Transcript Pharmaceutical drug development * an overall perspective

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PHARMACEUTICAL DRUG DEVELOPMENT –
AN OVERALL PERSPECTIVE
GÖRAN LIDGREN, JYNX CONSULTING
[email protected]
ANNA RYDBECK, BULB INTELLIGENCE
[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
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
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)
Knowledge
80
60
40
20
Applications & Authorities
phase IV
Marketing Authorisation Application
phase III
phase I I
phase I
Clinical Trials Application
Safety, Tox, Pharmacology
in vitro and in vivo
Chemistry, biochemistry
DRUG DEVELOPMENT
100
0
10 - 15 yrs
6
IMPD / IND
Patent
Applications
1
3
5
DISCOVERY
MAA / NDA
7
9
11
13
15
19
Years
DEVELOPMENT
Identification of target
and lead compound
Proof of Concept
Product life cycle support
launch
Clinical Trials
2
1
3
4
Medicinal Chemistry
Pharmacology / biology
Safety studies and PK/PD (ADMET)
Pharmaceutical and analytical development
Process development and Manufacturing
Regulatory Affairs
Sales marketing
No compounds
10 000
21
10-15
1-8
1-3
CD Selection
KNOWLEDGE
FROM MOLECULE TO FINISHED PRODUCT ON THE MARKET
Clinical
Pre-Clinical
Statistics - data
management
IP Patents, Law
The Team
Market
Regulatory Affairs
Health Economics
Manufacturing
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)
10. DERMATOLOGICS (28)
2.
ANTIDIABETICS (64)
11. ANTICOAGULANTS (27)
3.
PAIN (60)
12. GI PRODUCTS (25)
4.
ANTIHYPERTENSIVES, PLAIN & COM (48)
13. ANTI-ULCERANTS (25)
5.
ANTIBACTERIALS (40)
14. HIV ANTIVIRALS (23)
6.
RESPIRATORY AGENTS (40)
15. OTHER CARDIOVASCULARS (23)
7.
MENTAL HEALTH (39)
16. NERVOUS SYSTEM DISORDERS (22)
8.
AUTOIMMUNE DISEASES (36)
17. OTHER CNS (20)
9.
LIPID REGULATORS (28)
18. VIRAL HEPATITIS (18)
TOP DRUGS BY GLOBAL SALES 2015
1. HUMIRA (RHEUMATIC ARTHRITIS, ABBVIE)
9. REVLIMID (ONCOLOGY, CELGENE)
2. HARVONI (HEPATITIS C, GILEAD)
10. SOVALDI (HEPATITIS C, GILEAD)
3. ENBREL (RHEUMATIC ARTHRITIS, AMGEN)
11. SERETIDE, ADVAIR (ASTHMA, COL, GSK)
4. REMICADE (RHEUMATIC ARTHRITIS, CROHNS, JOHNSON&JOHNSON) 12. CRESTOR (CARDIOVASCULAR, ASTRAZENECA)
5. MABTHERA, RITUXAN (ONCOLOGY, ROCHE)
6. LANTUS (DIABETES, SANOFI)
RED = BIOLOGICAL
7. AVASTIN (ONCOLOGY, ROCHE)
BLACK = SMALL MOLECULE
8. HERCEPTIN (ONCOLOGY, ROCHE)
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-SJUKVARDENFAKTA-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
• OREXO
• FRESENIUS KABI
• MEDIVIR
• OCTAPHARMA
• FERRING (POLYPEPTIDES)
• SOBI
• GALDERMA
• RECIPHARM
• CCS
• MEDA
• QPHARMA
• CAMBREX
• ALLIGATOR BIOSCIENCE
• APL
• BIOINVENT
• PFIZER
• BAXTER
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)
•
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
LÄKEMEDELSVERKET
HTTPS://LAKEMEDELSVERKET.SE
18
ICH
WWW.ICH.ORG
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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) – 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.
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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.
22
• 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
PHARMACEUTICAL DRUG DEVELOPMENT
KEY ELEMENTS
SAFETY
EFFICACY
RISK
BENEFITS
QUALITY
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QUALITY (GXP)
• GLP - GOOD LABORATORY PRACTICE
• GMP - GOOD MANUFACTURING PRACTICE
• GCP - GOOD CLINICAL PRACTICE
• GDP – 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
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
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Market
Clinical Trials
Safety studies
Animal models
PK/PD,
Toxicology
In vitro
Screens
Chemistry
Target identification
Molecular biology
of disease process
understood
RISK?
RISK?
DEVELOPMENT
DISCOVERY
1
År
3
PATENTS
5
CD
7
9
11
13
15
MAA
Clinical Trials
1
2
3
4 post-market
Proof of Concept
Medicinal chemistry and Biology
Safety, Toxicology and Pk/Pd studies (ADME)
Pharmaceutics and analytical chemistry
Process chemistry and large scale manufacturing
Regulatory Affairs
Sales and marketing
No. compounds
10 000
10-15
1-8
1-3
21
Product Life Cycle Support
CTA
Optimisation of
Identify target
and lead compound lead
19
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 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
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
Overview of Pathway to Commercialization
FILE PROVISIONAL
FILE PCT
(~$25K)
APPLICATION (~$10k)
EVALUATION
3 MONTHS
Evaluation:
Can this invention be
patented?
Is there any prior
art? Is this
invention new,
useful, & nonobvious?
Is it worthwhile to
patent this invention?
What product
could come from
this patent? Is
there a market
for said product?
DISCLOSURE
12 MONTHS
6 MONTHS
RE-EVALUATION
ADDITIONAL PUBLICATIONS W/
INTERESTING ANIMAL DATA,
PROTOTYPING, FURTHER
COMMERCIALIZATION
PATENTABILITY &
MARKETING EVALUATION
MARKETING/SEARCH FOR LICENSEE
GENERATE NCD
ENTER NATIONAL PHASE
& PROSECUTION (~$20k)
12 MONTHS
RARELY GET
THIS FAR
W/O LICENSEE
8 MONTHS
INITIAL
PUBLICATION
PCT
PUBLICATION
RE-EVALUATION
RE-EVALUATION
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
Executive Management
Development projects
Corporate Development
Focus groups and sourcing units
Investor Relations
DRU, BRU
(early projects)
Competitive
Intelligence
Commercial planning
Regulatory Affairs
Brand teams
Device R&D
Major Affiliates
Competitive Intelligence in Life Sciences
20 May
2015
Competitive Intelligence
Examples
40
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
Competitive Intelligence
Sources of Information
41
• 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
PATENT DOCUMENTS REPRESENT A VALUABLE
SOURCE OF TECHNICAL INFORMATION
• 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)
Competitive Intelligence
sources literature
36 million records
16 000 journals
Embase
28 million records
8 400 journals
30
Medline
75
0
5 500 journals
21 million records
5 600 journals
• No need to access all literature
• Choose only relevant literature
43
Literature
Patent
Pipeline
Clinical trials
Regulatory
Market
Literature alerts
Novelty search
Competitor search
Competitor search
Alliances search
KOL search
Validity search
MoA search
MoA search
Application search
Market authorisation
search
Citation search
Infringment search
Target search
Target search
Pediatric approval search Sales search
Substance search
Substance search
SPC search
Pharmacovigilance search FTO 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
R&D Investments search
Epidemiology search
Stop
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.
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
TPP - TARGET PRODUCT PROFILE
BEGINNING WITH THE GOAL IN MIND
MOLECULAR TARGETS
• 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
MEDICINAL CHEMISTRY (SMALL MOLECULES)
• HIT TO LEAD
• LEAD GENERATION
• LEAD OPTIMISATION
• DRUG DESIGN (CHEMICAL LIBRARIES, PHARMACOPHORE ……)
• PATENTS !
• CANDIDATE DRUG (CD) SELECTION
BIOLOGICS - DIFFERENCES WITH SMALL MOLECULES
•
•
•
•
•
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
50
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.
Discovery
Development
Lead
optimisation
Candidate preclinical
evaluation
Candidate drug
(CD) selection
Clinical
Evaluation
CTA
PHARMACOKINETICS AND
PHARMACODYNAMICS (PK/PD)
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
ADME
• ABSORPTION
• DISTRIBUTION
• METABOLISM
• EXCRETION
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
NON- CLINICAL SAFETY STUDIES
• SAFETY PHARMACOLOGY
• GENERAL TOXICITY (CNS, CV, RESPIRATORY ………)
• GENOTOXICITY
• CARCINOGENICITY
• REPRODUCTIVE TOXICITY
• LOCAL TOLERANCE
SINGLE AND REPEATED-DOSE TOXICITY
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
Formulation/Dosage forms
Examples:
–
Tablet
Oral
Solid
–
Cream
Topical
Semisolid
–
injection
infusion
Parenteral
Liquid
–
IMPD - Investigational Medicinal Product Dossier
Discovery/Preclinical development (5-7 yrs)
 Target identification
 Screening methods
 Identification of lead compound
 Lead optimisation
 CD selection
IMPD Investigational Medicinal Product Dossier
 CD preclinical evaluation





Formulation
Analytical methods
PK/PD, DMPK (ADME)
Toxicology / Safety evaluation
Start Dose?
Good Laboratory Practice (GLP)
CTA
Clinical Trials
Application
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
Clinical Trials
Good Clinical Practice
Phase I
Phase II
Phase IV
Phase III
MAA
Approval
Product launched
PHASE I TRIALS - FIRST TIME IN HUMANS
Objectives
•
•
•
•
Identify a safe dose range
Dose limiting toxicities (DLTs)
Maximum tolerated dose
Define recommended phase II dose
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.
CLINICAL TRIALS
Sponsor
CLINICAL TRIAL
LEADER
Monitor
Monitor
CT
Coordinator
Investigator
CT Site
CT Site
CT Site
Investigator
CT Site
CT Site
CT Site
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Only 1 out of 10 substances that enter Clinical
Trials in humans reach the market as a registered
product.
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
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”EXAMPLES ON WHAT AN INVESTIGATOR AT THE SWEDISH
MEDICAL PRODUCTS AGENCY LOOK FOR”
REFERENCE: INFORMATION FRÅN LÄKEMEDELSVERKET 4:2015 SID 15
STATISTICIAN - STATISTIKER
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)?
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?
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?
PRECLINICAL EXPERT - PREKLINIKER
•
ÄR STUDIEDESIGNEN OCH UTFALLSMÅTTEN LÄMPLIGA?
•
FINNS STÖD FÖR STUDIENS RATIONAL INKLUSIVE DOSREGIM SAMT SÄKERHET,
UTIFRÅN IN VITRO-DATA OCH RELEVANTA DJURMODELLER?
•
ÄR INKLUSIONS- OCH EXKLUSIONSKRITERIER ACCEPTABLA, DOSVALET RIMLIGT OCH
METODER/ PROVER FÖR UPPFÖLJNING AV SÄKERHET RELEVANTA?
•
HAR POTENTIELLT KLINISKT RELEVANTA FYND I TOXSTUDIER I DJUR HANTERATS I
STUDIEPROTOKOLLET?
•
ÄR NYTTA/RISK-BALANSEN POSITIV FÖR STUDIEN?
•
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ÄR PATIENTEN BESLUTSKOMPETENT OCH KAN FÖRSTÅ PATIENTINFORMATIONEN?
ORGANISATION – MARKET COMPANY
Market Access
Key Account Managers
Health Economist
Clinical project
manager
Clinical Research
Coordinator
Data Manager
Medical Advisor
Regulatory Affairs
Compliance Officers
Monitor (CRA)
69
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
CTD COMMON TECHNICAL DOCUMENT
Notice to Applicants, Volume 2B, incorporating the CTD
71
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
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MORE TRENDS
• PRIME
• OUTSOURCING
• VIRTUAL COMPANIES
• GENERICA
• RE-PURPOSING
• REPEATED REORGANISATIONS
• MERGERS AND ACQUISITIONS
• LEAN SIX SIGMA
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TRENDER FDA
HTTP://WWW.FDA.GOV/FORPATIENTS/APPROVALS/FAST/DEFAULT.
HTM
74
LIFE CYCLE MANAGEMENT
Development
Approval
update
Scientific
Advice
Variations
new indication
Approval
Safety
updates
Inspections
Surveillance
TACK FÖR DENNA GÅNG!
www.fokuspharma.se
[email protected]
[email protected]
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