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2016-11-28 Mentlife seminar: Pharmaceutical Drug Development; An Overall Perspective

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This seminar provided an understanding of modern pharmaceutical drug development – the different phases of drug development and insight into different jobs.

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2016-11-28 Mentlife seminar: Pharmaceutical Drug Development; An Overall Perspective

  1. 1. PHARMACEUTICAL DRUG DEVELOPMENT – AN OVERALL PERSPECTIVE GÖRAN LIDGREN, JYNX CONSULTING ANNA RYDBECK, BULB INTELLIGENCE GORAN.LIDGREN@FOKUSPHARMA.SE ANNA@BULBINTELLIGENCE.COM 28TH NOVEMBER 2016, LUND, SWEDEN ary@cisolutions.se
  2. 2. PHARMACEUTICAL DRUG DEVELOPMENT - AN OVERALL PERSPECTIVE • 08:30-09:00 REGISTRATION • 09:00-10:00 DRUG DEVELOPMENT – FROM IDEA TO THE MARKET • 10:00-10:20 COFFEE/TEA • 10:20-10:50 CLINICAL DEVELOPMENT - PHASE I, II, III, IV • 10:50-11:30 REGULATORY AFFAIRS • 11:30-11:50 PRODUCT LIFE CYCLE MANAGEMENT AND CURRENT TRENDS • 11:50-12:00 Q&A
  3. 3. ABBREVIATIONS ATC CODE ANATOMIC THERAPEUTIC CHEMICAL CLASSIFICATION SYSTEM ATMP ADVANCED THERAPY MEDICINAL PRODUCT CD CANDIDATE DRUG CFR CODE OF FEDERAL REGULATIONS (US) CI COMPETITIVE INTELLIGENCE CMC CHEMISTRY, MANUFACTURING AND CONTROLS CMS CONCERNED MEMBER STATE CP CENTRALISED PROCEDURE CTA CLINICAL TRIAL APPLICATION CTD COMMON TECHNICAL DOCUMENT DCP DECENTRALISED PROCEDURE EEA EUROPEAN ECONOMIC AREA EMA EUROPEAN MEDICINES AGENCY EFPIA EUROPEAN FED. OF PHARMACEUTICAL INDUSTRIES ASSOC. FDA FOOD AND DRUG ADMINISTRATION (US) GCP GOOD CLINICAL PRACTICE GDP GOOD DISTRIBUTION PRACTICE GLP GOOD LABORATORY PRACTICE GVP GOOD PHARMACOVIGILANCE PRACTICES GMP GOOD MANUFACTURING PRACTICE ICH INTERNATIONAL CONFERENCE ON HARMONISATION IMPD (EU) INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER IND (US) INVESTIGATIONAL NEW DRUG APPLICATION IP INTELLECTUAL PROPERTY LIF LÄKEMEDELSINDUSTRIFÖRENINGEN MAA MARKETING AUTHORISATION APPLICATION MAH MARKETING AUTHORISATION HOLDER MPA MEDICAL PRODUCTS AGENCY (SWEDEN) MRP MUTUAL RECOGNITION PROCEDURE NCE NEW CHEMICAL ENTITY NDA NEW DRUG APPLICATION NME NEW MEDICAL ENTITY PIP PAEDIATRIC INVESTIGATION PLAN PSUR PERIODIC SAFETY UPDATE REPORT R&D RESEARCH & DEVELOPMENT RMP RISK MANAGEMENT PLAN RMS REFERENCE MEMBER STATE (EU) SME SMALL AND MEDIUM-SIZED ENTERPRISES SMPC (SPC) SUMMARY OF PRODUCT CHARACTERISTICS WHO WORLD HEALTH ORGANISATION 3
  4. 4. TOPICS COVERED • INTRODUCTION TO DRUG DEVELOPMENT • THE MARKET • THE REGULATORY LANDSCAPE • PRECLINICAL (NON-CLINICAL) DEVELOPMENT • CLINICAL DEVELOPMENT • REGULATORY AFFAIRS • TRENDS • LIFE CYCLE MANAGEMENT
  5. 5. DRUG DEVELOPMENT – SOME CHARACTERISTICS • LONG DEVELOPMENT TIME SPAN – 10-15 YEARS • HIGH COSTS – 1.8 BILLION USD (2015) AVERAGE COST FOR A NEW CHEMICAL ENTITY • INTELLECTUAL PROPERTIES (IP) AND PATENTS VERY IMPORTANT • INVOLVES MANY COMPETENCES AND • EVERY DEVELOPMENT STEP IS HIGHLY REGULATED • CONTINOUSLY REPORTING & CONTACTS WITH AUTHORITIES (THROUGH ALL OF THE PRODUCT LIFE CYCLE) • HIGH RISK BUT ALSO HIGHLY PROFITABLE (RETURN OF INVESTMENT, ROI)
  6. 6. DRUG DEVELOPMENT 6 0 20 40 60 80 100 Knowledge 10 - 15 yrs Safety,Tox,Pharmacology invitroandinvivo Chemistry,biochemistry phaseI phaseII phaseIII phaseIV ClinicalTrialsApplication Applications & Authorities MarketingAuthorisationApplication
  7. 7. Years No compounds 3 10 000 10-15 5 7 9 11 13 15 19 211 1-8 DEVELOPMENT Clinical Trials Identification of target and lead compound Proof of Concept launch Product life cycle support Sales marketing Regulatory Affairs Process development and Manufacturing Pharmaceutical and analytical development Safety studies and PK/PD (ADMET) 1-3 DISCOVERY Medicinal Chemistry 1 2 3 4 Patent Applications IMPD / IND MAA / NDA CD Selection Pharmacology / biology KNOWLEDGE
  8. 8. FROM MOLECULE TO FINISHED PRODUCT ON THE MARKET IP Patents, Law The Team Market Pre-Clinical Health Economics Manufacturing Regulatory Affairs Statistics - data management Clinical
  9. 9. DRUG MARKET SALES 2014 • GLOBAL MARKET 2014: 937 BILLIONS USD (CA. 8-9000 MILJARDER SEK) • SWEDISH MARKET 2015: CA. 40 BILLIONS SEK SOURCE: IMS HEALTH AND LIF
  10. 10. TOP 18 THERAPY CLASSES BY GLOBAL PHARMACEUTICAL SALES IN 2014 (IN BILLION U.S. DOLLARS, SOURCE IMS HEALTH) 1. ONCOLOGICS (74) 2. ANTIDIABETICS (64) 3. PAIN (60) 4. ANTIHYPERTENSIVES, PLAIN & COM (48) 5. ANTIBACTERIALS (40) 6. RESPIRATORY AGENTS (40) 7. MENTAL HEALTH (39) 8. AUTOIMMUNE DISEASES (36) 9. LIPID REGULATORS (28) 10. DERMATOLOGICS (28) 11. ANTICOAGULANTS (27) 12. GI PRODUCTS (25) 13. ANTI-ULCERANTS (25) 14. HIV ANTIVIRALS (23) 15. OTHER CARDIOVASCULARS (23) 16. NERVOUS SYSTEM DISORDERS (22) 17. OTHER CNS (20) 18. VIRAL HEPATITIS (18)
  11. 11. TOP DRUGS BY GLOBAL SALES 2015 1. HUMIRA (RHEUMATIC ARTHRITIS, ABBVIE) 2. HARVONI (HEPATITIS C, GILEAD) 3. ENBREL (RHEUMATIC ARTHRITIS, AMGEN) 4. REMICADE (RHEUMATIC ARTHRITIS, CROHNS, JOHNSON&JOHNSON) 5. MABTHERA, RITUXAN (ONCOLOGY, ROCHE) 6. LANTUS (DIABETES, SANOFI) 7. AVASTIN (ONCOLOGY, ROCHE) 8. HERCEPTIN (ONCOLOGY, ROCHE) 9. REVLIMID (ONCOLOGY, CELGENE) 10.SOVALDI (HEPATITIS C, GILEAD) 11.SERETIDE, ADVAIR (ASTHMA, COL, GSK) 12.CRESTOR (CARDIOVASCULAR, ASTRAZENECA) RED = BIOLOGICAL BLACK = SMALL MOLECULE
  12. 12. TOP 10 PHARMACEUTICAL COMPANIES 2016
  13. 13. THE MARKET SOURCES OF INFORMATION: • QUINTILES IMS (FORMER IMS HEALTH) • HTTPS://WWW.QUINTILESIMS.COM • HTTP://WWW.IMSHEALTH.COM • HTTP://WWW.LIF.SE/STATISTIK/LAKEMEDELSMARKNADEN-OCH-HALSO--OCH- SJUKVARDEN-FAKTA-20141/LAKEMEDELSMARKNADEN/
  14. 14. PHARMACEUTICAL COMPANIES IN SWEDEN • 85 BIG PHARMA - MARKET COMPANIES • 25 GENERIC DRUG COMPANIES • 150 MEDTECH COMPANIES • MORE THAN 200 SMALL RESEARCH COMPANIES • 20-30 CONTRACT COMPANIES (CMO, CRO) • CONSULTANTS, EXPERTS
  15. 15. EXAMPLES OF PHARMACEUTICAL COMPANIES IN SWEDEN • ASTRAZENECA • FRESENIUS KABI • OCTAPHARMA • SOBI • RECIPHARM • MEDA • CAMBREX • APL • PFIZER • BAXTER • OREXO • MEDIVIR • FERRING (POLYPEPTIDES) • GALDERMA • CCS • QPHARMA • ALLIGATOR BIOSCIENCE • BIOINVENT
  16. 16. THE REGULATORY ENVIRONMENT • REGULATIONS (EUDRALEX (EU); CODE OF FEDERAL REGULATIONS (US) AND ICH GUIDELINES) • AUTHORITIES • APPLICATIONS, APPROVALS AND AUTHORIZATION • CONTROL, SUPERVISION, SURVEILLANCE, INSPECTIONS • CONTINOUS REPORTING
  17. 17. AUTHORITIES • EU EMA (EUROPEAN MEDICINES AGENCY) NATIONAL AUTHORITIES E.G. LÄKEMEDELSVERKET (MEDICAL PRODUCTS AGENCY) • USA FDA (FOOD AND DRUG ADMINISTRATION) • JAPAN • NIPH (NATIONAL INSTITUTE OF PUBLIC HEALTH) • CHINA • SFDA (STATE FOOD AND DRUG ADMINISTRATION) AND CDE (DRUG EVALUATION CENTER) BUT THERE ARE MANY MORE E.G.: • AUSTRALIA • TGA (THERAPEUTIC GOODS ADMINISTRATION) • RUSSIA • FEDERAL SERVICE ON SURVEILLANCE IN HEALTHCARE AND SOCIAL DEVELOPMENT 17
  18. 18. LÄKEMEDELSVERKET HTTPS://LAKEMEDELSVERKET.SE 18
  19. 19. ICH WWW.ICH.ORG 19
  20. 20. DIFFERENT REGULATIONS FOR DIFFERENT TYPES OF MEDICINAL PRODUCTS • HUMAN MEDICINAL PRODUCTS • GENERIC DRUGS (GENERISKA LÄKEMEDEL) • BIOLOGICALS (BIOLOGISKA LÄKEMEDEL (VACCINER, BIOTECHPRODUKTER, ANTIKROPPAR); ATMP AVANCERADE TERAPIER (GENTERAPI, CELLTERAPI…)) • BIOSIMILARS • ORPHAN DRUGS (SÄRLÄKEMEDEL) • OTC PRODUCTS (RECEPTFRIA LÄKEMEDEL) • HERBAL MEDICINAL PRODUCTS, TRADITIONAL HERBAL MEDICINAL PRODUCTS AND NATURAL REMEDIES (VÄXTBASERADE LÄKEMEDEL; TRADITIONELLA VÄXTBASERADE LÄKEMEDEL; NATURLÄKEMEDEL) • CERTAIN MEDICINAL PRODUCTS FOR EXTERNAL USE (VISSA UTVÄRTES MEDEL (VUM)) • VETERINARY MEDICINAL PRODUCTS (VETERINÄRLÄKEMEDEL) • HOMEOPATHIC MEDICINAL PRODUCTS (HOMEOPATISKA LÄKEMEDEL) 20
  21. 21. ORPHAN DRUGS (OMP) – SÄRLÄKEMEDEL ORPHAN DESIGNATION (EU) TO QUALIFY FOR ORPHAN DESIGNATION, A MEDICINE MUST MEET A NUMBER OF CRITERIA: • IT MUST BE INTENDED FOR THE TREATMENT, PREVENTION OR DIAGNOSIS OF A DISEASE THAT IS LIFE-THREATENING OR CHRONICALLY DEBILITATING; • THE PREVALENCE OF THE CONDITION IN THE EU MUST NOT BE MORE THAN 5 IN 10,000 OR IT MUST BE UNLIKELY THAT MARKETING OF THE MEDICINE WOULD GENERATE SUFFICIENT RETURNS TO JUSTIFY THE INVESTMENT NEEDED FOR ITS DEVELOPMENT; • NO SATISFACTORY METHOD OF DIAGNOSIS, PREVENTION OR TREATMENT OF THE CONDITION CONCERNED CAN BE AUTHORIZED, OR, IF SUCH A METHOD EXISTS, THE MEDICINE MUST BE OF SIGNIFICANT BENEFIT TO THOSE AFFECTED BY THE CONDITION. • THE EVALUATION PROCESS TAKES A MAXIMUM OF 90 DAYS FROM VALIDATION. 21
  22. 22. ORPHAN DRUGS (OMP) – (EU) AFTER ORPHAN DESIGNATION • SPONSORS WHO OBTAIN ORPHAN DESIGNATION BENEFIT FROM A NUMBER OF INCENTIVES, INCLUDING • PROTOCOL ASSISTANCE, A TYPE OF SCIENTIFIC ADVICE SPECIFIC FOR DESIGNATED ORPHAN MEDICINES, AND • MARKET EXCLUSIVITY ONCE THE MEDICINE IS ON THE MARKET. • FEE REDUCTIONS ARE ALSO AVAILABLE DEPENDING ON THE STATUS OF THE SPONSOR AND THE TYPE OF SERVICE REQUIRED. • ELIGIBLE FOR RESEARCH GRANTS • SPONSORS MUST SUBMIT AN ANNUAL REPORT TO THE AGENCY SUMMARIZING THE STATUS OF DEVELOPMENT OF THE MEDICINE. • APPLICATIONS FOR MARKETING AUTHORISATION FOR DESIGNATED ORPHAN MEDICINES ARE ASSESSED BY THE COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP). • SPONSORS ALSO NEED TO SUBMIT AN APPLICATION FOR MAINTENANCE OF THE ORPHAN DESIGNATION IN ORDER TO BE ELIGIBLE FOR THE 10-YEARMARKET EXCLUSIVITY INCENTIVE. • SPONSORS MAY ALSO NEED TO SUBMIT AN EVALUATION OF ORPHAN SIMILARITY. 22
  23. 23. INCENTIVES IN THE EU FOR ORPHAN PRODUCTS •Market Exclusivity – 10 years for all orphan medicines (from marketing authorization) – plus 2 years if Paediatrics Investigational Plan (PIP) results are included in the MAA and this is reflected in the SmPC • Fee Waivers/Reductions for product development – Application for Orphan Designation: free of charge – Protocol assistance and follow up: free of charge – Application for Marketing Authorisation: free of charge for SMEs, 50% for others - plus extended incentives for SMEs in post authorization phase • EU Marketing Authorisation through unique centralized procedure Å Holmgren Page 23
  24. 24. INCENTIVES IN THE US FOR ORPHAN PRODUCTS • NO APPLICATION FEE • 50% TAX CREDIT FOR CLINICAL STUDY COSTS • CAN APPLY FOR FDA ORPHAN GRANTS PROGRAM TO SUPPORT CLINICAL RESEARCH • 7 YEARS MARKET EXCLUSIVITY FOR APPROVED ORPHAN PRODUCT
  25. 25. QUALIT Y EFFICAC Y SAFETY RISK BENEFIT S 25 PHARMACEUTICAL DRUG DEVELOPMENT KEY ELEMENTS
  26. 26. QUALITY (GXP) • GLP - GOOD LABORATORY PRACTICE • GMP - GOOD MANUFACTURING PRACTICE • GCP - GOOD CLINICAL PRACTICE • GDP – GOOD DISTRIBUTION PRACTICE
  27. 27. PHARMACEUTICAL DRUG DEVELOPMENT - AN OVERALL PERSPECTIVE • 10:00-10:20 COFFEE/TEA • 10:20-10:50 CLINICAL DEVELOPMENT - PHASE I, II, III, IV • 10:50-11:30 REGULATORY AFFAIRS • 11:30-11:50 PRODUCT LIFE CYCLE MANAGEMENT AND CURRENT TRENDS • 11:50-12:00 Q&A
  28. 28. WHY REGULATIONS?  POORLY PERFORMED STUDIES ON ANIMALS AND HUMANS  THE THALIDOMIDE TRAGEDY AND OTHER TRAGEDIES AND INCIDENTS  INCREASED NUMBERS OF REGULATIONS  INCREASED FOCUS ON PRE-CLINICAL SAFETY STUDIES  DECLARATION OF HELSINKI (1964) - A STATEMENT OF ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS  INCREASED DEMANDS FOR DOCUMENTATION AND REPORTS ON ADVERSE EFFECTS  INSURANCES 28
  29. 29. Molecular biology of disease process understood Target identification Chemistry In vitro Screens Safety studies Animal models PK/PD, Toxicology Clinical Trials Market
  30. 30. RISK?
  31. 31. RISK?
  32. 32. År No. compounds 3 10 000 10-15 9 11 13 15 19 211 1-8 DEVELOPMENT Clinical TrialsOptimisation of lead Identify target and lead compound Proof of Concept Product Life Cycle Support Sales and marketing Regulatory Affairs Process chemistry and large scale manufacturing Pharmaceutics and analytical chemistry Safety, Toxicology and Pk/Pd studies (ADME) 1-3 DISCOVERY Medicinal chemistry and Biology 1 2 PATENTS CTA MAA CD 5 7 3 4 post-market
  33. 33. INTELLECTUAL PROPERTY & COMPETITIVE INTELLIGENCE
  34. 34. WHAT IS A PATENT? • A LEGAL PROTECTION WHICH GIVES AN INVENTOR THE RIGHT TO EXCLUDE OTHERS FROM PERFORMING CERTAIN ACTIVITY IN THE COUNTRY OF ISSUANCE • SANCTIONED MONOPOLY FOR A SET NUMBER OF YEARS IN EXCHANGE FOR DISCLOSURE TO THE PUBLIC • DOES NOT GIVE THE INVENTOR THE RIGHT TO MAKE, USE OR SELL THE PATENTED INVENTION
  35. 35. WHAT CAN BE PATENTED? • MUST BE: • NOVEL: NOT PREVIOUSLY KNOWN OR USED BY OTHERS • USEFUL: HAVE A KNOWN USE OR PRODUCE A CONCRETE AND TANGIBLE RESULT • NON-OBVIOUS: • IS IT OBVIOUS TO A PERSON HAVING ORDINARY SKILL IN THE ART? • CAN NOT BE FOUND IN A SINGLE OR REASONABLE COMBINATION OF PATENTS THAT WOULD YIELD A PREDICTABLE RESULT • CAN NOT BE: • IDEA • LAW OF NATURE • SCIENTIFIC PRINCIPLE
  36. 36. WHAT ARE THE PARTS OF A PATENT? • ABSTRACT • BACKGROUND OF THE INVENTION • SUMMARY OF THE INVENTION • FIGURES WITH BRIEF DESCRIPTIONS • DETAILED DESCRIPTION OR “SPECIFICATION” • FULLY DISCLOSES WHAT THE INVENTION IS • HOW IT IS MADE? • HOW IT CAN BE USED? • CLAIM(S): SETS THE LEGAL BOUNDARIES OF PROTECTION
  37. 37. DISCLOSURE INITIAL PUBLICATION RE-EVALUATION RE-EVALUATIONRE-EVALUATION Overview of Pathway to Commercialization FILE PROVISIONAL APPLICATION (~$10k) EVALUATION 3 MONTHS FILE PCT (~$25K) PCT PUBLICATION 8 MONTHS 12 MONTHS 6 MONTHS 12 MONTHS ENTER NATIONAL PHASE & PROSECUTION (~$20k) RARELY GET THIS FAR W/O LICENSEE PATENTABILITY & MARKETING EVALUATION MARKETING/SEARCH FOR LICENSEE GENERATE NCD ADDITIONAL PUBLICATIONS W/ INTERESTING ANIMAL DATA, PROTOTYPING, FURTHER COMMERCIALIZATIONEvaluation: Can this invention be patented? Is there any prior art? Is this invention new, useful, & non-obvious? Is it worthwhile to patent this invention? What product could come from this
  38. 38. A WINDOW INTO YOUR COMPETITORS’ COMMERCIAL PLANS BUSINESS GOALS SUPPORTS DICTATE IP STRATEGY (PATENT, TMS, ETC) • PATENT DOCUMENTS PROVIDE AN “EARLY- WARNING RADAR” FOR THE COMMERCIAL INTERESTS OF YOUR COMPETITORS
  39. 39. OUR KEY STAKEHOLDERS Competitive Intelligence in Life Sciences 20 May 2015 Development projects DRU, BRU (early projects) Regulatory Affairs Focus groups and sourcing units Device R&D Corporate Development Investor Relations Commercial planning Brand teams Major Affiliates Competitive Intelligence Executive Management
  40. 40. 4 0 Competitive Intelligence Examples Activity in CI WHY? • Investigation of active researchers Establish crucial collaborations • Novelty search File patent application • Freedom to Operate Patent/publish in FTO area • Pipeline summary Identify competitors • Market surveillance Find new market opportunities
  41. 41. 4 1 Competitive Intelligence Sources of Information • Soft information Conferences, rumours, gossip • Scientific Literature Literature databases, PubMed Embase • Patent publications Patent databases, Espacenet • Info on drugs in development Pipeline databases, clinical trial databases • Info on sales of drugs Market databases, Quintiles etc
  42. 42. • UP TO 80% OF SCIENTIFIC AND TECHNICAL INFO CAN BE FOUND ONLY IN PATENT DOCUMENTS (EPO STUDY) • PATENT APPLICATIONS ARE PUBLISHED 18 MONTHS FROM THEIR PRIORITY/FILING DATE (OFTEN YEARS BEFORE A PRODUCT IS PUT ON THE MARKET) • ONLINE DATABASES (MANY FREE-TO-ACCESS) PATENT DOCUMENTS REPRESENT A VALUABLE SOURCE OF TECHNICAL INFORMATION
  43. 43. 43 Competitive Intelligence sources literature Embase Medline 30 75 0 • No need to access all literature • Choose only relevant literature 36 million records 16 000 journals28 million records 8 400 journals 21 million records 5 600 journals 5 500 journals
  44. 44. Literature Patent Pipeline Clinical trials Regulatory Market Literature alerts Novelty search Competitor search Competitor search Application search Alliances search KOL search Validity search MoA search MoA search Market authorisation search R&D Investments search Citation search Infringment search Target search Target search Pediatric approval search Sales search Pharmacovigilance search FTO search Substance search Substance search SPC search Epidemiology search Clinical evaluation search State of the art search Therapeutic area search Therapeutic area search Patent landscape search Indication search Indication search Patent watch Legal status watch Chemical structure search MARKUSH search Chemical structure search Bio sequence search Bio sequence search Bio sequence search
  45. 45. Case study 1 PHARMA COMPANY  RECEIVES 400 MSEK FROM INVESTORS FOR CLINICAL TRIAL.  FINDS OUT AFTER INVESTMENT THAT SIMILAR TRIAL ALREADY PERFORMED AND FAILED TAKE HOME MESSAGE  IMPLEMENT COMPETITIVE INTELLIGENCE TO AVOID SUCH SITUATIONS. Stop
  46. 46. Product Profile will it make a difference ?  Effective  Safe  Stabile and easy to manufacture  ”Beneficial metabolism”  Oral Formulation preferrable  Significant economical return - Patents! Product must have more competetive advantage than the current remedy on the market
  47. 47. TPP - TARGET PRODUCT PROFILE BEGINNING WITH THE GOAL IN MIND
  48. 48. • TARGETS – USUALLY PROTEINS E.G. G-PROTEIN COUPLED RECEPTORS, ENZYMES, HORMONS • TARGET VALIDATION – TO EVALUATE IF THE CHOSEN TARGET IS RELEVANT FOR THE SELECTED INDICATION. • TARGET VALIDATION IS CONTINOUSLY ONGOING MOLECULAR TARGETS
  49. 49. MEDICINAL CHEMISTRY (SMALL MOLECULES) • HIT TO LEAD • LEAD GENERATION • LEAD OPTIMISATION • DRUG DESIGN (CHEMICAL LIBRARIES, PHARMACOPHORE ……) • PATENTS ! • CANDIDATE DRUG (CD) SELECTION
  50. 50. 50 • Protein structure, highly targeted and specific, inactive metabolites • LC/MS/MS vs ELISA assays • Manufacturing sensitive and scale up may alter product • Functional assays often needed • Immunogenicity • Results in animals not necessarily predictive of humans and relevant animal species may be limited (Non-human primate) • Ethical issues •GLP requirements for studies are the same •Tissue cross-reactivity studies needed for monoclonal antibodies – ability to bind to target and non-target tissues May not be required: • Metabolism • Limited safety pharmacology • Genotoxicity • Carcinogenicity BIOLOGICS - DIFFERENCES WITH SMALL MOLECULES
  51. 51. PRECLINICAL (NON-CLINICAL) DEVELOPMENT • IN VITRO STUDIES IN ANIMAL AND HUMAN SYSTEMS AND IN VIVO ANIMAL STUDIES • DETERMINE SYSTEMIC UPTAKE AND EXPOSURE, METABOLISM, PHARMACOLOGICAL EFFECT, POTENTIAL TOXICITIES AND TARGET ORGANS OF A DRUG • EFFICACY – PHARMACOLOGICAL RATIONAL ” MODE OF ACTION” • SAFETY – TO IDENTIFY RISKS WITH THE DRUG AND TO SELECT SAFETY PARAMETERS FOR MONITORING IN THE CLINICAL TRIALS • TO GIVE GUIDANCE ABOUT STARTING DOSE IN THE FIRST CLINICAL TRIALS (FIH - FIRST IN HUMANS)
  52. 52. ANIMAL STUDIES – THE PRINCIPLES OF 3R • REPLACE: WITH METHODS WHICH AVOID OR REPLACE THE USE OF ANIMALS IN RESEARCH • REFINE: USE METHODS THAT MINIMIZE POTENTIAL PAIN, SUFFERING OR DISTRESS, AND ENHANCE ANIMAL WELFARE FOR THE ANIMALS USED. • REDUCE: USE METHODS THAT ENABLE RESEARCHERS TO OBTAIN COMPARABLE LEVELS OF INFORMATION FROM FEWER ANIMALS, OR TO OBTAIN MORE INFORMATION FROM THE SAME NUMBER OF ANIMALS.
  53. 53. Lead optimisation Candidate preclinical evaluation Clinical Evaluation Candidate drug (CD) selection CTA Discover y Development
  54. 54. Pharmacokinetics - DMPK – What the body does to the compound Pharmacodynamics – What the compound does to the body Essential to understand how the compound acts on the target PHARMACOKINETICS AND PHARMACODYNAMICS (PK/PD)
  55. 55. ADME • ABSORPTION • DISTRIBUTION • METABOLISM • EXCRETION
  56. 56. QUESTIONS TO ANSWER BEFORE CLINICAL TRIALS IN HUMANS • HOW MUCH IS ABSORBED? • DISTRIBUTION IN THE BODY? • DURATION? • EXCRETION? • METABOLITES? • EFFECTIVE DOSE? • DOSE FOR ADVERSE EFFECTS? • ARE THE ADVERSE EFFECTS CAUSED BY METABOLITES? • IN VITRO AND IN VIVO STUDIES
  57. 57. NON- CLINICAL SAFETY STUDIES • SAFETY PHARMACOLOGY • GENERAL TOXICITY (CNS, CV, RESPIRATORY ………) • GENOTOXICITY • CARCINOGENICITY • REPRODUCTIVE TOXICITY • LOCAL TOLERANCE SINGLE AND REPEATED-DOSE TOXICITY
  58. 58. PRE-CLINICAL GUIDELINES • ICH M3 - GUIDANCE ON NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR PHARMACEUTICALS M3(R2) • ICH S6 - PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS S6(R1) 58
  59. 59. Formulation/Dosage forms Examples: – Tablet – Cream – injection – infusion Solid Semisolid LiquidParenteral Topical Oral
  60. 60. IMPD - Investigational Medicinal Product Dossier Discovery/Preclinical development (5-7 yrs)  Target identification  Screening methods  Identification of lead compound  Lead optimisation  CD selection  CD preclinical evaluation  Formulation  Analytical methods  PK/PD, DMPK (ADME)  Toxicology / Safety evaluation  Start Dose? Good Laboratory Practice (GLP) CTA Clinical Trials Application IMPD Investigational Medicinal Product Dossier
  61. 61. CLINICAL TRIALS • APPROVAL NEEDED FROM AUTHORITIES • THE APPLICATION IS DONE BY THE SPONSOR • STUDY PROTOCOL • APPROVAL NEEDED ALSO FROM THE REGIONAL ETHICAL REVIEW BOARDS (ETIKPRÖVNINGSNÄMND (EPN)) 61
  62. 62. Phase I Phase II Phase III Clinical Trials Approval Product launched Phase IV MAA Good Clinical Practice
  63. 63. Objectives • Identify a safe dose range • Dose limiting toxicities (DLTs) • Maximum tolerated dose • Define recommended phase II dose PHASE I TRIALS - FIRST TIME IN HUMANS
  64. 64. CLINICAL DEVELOPMENT Phase I • 20-80 healthy volunteers. To determine if the compound is tolerated and to find the appropriate dose for further evaluation in phase II. Phase II • 100-300 patients. Is the compound effective in patients with the disease? and to determine the appropriate dose for phase III Phase III • Several thousands of patients. To gather information on the effectiveness. To evaluate benefit – risk.
  65. 65. CLINICAL TRIALS 65 CLINICAL TRIAL LEADER Monitor Monitor CT Site CT Site CT Site CT Site CT Site CT Site Sponso r CT Coordinat orInvestigat or Investigat or
  66. 66. Only 1 out of 10 substances that enter Clinical Trials in humans reach the market as a registered product.
  67. 67. NO. OF CLINICAL TRIALS REFERENCE: INFORMATION FRÅN LÄKEMEDELSVERKET 4:2015 ~300 CLINICAL TRIALS APPLICATIONS IN SWEDEN 2014 • PHASE I: 32 (50% ABOUT BIOLOGICAL MP) • PHASE II: 75 • PHASE III: 135-140 • PHASE IV: 50 67
  68. 68. ”EXAMPLES ON WHAT AN INVESTIGATOR AT THE SWEDISH MEDICAL PRODUCTS AGENCY LOOK FOR” REFERENCE: INFORMATION FRÅN LÄKEMEDELSVERKET 4:2015 SID 15 STATISTICIAN - STATISTIKER • ÄR STUDIEDESIGNEN ADEKVAT OCH DIMENSIONERAD FÖR ATT BESVARA STUDIENS FRÅGESTÄLLNINGAR? • HUR SKA STUDIEN UTVÄRDERAS? • •HUR HANTERAS BORTFALL AV PATIENTER? PHARMACEUTICAL INVESTIGATOR - FARMACIUTREDARE • TILLVERKAS, MÄRKS OCH HANTERAS PRÖVNINGSLÄKEMEDLET PÅ ETT SÄKERT OCH KONTROLLERAT SÄTT? • UPPFYLLER MÄRKNINGSTEXTEN KRAVEN? • ÄR LÄKEMEDLETS KEMISKA OCH FARMACEUTISKA EGENSKAPER TILLRÄCKLIGT DOKUMENTERADE? PRECLINICAL EXPERT - PREKLINIKER • FINNS STÖD FÖR STUDIENS RATIONAL INKLUSIVE DOSREGIM SAMT SÄKERHET, UTIFRÅN IN VITRO-DATA OCH RELEVANTA DJURMODELLER? • HAR POTENTIELLT KLINISKT RELEVANTA FYND I TOXSTUDIER I DJUR HANTERATS I STUDIEPROTOKOLLET? PHARMACOKINETIC INVESTIGATOR - FARMAKOKINETIKER • ÄR DOSVALET LÄMPLIGT FÖR TÄNKT STUDIEPOPULATION? • FINNS INTERAKTIONSPROBLEMATIK? • FINNS BEHOV AV DOSJUSTERING FÖR VISSA PATIENTGRUPPER • (T.EX. MED NEDSATT NJUR- OCH LEVERFUNKTION)? FINAL INVESTIGATOR - SLUTHANDLÄGGARE* • UPPFYLLER PROTOKOLLET REGULATORISKA KRAV, T.EX. GOD KLINISK SED (GCP)? • ÄR DEN ÖVERGRIPANDE BEDÖMNINGEN ATT PRÖVNINGEN ÄR GODTAGBAR ELLER EJ? CLINICAL EXPERT - KLINIKER* • STYRKER RATIONALEN BEHOVET AV STUDIEN? • ÄR STUDIEDESIGNEN OCH UTFALLSMÅTTEN LÄMPLIGA? • ÄR INKLUSIONS- OCH EXKLUSIONSKRITERIER ACCEPTABLA, DOSVALET RIMLIGT OCH METODER/ PROVER FÖR UPPFÖLJNING AV SÄKERHET RELEVANTA? • ÄR NYTTA/RISK-BALANSEN POSITIV FÖR STUDIEN? • ÄR PATIENTEN BESLUTSKOMPETENT OCH KAN FÖRSTÅ 68
  69. 69. ORGANISATION – MARKET COMPANY 69 Market Access Key Account Managers Health Economist Medical Advisor Regulatory Affairs Compliance Officers Clinical project manager Clinical Research Coordinator Data Manager Monitor (CRA)
  70. 70. MARKET AUTHORIZATION APPLICATION THE MAA FOR A NEW MEDICAL ENTITY INCLUDES SCIENTIFIC DOCUMENTATION FROM 3 MAIN AREAS: • QUALITY - (CMC DOCUMENTATION) • SAFETY (TOXICOLOGICAL - PHARMACOLOGICAL DOCUMENTATION AND CLINICAL DOCUMENTATION ) • EFFICACY (CLINICAL DOCUMENTATION) 70
  71. 71. CTD COMMON TECHNICAL DOCUMENT 71 Notice to Applicants, Volume 2B, incorporating the CTD
  72. 72. TRENDS • BIOLOGICALS • ADAPTIVE PATHWAYS ETC. • PERSONALIZED MEDICINE (PRECISION MEDICINE, STRATIFIED MEDICINE) • COMPANION DIAGNOSTICS • RE-PURPOSING • PHARMACOVIGILANS, PSUR • SME PROGRAM • PEDRIATIC INVESTIGATION PLANS • CONDITIONAL MARKETING AUTHORISATION • RISK MANAGEMANT PLANS (RMP) • PASS – PAES • ”COMPASSIONATE USE” PROGRAM • HEALTH ECONOMY 72
  73. 73. MORE TRENDS • PRIME • OUTSOURCING • VIRTUAL COMPANIES • GENERICA • RE-PURPOSING • REPEATED REORGANISATIONS • MERGERS AND ACQUISITIONS • LEAN SIX SIGMA 73
  74. 74. TRENDER FDA HTTP://WWW.FDA.GOV/FORPATIENTS/APPROVALS/FAST/D EFAULT.HTM 74
  75. 75. LIFE CYCLE MANAGEMENT Development Scientific Advice Approval Inspections Surveillance Safety updates Variations new indication Approval update
  76. 76. TACK FÖR DENNA GÅNG! 76 www.fokuspharma.se goran.lidgren@fokuspharma.se anna@bulbintelligence.com

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