Biotechnology Industry Research and Practice Part The Exploding Science

Biotechnology & Industry Research and Practice Part 1 The Exploding Science The Expanding Products The Usage Challenges and Opportunities Ronald P. Evens, Pharm.D., FCCP Pharm.D., President, MAPS 4 Biotec, Inc Biotec, Clinical Professor, University of Florida Key Factors in a Product Profile “Need” & “Novelty” & “Competitive Advantage” & “Fit” • Disease: • Market: • Product: 2 UF Fall 1 Biotec slides ’05 Page 1 Key Factors in a Product Profile “Need” & “Novelty” & “Competitive Advantage” & “Fit” • Disease: Unmet medical need & Stand alone vs Add-on Add• Market: – – – – – – – – – – – Corporate fit (R&D & S&M) # addressable patients 5 year revenue (blockbuster ??) Reimbursement climate (Favorable) Competition (Products, Company, Tactics) Category & MOA (Novelty) Efficacy (Competitive advantage) Dose / Schedule (Practical) Formulation (Convenience) Safety (Less AEs) AEs) Pharmacokinetics (Disease fit) / Drug Interactions (Less) 3 • Product: Prevalence and Costs Selected Diseases in U. S. (2000-2004 Statistics) (2000Disease Alzheimer’sa Arthritis/Joint Cancerc Cardiovascular dis.d Heart diseased Depressione Diabetes mellitusf Diseasesg Digestive Migrainei dis.b Prevalence Annual Economic Products in in millions Cost ($Billions) Development* 4.5 66 3 64.4 13 18.8 18.2 65 44 28 61-100 6186 190 394 255 50+ (120 all MH) 132 107 18 (Fx) (Fx) 13+ 27 38 13 21 17 28 316 Osteoporosish *PhRMA 1999, a Alzheimer’s Association, b Arthritis Foundation, c Am. Cancer Society, d Am. Heart Association, e Nat'l Institutes of Mental Health, f Am. Diabetes Association, g Nat’l Institute DDK, h Nat’l Osteoporosis Foundation, i Nat’l Headache Foundation 4 UF Fall 1 Biotec slides ’05 Page 2 Definition of Biotechnology The use of living systems, such as organisms, tissue cultures, live cells, or cell enzymes, to make a defined biological product or to elucidate a biological target and its function, to be mitigated by a drug or biological product 5 Origins of Biotechnology • Fermentation • Tools/sources – Grains – Yeast – Vessels • Products 6 UF Fall 1 Biotec slides ’05 Page 3 Evolution of Biotechnology Double helix of DNA structure A C T A T C T G G A T G A C C T A T G G Combinatorial chemistry Recombinant insulin approved Pharmacogenomics Gene therapy DNA cloned Biologicals approved for clinical use Monoclonal antibodies produced Genomics G T C G C A T A G A T C Genetic code elucidated Human gene cloned PCR reported Human genome mapped 1953 ’61–’65 ’73 ’75 ’77 ’82 ’86 1986 - 1999 2000 + 7 Patients Benefiting Medical breakthroughs hallmark biotechnology products: • • • • • • • • • • • Heart failure Heart attack AIDS Anemia Hepatitis C + B Cystic Fibrosis Breast cancer Lymphoma Stroke Psoriasis Asthma • • • • • • • • • • • Hemophilia Dwarfism Crohn’s disease Rheumatoid arthritis Sepsis Diabetes Multiple Sclerosis Kidney disease Fungal infections Skin ulcers Leukemia 8 UF Fall 1 Biotec slides ’05 Page 4 Impact on Providers • Science – Technological advances unlock disease mechanisms – Disease management changed, before (vs after) biologics – Untreatable diseases are now manageable • Products – More choices with unique profiles – Usage questions, replacement vs adjunctive vs novel product – Special handling and/or administration • Practice – Patient interested in novel, current care – Cost of care and reimbursement – Integration with existing drugs – Staying up-to-date up- to9 Impact on Payers • Disease/science – Untreatable diseases now manageable – Patient demand for novel therapy – Quality-of-life increases in importance Quality- ofProduct – Integration with existing drugs – Formulary decisions – Lack of expertise on products Practice – Focuses: Cost of care – Customer Satisfaction – Availability – Pharmacoeconomics of product use vs costs of overall care – Match of program objective with type of payer – Guidelines for product use – Educational demands for staff and providers 10 • • UF Fall 1 Biotec slides ’05 Page 5 Societal Impact of Biotechnology Medicine Research support Agriculture Environment Industry 11 Agronomic Traits from Biotechnology • • • • • • • • • • Herbicide tolerance Insect resistance Disease resistance Abiotic stress, e.g., water, temperature, salt, metals Value added traits, e.g., oil, vitamins, minerals Nutritional quality, e.g., proteins, fats, carbohydrate; Plant properties, e.g., shelf-life, flavors, fragrance shelfAllergen reduction Nitrogen fixation Yield Pharmaceutical production, e.g., vaccines, proteins 2001: GMO 130 MM acres (75% U.S.), e.g., cotton, soybean, corn, canola, rice Overall Benefits: Less cost/acre, More yield, Less pollution 12 UF Fall 1 Biotec slides ’05 Page 6 Development of GM Foods, Safety Toxicity AND Unintended Effects: Regulatory Bodies: FDA, USDA, EPA, OECD, NAS, etc • • • • • • • • • Direct health effects (toxicity) Allergic reactions Components with nutritional properties Components with toxic properties Stability of inserted gene Transfer to non-GM plants (genetic drift; refuges; %GM) nonUnintended effects of GM product (other genetic changes) Unintended effects mediated via environment Labeling of GM foods 13 A Definition of Biotherapy • The use of biological products for the treatment of disease by four potential mechanisms: – Correcting deficiencies of endogenous biological compounds – Enhancing natural physiological processes – Blocking dysfunctional proteins or nucleic acids – Blocking natural, but excessive, physiological processes 14 UF Fall 1 Biotec slides ’05 Page 7 The Central Dogma of Biology Cytoplasm Nucleus r-RNA Protein mRNA Ribosome Vacuole Cell DNA Post-Translational PostModifications: Glycosylation SO4/PHO4 Folding Cross-linking CrossIsoforms Secretion t-RNA amino acid m-RNA Translation Complete protein Transcription 15 Proteins: Description (Granulocyte Colony-Stimulating Factor [G-CSF]) 16 UF Fall 1 Biotec slides ’05 Page 8 3-Dimensional Proteins Structure (Granulocyte Colony-Stimulating Factor [G-CSF]) 17 Chromosomes, Genes, DNA 1 Human cell with nucleus 3 Billion nucleotide base pairs 46 Chromosomes • 23 maternal • 23 paternal • Female: XX • Male: XY 18 30,000 – 40,000 Genes UF Fall 1 Biotec slides ’05 Page 9 Proteins Functions (Potential Products & Targets) • Structure • Immune defense / reactions • Communication/Mediation Intercellular • Cell Function • Functional 19 Proteins Functions (Potential Products & Targets) • Structure – Muscle, bone, epithelium, endothelium, nerves, hair, cells • Communication/Mediation Intercellular – Hormones – Stimulating Factors – Interleukins – Interferons – Receptors • Functional – Catalysis (Enzymes) – Blood clotting – Glucose processing • Immune defense / reactions – Identification – Recognition – Tagging – Adhesion • Cell Function – Signaling – Chaperones – Degradation – Differentiation – Reproduction – Energy production – Death 20 UF Fall 1 Biotec slides ’05 Page 10 The Genetic Code (Triplets) A U C C G A A U A A G G G A U A A C G U A G C UUU UUC UUA UUG CUU CUC CUA CUG AUU AUC AUA AUG GUU GUC GUA GUG Phe Phe Leu Leu Leu Leu Leu Leu Ile Ile Ile Met Val Val Val Val UCU UCC UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG Ser Ser Ser Ser Pro Pro Pro Pro Thr Thr Thr Thr Ala Ala Ala Ala UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC AAA AAG GAU GAC GAA GAG Tyr Tyr Stop Stop His His Gln Gln Asn Asn Lys Lys Asp Asp Glu Glu UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG Cys Cys Stop Trp Arg Arg Arg Arg Ser Ser Arg Arg Ile Arg Ile Arg Asp Asn Gly Arg GGU Gly GGC Gly GGA Gly GGG Gly 64 Nucleic Acid Codes for 20 Amino Acids mRNA Translation Protein 21 Introns and Exons in Gene Processing Chromosome “Gene” on chromosome (DNA) Transcription pre-mRNA pre- Exon 1 Intron 1 Exon 2 Intron 2 Exon 3 Spliceosome Stop sequence mRNA Leader sequence Translation Protein 22 UF Fall 1 Biotec slides ’05 Page 11 Y - Chromosome Self-confidence (Gump) (Note: Unlinked to Ability) Catching & Throwing (BB) Channel Flipping (FLP) Gadgetry (Mac-locus) Testis Determining Factor (TDF) Ability to Remember & Tell Jokes (GOT-1) Sports Page (JOK) 1.21 1.22 Q 1.23 12 Stock Cars (RACE) 11.32 11.31 P 11.2 11.1 11.1 Total Lack of Recall for Dates (OOPS) Selective Hearing Loss (HUH?) Inability to Express Affection Over the Phone Sitting on the John Reading (SIT) Addiction to Death-and-destruction Movies (T-2) Air Guitar (Bubba) Ability to Identify Aircraft (DC10) (Who ME) Spitting (P2E) Preadolescent Fascination with Arachnida & Reptilia (DAD4U) 23 R & D Planning Drug Development - Phases and Content FDA meetings Continuous Processes III Submit IND V IV Approval & Launch (6-18 mo.s) I II Submit NDA/PLA FDA - CDER Review Co. Present Safety Efficacy VI Sales - Commercial use P & T Committee apps Clinical trials (P. IV) Adverse event reporting FDA Promotional/ advertising review Educational programs Second Indications Molecular biology Rational design Genomics Proteomics Biochemistry rDNA / Mab Med. Chemistry HTS / Microarray 1. Animal testing • Pharmacology • Toxicology • P’cokinetics 2. Formulations 3. Manufacturing, Process Enginrg CDER Review 1ST use in man Phase I 20-50 subjts. 20subjts. Phase II 100 – 300 pts 1,000-5,000 pts 1,000- Phase IIIa, b IIIa, Pharmacoeconomics Labeling FDA: audits & inspects research, manufacturing, clinical Audits Manufacturing & QA: ongoing product testing & Scale-up ScaleMarket research: ongoing market analysis, competitive analysis, target audience 24 UF Fall 1 Biotec slides ’05 Page 12 Healthcare & Industry Overview Health Care Improvements 1980 Disability Rate Death Rates - Overall (per 100,000) Heart Attack Stroke Breast Cancer Life Expectancy (years) 26.2 1039.1 345.2 96.2 32.3 73.7 1990 23.5 938.7 249.6 65.3 31.8 75.3 2000 19.7 872.0 186.9 60.8 25.4 76.8 % Change 25% Decr 16% Decr 46% Decr 37% Decr 21% Decr 4% Incr 25 FIPCO Fully Integrated Pharmaceutical Company Pharma Biotech R&D Finance Human Resources Legal & Regulatory Global US, EU, AS Manufacturing FIPCO Medical Affairs S&M 26 UF Fall 1 Biotec slides ’05 Page 13 Pharmaceutical Industry Development (Clinical Research) JOB: Phases of Clinical Research I – IIa – IIb – III - IIIb • Project Management • Clinical Management - Managers (Protocols & Reports; MD, PhD, PharmD) PharmD) - Monitors (Site Visits, CRFs, Data; B.S., M.S.) CRFs, CROs (Clinical Research Organizations) Data Management (Forms & Data) Biostatistics Medical Writing Quality Assurance (Audits) Regulatory Affairs Metabolism (ADME) 27 • • • • • • • Pharmaceutical Industry Industry Organization: Marketing Phase: “R&D” Promotion Salesforce Aids “Launch” Phase Educational Programs DTC Sales Plans “POAs” POAs” “Strategy” Market Research Liaison R&D & Medical Sales Forecasting & Tracking “Life Cycle E” Professional Affairs “Life Cycle L” 6 Steps: Situation analysis – Strategy – Programs – Budgeting – Roll out - Assess 28 UF Fall 1 Biotec slides ’05 Page 14 Pharmaceutical Industry Industry Organization: Salesforce Size=Reach & Frequency # 100,000 = $ 2B Compensation Base $62,000 - $100,000 Turnover 10% Sales Calls: GP* Education* Perform: 60-140% 60Bonus-Cash-Stock Bonus- CashSpec. Achievemt Promotion New Products* 29 Biotech Differences ?? Pharmaceutical Industry Manufacturing Process Engineering Distribution Inventory Control Formulations Scale-Up Sales Forecasts Plants Product Out–the-Door QC Stability US & ROW Package Engineering 30 UF Fall 1 Biotec slides ’05 Page 15 Pharmaceutical Industry Medical Affairs – Professional Services Customers – Providers, Payers, Patients & Company Medical Info MSL Medical Sci. Liaison Marketing Support Pharmacoeconomics Phase 4 Clinical Trials 31 Pharmaceutical Industry Global Operations Cultures & Language Pricing Committees Global Approvals EMEA etc EU-Asia-ROW US Manufacturing Distribution S&M US-ROW Integration Development 32 UF Fall 1 Biotec slides ’05 Page 16 R & D Planning & Governance, Product Plans (WW, All groups, Timing, All Resources) • PreClinical (Tox - P’col - Pkin) Pkin) • Formulations / Pharmacokinetics • Manufacturing: • Safety • Market research: – Disease & Product – Pricing & Sales – Clinical trial & Marketed product – Competition – Engineering: Process, Packaging – Quality control: analyses, stability • Business plans: – Publications – 5 year plan, inventory, SKUs – Thought-leaders Thought– Distribution channels – Reimbursement • Clinical Trials: – Launch: market program, – Indications, dosing medical, staffing / sales – PIs, sites, patients; CROs – Partnerships – Data management, stats, writing – Life cycle – Phase 1, 2 & 3, QOL, PE • Medical: Phase 4, Med. Info. & Comm.• Patent status & Trademarks • Financial: • Regulatory: – COGS, Budgets, Costs – IND, NDA, sNDA – P&Ls, Revenues, NPV 33 P&Ls, – FDA meetings, Audits R & D Planning Drug Development - Phases and Content FDA meetings II. Preclinical Research I. Discovery (2-10 yrs) (2-4 yrs) Continuous Processes “ Product Management ” Approval & Launch (6-18 mo.s) Submit IND/ CTA IV. Clinical R&D (4-8 yrs) Submit NDA/BLA /CTD FDA - CDER Review Co. Present Safety Efficacy VI. Post-approval activities Sales - Commercial use P & T Committee apps Clinical trials (P. IV) Adverse event reporting FDA Promotional/ advertising review Educational programs Second Indications Molecular biology Rational design Genomics Proteomics Biochemistry rDNA / Mab Med. Chemistry HTS / Microarray 1. Animal testing • Pharmacology • Toxicology • P’cokinetics 2. Formulations 3. Manufacturing, Process Enginrg CDER Review 1ST use in man Phase I 20-50 subjects 20Phase II 100 – 300 pts 1,000-5,000 pts 1,000- Phase IIIa, b IIIa, Pharmacoeconomics Labeling FDA: audits & inspects research, manufacturing, clinical Audits Manufacturing & QA: ongoing product testing & Scale-up ScaleMarket research: ongoing market analysis, competitive analysis, target audience 34 UF Fall 1 Biotec slides ’05 Page 17 Biotechnology Companies Culture • • • • • • • • • • • University style – academic (origin) Research predominates Scientists predominate CEO & Board scientists Dress casual Communications very open & challenging Cutting edge science Small companies Team concepts for decision making Best ideas predominate Naivete’ in marketing & product needs Naivete’ 35 R & D Challenges in Drug Development Medical Needs Opportunities Investors Venture, IPO, Alliance Products < to Market >Competition R&D Costs & Efficiencies Shareholder Expectation Blockbuster Products Globalization Regulatory Changes Biotech & Science Revolution Rx Drug Policy Gov’t 36 Ref.: Tufts Center for Study of Drug Development, Outlook 2003. PhRMA, Prescription Medicines 24 Years ago and Today: Changing Trends, Enduring Needs PhRMA, Trends, UF Fall 1 Biotec slides ’05 Page 18 Discovery Process (Steps) in Drug Development Target Identification Disease Biology Mechanisms Target Validation “Product Candidates” Proof of Principle PreClinical “Lead” Optimization 37 Lead Identification “ Hit ” “Lead Validation” Discovery Overall Goals in Drug Development More Cmpds [#, Type, Use] More Rapid Discovery New Properties “ Hits ” & “ Leads ” Less Cost Of Discovery Novel Targets 38 More Activity UF Fall 1 Biotec slides ’05 Page 19 Current Discovery Focus – 2003/2004 Cancer Infectious Diseases Central Nervous System Cardiovascular Immune System Hormonal System Musculoskeletal Gastrointestinal HIV infections Biotech Respiratory Pharmaceutical Pain Dermatology Eye and ear Genitourinary Miscellaneous Hematological Diagnostic/imaging agents/delivery • Therapeutic areas • • Cancer is number 1 target for both biotech & pharmaceutical companies Infectious disease & central nervous system disorders represent 2nd & 3rd highest targets, followed by cardiovascular and immune system disorders By mid 2004, number of discovery/preclinical candidates has nearly tripled in all areas 0 Number of drug candidates 100 200 300 400 500 Discovery and Preclinical Pipeline – 2003; Lawrence. Acumen Journal of Sciences 2003;1:23 and BioPharm Insight 39 Product Choices – Drugs vs. Biologics • Drugs – Small molecule organic compounds obtained by screening large libraries of natural or synthetic compounds – Molecular weight typically < 500 Daltons – Produced by chemical or semi-synthetic synthesis semi– Effective against intracellular and extracellular targets – Examples include most antibiotics and existing pharmaceuticals – Medicinal chemistry for structural manipulation • Biologics – Protein-based therapeutics obtained from humans, Proteinanimals and plants – Molecular weight typically > 5,000 Daltons (5 kDa) kDa) – Purified from natural sources or, more commonly, produced by recombinant methods or Mab – Primarily effective against extracellular targets – Examples include antibodies, hormones, enzymes, cytokines & vaccines – Specificity to disease pathogenesis is high 40 UF Fall 1 Biotec slides ’05 Page 20 Targets in Oncology Era of Biotechnology 1950-1990 1950- • Cell cycle stages (S, G,M) – DNA cross-linking cross• Alklators • Platins • Antibiotic – Antimetabolites (S phase) • Purines / Pyrimidines – G2 or S DNA binding – Mitosis arrest – Spindle tubulin binders – Topoisomerase inhibitor • • • • Interferons Hormones Corticosteroids Radiation • • • • • • • • • • • • • • • 2000 to Future Mabs Interleukins Cell differentiation/proliferation Oncogenes Tumor suppressor genes Apoptosis proteins Immortality, telomerase Tumor antigens Metastasis Cell receptors Tyrosine kinase in cells JAK / STAT cell signal arrest Angiogenesis Oxygenation of tumor Radionuclides 41 Serendipity vs. Rational Design • Many drugs are result of chance observations – Alexander Fleming and Penicillin • • • Searching for agents that could kill Staphylococci Observed that bacteria on culture plates were lysed around contaminating airborne molds Concluded that something in the Penicillium mold was killing bacteria • “Rational” drug design often follows tortuous path – Viagra (PDE-5 inhibitor - 2003 US sales of $1.0 billion) (PDE• • • Initially developed as anti-hypertensive drug, but specificity antiwas low Development was changed to focus on angina, but potency was low During clinical trials, patients commented on decreased erectile dysfunction • Once used to describe knowledge-based development knowledgedecisions, “rational drug design” now focuses on underlying biology of disease, as an aid to appropriate target selection 42 UF Fall 1 Biotec slides ’05 Page 21 Analytical Assays Development • Multiple assays are needed to ensure product consistency and potency • Common product consistency assays include: – Appearance, concentration, pH, ionic strength, sterility, endotoxin, purity endotoxin, • Potency assays focus on specific properties of products: – Antibodies – Binding, ADCC, functional inhibition – Enzymes – Catalytic activity – Recombinant proteins – Functional activity or inhibition; Structure (1*, 3*, 3D) – Drugs – Functional activity or inhibition PK (ADME) • Current trends include greater emphasis on biological or cell-based cellassays versus simple binding assays • • All assays must be well controlled & reproducible by anyone trained trained – Matrix effects - Blood, urine, sputum, mice vs. humans, etc. – Assay validation is not usually required until later in review process process Image from Amersham Biosciences (http://www.bioprocess.amershambiosciences.com) 43 Discovery Process Needs for Best Product Development Goals = Number, Speed & Quality Hit & Lead Rapid Analysis Disease Markers Outreach Science Alliances Product Candidates Informatics Metabolism & Kinetics Earlier Toxicology Earlier Innovative Technologies 44 UF Fall 1 Biotec slides ’05 Page 22 Pharmaceutical Industry Issues in Drug Discovery & Collaborations • Industry Needs - Expand targets & hits for unmet patient needs • Rationale - Expansion & more sophistication of technology • Drug discovery companies (#550, mostly biotech)) - Tools – analysis, HTS, product system, informatics - Targets / Diseases (100 hits/100,000 screens; 1 lead) - Databases - genome, biology, proteome, - Millennium, Pharmacopeia, Icos, ArQule, Medarex Pharmacopeia, Icos, ArQule, • Challenges - Not invented here; Co. Integration; Value vs cost; NIH; Attrition – risk & cost shared; DD co. capabilities (deliver?) • Partnerships for Biotech & Pharma - Pfizer, Novartis, GSK, Merck, Lilly (2003: P-B 383; B-B 435) Novartis, PB- • $3.6B in 2003, 15% growth, 5-10 % of Research $$ 5• Buy-outs (M&A) #128 in 2003 BuyKing J. R&D Directions 2004;10(2):28-39. . 45 Alliances in Discovery with Universities • University research (basic) scientists (many disciplines) – – – – – – – – Medicinal chemists (leads) & Pharmaceutists (formulations) Disease processes (physiologists, biologists, geneticists) Protein chemists & Molecular biologists Pharmacokineticists, Pharmacologists & Toxicologists Pharmacokineticists, Research network (expanded brain power) Technologies Disease targets Product leads & candidates • Access for company • Access for universities – Grants – Patents – Publications 46 UF Fall 1 Biotec slides ’05 Page 23 Early Product Development Work in Research Pre-Clinical (Laboratory / Animals) Pre- • • • • • • • Pharmacokinetics Purification Manufacturing scale-up (Lab to Clinic) scaleAnalytical validation Formulation Stability testing Toxicology 47 PreClinical Work in Research Safety Evaluations of Biotechnology Products Types of Animal Tests: - AEs (short, long-term) long- Dosing (#7 types) - Species - Immunogenicity - Carcinogenicity - Genotoxicity - Pharmacogenomics - Reproductive “5 1* Q: Frequency-Seriousness-Presents-Varies-Treatment” Frequency- Seriousness- Presents- Varies48 Animal Testing: - Biology in vivo - Relevant species - Proteins/animals, predict - Tissue binding in animals - Concentration in tissues - Transgenics, h-receptors Transgenics, h- Analytical limits, humans UF Fall 1 Biotec slides ’05 Page 24 Requirements & Costs for IND Studies Test Acute Toxicity (rodents) Subacute toxicity (4 weeks in rats-dogs) ratsSubacute toxicity (4 weeks in monkeys) Subacute toxicity (13 weeks in rats-dogs) ratsSubacute toxicity (13 weeks in monkeys) Chronic toxicity (26 weeks in rats & 39 weeks in dogs) Chronic toxicity (39 weeks in monkeys) Mutagenic potential (3 basic tests) Carcinogenic potential (mice or rats) Effect on reproductive performance Complete Toxicology Budget PLUS 1. Pharmacology (activity & efficacy, >>doses) 2. Pharmacokinetics (ADME) 3. Pharmacogenetics?? Pharmacogenetics?? Cost Range (Euros) 39,000 - 46,000 143,000-183,000 143,000125,000 213,000-305,000 213,000190,000 366,000-488,000 366,000290,000 25,000-69,000 25,0001,124,000-2,287,000 1,124,000313,000-458,000 313,0002,590,000-6,000,000 2,590,000500,000-1,000,000 500,000?? 49 The Problem with Drug Development Small Molecules 5,000 500 10 5 1 Synthesis - Biology Preclinical Development Clinical Approval Biologics Hundreds 50 10 5 1 Most Candidates Never Make it to Market 50 UF Fall 1 Biotec slides ’05 Page 25 Molecule Attrition from Research to Product 51 Molecule Attrition from Research to Product • Disease biology incomplete • In vitro assay not mimic disease accurately • Low target affinity needs excessive dose in humans • Proteins, neutralizing antibodies • In vivo models not mimic disease accurately • Human protein rejection in animals research • Acute models vs chronic human diseases • Animal-human species Animaldifferences • Human population more heterogeneous • • • • Formulations untenable ADME problems Drug interactions Inadequate disease activity in humans commercial quantities • Toxicology only found in humans • Can not be manufactured in • Cost to manufacture too high 52 • Pharmacokinetics, animal vs humans differences UF Fall 1 Biotec slides ’05 Page 26 Investigational New Drug (IND) Application • Introductory Statement • General Investigational Plan • Plans: Study protocol(s) • Plans: Investigators, Facilities, and Institutional Review Board • Data: Chemistry, Manufacturing, and Quality control • Data: Pharmacology and Toxicology • Data: Previous Human Experience • Data: Investigator Brochure FDA / EMEA Content: • Animal data • Human studies FDA / EMEA Focus: • Safety in animals • Activity in disease • Product Quality 53 UF Fall 1 Biotec slides ’05 Page 27