1. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 1 Roger J. Porter, M.D. Consultant Chief Scientific Officer, ETP Adjunct Professor of Pharmacology, USUHS Adjunct Professor of Neurology, Univ. of Pennsylvania Former Deputy Head, CR&D, Wyeth-Ayerst Research Former Deputy Director, NINDS, NIH What Have We Not Discussed? The Next Steps Toward The Clinic ASENT: February 25, 2012

2. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 2 Source: FDA Council Congressional Briefing Series, “Molecules to Miracles,” 1997. Consumers Cures, Treatments, and Prevention BASIC RESEARCH (Discovery) TRANSLATIONAL RESEARCH APPLIED RESEARCH (Development) Knowledge About Disease Government NIH Private Sector Biomedical Research Companies Non-Profit Foundations Government NIH Private Sector Biomedical Research Companies Non-Profit Foundations Private Sector Biomedical Research Companies The Process of Discovery and Development

3. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 3 COMMENT: The Overall Process Everybody is doing everything Everybody is doing everything Example: Substantial Activity from Non-Profits in all Areas of Neurological Research Example: Substantial Activity from Non-Profits in all Areas of Neurological Research

4. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 4 Non-Profit Contributions to Research in Neurologic Disorders Annual $$ in Grants from IRS 990 Multiple Sclerosis Society: $32M (2009) Muscular Dystrophy Assn.: $49M (2010) Parkin. Dis.---2 orgs+MJF: $56M (2009-10)

5. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 5 Molecular Opportunity Project Initiation Project Initiation Market Opportunity

6. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 6 COMMENT: The Market Think About The Market Early In The Process Of Drug Development— Think About The Market Early In The Process Of Drug Development— - Will The Intellectual Property Of The Compound Be Sufficient To Attract A Company? - If The Intellectual Property Is Weak, Is There An Alternate Path?

7. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 7 DRUG PRODUCT FLOW Lead Finding IND Track Phase I Phase II Phase III Registration Development Discovery

8. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 8 (DISCOVERY) PHARMACEUTICAL DEVELOPMENT MEDICINAL CHEMISTRY DRUG METABOLISM DRUG SAFETY REGULATORY INPUT

9. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 9 DRUG PRODUCT FLOW Lead Finding IND Track Phase I Phase II Phase III Registration Development Discovery

10. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 10 Phase I The first 2-3 studies in humans.

11. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 11 COMMENT:Phase I --A stage of drug development --Sometimes erroneously used to describe the Clinical Pharmacology studies which are performed throughout the entire period of the drug’s development.

12. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 12 Typical Phase I Studies 1) Single Ascending Dose (SAD) ---also usually the “FIM” ---also usually the “FIM” 2) Multiple Ascending Dose (MAD) ----------------------------------- 3) Effect of Food (Prelim) 4) Effect of Age and/or Gender (Prelim)

13. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 13 Additional Studies Performed by Clinical Pharmacology 1) Are performed throughout development 2) Include: drug interactions, dose proportionality, renally impaired, hepatically impaired, bioequivalence/bioavailability, mass balance, etc.

14. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 14 DRUG PRODUCT FLOW Lead Finding IND Track Phase I Phase II Phase III Registration Development Discovery

15. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 15 Phase II Is The Drug Effective at a Safe Dose?

16. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 16 1200 900 600 300 1815222936435057 113 -56 Screening Seizure Baseline Titration Maintenance 0 148 Taper Interim 600 500 400 900 800 700 1200 1100 1000 Optional Long- Term extension study or Tapering mg Days Placebo 450 750 1050 168 205-EU/AU/US : Study Design 500 400 800 700 1100 1000

17. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 17 COMMENT: The Federal Government is Much Less Efficient Than The Industry In the Conduct of Clinical Trials!

18. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 18 Phase III Is The Drug Safe and Effective in a Larger Population? --For Drugs, Typically 2 RCCTs --For Devices, Typically 1 RCCT

19. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 19 NO COMMENT Phase III is hard work

20. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 20 Regulatory Process How Long Does It Really Take To Get Regulatory Approval?

21. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 21 COMMENT Is The Regulatory Process Broken? Ezogabine (Retigabine) Filed (FDA accepted) December,2009 Approved in Europe in March, 2011 DEA approval this week? NeuroPace RNS System Filed (FDA accepted) Nov, 2010 Adv Comm Mtg not yet scheduled Adv Comm Mtg not yet scheduled

22. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 22 Neurological Science and New Therapies In Spite of All These Hurdles, We Are Making Slow But Steady Progress

23. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 23 STOP!

24. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 24 PHARMACEUTICAL R&D IN THE NEW MILLENNIUM OPPORTUNITY Scientific and Medical Breakthroughs Scientific and Medical Breakthroughs Technology Breakthroughs Technology Breakthroughs CHALLENGE Complexities of Scientific Environment/Regulatory Hurdles Complexities of Scientific Environment/Regulatory Hurdles Cost Containment Cost Containment 

25. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 25 Access to Medicines (Medicare) Mergers & Acquisition Legislation & Regulation Pricing Intellectual Property Protection Patient Privacy Liability & Litigation Issues Affecting The Pharma Industry

26. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 26 Late-Stage Pipeline - U.S. Leads the World 104% increase in U.S. Source: Adis R&D Insight Database, customized run, December 2005. Notes: Comparisons for were completed for June of each year. Some compounds will be at different phases for different indications.

27. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 27

28. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 28 Drop in Death Rate for Diseases Treated with Pharmaceuticals 1965-1996 90%80%70%60%50%40%30%20%10%0% Rheumatic Fever and Rheumatic Heart Disease Atherosclerosis Ulcer of Stomach and Duodenum Antibiotics ACE inhibitors, beta blockers, nitrates H 2 blockers, proton pump inhibitors 83% 74% 72% Percent Drop in Age-Adjusted Death Rate Source: PhRMA, 1998, based on Boston Consulting Group, 1993, and U.S. National Center for Health Statistics, 1998 DiseaseTreatment

29. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 29 Hepatitis A Incidence Falls to Historic Lows with Increased Use of Vaccine In 1999, it was recommended that children in 17 states with higher than average hepatitis A incidence be vaccinated routinely. Drop in incidence States NOT Routinely Vaccinating Children ↓ 53% States Routinely Vaccinating Children ↓ 88% Overall ↓ 76% A. Wasley, T. Samandari, B.P. Bell, “Incidence of Hepatitis A in the United States in the Era of Vaccination,” Journal of the American Medical Association, 294 (2005): 2, 194-201.

30. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 30 Recent study found that new drugs account for 50-60% of the increase in six-year cancer survival rates since 1975.* *F.R. Lichtenberg, “The Expanding Pharmaceutical Arsenal in the War on Cancer,” National Bureau of Economic Research Working Paper No. 10328 (Cambridge, MA: NBER, February 2004). National Cancer Institute, National Institutes of Health, Department of Health and Human Services, “Cancer Trends Progress Report – 2005 Update,” (Bethesda, MD: NCI, December 2005), http://progressreport.cancer.gov/ (Accessed 26 January 2006).http://progressreport.cancer.gov/ Cancer Survival Increasing

31. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 31 Investment in Research and Development Continues to Grow Sources: Burrill & Company, analysis for Pharmaceutical Research and Manufacturers of America, 2006. PhRMA Annual Member Survey. * Note: The “Biopharmaceutical R&D” figures include PhRMA research associates and non-members, which are not included in “PhRMA Member Companies’ R&D Expenditures”. The first year this data was reported by PhRMA was 2004. (est.)

32. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 32 Components of The Pharmaceutical Industry Big Pharma Big Pharma Generally Large Companies Generally Large Companies - Small Number - Established Products Fully Integrated Fully Integrated - Research &Development - Manufacturing/Distribution - Sales/Marketing Venture Funded Companies Venture Funded Companies - Based on New Science/Technology - Strong R&D Emphasis Product Discovery & Early Development Stage Focus Product Discovery & Early Development Stage FocusBiotech

33. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 33 TYPICAL ORGANIZATION OF A PHARMACEUTICAL COMPANY

34. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 34 RESEARCH AND DEVELOPMENT CONSIDERATIONS: What are the Strengths and What are the Strengths and Weaknesses of the Organization? Weaknesses of the Organization? How Innovative Can We Be? How Innovative Can We Be? How Innovative Can We Afford to Be? How Innovative Can We Afford to Be? How Much Risk is Management How Much Risk is Management Willing to Take? Willing to Take?

35. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 35 Molecular Opportunity Project Initiation Project Initiation Market Opportunity

36. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 36 Record of Invention  Biological Lead  Pharmacological Lead  IND Track (Clinical Lead)

37. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 37 Biological Lead Chemical Development Efficiency of Kg Batches Suppliers Synthesis For Who Can Toxicology Make It

38. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 38 THE MEDICINAL CHEMIST: Vary Greatly in their Innovative, Vary Greatly in their Innovative, Goal-Oriented Capacity Goal-Oriented Capacity May Well Determine the Differences May Well Determine the Differences Between Failure and Success Between Failure and Success Can Always Propose More Structures that Can Always Propose More Structures that they Can Actually Create they Can Actually Create Combination of Imagination and Focusing Combination of Imagination and Focusing is Required is Required

39. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 39 DRUG METABOLISM Animal Studies: - Make a Simple Assay - Look at Kinetics in Rats, Dogs (Absorption and Distribution - Look for Toxicokinetics - Look for Effect of Food, First Pass Metab, Formulation Effect, Sex Effect - C14 to Evaluate Metabolites (Rats and Dogs) - ADME - Cytochrome P450 Studies - Develop a Clinical Analytical Method Clinical Studies - Tox Support - Clinical Support

40. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 40 DRUG SAFETY STUDIES: Pilot Tox-Screen, Seek Target Organ Pilot Tox-Screen, Seek Target Organ 2 Week Studies-Dose Ranging (Rats and Dogs) 2 Week Studies-Dose Ranging (Rats and Dogs) 4 Week Studies-Allows for 2 Weeks in Man (101,102) 4 Week Studies-Allows for 2 Weeks in Man (101,102) Gentox Gentox Reproduction Studies Reproduction Studies - Seg l Fertility - Seg ll Fetal Tox - Seg lll Perinatal and Developmental Defects 3 Month Studies (Could Be Extended to 6-12 Mos) 3 Month Studies (Could Be Extended to 6-12 Mos) Carcinogenicity Studies Carcinogenicity Studies

41. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 41 IND Investigational New Drug (application) --Results of all preclinical work --Chemical structure --Mechanism of action (if known) --Adverse effects in animal studies --How the compound will be manufactured --Clinical Plan and first protocol

42. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 42 AT THE CLINICAL DEVELOPMENT STAGE, THE TWO MOST IMPORTANT FACTORS ARE: 1. The Therapeutic Improvement Offered by the Product 2. The Order of Its Entry Into the Marketplace of Similar

43. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 43 DEVELOPMENT PROJECTS - PRIORITY IN DESCENDING ORDER: 1. The Product is of a New Therapeutic Class and is First to the Marketplace 2. The Product Is Not the First of the Class, But is Significantly Better Than Other Therapies 3. The Product Is the Second to be Marketed, Either in a New Therapeutic Class (#1 Above) or in a Category of Improvement (#2 Above) 4. The Product Provides Only a Minor Improvement Over Existing Therapy in Efficacy, Safety or Convenience b. Adds No Value 5. The Product is Third of Fourth to the Market 6. The Product Offers No Improvement Over Existing Therapy and is Late to the Marketplace

44. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 44 TYPICAL ORGANIZATION OF A CLINICAL RESEARCH DEPARTMENT

45. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 45 Aims of Phase I Studies 1) To define the acute and subacute tolerability and toxicity of the drug at various exposure levels in humans. --intensive, in-patient, small no’s. 2) To define, inasmuch as possible, the desired pharmacologic action of the drug (efficacy) 3) To collect pharmacokineic information and to correlate this informationt with both the toxicity and the desired action of the drug.

46. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 46 Determining Tolerability and Toxicity Toxicity Evaluations Include: - Intensity - Duration - Degree of Reversibility ---all as a function of dose and duration of dosing ---usually in normal human volunteers ---the MTD is usually sought

47. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 47 Determining The Desired Pharmacological Effect Efficacy evaluation requires a specific response which is expected from the mechanism of action of the drug is both: 1) Predictive of the Therapeutic Effect and 2) Readily Assessable

48. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 48 Determining The Pharmacokinetic Profile Pharmacokinetic Information can provide data on: Absorption (w/wo food) Absorption (w/wo food) Distribution Distribution Metabolism (if expected metabolites are already identified) Metabolism (if expected metabolites are already identified) Elimination Elimination --Relationship of above to dose (linearity) --Relationship of above to dose (linearity)

49. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 49 Summary: Aims of The Phase I Program To provide information for the rational design of Phase II dose-response trials-- specifically: Selection of doses for optimal dose response Selection of doses for optimal dose response Development of a safety monitoring strategy Development of a safety monitoring strategy Optimization of dosing in relation to meals Optimization of dosing in relation to meals

50. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 50 One Example of a Phase I Program Retigabine--an antiepileptic drug (from published data) (from published data)

51. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 51 Retigabine F HHN N NH 2 O O Retig--13008

52. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 52 Retigabine is Effective in the Following Models of Epilepsy: 1. Maximal electroshock 2. Pentylenetetrazol 3. Picrotoxin 4. Kainate 5. Audiogenic 6. Corneal kindling 7. Cortical penicillin 8. Kindling development 9. Fully-kindled Retigabine is Ineffective in the Following Models of Epilepsy: 1. Voltage-dependent sodium channels 2. Calcium channels Retig--13004

53. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 53 RETIGABINE OPENS KCNQ2/3 POTASSIUM CHANNELS Rundfeldt and Netzer, Neuroscience Letters (17Mar2000) 282: 73-76. Retigabine shifts the KCNQ2/3 activation V 1/2 ~ -20 mV.

54. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 54 Retigabine: Some of the more important Clinical Pharmacology studies completed Single-dose Tolerance : 100-GE (12) Single-dose Tolerance : 100-GE (12) Multiple-dose Tolerance : 101-GE (46) Multiple-dose Tolerance : 101-GE (46) Multiple-dose Tolerance : 102-US (40) Multiple-dose Tolerance : 102-US (40) Age gender : 105-EU (48) Age gender : 105-EU (48) Food interaction : 106-EU (24) Food interaction : 106-EU (24) Dose Titration Tolerance : 107-US (9) Dose Titration Tolerance : 107-US (9) Mass balance : 108-US (6) Mass balance : 108-US (6) Lamotrigine interaction : 109-US (29) Lamotrigine interaction : 109-US (29) OC interaction : 112-US (16) OC interaction : 112-US (16) Phenobarbital interaction : 113-US (15) Phenobarbital interaction : 113-US (15)

55. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 55 Retigabine Phase I Results Tolerability and Toxicity MTD was achieved in normal volunteers MTD was achieved in normal volunteers MTD was achieved in patients MTD was achieved in patients Adverse effects were largely CNS Adverse effects were largely CNS

56. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 56 Retigabine Phase I Results Desired Pharmacologic Effect Mechanism of action less well defined Mechanism of action less well defined Cannot measure either seizure frequency or a surrogate in normal volunteers. Cannot measure either seizure frequency or a surrogate in normal volunteers. Only reliable measure of the desired pharmacologic effect (efficacy) is RCCT. Only reliable measure of the desired pharmacologic effect (efficacy) is RCCT. Phase I cannot contribute data to support the desired pharmacologic effect (efficacy) in this case Phase I cannot contribute data to support the desired pharmacologic effect (efficacy) in this case

57. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 57 Retigabine Phase I Results Pharmacokinetics Pharmacokinetics well defined Rapid and almost complete absorption Rapid and almost complete absorption Dose proportional Dose proportional No self induction or inhibition No self induction or inhibition T 1/2 of 6-8 hours T 1/2 of 6-8 hours Oral clearance of 0.7L/hr/kg Oral clearance of 0.7L/hr/kg No significant drug interactions No significant drug interactions

58. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 58 CONCLUSION: Phase I Studies How well does Phase I measure? ! Tolerability and toxicity ! Desired pharmacologic effect (efficacy) ! Pharmacokinetics How well does Phase I prepare the investigator for Phase II? ! Selection of doses ! Safety monitoring strategy

59. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 59 Phase II Controlled clinical trials (randomized, blinded, etc) Controlled clinical trials (randomized, blinded, etc) Typically 100-500 patients with disorder Typically 100-500 patients with disorder Biggest goal is proof of concept Biggest goal is proof of concept Second biggest goal is dose determination Second biggest goal is dose determination Critical are the categorization of the adverse effects Critical are the categorization of the adverse effects Also: dosing schedule Also: dosing schedule

60. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 60 Baseline TitrationRetigabine Monotherapy MTD Add-on Retigabine Background Medication Carbamazepine, Phenytoin, Topiramate or Valproate. PK Tapering Background Medication 202-US, MTD Study : 60 pts., Open Label

61. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 61 Retigabine Phase II Study Three doses versus placebo Three doses versus placebo Add-on to other drugs Add-on to other drugs 397 patients randomized 397 patients randomized 400 mg t.i.d. maximum dose 400 mg t.i.d. maximum dose

62. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 62 Phase III Controlled clinical trials Controlled clinical trials Larger number of patients Larger number of patients - Sometimes 1000-5000 May involve hospitals, clinics, physician offices Object: Confirm effectiveness & confirm knowledge of adverse effects

63. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 63 Parallel to Phase III Ongoing toxicity tests Ongoing toxicity tests Dosage forms Dosage forms Production scale-up Production scale-up Package design Package design Begin preparation for NDA Begin preparation for NDA

64. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 64 NDA New Drug Application (FDA) New Drug Application (FDA) Analysis of all data is complete Analysis of all data is complete Drug is safe and effective Drug is safe and effective All data submitted to the FDA (or other foreign agency) All data submitted to the FDA (or other foreign agency) (May require a big truck) Wait for questions Wait for questions

65. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 65 NDA Review/Approval FDA scientists review all the data FDA scientists review all the data May require an Advisory Panel review May require an Advisory Panel review “Cleared for Marketing” means it is now available “Cleared for Marketing” means it is now available --FDA took an average of 16.9 months in 2003* --Rejected applications stable at 10-15%* * PhRMA, 2007

66. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 66 Post-Marketing Events Monitoring is critical --e.g, felbamate --periodic reports to the agencies Additional Studies may be required by agencies Additional studies may be initiated by the company (Postmarketing studies sometimes call “Phase IV”)

67. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 67 Discovery (2-10 Years) Preclinical Testing Laboratory and animal testing Phase I 20-80 healthy volunteers used to determine safety and dosage Additional Postmarketing Testing Phase II 100-300 patient volunteers used to look for efficacy and side effects FDA Review/ Approval Phase III 1,000-5,000 patient volunteers used to monitor adverse reactions to long-term use Years Compound Success Rates by Stage Compound Success Rates by Stages Source: PhRMA, based on data from Center for the Study of Drug Development, Tufts University, 1995. 5,000-10,000 screened 1 approved by the FDA 250 enter preclinical testing 5 enter clinical testing

68. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 68 SCIENTIFIC EXCELLENCE Study Design Study Design Choice of Investigator Choice of Investigator Execution (Monitoring) Execution (Monitoring) Data Collection and Analysis Data Collection and Analysis Freedom from: Freedom from: - Bias - Sloppiness - Unexpected Events - Fraud

69. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 69 BIAS IN CLINICAL TRIALS The Investigator The Investigator The Nurse The Nurse The Technician The Technician The Patient The Patient The Patient’s Relatives The Patient’s Relatives The Drug Company The Drug Company

70. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 70 STANDARD METHODS OF BIAS CONTROL Protocol (Plan) Protocol (Plan) Randomization Randomization Blinding Blinding Placebo Placebo

71. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 71 SURVEILLANCE OF CLINICAL TRIAL PREFORMANCE Record Keeping and Data Integrity Record Keeping and Data Integrity Time and Resources for Investigator and Staff Time and Resources for Investigator and Staff Auditing Financial Records Auditing Financial Records Patient Accrual Rate Monitoring Patient Accrual Rate Monitoring Performance Milestones Performance Milestones Protocol Adherence Protocol Adherence Regulatory Compliance Regulatory Compliance Sponsor Communications Sponsor Communications Sponsor Satisfaction Assessment Sponsor Satisfaction Assessment

72. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 72 THE CHAIN OF TRUTH IN DRUG DISCOVERY AND DEVELOPMENT Molecular Development Molecular Development  Synthesis Scale-Up Synthesis Scale-Up  Basic Pharmacology Basic Pharmacology  Early Toxicology Early Toxicology  Pharmaceutical Development Pharmaceutical Development  Phase I in Humans Phase I in Humans  Phase II in Humans Phase II in Humans  Phase III in Humans Phase III in Humans  Registration Registration

73. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 73 STOP!

74. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 74 Backup Slides

75. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 75 MARKET RESEARCH: Not Inherently Innovative Not Inherently Innovative Needs to Follow an Innovative Needs to Follow an Innovative Scientific Idea (These Ideas Come Scientific Idea (These Ideas Come From Basic & Clinical Investigators) From Basic & Clinical Investigators)

76. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 76 Companies Are Desperate to Obtain Critical Information As Rapidly as Possible on Each Product. For Products of High Market Value, the Pace Is Often Frenzied

77. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 77 INDUSTRY NEEDS ACADEMIA FOR: Consultations on Large Decisions Access to Critical Masses of Patient Populations

78. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 78 CRITICAL ELEMENTS IN ACADEMIC- INDUSTRY COLLABORATION 1) The Contract Research Element 2) The Consultantship Element 3) The Employee Element 4) The Technology Transfer Element 5) The Gift Element (Waugaman & Porter, 1992) (Waugaman & Porter, 1992)

79. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 79 POTENTIAL BENEFITS FOR ACADEMIC HEALTH CENTERS Additional Clinical Trial Opportunities, Revenues Additional Clinical Trial Opportunities, Revenues Access to Latest Drug and Device Technology Access to Latest Drug and Device Technology Increased Visibility in Publications Increased Visibility in Publications Increased Patient Numbers Increased Patient Numbers Retention of Clinical Faculty Researchers Retention of Clinical Faculty Researchers

80. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 80 ACADEMIC COLLABORATION WITH INDUSTRY -THE UPSIDE 1) Provides Source of Income 2) Provides Source of Publications 3) Applied Science  Fruits for Patients Are In The Near Term Patients Are In The Near Term 4) Basic Science Discoveries May Be Exploited More Rapidly Exploited More Rapidly (Waugaman & Porter, 1992) (Waugaman & Porter, 1992)

81. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 81 ACADEMIC COLLABORATION WITH INDUSTRY - THE DOWNSIDE 1) Income Is Often Unpredictable/Unstable 2) Publications Can Be Reviewed/Delayed 3) Peer Recognition Marginal 4) Few Basic Science Opportunities For Collaboration Collaboration 5) Fear Of Publication May Preclude Academia (Waugaman & Porter, 1992) (Waugaman & Porter, 1992)

82. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 82 PROBLEM WITH INDUSTRY/ACADEMIC RELATIONSHIPS 1) Benefits Are Not Uniformly Spread Through Academia 2) Companies Are Not Uniform In Their Dealings - Company to Company - Project to Project 3) Business Leaders Are Impatient With Universities’ Needs and Points of View 4) All This Made More Difficult By - Changes In Tax Law - Corporate Restructuring - Difficult Market Conditions (Waugaman & Porter, 1992)

83. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 83 Industry needs from Academic Medical Centers: a) Patents b) Prestige c) Patients d) Publications e) Personnel f) Profit “These elements will be even more important as cost-containment measures impinge on the revenue stream, and as technological sophistication and increasing regulatory requirements drive up the cost of the drug development.” (Cooper & Novitch, 1992)

84. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 84 Many…“ISTs” Involved in Pharma R&D From D. Tobias, Wyeth Research

85. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 85 Many…“ISTs” Involved in Pharma R&D Chemists Chemists Organic Organic Physical Physical Analytical Analytical Combinatorial Combinatorial Synthesis Synthesis

86. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 86 Many…“ISTs” Involved in Pharma R&D Chemists Chemists Organic Organic Physical Physical Analytical Analytical Combinatorial Combinatorial Synthesis Synthesis Biologists Biologists Pharmacologists Pharmacologists Cellular Cellular Molecular Molecular Bacteriologists Bacteriologists Virologists Virologists

87. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 87 Many…“ISTs” Involved in Pharma R&D Chemists Chemists Organic Organic Physical Physical Analytical Analytical Combinatorial Combinatorial Synthesis Synthesis Biologists Biologists Pharmacologists Pharmacologists Cellular Cellular Molecular Molecular Bacteriologists Bacteriologists Virologists Virologists Pharmacists Pharmacists Formulations Formulations Clinical Supply Clinical Supply Product Stability Product Stability Analytical Analytical

88. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 88 Many…“ISTs” Involved in Pharma R&D Chemists Chemists Organic Organic Physical Physical Analytical Analytical Combinatorial Combinatorial Synthesis Synthesis Biologists Biologists Pharmacologists Pharmacologists Cellular Cellular Molecular Molecular Bacteriologists Bacteriologists Virologists Virologists Clinical Specialists Clinical Specialists Medical Monitors Medical Monitors Clinical Scientists Clinical Scientists Medical Writers Medical Writers Biostatisticians Biostatisticians Data Management Specialists Data Management Specialists Pharmacists Pharmacists Formulations Formulations Clinical Supply Clinical Supply Product Stability Product Stability Analytical Analytical

89. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 89 Many…“ISTs” Involved in Pharma R&D Specialists Specialists Toxicologists Toxicologists Drug Metabolism Drug Metabolism Project Managers Project Managers Human Relations Human Relations Regulatory Regulatory Legal Legal Safety Surveillance Safety Surveillance Communications Communications Chemists Chemists Organic Organic Physical Physical Analytical Analytical Combinatorial Combinatorial Synthesis Synthesis Biologists Biologists Pharmacologists Pharmacologists Cellular Cellular Molecular Molecular Bacteriologists Bacteriologists Virologists Virologists Clinical Specialists Clinical Specialists Medical Monitors Medical Monitors Clinical Scientists Clinical Scientists Medical Writers Medical Writers Biostatisticians Biostatisticians Data Management Specialists Data Management Specialists Pharmacists Pharmacists Formulations Formulations Clinical Supply Clinical Supply Product Stability Product Stability Analytical Analytical

90. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 90 GENERAL PHARMACOLOGY Candidate Nomination for Development Discovery Screening Phase IV Monitoring IND NDA Clinical Trials Investigate Side- Effect Issues and Other Therapeutic Indications Mechanistic Follow-up Studies and Other Therapeutic Indications General Pharmacology Profiles and Special Models Investigate Side- Effect Issues Specific Tests to Aid in Selection (e.g. Bioassay or in vitro Functionality) Investigate Side-Effect Issues and Other Therapeutic Indications (Figure 1. Flow Diagram Illustrating Where General Pharmacology Studies Can Impact During the Typical Drug Discovery and Development Process. IND, Investigational New Drug; NDA, New Drug Application (From Fossa and Bucholtz, 1994)

91. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 91 BACK-UP SLIDES

92. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 92 Chronology of Drug Innovation Source: Lehman Brothers Pharmaceutical Research New Therapeutic Cycles 1900195019601970198019902000201020202030PenicillinsSulphanamidesaspirin psychotropics NSAIDs H2-antagonists Beta blockers Lipid lowerers, ACE-inhibitors Biotechdrugs ChronicDegenerativeDiseaseAssociated with aging, Inflammation,cancer Cell pharmacology/ Molecular biology geneticengineering enzymes receptors serendipity Natural products And derivatives Sources/Innovations

93. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 93 THE DYNAMISM OF COMPANY PRIORITIES: Shifting of Company Priorities - Up or Down - Can Occur Because of Internal News on an Existing Product in the Pipeline of From Competitive Intelligence that Boosts or Damages Such a Produce. Rapidly Conducted Investigations of High Quality, Coupled the Continuous Flow of Information About Each Compound as Its Eventual Likelihood of Success Are the Drivers of the Business; It Is Not Simply a Quest for New Knowledge for Its Own Sake

94. 29052-PorterJ32.ppt 6/9/2016 4:38:27 AM /xx/fh/BF/ms/gb/SSKMulti-Media 94 The Role of the Champion in Drug Development