![Pre-Clinical Studies
Once the drug is designed it have to be tested
In vitro [ in laboratory conditions-glass wares].
In vivo [in animals (rodents and non rodents, lab
models)].](https://image.slidesharecdn.com/clinicalresearch-overview-151217063554/85/Clinical-research-Overview-ppt-32-320.jpg)
Clinical research Overview ppt
- 1. Drug Discovery and Development How are drugs discovered and developed?
- 2. Overview Outline here the fundamental concepts and processes of drug discovery Drug discovery Pre clinical study Investigational New Drug Clinical research New Drug Approval Process Marketing
- 3. Drug Discovery and Development Drug discovery Pre clinical study Clinical research Marketing IND NDA
- 4. Drug Discovery Process Lead Discovery Pre- clinical Clinical Review/ Approval Post Marketing Number of years: 2-3 2-3 5-8 1-2 Number of subjects: Ph I Ph II Ph III Ph IV <50 <500 <5-5000 100s- 1000s Cost $1 Billion
- 5. Process for Successful Molecule Phase 1 5-10,000 Molecule Phase 2 250 Molecule Phase 3 5 Molecule NDA 1 Molecule
- 6. Identify disease Isolate protein involved in disease (2-5 years) Find a drug effective against disease protein (2-5 years) Preclinical testing (1-3 years) Formulation Human clinical trials (2-10 years) Scale-up FDA approval (2-3 years) Drug Discovery Process
- 7. The Steps Involved In Drug Discovery Choose a Disease Target Identification Target Validation Lead Identification Lead Optimization Preclinical studies Clinical Studies Marketing
- 8. Choosing a Disease Number of deaths Causes of death in developed countries Number of deaths HIV-AIDS 2,678,000 Ischaemic heart disease 3,512,000 Lower respiratory infections 2,643,000 Cerebrovascular disease 3,346,000 Ischaemic heart disease 2,484,000 Chronic obstructive pulmonary disease 1,829,000 Diarrhea 1,793,000 Lower respiratory infections 1,180,000 Cerebrovascular disease 1,381,000 Lung cancer 938,000 Malaria 1,103,000 Stomach cancer 657,000 Tuberculosis 1,021,000 Hypertensive heart disease 635,000 Chronic obstructive pulmonary disease 748,000 Tuberculosis 571,000
- 9. Target Identification Most of the drugs act on the cellular receptor or biological molecules in the body, which are associated with disease, is known as Targets. Various methods are used to identify target. Interactions and role of target in disease are studied.
- 10. TARGET IDENTIFICATION PROTEINS Hormones Receptors Enzymes Ion Channels DNA RNA AND RIBOSOMES Drug targets fall into one of three main classes Most current drugs are aimed at protein targets. However, current existing therapies only hit about 400 different drug targets out of an estimated pool ten times this size.
- 12. Potential Drug Targets Agonist Agonist Agonist AgonistNa Na Activation of conductance G- Protein Activation Generation of Second Messenger Activation of cell signaling Phosphorylation of Tyrosines on key signaling Molecules Activation of cell Signaling Transport to the Nucleus Activation of transcription and translation
- 13. Target Validation To identify the most useful target Compare target in association with specific disease Design and execute relevant studies to identify the target
- 14. Lead Identification Lead molecule - A molecule that is believed to have potential to treat disease. Scientists compare standard drug in the specific disease with new molecule to determine the successful action. Leads are developed as collections , libraries, individual molecules etc. Evaluation is done to confirm it’s effect on the target.
- 15. Lead Identification -Process 1.Computer- aided Drug Design (CADD) And Structure- based Drug Design (SBDD) 2..Virtual (In- silico) Screening Leads to HITS 3.Synthesis And Combinatori al Chemistry 4.IN SILICO Predictive Toxicity 5.Assay Development —HTS Leads to LEAD Compound Lead Identification
- 16. Tools for Drug Discovery x-ray crystallography NMR Computer- aided drug design (CADD) and structure- based drug design (SBDD)
- 17. 1.Computer-aided Drug Design (CADD) And Structure-based Drug Design (SBDD) IN SILICO SCREENING SCREENING THROUGH CADD/SBDD HITS COMBINATORIAL CHEMISTRY HIGH THROUGHPUT SCREENING LEADS
- 18. 2.Virtual (in-silico) screening Virtual (in-silico) screening sifts through large numbers of compounds based on a user-defined set of selection criteria. Physical property such as molecular weight or charge Chemical property such as number of hetero-atoms, number of hydrogen-bond acceptors or donors Three dimensional description of a binding pocket of the target protein, including chemical functionality and solvation parameters Docking of ligands to a target site
- 19. 3.Hits to Synthesis and Combinatorial Chemistry 1 • Hits to Synthesis and Combinatorial Chemistry 2 • New Compounds are supplied by chemist • New compounds are converted to large amount of precursor 3 • By rule of thumb, one chemist synthesizes, purifies, and characterizes about 100 novel compounds per year • Which give 10,000 compound to develop one drug
- 20. Mutagenicity Carcinogenicity Reproductive Toxicity 4.IN SILICO Predictive Toxicity
- 21. 5.Assay Development—HTS Development of Assay Screening of compounds Primary screens will identify Hits Confirmation screens and counter screens will identify leads out of the pool of hits High-throughput screening (HTS) aims to quickly review the goings-on of a large number of compounds.
- 22. Lead Optimization • Quantitative structure activity relationship (QSAR) Lead Optimization • Structure Activity Relationship Lead Optimization • Animal PK/PD Lead Optimization • Toxicity Lead Optimization • Formulation and Delivery Lead Optimization
- 23. 1.Quantitative structure activity relationship (QSAR)- Lead Optimization Quantitative Structure Activity Relationship (QSAR) The derived function group is used as a guide to select best candidate for drug design. Reflects the property of binding cavity on protein target. Derive a functional group that links biological activity
- 24. 2.Structure Activity Relationship Pharmacological assay for lead assessment Optimization of pharmacological properties Determination of Potency, selectivity and MOA Data into next optimization cycle Lead Optimization
- 25. 3.Animal PK/PD-Lead Optimization Animal pharmacokinetics (ADME) and pharmacodynamics (PD) assess the general pharmacology and mechanisms of action of drugs.. Lead molecules are administered via different routes: intravenous (iv), intraperitoneal (ip), subcutaneous (sc), intramuscular (im), rectal, intranasal (IN), inhalational, oral , trans dermal, topical, etc The main models used are rodents including mouse and rat, but larger animals such as dogs, pigs, and, more rarely, monkeys, are also used under certain circumstances.
- 26. 3.Animal PK/PD-Parameters • PK/PD studies rely heavily on analytical methods and instrumentation. The recent innovation and progress in mass spectroscopy, (whole-body) imaging, and chromatography technology (HPLC, LC-MS, GC-MS) have tremendously increased the quantity and quality of data generated in PK/PD experiments. A large number of parameters is assessed. Here is a partial list: (ADME); bioavailability (F) and protein binding; stability and half-life (t1/2); maximum serum concentration (Cmax); total exposure or area under the curve (AUC); clearance (Cl); volume of distribution (Vd); drug drug interactions; onset of drug action; multicompartmental analysis of blood, liver, and other tissues.
- 27. Principles and applications of LC-MS in new drug discovery
- 28. 4.Toxicity-Lead Optimization The toxicity is the degree to which a substance or mixture of substances can harm human or animals. Acute Toxicity Acute toxicity involves harmful effects in an organism through a single or short-term exposure. Chronic Toxicity Chronic toxicity is the ability of a substance or mixture of substances to cause harmful effects over an extended period.
- 32. Pre-Clinical Studies Once the drug is designed it have to be tested In vitro [ in laboratory conditions-glass wares]. In vivo [in animals (rodents and non rodents, lab models)].
- 33. Difference between In Vivo And In Vitro In Vivo In Animals Generates Pharmacokinetic, Pharmacodynamic and toxicokinetic data Gives an understanding of dose, dose range, side effects, drug receptor binding capabilities, In Vitro In Test Tubes Generates Pharmacodynamic data Gives an understanding on pharmacological action of drug, mechanism of action of drug,Mutagenicity
- 34. Objective of Preclinical Studies Pharmacokinetic Studies Toxicokinetic Studies Pharmacodynamic Studies
- 35. Importance Of Pharmacokinetic Studies Research and selection of a promising molecules Formulation Dosage Toxicology and safety assessment Dosing recommendation for age groups and subgroup population Effect of meals and dosing
- 36. Importance of Toxicokinetic Studies Toxicokinetic Studies Single dose Toxicity Repeated- dose toxicity Reproductive toxicity Genotoxic potential Carcinogenicity Safety pharmacology.
- 37. Coordination of preclinical and clinical studies.
- 38. Coordination of preclinical and clinical studies Drug information journal Vol. 35, pp. 321-336,2001
- 39. Investigational New Drug Application (INDA) •What is an INDA? Sponsors IND FDA To initiate the conduct of clinical trials
- 40. Contents of INDA INDA Table of content Cover Letter Introductory Statement and General Investigational Plan Investigator’s Brochure Clinical Protocol Chemistry Manufacturing and Controls Information Pharmacology and Toxicology Information Previous Human Experience Additional Information
- 41. Clinical Trials Phase I:- Studies in normal healthy volunteers to understand pharmacokinetics Phase II: Dose ranging efficacy safety studies to determine the optimal dose for a particular indication Phase III:Large scale multicentre comparative studies to assess efficacy safety of the study drug v/s currently accepted treatment. Phase IV: Post Marketing Studies.
- 42. Clinical Trial – Phase I Phase 1 Done in 20- 100 subjects. Usually healthy volunteers To understand the metabolic and pharmacological action of drug Maximum Test Dose determination, etc Provide information of pharmacology effects of drug. Safety is the major aspect of study.
- 43. Types of Phase I Trial:
- 44. Phase II Phase 2 Rigid and well- controlled small population between 100-300. Double blind studies using placebo or standard treatment are done. Efficacy and safety are evaluated. Pharmacokinetic and other pharmacological studies are done.
- 45. Types of Phase II Studies Phase 2 Trials Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).
- 46. Phase III Phase 3 Done in a large population- above 300 Evaluation of efficacy and safety profile (initial risk benefit assessment) Identification of the disease sub types for which drug is effective. Comparison with other standard drugs. Pharmacokin etics with others drugs and Quality of life (depends) are evaluated.
- 47. Done while the New Drug Application (NDA) is submitted to FDA. Studies which start pre-launch but which are not intended to form part of Regulatory dossier are referred to as Phase III-b. The data of this study also submitted to FDA. Types of Phase III
- 48. Difference between Phase I,II and III Trials Phase 1 • Safety • Dose Ranging Phase 2 • Safety • Efficacy • Dose • Route Phase3 • Efficacy vs. standard • Defined endpoints
- 49. The formal request to be allowed to market a drug. Sponsor submit NDA to FDA after phase III trials are competed. Have to submit everything that is known about the drug to date, all protocols, case report forms. Regulation for NDA are found in 21 CFR 314. New Drug Application (NDA)
- 50. New Drug Application (NDA) Drug Discovery and development Preclinical Clinical FDA Manufacturing Initial Synthesis of chemical Research and development FDA Expects Review data Drug appears on the market Lab and animal Studies Testing in healthy volunteers Company address FDA Concerns Post marketing Surveillance IRB Testing in disesed individual Advisory- Hearing may be called Follow up Studies and inspection Large scale studies with diseased individuals IND NDA FDA
- 51. Phase IV
- 52. S.No Phases No of People Population Group Safety/Efficacy Goal 1 Phase I 20-100 Healthy Individuals Safety The main goal of a Phase 1 trial is to discover if the drug is safe in humans. Researchers look at the pharmacokinetics of a drug. How is it absorbed? How is it metabolized and eliminated from the body? They also study the drug’s Pharmacodynamic: Does it cause side effects? Does it produce desired effects? Dose ranging studies ,Safety Studies 2 Phase II 100-500 Diseased Individuals Safety and efficacy In Phase 2 trials researchers evaluate the candidate drug’s effectiveness Examine the possible short-term side effects (adverse events) and risks associated with the drug. Researchers also analyze optimal dose strength and schedules for using the drug.
- 53. S.No Phases No of People Population Group Safety/Efficacy Goal 3 Phase III 1000-5000 Diseased Individuals Safety and efficacy and benefit-risk relationship This phase of research is key in determining whether the drug is safe and effective. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines). 4 Phase IV >5000 Real Life Population Ongoing monitoring of safety of drug These trials can be set up to evaluate long-term safety or how the new medicine affects a specific subgroup of patients.
Editor's Notes
- #3: Mention abt all the three module,content should match up with the audio, everything shd not be visible Summary to be given
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- #13: EXPLANATION AUDIO
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- #26: a.This slides helps us to understand the Pharmacokinetics .Pharmacokinetics is the study of adsorption, distribution ,metabolism and excreation. It help us to generate a data on ADME from animals b. The lead molecules are administered to the animals via different rout of administration and should be same as intended to be in humans. c. The animals used can be rodents and nonrodents and the use of the these animals depends upon the similarity of physiology, pharmacokinetic aspects and the receptor binding cabality.
- #28: Aliquot in chemistry, a portion of a total amount of a solution Each content to appear one after another,letter to be more clear
- #29: Please find a similar as it s taken from net http://www.sana-pharma.com/services.html
- #32: This modules explains about the preclinical studies.
- #33: Preclinical studies are of two types in vitro In Vivo
- #34: This slides explains about the difference between in vivo and vitro
- #35: This slides explains the aim and objective of preclinical studies.Ths basic aim of preclinical studies is to evaluate safety. But, in order to estimate or evaluate the safety, its important that preclinical studies includes Pharmacokinetic Studies Toxicokinetic Studies Pharmacodynamic Studies
- #36: This slides describes the importance of pharmacokinetic studies. Pharmacokinetic studies in animals helps to gather data on the following Research and selection of a promising molecules Formulation Dosage Toxicology and safety assessment Dosing recommendation for age groups and subgroup population Effect of meals and dosing
- #37: This slides explains about the different types of toxicological studies which are done in order to produce a data on toxic effect. The following mentioned below are the different types of toxicological studies Single dose Toxicity Repeated-dose toxicity Reproductive toxicity Genotoxic potential Carcinogenicity Safety pharmacology.
- #40: Prior to initiating testing on humans, the drug’s sponsor is required to provide the Regulatory with an Investigational New Drug (IND). The application includes The results of the preclinical Studies, Chemical structure and How it is thought to work in the body A listing of any side effects and manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where and by whom the studies will be performed. New drugs are approved by the regulatory, if the drug does not cause any unreasonable risk to the subject. Clinical trials, basically research studies carried out in humans, are used to evaluate the safety and effectiveness of a new drug,
- #41: This slides explains the content of investigation new drug application.The following are the contents Table of content Cover Letter Introductory Statement and General Investigational Plan Investigator’s Brochure Clinical Protocol Chemistry Manufacturing and Controls Information Pharmacology and Toxicology Information Previous Human Experience Additional Information
- #42: There are different phases of clinical trial which takes place once the drugs gets an IND Approval Phase 1 studies evaluate the safety of the drug Phase 2 evaluates the safety and efficacy of drug in diseased individual Phase 3 Evaluates the safety and efficacy of the drugs in and diseased individual in much larger population Phase 4:Evaluates the ongoing monitoring of the marketed drugs
- #43: Phase one trails are done in a Small group of population Healthy or target population to understand the pharmacological action of drugs Is a dose ranging studies Is also evaluates structural activity relationship Phase one studies are safety studies Phase I studies are designed to determine metabolic and pharmacological actions of the drug in humans Pharmacokinetics and pharmacodynamic data side effects associated with increasing doses Dose escalation studies if possible, to gain early evidence on effectivenes
- #44: The different types of phase 1 studies are Single ascending dose Multiple ascending dose Single escalating dose study Primary: To assess the safety of single doses of drug. Secondary: To gather preliminary information about the subjective, performance-altering, and effects of single doses of drug Repeated IM doses study Primary: To determine the maximum tolerated sub-chronic (4 days) daily dose of drug. Secondary: To determine the minimum number of individual doses into which that maximum tolerated sub-chronic daily dose of drug must be divided, and to test whether the dose and schedule so determined can also be tolerated during a treatment period of seven days
- #45: Phase 2 studies are done in diseased individual to evaluate the safety and efficacy of the drug It is also called as therapeutic exploratory studies Done in a population size of 100-300
- #46: Phase 2 studies are of 2 types phase 2 A and Phase 2 B The objective of phase 2A Studies is to evaluate dosing requirement Phase 2B is to evaluate efficacy
- #47: Phase 3 Done in a large population- above 300 Evaluation of efficacy and safety profile (initial risk benefit assessment) Identification of the disease sub types for which drug is effective. Comparison with other standard drugs. Pharmacokinetics with others drugs and Quality of life (depends) are evaluated. Done in a large group of people around 300-3000 Done in a diseased individuals Phase 3 trials are randomized controlled trial It is also called as multicentre trial It is a therapeutic confirmatory study Clinical Trials are expanded controlled and uncontrolled trials. They are carried out on 500 to 3,000 patients in situations similar to those of actual clinical practice—in clinics, outpatient hospital facilities, and private practice. These studies are performed after a drug’s efficacy has been established, at least to some degree, and are intended to gather additional evidence of drug effectiveness, to discover rarer drug effects or effects that develop after longer periods, and to better define the frequency and severity of more common effects as well as the proper use of the drug
- #50: Once the phase 3 trial shows greater benefits then risk the NDA application is filed with regulatory .NDA constitutes of administrative as well as data from the clinical trial. The review and approval process takes around 2-3 years After the NDA is filed, a team of FDA reviewers analyzes the sponsor’s summaries of the data or, when needed, the actual data. The review team includes a physician, who reviews the clinical test results; a pharmacologist, who reviews the animal test results; and a chemist, who reviews the chemical data and manufacturing controls and processes; supported by a biopharmaceutical specialist, a biometrician, and, when applicable, a microbiologist. The main objective of the process is to ensure that the data from the clinical experiments support the claims for the drug’s safety and efficacy in the labeling the sponsor submitted. NDAs may be presented for consideration to advisory committees composed of experts (mostly nongovernmental) in the various subspecialties of medicine, in clinical pharmacology, and in biometrics. The committees recommend whether or not an NDA should be approved to market a drug and, if the drug is approved, what wording should appear in its labeling. They also may recommend whether the sponsor should be requested to carry out additional studies after the drug is marketed. If the committees recommend against approval, they identify deficiencies and may suggest new studies that need to be done by the sponsor to further investigate the drug’s safety and efficacy.
- #51: Pre nda meet
- #52: Please find a similar pic as taken from net
- #54: Summarize