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PHARMACOPOLITICS - DRUG REGULATION IN THE UNITED STATES AND GERMANY BY ARTHUR A. DAEMMRICH THE UNIVERSITY OF NORTH CAROL

PHARMACOPOLITICS - DRUG REGULATION IN THE UNITED STATES AND GERMANY BY ARTHUR A. DAEMMRICH THE UNIVERSITY OF NORTH CAROLINA PRESS - 2004. OUTLINE. OVERVIEW OF PHARMACEUTICAL INDUSTRY ORGANIZATIONAL ISSUES PORTFOLIO STRATEGY TARGET SELECTION OPERATING IN A REGULATED ENVIRONMENT.

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PHARMACOPOLITICS - DRUG REGULATION IN THE UNITED STATES AND GERMANY BY ARTHUR A. DAEMMRICH THE UNIVERSITY OF NORTH CAROL

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  1. PHARMACOPOLITICS - DRUG REGULATION IN THE UNITED STATES AND GERMANY BY ARTHUR A. DAEMMRICH THE UNIVERSITY OF NORTH CAROLINA PRESS - 2004

  2. OUTLINE • OVERVIEW OF PHARMACEUTICAL INDUSTRY • ORGANIZATIONAL ISSUES • PORTFOLIO STRATEGY • TARGET SELECTION • OPERATING IN A REGULATED ENVIRONMENT

  3. DRUG DISCOVERY & DEVELOPMENT • IT IS DIFFICULT, RISKY, COSTLY AND REGULATED • IT HAS TO BE DONE WITH THE UNDERSTANDING THAT WHAT IS • BEST FOR THE PATIENT COMES FIRST • THE KEY OBJECTIVE IS TO FIND OUT WHETHER OR NOT THE DRUG • WORKS IN HUMANS • IF IT IS SAFE AND EFFICACIOUS IN HUMANS, IT MUST BE • MANUFACTURABLE AND MARKETABLE • TO PROVE THAT THE DRUG IS SAFE AND EFFICACIOUS, YOU MUST • STUDY “WHAT THE DRUG DOES TO THE BODY” AND ” WHAT THE • BODY DOES TO THE DRUG”

  4. Drug Discovery Process • Identify unmet or poorly met medical need • Link disease to a molecular mechanism • “Search” for a chemical lead (0.5-1 yr) • Optimize lead for potency, selectivity (1-2 yrs) • Optimize based on ADMET and safety (1-2 yrs) • Optimize based on feedback from clinical studies (2-3 yrs) • Key decision points require maximum information • There are opportunities for increased speed and effectiveness at every step of the multidisciplinary process

  5. Drug Development Process IND NDA PRECLINICAL R & D CLINICAL DEVELOPMENT PHASE I, II,II MARKET • For every 10 drug candidates that enter development, only 1 new drug reaches the market • Average cost to market>$500,000,000 • Average time to market ∼ 10-12 yrs • U.S. patent life is 17 yrs—clock starts in discovery phase • Drug hunting is high risk, expensive, and results in a relatively “short” business opportunity

  6. ORGANIZATIONAL SCHEME DISCOVERY DEVELOPMENT MEDICINAL CHEMISTRY PROCESS CHEMISTRY PRE-CLINICAL BIOLOGY PHARMACEUTICS ADME DRUG METABOLISM SAFETY PHARMACOLOGY SAFETY ASSESSMENT PATENT DEPT. PATENT DEPT. CLINICAL RESEARCH REGULATORY GROUP MARKETING GROUP PROJECT MANAGEMENT PROJECT MANAGEMENT

  7. DRUG DISCOVERY & DEVELOPMENT • IDENTIFY THERAPEUTIC TARGET • ADDRESS UNMET CLINICAL NEED • IDENTIFY LEAD COMPOUND(S) • THIS CAN BE DONE BY SCREENING OR DESIGN • OPTIMIZE LEAD COMPOUND • LEAD NEEDS TO BE OPTIMIZED FOR POTENCY, SELECTIVITY, • ADME, SAFETY, SYNTHESIS AND PHARMACEUTICS • TEST OPTIMIZED LEAD IN HUMANS (PHASE I, II & III) • EXPOSURE, SAFETY & EFFICACY ARE THE ISSUES • MARKET DRUG • OBTAIN APPROVAL BASED ON SPECIFIC CLAIMS

  8. TARGET SELECTION “THE CHOICES ARE MADE BY ASSESSING COMPETING IDEAS WHICH ARE INVITED FROM ALL THE STAFF. THE BEST IDEAS ARE SIMPLE, PRACTICABLE WITH THE AVAILABLE RESOURCES AND, ABOVE ALL, NOVEL ENOUGH TO YIELD MEDICINES THAT ARE LIKELY TO BE BETTER THAN PROBABLE COMPETITORS IN WAYS THAT WILL BE OBVIOUS BOTH TO DOCTORS AND THEIR PATIENTS.” SIR DAVID JACKS

  9. STAKEHOLDERS IN TARGET SELECTION • PATIENTS • MEDICAL PROFESSION • REGULATORY AGENCY • DRUG HUNTER • RESEARCH DIRECTOR • FINANCIAL ANALYSTS • MARKETING GROUP • CONSUMER ADVOCATES

  10. FIELDS OF DRUG RESEARCH • CNS DEPRESSION • CARDIOVASCULAR HYPERTENSION • INFECTION HIV • CANCER BREAST • INFLAMMATION/ALLERGY ARTHRITIS • RESPIRATORY DISEASES ASTHMA • GASTROINTESTINAL DISEASES PEPTIC ULCER • METABOLIC DISEASES DIABETES

  11. FACTORS IN TARGET SELECTION • CURRENT UNDERSTANDING OF DISEASE • ANALYSIS OF UNMET MEDICAL NEED • CRITICAL PROFILING OF CURRENT THERAPY • FINANCIAL ANALYSIS OF OPPORTUNITY • ANALYSIS OF REGULATORY CHALLENGES

  12. TYPES OF TARGETS • SPECULATIVE RESEARCH TARGETS • INNOVATIVE IMPROVEMENT TARGETS • “ME TOO” TARGETS EACH TYPE OF TARGET AFFORDS OPPORTUNITIES TO IMPROVE EFFICACY OR EFFICIENCY

  13. TYPES OF TARGETS • SPECULATIVE RESEARCH TARGET • EXAMPLES: HMG-CoA REDUCTASE INHIBITOR • ACE INHIBITOR • MUST SHOW THAT BIOLOGICAL ACTION HAS THERAPEUTIC UTILITY. PHASE II AND PHASE III STUDIES REQUIRED

  14. TYPES OF TARGETS • INNOVATIVE IMPROVEMENT TARGET IMPROVE ON AGENT WITH KNOWN THERAPEUTIC UTILITY EXAMPLE: PROPRANOLOL ATENOLOL BETA SELECTIVE NO YES DOSE/DAY 3/DAY 1/DAY DOSE HIGH LOW SAFETY --- BETTER

  15. TYPES OF TARGETS • “ME TOO” TARGETS NOVEL CHEMICAL STRUCTURES WITHOUT SIGNIFICANT IMPROVEMENT AS MEDICINES EXAMPLE: ATENOLOL VS BETAXOLOL AND BISOPROLOL

  16. IMPROVE EFFICACY THIS IS FREQUENTLY DONE BY USE OF A DIFFERENT MECHANISM OF ACTION EXAMPLE: CHOLESTEROL CONTROL FIBRATES LOWER BY 10-15 % STATINS LOWER BY 20-40 %

  17. IMPROVE EFFICIENCY THIS IS FREQUENTLY DONE WITH THE SAME MECHANISM OF ACTION EXAMPLE: CALCIUM ANTAGONISTS AMLODIPINE HAS IMPROVED PHARMACOKINETICS AND POTENCY COMPARED TO FELODIPINE BUT THE SAME MECHANISM OF ACTION

  18. BIOLOGICAL PROPERTIES OF NSAIDs • ANALGESIC • ANTI-INFLAMMATORY • ANTIPYRETIC • GASTRIC INTOLERANCE • INHIBITION OF PLATELET AGGREGATION

  19. KEY EVENTS IN DISCOVERY OF COX-2 • VANE PROPOSES THAT ASPIRIN BLOCKS ARACHIDONIC ACID • CONVERSION TO PROSTAGLANDINS - 1971 • ANTI-INFLAMMATORY ACTIVITY CORRELATED WITH COX • INHIBITION - 1974 • DUP697 DESCRIBED AS NSAID WITH IMPROVED SAFETY PROFILE - 1990 • IDENTIFICATION OF GENE THAT CODES FOR ALTERNATIVE FORM OF • COX - 1991 • INFLAMMATION-INDUCIBLE FROM OF COX IDENTIFIED AS SPECIES • THAT HAD BEEN CLONED IN 1991 - 1992 • COX-1/COX-2 mRNA DIFFERENTIALLY EXPRESSED IN HUMAN TISSUE • HYPOTHESIS: COX -1 INHIBITORS = SIDE EFFECT • COX -2 INHIBITORS = THERAPEUTIC EFFECT

  20. HISTORY OF NSAID DISCOVERY AND DEVELOPMENTCOX -1 INHIBITORS

  21. COX -1/COX -2 INHIBITORS

  22. LEAD DISCOVERY • DESIGN - VARIATION OF KNOWN ACTIVE COMPOUND

  23. PORTFOLIO PLANNING SCHEME • CORPORATE STRATEGY CNS DRUGS • BUSINESS STRATEGY DEGENERATIVE DISEASES • R & D STRATEGY ALZHEIMER’S DISEASE • PORTFOLIO ENZYME INHIBITORS • TARGET SELECTION BETA SECRETASE IN GENERAL LARGER COMPANIES SELECT MORE TARGETS AND HAVE A BROADER DISTRIBUTION OF TARGETS THAN IS THE CASE WITH SMALLER COMPANIES

  24. SIZE OF MAJOR THERAPEUTIC AREAS

  25. CONSIDER GROWTH RATES IN PORTFOLIO CONSTRUCTION

  26. CONSIDER SUCCESS RATES IN PORTFOLIO CONSTRUCTION

  27. PORTFOLIO PLANNING NEUROSCIENCE (CNS) AFFECTIVE DISORDERS - ANTIDEPRESSANTS, TRANQUILIZERS SCHIZOPHRENIA - ANTIPSYCHOTICS HYPNOTICS - SEDATIVES, HYPNOTICS ANALGESICS - NARCOTICS, NON-NARCOTICS NEURO-DEGENERATION - ANTI-ALZHEIMER, ANTI-PARKINSON NEURONAL HYPEREXCITABILITY - ANTI-EPILEPTICS, ANTI-MIGRAINE OTHER - PSYCOSTIMULENTS, ANTI-SMOKING

  28. EARLY LEAD OPTIMIZATION LEADS ARE OPTIMIZED FOR POTENCY AND SELECTIVITY WHILE THIS IS HAPPENING, IT IS IMPORTANT TO ADDRESS THE FOLLOWING ISSUES SOLUBILITY CHEMICAL STABILITY FEASIBILITY OF SYNTHESIS Caco-2 CELL PERMEABIITY IV/ORAL PHARMACOKINETICS INHIBITION OF P450 MICROSOMAL STABILITY IDENTIFICATION OF METABOLITES PROTEIN BINDIN AMES TEST HERG ACTIVITY IF YOU ARE GOING TO FAIL, FAIL EARLY

  29. IS OPTIMIZED LEAD DEVELOPABLE? METABOLISM PLASMA PROTIN BINDING EXCRETION BALANCE & METABOLITE IDENTIFICATION-RAT EXCRETION BALANCE & METABOLITE IDENTIFICATION-DOG IDENTIFY P450 ENZYMES QUANTITATIVE TISSUE DISTRIBUTION SAFETY PHARMACOLOGY CARDIOVASCULAR SAFETY-TELEMETRY IN CONSCIOUS DOG NORMAL PULMONARY FUNCTION - RAT IRWIN TEST OF BEHAVIOR - RAT TOXICOLOGY IN VIVO MICRONUCLEUS TEST IN RODENTS REPRODUCTIVE TOXICOLOGY RAT TOXICOLOGY AFTER FOUR WEEKS EXPOSURE DOG TOXICOLOGY AFTER FOUR WEEKS ESPOSURE FORMULATION STABLE FORMULATION

  30. KEY QUESTIONS -1 CAN THE DRUG CANDIDATE BE MEASURED IN BIOLOGICAL MATRICES? DOES IT HAVE REASONABLE METABOLIC STABILITY? WHAT ARE THE METABOLITES & ARE THEY ACTIVE OR TOXIC? DOES THE DRUG HAVE ADEQUATE ORAL BIOAVILABILITY? IS THE DURATION OF ACTIVITY SUFFICIENT? IS THE DRUG MUTAGENIC OR CYTOTOXIC? WHAT IS THE MTD & DOSE-LIMITING TOXICITY? CAN THE ACTIVE PHARMACEUTICAL INGREDIENT(API) BE SYNTHESIZED AT REASONABLE COST AND IS IT STABLE? CAN THE DRUG BE FORMULATED FOR ANIMAL TOXICOLOGY STUDIES AND EARLY CLINICAL STUDY?

  31. KEY QUESTIONS - 2 CAN THE DRUG BE SYNTHESIZED AND FORMULATED ACCORDING TO GOOD MANUFACTURING PRACTICE(GMP)? IS THERE DOSE-RELATED EXPOSURE IN ANIMALS? WHAT IS THE MAXIMUM NO-EFFECT DOSE ON REPEATED EXPOSURE? WHAT ORGANS ARE AFFECTED BY REPEATED DOSING? WHAT IS THE SAFETY MARGIN? WHAT ENZYMES ARE INVOLVED IN DRUG’S METABOLISM? HOW IS THE DRUG CLEARED & WHAT IS THE HALF LIFE? DOES THE DRUG HAVE CARDIOVASCULAR EFFECTS? DOES THE DRUG HAVE BEHAVIORAL EFFECTS? DOES THE DRUG HAVE PULMONARY EFFECTS? DOES THE DRUG AFFECT REPRODUCTIVE FUNCTION IN RATS? IS THE DRUG TERATOGENIC OR MUTAGENIC IS THE DRUG CARCINOGENIC? WHAT IS THE POTENTIAL FOR DRUG-DRUG INTERACTIONS?

  32. STUDIES THAT ANSWER QUESTIONS DEVELOP BIOANALYTICAL ASSAY MICROSOMAL STABILITY & METABOLISM SYNTHESIZE & TEST METABOLITES STUDY IV/ORAL PHARMACOKINETICS IN RODENT STUDY IV/ORAL PHARMACOKINETICS IN NON-RODENT RUN AMES BACTERIAL MUTAGENCITY ASSAY DEFINE LIMITING TOXICITY IN RODENT AND NON-RODENT USING SINGLE AND REPEAT DOSE ESCALATION DEFINE CHEMICAL API STABILITY AND PURITY CRITERIA DEVELOP AND STABILITY TEST FORMULATION OF API ESTABLISH GMP RELEASE CRITERIA FOR FORMULATION TWO WEEK TOXICOLOGY STUDY IN RODENT & NON-RODENT CARDIAC IN VIVO TELEMETRY STUDY IRWIN BEHAVIORAL TEST

  33. STUDIES THAT ANSWER QUESTIONS STUDY TISSUE DISTRIBUTION OF DRUG STUDY INHIBITION & INDUCTION OF P450 ENZYMES STUDY SEGMENT I REPRODUCTIVE TOXICOLOGY STUDY SEGMENT II REPRODUCTIVE TOXICOLOGY SIX MO TO ONE YEAR TOXICOLOGY LIFETIME EXPOSURE IN RAT AND/OR MOUSE METABOLIC PROFILE IN ANIMALS AND HUMANS IDENTIFY METABOLISING ENZYMES IN BOTH

  34. AMERICAN DRUG REGULATION 1906 PURE FOOD AND DRUG LAW FDA REVIEWS FOOD & DRUG LABELS AND CAN SEIZE AND REMOVE IMPROPERLY LABELED PRODUCTS 1938 FEDERAL FOOD, DRUG & COSMETIC ACT MANUFACTURERS MUST TEST DRUG FOR SAFETY AND FDA HAS 60 DAYS TO REVIEW, POSE QUESTIONS OR FILE OBJECTIONS 1962 KEFAUVER-HARRIS AMENDMENTS FDA RESPONSIBLE FOR DRUG SAFETY & EFFICACY FDA MUST APPROVE A DRUG PRIOR TO MARKETING FDA CAN REQUIRE MARKET WITHDRAWALS FDA SETS STANDARDS FOR EVERY STAGE OF DRUG TESTING FDA DEFINES GOOD MANUFACTURING PRACTICE (GMP) & INSPECTS PLANTS FOR COMPLIANCE

  35. IND - ENABLING STUDIES • PHARMACOLOGY • Primary • Secondary • ADME • Pharmacokinetics • Tissue distribution • Enzyme induction/inhibition • Metabolism pathway/profile • Excretion patterns • SAFETY PHARMACOLOGY • CNS • Cardiovascular • Respiratory • TOXICOLOGY • Genotoxicity • General toxicity • Reproductive toxicology

  36. IND - ENABLING STUDIES • DRUG SUBSTANCE • API manufacture (GLP/GMP), supporting stability, analytics • Radiolabeled API for metabolism/distribution studies • FORMULATION DEVELOPMENT • Preclinical (maximum exposure, tolerability) • Clinical • ANALYTICS • Verify drug concentrations from all GLP in vitro/in vivo studies • Stability and homogeneity of formulation • BIOANALYTICS • Drug/metabolite analysis from ADME, toxicology & safety • pharmacology studies.

  37. IND - ENABLING STUDIES RELEVANT ICH GUIDELINES ICH M3 Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals (1997) ICH S2A Specific aspects of regulatory genotoxicity tests for pharmaceuticals (1996) ICH S2B A standard battery for genotoxicity testing of Pharmaceuticals(1998) ICH S3A Toxicokinetics: The assessment of systemic exposure in toxicity studies (1995) ICH S5A Detection of toxicity to reproduction for medicinal products (1994) ICH S3B Pharmacokinetics: Guidance for repeated dose tissue distribution studies (1995) ICH S7A Safety pharmacology for human pharmaceuticals (2001) ICH S7B Safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (2002) ICH = International Conference on Harmonization

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