATION OF NEW DRUGS Drug discovery & development is a challenging & expensive activity of the pharmaceutical industry. With the advent of technologies in biological screening procedures of new chemical entities , the time involved in drug discovery has gone down in recent years but, the cost of drug discovery has touched a new high of US $ 1 billion per molecule from conception to drug launch.+ Target identification & * Phave| Healy || + NDA/ ANDA/ BLA Validation Volunteer Study Applicaton © Hit Discovery * Phase ll ond Phase ll |) + FDA Approval © Assay Development & See) co + Drug Registration Population Screening | « Des Etlaon, Single ’ e eee) | tome Ascending & Malle oa Opinion & Dase Studs + Hit Lod Fioavabiliy Pata * Lead Optimization * Pharmacokinetic Analysis * Bioanalytical Method Development and ValidationAim: = Develop clinically efficacious & safer drug . = Economically Viable = Discover entirely new class of drugs = Explore the mechanism or Pharmacodynamic properties It takes nearly 8-14 years for the development process. For every 6200 compounds sythesized ,only 21 will reach testing stage for Sub-acute toxicity. Only 2-6 of these compounds will reach clinical trials & subsequent evaluation. Ultimately, one of these compounds may become a drug. To get approval for marketing a new drug it must be thoroughly tested for safety & efficacy for its intented use.een al ulema ntDRUG DISCOVERY The combined efforts of Chemists, Biologists, Pharmacologists, Toxicologists,Statistcians,Clinici ans,Pharmacists,Pharmaceutcal scientists, Engineers, & many others are involved in the drug discovery & development process. New Drugs SOURCE: Natural sources — Plants, Animals, Minerals,Marine or chemically synthesised in the laboratory. Recently, the advent of Genetic engineering & sub-microscopic DNA manipulation techniques, the development of pharmaceutical products has witnessed a new era.Methods of Drug Discovery Most drugs nowadays are the result of carefully designed v Research programmes of screening, ¥ Molecular modification & Y Mechanism based Drug design. Biological Characterisation: Prospective drug substances must undergo preclinical testing for biologic activity n order to assess their potential as useful therapeutic agents. These studies fall in to general areas of Pharmacology, Drug Metabolism,& Toxicology & involves many types of biologic scientists.Pre-Clinical Testing * In drug development, preclinical development, also named preclinical studies and nonclinical studies, is a stage of research that begins before clinical trials. * During this important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals. * The main goals of preclinical studies are to determine a starting, safe dose for first-in-human study and assess potential toxicity of the product, which typically include new medical devices, prescription drugs, and diagnostics.Each class of product may undergo different types of preclinical research. For instance, drugs may undergo Pharmacodynamics, Pharmacokinetics, ADME, and Toxicology testing. It allows researchers to estimate a safe starting dose of the drug for clinical trials in humans. Typically, both in vitro and in vivo tests will be performed. Studies of drug toxicity include which organs are targeted by that drug, as well as if there are any long- term carcinogenic effects or toxic effects causing illness.Pre-clinical Animal Models: Rabbits ¢ Rats * Mice Guinea pigs Hamsters * Dogs Swine Sheep CalvesTreatments may be administered via the following routes of administration: * Oral y Intravenous e Subcutaneous° Intracutaneous Intraperitoneal Continuous infusion Intratracheal Intrathecal DermalInvestigational Areas: Cardiovascular Endocrine Anti-infective Oncology Musculoskeletal Dermal Central Nervous SystemPreclinical Tests Information * Exploratory Studies such as ADME and PK studies. ¢ Regulatory Studies including toxicity, immunogenicity, and safety pharmacology. * Formulation Support * Microdosing studies for ultralow dose clinical studies. * Downloadable Test Timing ChartInformation Contents Previous Investigative Human Use e A Plan Investigational New Drug Pharmacology te) . Reserved (Toxicology Clinical Investigator Brochure Clinical Protocol Sponsor Information Additional Table of Manufacturing and Control:The IND application must contain information in three broad areas: * Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans. * Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and = poy consistent batches of the rug. * Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.Also, information on the qualifications of clinical investigators-- professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.CLINICAL TRIAL PHASES CLINICAL TRIAL Ae DO a AM) ROTO a Mt | A ba i f "i a ne Le ak it COPRECLINICAL \_ CLINICAL RESEARCH FINAL DATA FOLLOWUP TESTING ANALYSIS Laboratory tests Biostatistical New therapy shown to a > 2> a> ( analysis besaleandeectve 7 Waa TT Ut a eT . £ ead ail ‘ ’ J "Comparison of i I} % mT ie ‘ew with standard y | VeTRIALS co) PATIENTS LENGTH PURPOSEPHASE 0: It is Explanatory, First in human trials . Also called as Human Microdosing studies in small group of healthy volunteers (10-15 numbered) to speed up the development of promising drugs. This Phase doesn’t give safety & efficacy but gives an idea on ranking the promising drug candidates to take forward the drug development studies. PHASE 1: In small number of normal human volunteers , it is conducted(20-30). Here, the acute effects of the agents are studied over a broad range of dosage, starting with one that produces no detectable effect &progressing to one that produces cither a major therapeutic response or minor toxic effect.PHASE 2: To evaluate drugs in a moderate number of patients(100-500) with a target disease. A placebo or positive control drug s included in single blind / double blind design. The goal s to determine whether the agent has the desired therapeutic effects at doses that are tolerable by patients. PHASE 3: It consists of large design involving may patients(1000-5000) & many clinicians who are using the drug in manner proposed for its ultimate general use (OUTPATENTS). The goal is to explore further the spectrum of beneficial actions of the new drug, to compare it with older therapies & to discover toxicities.PHASE 4: It represents the Post-marketing survillance phase of evaluation, in which it is hoped that toxicities occur very infrequently will be detected & reported early enough to prevent major therapeutic disasters. NDA application is the vehicle through which the drug sponsors formally propose that the FDA approve a new pharmaceutical foe sale & marketing in the U.S. The data gathered during the animals study & human clinical trials of an IND become an NDA.