2016-11-28 mentlife seminar: pharmaceutical drug development; an overall perspective
TRANSCRIPT
PHARMACEUTICAL DRUG DEVELOPMENT – AN OVERALL
PERSPECTIVEGÖRAN LIDGREN, JYNX CONSULTING ANNA RYDBECK, BULB INTELLIGENCE [email protected] [email protected]
28TH NOVEMBER 2016, LUND, SWEDEN
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
ABBREVIATIONSATC CODE ANATOMIC THERAPEUTIC CHEMICAL
CLASSIFICATION SYSTEMATMP ADVANCED THERAPY MEDICINAL PRODUCTCD CANDIDATE DRUGCFR CODE OF FEDERAL
REGULATIONS (US)CI COMPETITIVE INTELLIGENCECMC CHEMISTRY, MANUFACTURING AND
CONTROLSCMS CONCERNED MEMBER STATECP CENTRALISED PROCEDURECTA CLINICAL TRIAL APPLICATIONCTD COMMON TECHNICAL DOCUMENTDCP DECENTRALISED PROCEDUREEEA EUROPEAN ECONOMIC AREAEMA EUROPEAN MEDICINES AGENCY EFPIA EUROPEAN FED. OF PHARMACEUTICAL
INDUSTRIES ASSOC.FDA FOOD AND DRUG ADMINISTRATION (US)GCP GOOD CLINICAL PRACTICEGDP GOOD DISTRIBUTION PRACTICEGLP GOOD LABORATORY PRACTICEGVP GOOD PHARMACOVIGILANCE PRACTICESGMP GOOD MANUFACTURING PRACTICE
ICH INTERNATIONAL CONFERENCE ON HARMONISATION
IMPD (EU) INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER
IND (US) INVESTIGATIONAL NEW DRUG APPLICATION
IP INTELLECTUAL PROPERTYLIF LÄKEMEDELSINDUSTRIFÖRENINGENMAA MARKETING AUTHORISATION APPLICATIONMAH MARKETING AUTHORISATION HOLDERMPA MEDICAL PRODUCTS AGENCY (SWEDEN)MRP MUTUAL RECOGNITION PROCEDURENCE NEW CHEMICAL ENTITYNDA NEW DRUG APPLICATIONNME NEW MEDICAL ENTITYPIP PAEDIATRIC INVESTIGATION PLANPSUR PERIODIC SAFETY UPDATE REPORTR&D RESEARCH & DEVELOPMENTRMP RISK MANAGEMENT PLANRMS REFERENCE MEMBER STATE (EU)SME SMALL AND MEDIUM-SIZED ENTERPRISESSMPC (SPC) SUMMARY OF PRODUCT CHARACTERISTICSWHO WORLD HEALTH ORGANISATION
TOPICS COVERED
• INTRODUCTION TO DRUG DEVELOPMENT• THE MARKET• THE REGULATORY LANDSCAPE• PRECLINICAL (NON-CLINICAL) DEVELOPMENT• CLINICAL DEVELOPMENT• REGULATORY AFFAIRS• TRENDS• LIFE CYCLE MANAGEMENT
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)
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DRUG DEVELOPMENT
Series10
20
40
60
80
100
10 - 15 yrs
Kno
wle
dge
Saf
ety,
Tox
, Pha
rmac
olog
y in
vitr
o an
d in
viv
o
Chem
istry
, bio
chem
istry
phas
e I
phas
e I
I
phas
e II
I
phas
e IV
Clin
ical
Tria
ls A
pplic
atio
n
Applications & Authorities
Mar
ketin
g Au
thor
isatio
n Ap
plica
tion
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
FROM MOLECULE TO FINISHED PRODUCT ON THE MARKET
IP Patents, Law
The TeamMarket
Pre-Clinical
Health Economics Manufacturing
Regulatory Affairs
Statistics - data management
Clinical
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
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)
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 = BIOLOGICALBLACK = SMALL MOLECULE
TOP 10 PHARMACEUTICAL COMPANIES 2016
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-SJ
UKVARDEN-FAKTA-20141/LAKEMEDELSMARKNADEN/
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
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
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
AUTHORITIES• EU
EMA (EUROPEAN MEDICINES AGENCY)NATIONAL AUTHORITIES E.G. LÄKEMEDELSVERKET (MEDICAL PRODUCTS AGENCY)
• USAFDA (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
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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)
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ORPHAN DRUGS (OMP) – SÄRLÄKEMEDELORPHAN 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.
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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.
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
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
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QUALITY
EFFICACY
SAFETY
RISK BENEFITS
PHARMACEUTICAL DRUG DEVELOPMENT KEY ELEMENTS
QUALITY (GXP)
GLP - Good Laboratory PracticeGmP - Good Manufacturing PracticeGCP - Good Clinical PracticeGdp – good distribution practice
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
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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
Molecular biology of disease process understood
Target identification
Chemistry
In vitroScreens
Safety studies Animal modelsPK/PD, Toxicology
Clinical Trials
Market
RISK?
RISK?
År
No. compounds
3
10 000 10-15
9 11 13 15 19 211
1-8
DEVELOPMENT
Clinical TrialsOptimisation of
leadIdentify targetand lead compound Proof of Concept
Product Life Cycle Support
Sales and marketingRegulatory Affairs
Process chemistry and large scale manufacturing
Pharmaceutics and analytical chemistrySafety, Toxicology and Pk/Pd studies (ADME)
1-3
DISCOVERY
Medicinal chemistry and Biology
1 2
PATENTS CTAMAA
CD
5 7
3 4 post-market
INTELLECTUAL PROPERTY & COMPETITIVE INTELLIGENCE
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
WHAT CAN BE PATENTED?Must be:Novel: not previously known or used by othersUseful: have a known use or produce a concrete and tangible resultNon-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:IdeaLaw of NatureScientific Principle
WHAT ARE THE PARTS OF A PATENT?
AbstractBackground of the Invention Summary of the InventionFigures with brief descriptionsDetailed description or “specification”Fully discloses what the invention isHow it is made?How it can be used?Claim(s): sets the legal boundaries of protection
DISCLOSURE INITIALPUBLICATION
RE-EVALUATION RE-EVALUATIONRE-EVALUATION
Overview of Pathway to Commercialization
FILE PROVISIONAL APPLICATION (~$10k)
EVALUATION
3 MONTHS
FILE PCT(~$25K)
PCTPUBLICATION
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, FURTHERCOMMERCIALIZATION
Evaluation: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 patent? Is there a market for said product?
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
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
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Competitive Intelligence
Examples
Activity in CIWHY?
• Investigation of active researchers Establish crucial collaborations
• Novelty search File patent application
• Freedom to OperatePatent/publish in FTO area
• Pipeline summaryIdentify competitors
• Market surveillance Find new market opportunities
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Competitive Intelligence
Sources of Information
• Soft informationConferences, 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
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
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Competitive Intelligence sources literature
Embase Medline
30 75 0
• No need to access all literature• Choose only relevant literature
36 million records16 000 journals28 million
records8 400 journals
21 million records5 600 journals
5 500 journals
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 searchMarket 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 searchPatent landscape search Indication search Indication search
Patent watch
Legal status watch
Chemical structure search MARKUSH searchChemical structure search
Bio sequence search Bio sequence search Bio sequence search
Case study 1Pharma 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
Product Profilewill 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
TPP - TARGET PRODUCT PROFILEBEGINNING WITH THE GOAL IN MIND
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
MEDICINAL CHEMISTRY (SMALL MOLECULES)
HIT to leadLead generationLead optimisationDrug design (chemical libraries, pharmacophore ……)Patents !Candidate drug (CD) selection
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• 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
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)
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.
Lead optimisation
Candidate preclinical evaluation
ClinicalEvaluation
Candidate drug (CD) selection CTA
Discovery
Development
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)
ADME
ABSORPTIONdistribution metabolism Excretion
QUESTIONS TO ANSWERBEFORE 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
NON- CLINICAL SAFETY STUDIES
Safety PharmacologyGeneral Toxicity (CNS, CV, respiratory ………)GenotoxicityCarcinogenicityReproductive ToxicityLocal Tolerance
Single and Repeated-Dose Toxicity
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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)
Formulation/Dosage formsExamples:
– Tablet
– Cream
– injection– infusion
Solid
Semisolid
LiquidParenteral
Topical
Oral
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)
CTAClinical Trials Application
IMPD Investigational Medicinal Product Dossier
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))
Phase I Phase II Phase III
Clinical Trials
ApprovalProduct launched
Phase IV
MAA
Good Clinical Practice
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
CLINICAL DEVELOPMENTPhase 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.
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CLINICAL TRIALS
CLINICAL TRIAL LEADER
Monitor Monitor
CT Site CT Site CT Site CT Site CT Site CT Site
Sponsor
CTCoordinat
orInvestigator
Investigator
Only 1 out of 10 substances that enter Clinical Trials in humans reach the market as a registered product.
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NO. OF CLINICAL TRIALSREFERENCE: 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
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”EXAMPLES ON WHAT AN INVESTIGATOR AT THE SWEDISH MEDICAL PRODUCTS AGENCY LOOK
FOR” REFERENCE: INFORMATION FRÅN LÄKEMEDELSVERKET
4:2015 SID 15STATISTICIAN - 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 PATIENTINFORMATIONEN?
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ORGANISATION – MARKET COMPANY
Market AccessKey Account ManagersHealth Economist
Medical AdvisorRegulatory AffairsCompliance Officers
Clinical project managerClinical Research CoordinatorData ManagerMonitor (CRA)
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)
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CTD COMMON TECHNICAL DOCUMENT
Notice to Applicants, Volume 2B, incorporating the CTD
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