This seminar provided an understanding of modern pharmaceutical drug development – the different phases of drug development and insight into different jobs.
2016-11-28 Mentlife seminar: Pharmaceutical Drug Development; An Overall Perspective
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. 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. 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. TOPICS COVERED
• INTRODUCTION TO DRUG DEVELOPMENT
• THE MARKET
• THE REGULATORY LANDSCAPE
• PRECLINICAL (NON-CLINICAL) DEVELOPMENT
• CLINICAL DEVELOPMENT
• REGULATORY AFFAIRS
• TRENDS
• LIFE CYCLE MANAGEMENT
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)
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. 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. 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. 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)
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. 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
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. 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
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. 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. 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. 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. 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
26. QUALITY (GXP)
• GLP - GOOD LABORATORY PRACTICE
• GMP - GOOD MANUFACTURING
PRACTICE
• GCP - GOOD CLINICAL PRACTICE
• GDP – GOOD DISTRIBUTION PRACTICE
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. 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. Molecular biology
of disease process
understood
Target identification
Chemistry
In vitro
Screens
Safety
studies
Animal
models
PK/PD,
Toxicology
Clinical Trials
Market
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
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. 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. 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. 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. 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. 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. 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. 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. • 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
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. 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. 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. 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. TPP - TARGET PRODUCT PROFILE
BEGINNING WITH THE GOAL IN
MIND
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. MEDICINAL CHEMISTRY (SMALL MOLECULES)
• HIT TO LEAD
• LEAD GENERATION
• LEAD OPTIMISATION
• DRUG DESIGN (CHEMICAL LIBRARIES, PHARMACOPHORE
……)
• PATENTS !
• CANDIDATE DRUG (CD) SELECTION
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. 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. 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.
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)
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. NON- CLINICAL SAFETY STUDIES
• SAFETY PHARMACOLOGY
• GENERAL TOXICITY (CNS, CV, RESPIRATORY ………)
• GENOTOXICITY
• CARCINOGENICITY
• REPRODUCTIVE TOXICITY
• LOCAL TOLERANCE
SINGLE AND REPEATED-DOSE TOXICITY
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
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. 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. Phase I Phase II Phase III
Clinical Trials
Approval
Product launched
Phase IV
MAA
Good Clinical
Practice
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. 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.
66. Only 1 out of 10 substances that enter
Clinical Trials in humans reach the
market as a registered product.
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. ”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. 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. 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
