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6. drug design and development


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6. drug design and development

  1. 1. The Drug Discovery and Development ProcessJune 7, 2012 Sokoine University of Agriculture
  2. 2. Lead To Proof Of Concept• Technologies & Solutions for Selecting Best Clinical Candidate – Medicinal Chemistry – Biological Screening Assays – High Throughput Purification & Analysis – ADME-PK – Data Management• Technologies and Solutions for Establishing POC – Process Chemistry & Development – Analytical Method Development & Validation – Bio-analytical – Regulatory & Clinical AffairsJune 7, 2012 Sokoine University of Agriculture
  3. 3. Overview of the Drug Development Process• Statistics related to Research and Development• Process of Drug Development• Phases Involved in Drug Development• Success vs Failures – What Accounts for Each?June 7, 2012 Sokoine University of Agriculture
  4. 4. What are the Characteristics of Pharmaceutical R&D?• Based on commercialization of biomedical research discoveries• Innovation is critical to the process• Specialized research is essential and development cycles are very long• Resulting drug candidates/products must: – be treatment breakthroughs – have better profiles than existing treatmentsJune 7, 2012 Sokoine University of Agriculture
  5. 5. Basic Statistics for Pharmaceutical Industry• Pharmaceutical R&D is high-risk and also very high cost• Average cost to discover and develop one compound = $0.8-1Billion• Takes on average 10 years to go from shelf to pharmacy shelf• Need to screen 5,000 – 10,000 compounds to generate an approved drug• About 3/10 drug products make profits that match or exceed R&D costsJune 7, 2012 Sokoine University of Agriculture
  6. 6. R&D Success Rates by Development Stage Discovery (2-10 yrs) Compound Success Rates by Stage 5,000 – 10,000 screened Preclinical Testing Lab & animal testing 250 Enter Pre-clinical Testing Phase I 20-80 healthy volunteers for safety & dosage 5 Enter Clinical Testing Phase II 100-300 patient volunteers used to 1 Approved by FDA for efficacy & side effects Phase III 1,000-5,000 patient volunteers used to monitor efficacy & side effects adverse reactions to long-term use FDA Review/Approval Additional Post-marketing testingYears0 2 4 6 8 10 12 14 16 Source: PhRMA based on data from Center for the Study of Drug Development, Tufts University
  7. 7. The Drug Development Process Process Development Screening Lead Formulation/Stability Identified Preclinical File PostDrug IND/CTC CTC/ File FilingSourcing Workup IND Phase I Phase II Phase III WMA Activities A Patent process P Metabolism R O V Toxicology A L Preclinical Registration Post-submissionDiscovery Screening Development Preparation Activity Up to 15 years
  8. 8. Pharmaceutical R&D Phases• Basic Drug Discovery Res. (6 mths – 16 yrs) – Evidence for role of enzyme, receptor, gene or pathway in disease – Drug target selection and validation – Compounds screening – natural & synthetics – Rational drug design/ molecular modeling – Hit-to-lead, lead optimization and selection • Safety assessment process begins
  9. 9. Clinical Development: Phase I• Approximately 10-40 patients – up to 1 yr• Safety and tolerability – healthy volunteers• Evidence of activity in some areas• Produce a clinical pharmacology package – Bioequivalence studies – Drug interactions – Different populations (pediatrics, elderly, kidney/liver dysfunction)
  10. 10. Clinical Development: Phase II• Phase IIA – 10-100 patients with target disease – Clinical/efficacy “Proof of Concept” – Normally lasts 9-12 months• Phase IIB – 100 – 200 patients – Dose ranging studies – Set minimum effective dose – Essential to design Phase III – Normally lasts 9-12 months
  11. 11. Clinical Development: Phase III• 1,000 – 4,000 patients• Also called “Pivotal Studies”• To Demonstrate Safety & Efficacy• Randomized, well-controlled, blinded• Patient outcomes included in the endpoints• Timing: 2-4 years
  12. 12. Clinical Development: Phase IV• Typically specified by the regulatory agencies – safety is the usual reason• Normally required/condition for approval• 10 – 1,000 patients• Could require outcomes/endpoint studies• Phase V Clinical Development – New claims, new dosage forms, market support, comparisons to competitors, etc.
  13. 13. New Molecular Entities (%) Entering Each Phase of Clinical Trials The price of innovation: New estimates of drug development costs Journal of Health Economics, Vol 22 (2003), pp 151-185.
  14. 14. Typical Drug Discovery Process “Pre-clinical “Hit” “Lead” candidate” Active-to-Hit Hit-to-Lead Lead Optimization HTS (AtH) (HtL) (LO)Compound Initial SAR, Iterative design Hit resynthesisacquisition near neighbor synthesis and synthesisChemistry Data analysis and mining Mol modeling, SAR dev Biology Screening Biochemical “mechanism of action” screens In vivo efficacy screens Acute tox Chronic tox DMPK Purity, identity determ Physchem prop screens ADME screens (in vitro perm, metab, safety) In vivo DMPK
  15. 15. Some Key Definitions• “Hit” = compound(s) which have demonstrated reproducible, dose-responsive activity in a primary biological assay• “Lead” = compound(s) which have been shown to exhibit properties (activity, selectivity, ADME, etc.) perceived to optimizable through iterative cycles of medicinal chemistry and biological evaluation• “Pre-clinical candidate” = compound which has in vivo efficacy, in vivo PK, selectivity and toxicological properties consistent with a pre-defined Target Product Profile
  16. 16. Failure: The Reality of Drug DiscoveryHistorically, the majority of Hit-to-Lead and Lead Optimization programs fail to deliver a pre-clinical candidate due to: – Lack of efficacy (in animal models) – Unexpected toxicity – Poor pharmacokineticsIf you must fail… “Fail early, fail cheap”
  17. 17. THANK YOUJune 7, 2012 Sokoine University of Agriculture
  18. 18. June 7, 2012 Sokoine University of Agriculture