Drud Discovery - Dr. Amsavel.pdf
- 1. Drug Discovery Process Dr. A. Amsavel, M.Sc., B.Ed., Ph.D. 1
- 2. An Overview • Introduction • Drug Discovery path • Pharma R & D –overview • Discovery & Development • Preclinical research • Clinical Trial • NDA and FDA Approval • Post marketing data • References 2
- 3. History of Drug Discovery • The history of drug discovery & development is as old as human civilizations. – Eg Ayurveda, Siddha in India, traditional medicines in China, Rome and Egypt are 3000-5000 years old & still in practice. • Modern medicine started from discovery of vaccine for smallpox by Edward Jenner (1796) • Synthetic medicine Aspirin produced by Bayer(1899) is popular medicine, highly used even today (40,000MT in 2021) . • After discovery of Penicillin by Sir Alexander Fleming (1928), drug discovery is speeded up. 3
- 4. Research in Pharma Industry • Discoveries in Biology & Chemistry are helped significantly in the drug discovery. • Pharma industries contribution is significant to the society by invention of new drugs for treatment of diseases; increased the life expectancy of human. • There are Scientific & financial challenges in Pharma industries. • R&D continuously working to develop new medicines, formulation & drug delivery ... • Drug research is complex nature & time taking process • Regulation for drugs is stringent since it is risk to life • Effective & safer drug approved to use after a thorough medical evaluation. 4
- 5. Why Drug Development is Costly? • Chemicals developed in non-pharmaceutical industries, can be used in 3 months- Eg chemicals in plastic, adhesive, paints and etc…. • But, Pharmaceuticals products take approx. 10-15 years from discovery to treatment • Cost for successful launch of a drug into the market is ~$1.0 to 1.5 billion – Discovery & preclinical is 32% and Clinical trial is 63% of total cost . • Advance technology, genomics research, gene sequencing, high- throughput screening (HTS) robotics, AI, computation helped to reduced the cost from $ 2.8B to $ 1.2B 5
- 6. Drug Discovery Process? • Drug discovery is a process which aims to identifying a compound therapeutically useful in curing and treating diseases. • This process involves – Discovery & Preclinical study- Identification of candidates, synthesis, characterization, validation, preclinical test ie toxicity & safety. – Clinical trials -therapeutic efficacy & safety – Regulatory approvals 6
- 7. The Process Involves Interdisciplinary team with expertise in Biochemistry, Molecular biology, Organic chemistry, Analytical Chemistry, Physiology, biochemistry, Pharmacology, Toxicology , Physiology, Medicine, IT etc Analytical Chemistry Animal Health Anti-infective Disease Artificial Intelligence Bacteriology Biochemistry Biology Biometrics Cardiology Cardiovascular Science Chromatogtaphy Clinical Research Communication Computer technology Cytogenetics Development Planning DNA Sequencing Diabetology Documentation Dosage Development Drug Absorption Drug Degradation Drug Delivery Electron Microscopy Electrophysiology Engineering Environmental Health & Safety Employee Resources Endocrinology Enzymology Facility Finance, Formulation Gastroenterology Graphic Design Histomorphology Instrumentation & analysis Intestinal Permeability, Library Science Medical Services Medicinal Chemistry Molecular Biology Molecular Genetics Molecular Models Natural Products Neurobiology Neurochemistry Neurology Neurophysiology Oncology Organic Chemistry Pathology Pharmacokinetics Pharmacology Photochemistry Physical Chemistry Physiology Process Development Project Management Psychiatry Public Relations Pulmonary Physiology Radiochemistry Radiology Robotics Spectroscopy Statistics Sterile Manufacturing Taxonomy Technical Information Toxicology Veterinary Science Virology X-ray Spectroscopy etc Drug Discovery Team? 7
- 8. Pharma R & D – Expenditures Pharma Companies Spend globally > $200 billion for Research 8
- 9. PhRMA - Pharmaceutical Research and Manufacturers of America. Ref: US Pharma R & D – Expenditures 9
- 10. R & D budget of Top Pharma Company Revenue (2019) R&D Expen (2020) R&D / Revenue (%) Roche $62.39 billion $13.9 billion (Cal.INR 97,300cr) 22.2 Merck & Co. $48.0 billion $13.6 billion 28.3 Johnson & Johnson $82.6 billion $12.15 billion 14.7 BMS $42.5 billion $11.14 billion 26.2 Pfizer $41.9 billion $9.4 billion 22.4 Novartis $48.65 billion $8.9 billion 18.2 GlaxoSmithKline $47.51 billion $7.7 billion 16.1 Pharma companies spend more than $100 billion per year for R&D R & D budget of top 7 Pharma companies in 2020 (>$75B) 10 Ref: Fierce pharma
- 11. How many Drugs are Approved in a Year? Any assumption?? 11
- 12. Approval of Drugs- Trend New drugs approved by FDA: 55 in 2021, 55 in 2020, 48 in 2019 & 58 in 2018 12
- 13. Drug Discovery • Ancient times: Natural products with biological activities are used as drugs.- Willow leaves & bark, Cinchona bark • Chemical Era: Synthetic organic compounds • Biochemical era: Biological compound -macromolecules. • Discovery research – Scientific approach: • Screening, chemical modification, validation/ testing and use • Serendipity (Accidental – Penicillin, Viagra etc) 13
- 14. Drug Discovery: Brief Pathway 14
- 15. Drug Discovery & Development 15
- 17. Discovery & Preclinical Research ~10000 molecules ~100 molecules 17
- 19. Drug Development Process There are five critical steps in Drug Development Process 1. Discovery and Development 2. Preclinical Research 3. Clinical Trials 4. FDA Review & Approval 5. FDA Post-market Safety Monitoring There are many phases and stages within each of the above steps 19
- 20. Step-1: Discovery & Development • Early period, identifying the active ingredients from traditional medicines or purely by chance. • Presently, pharmacology is used to identify the candidates • Identification of the biological origin of a disease, and the potential targets for intervention. • An ideal target should be efficacious, safe, meet clinical and commercial requirements and shall be Druggable. 20
- 21. Step-1: Discovery & Development Target (therapeutic agent) Identification: Researchers use the following for target Identification by disease association, bioactive molecules, cell-based models, protein interactions, signalling pathways analysis & functional analysis etc… – Form available data/ chemical libraries – HTS: High Throughput Screening – SAR: Structure – Activity - Relationship. 21
- 22. Target to drug path 22
- 23. High Throughput Screening (HTS) • Using robotics, data processing & control software, liquid handling devices, and sensitive detectors, we can conduct in millions of pharmacological, chemical, and genetic tests, rapidly to identifies active compounds Hit to Lead selection • Small molecule hits from an HTS are evaluated and selected (broad choice) the lead compounds. 23 Target
- 24. 2: Preclinical Research • Once a lead compound is found, preclinical research initiated to determine the efficacy and safety of the drug. • ADME: Absorption, distribution, metabolization, and excretion information (PK-measuring the ways, drug affects the body ) • Potential benefits and mechanisms of action – affinity and selectivity. – metabolic stability (half-life)& bioavailability • Best dosage, and administration route • Side effects/adverse events • Effectiveness compared to similar drugs 24
- 25. 2: Preclinical Methodology • Preclinical trials test the new drug on non-human subjects for efficacy, toxicity, and pharmacokinetic (PK) information. • Trials are conducted thro in-vitro & in-vivo with unrestricted dosages. • Regulation:21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. 25
- 26. Selecting Animal Model (in vivo) Regulatory requirement : One rodent and one non-rodent species. 26
- 27. 2: Pre-clinical Research Cont.. Drug Delivery Establish delivery methods like- Oral, Topical, Membrane, Intravenous, and Inhalation. Plan targeted delivery or controlled release of new drugs. The goal is to prevent the drug from interacting with healthy tissues . Formulation Optimization Ensure that drugs are delivered to the proper place at the right time and in the right concentration. 27
- 28. 2: Pre-clinical Research • Oral : Tablets, Capsules, Suspension etc. Easy, reliable, cost- effective, and convenient for patients. Delayed action, stomach enzyme destruction, absorption inconsistencies, or patients with gastrointestinal issues or upset can occur. • Topical: Ointments, creams, lotions, or transdermal patches that deliver a drug by absorption by skin into the body. • Parenteral Drug delivery by bodily membranes, intramuscular (IM), intraperitoneal (IP), etc. • Parenteral (Intravenous): Intravenous injection. Fastest drug delivery. IV injection ensures entire doses of drugs enter the bloodstream. • Parenteral (Inhalation): Inhalation. Rapidly absorbed into the mucosal lungs, nasal passages, throat, or mouth. 28
- 29. Preclinical Drug Characteristics Detailed Preclinical CMC Comprehensive ADME GLP Toxicology • Physico-chemical properties • Impurity analysis • Stability Testing • Develop prototype clinical formulation • Analytical method development • PK & TK • GLP • Comprehensive identification of metabolites • Acute study Sub- chronic • Repeat dose study • Genotoxicity • Safety • Pharmacology • GLP Toxicology Regulatory Submission to FDA 29
- 30. Preclinical conclusion • The data of the successful candidate have be to submitted to health authorities to get permission for conducting clinical investigations / trials 30
- 31. Investigational New Drug (IND) Investigational New Drug Filing (USFDA) • Investigational New Drug application to FDA before commencement clinical research. • IND application shall be included the below; – Preclinical and toxicity study data – Drug manufacturing information – Clinical research protocols for studies to be conducted – Previous clinical research data (if any) – Information about the investigator/ developer. 31
- 32. Step-3. Clinical Trials • Clinical trials shall be conducted for the drugs before human use. • To ensure the the drug works for its intended purpose. • Clinical trials must be safe, efficacious and shall be completed as per plan. • Follow GCP guidelines ICH Efficacy Guidelines E1- E20 32
- 33. Clinical Trials- Phase-I Healthy Volunteer Study • Drug is tested on humans; less than 100 healthy volunteers (USFDA-20-80) • to judge its safety, side effects and to find the correct drug dosage. • To determine effects on the body. Pharmacokinetics (pk) of the drug, absorption, metabolic, and elimination Only gross toxic effects will be observed at this stage Approximately 70% of drugs move to the next phase-USFDA 33
- 34. Step-3. Clinical Trial –Phase-II Phase-II Studies in Patients • Aim is assess the drug works in people who have a certain disease or condition. • Conducted in patient with population of 100-300 to assess drug Safety and Efficacy. • to study short-term side effects. • Compare with placebo or standard drug previously used as treatment. Adverse effects & risks are recorded and evaluated may be performed globally. USFDA : Length of Study: Several months to 2 years Approx.33% of drugs move to the next phase 34
- 35. Clinical Trial- Phase-III Studies in Patient Population • Conducted on larger patient populations 1000-3000 at different regions and countries, age, gender etc.. • To study safety and effectiveness at different populations and different dosages, and combination with other drugs. • May compare with other drugs that are currently in use (“comparators”) • The results from these trials ie Risk /Benefit analysis will be submitted to the regulatory authorities • FDA agrees to proceed , if the trial results are positive. GCP: monitoring & review by Independent Ethics Committee (IEC) or Institutional Review Board (IRB) USFDA :Length of Study: 1 to 4 years; Approximately 25-30% of drugs move to the next phase 35
- 36. Pharmacodynamic (PD) study The study of the biochemical and physiologic effects of drugs and the relationship between drug concentration and effect in test animals / human. Pharmacokinetic (PK) study It is an experimental trial that determines the theory of how a new drug behaves in the human body. The volume of distribution, clearance, and terminal half-life are deftermined. 36
- 37. • Bioanalytical test performed to test the analytes and metabolites (drug or biomarker) in biological or human samples to determine drug efficacy and safety. • Drug & Metabolite Stability – Drug and drug metabolites are susceptible to degradation, which can lower drug concentration over the life of the drug. – Determine the Stability of drugs in biological samples • Sample Analysis for Drug and Metabolites in blood, plasma, urine & feces 37
- 38. Clinical Trials Patient Protection – GCP, HIPAA, & Adverse Event Reporting • Human patients is protected during clinical trials • Follows Good Clinical Practices (GCP) guidelines • Health Insurance Portability and Accountability Act (HIPAA) • Adverse event reporting to IEC for review and approval – Opinion for approval/disapproval – modifications required prior to its approval – termination/suspension prior to its approval • Data Collection and Data Integrity are ensured IEC -independent Ethics committee (IEC)or Ethical review board (ERB) 38
- 39. 4: FDA Review • After clinical trials New Drug Application (NDA) has to be filed with full history of a drug molecule. • Drug candidate, preclinical data & Clinical 3 trial information . • Report of all the above studies, data, analysis result and clinical trial outcomes • Also must include: – Proposed labeling – Safety updates – Drug abuse information – Patent information etc • Purpose is to verify and approval by Regulatory authority that a drug is safe and effective for its proposed use. 39
- 40. 4: FDA Review Drug Failure FDA may reject the drug on following reasons. New drug applications may fail for a variety of reasons, eg. • Toxicity: If the toxicity of a new drug is too high in human • Efficacy: If a new drug’s efficacy is not high enough or lack of evidence • PK Properties or Bioavailability: – poor bioavailability due to low aqueous solubility, – inadequate action, duration and unanticipated drug interactions. – Inadequate Drug Performance 40
- 41. Drug manufacturing • API and FDP shall be manufactured under GMP and complies. • manufacturing process complies to – Validation, Qualification, characterization, stability, Storage/shelf life stability • Quality & Efficacy: Ensue Identity, purity, potency and Efficacy • FDA Inspection and approval of both API & Formulation 41
- 42. Step 5: Post-market Monitoring • Post-marketing studies / trials have to be performed after the medicine has been approved • The trials may involve many thousands of patients and continue for many years • To know the long term risk and benefit and may used for modification if required. • Problem Reporting: – Adverse Event Reporting System (FAERS) – FAERS helps FDA implement its post-marketing safety surveillance program. – Report from manufacturers, health professionals, and consumers 42
- 43. Summary : Purpose of Each Stages Pre Discovery Drug Discovery • Understand the diseases to be treated • Identify a Drug target • Test the target for research feasibility • Find a drug candidate • Conduct initial tests on all promising compounds • Optimize the leads for safety and effectiveness Pre Clinical • Test leads in Laboratory and animals • In vitro, In-Vivo • Develop and test processes of drug for clinical trial Clinical • Phase-I - III • Find safe dose ranges • Establish proof of efficacy & side effects • Efficacy/Adverse effects in large population of patents Reg. Approval • Submit new drug application (NDA) with data on findings, clinical trials and plan for manufacturing Commercial • Large scale manufacturing and distribution • Post approval monitoring ( phase-IV) 43
- 44. Facts & Figures • Global life expectancy (LE) increased from 66.8 years in 2000 to 73.3 years in 2019. • Pharmaceuticals Sales in 2020 is 1.1-1.2 trillion • Highest revenue of a blockbuster drugs ( sales in 2020) • AbbVie’s - Humira $20.39 billion • Merck & Co. - Keytruda $14.38 billion • Bristol Myers Squibb - Revlimid $12.15 billion • More than 60,000 clinical trials were registered worldwide in 2018 (as per WHO) • There are hundreds of clinical trials were suspended and postponed in 2020 due to Covid 44
- 46. References • Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018- Olivier J Wouters et al • Fierce Biotech The top 10 pharma R&D budgets in 2020-By Ben Adams Apr 6, 2021 • The Stages of Drug Discovery and Development Process Amol B. Deore et al.., Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67 • Research and Development in the Pharmaceutical Industry- Congressional Budget Office,-US • Drug Discovery: an Industrial Process - Drug Discovery Today - Dr Steve Carney, Elsevier • Global Pharmaceuticals Market Report 2021: 46
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