DRUG DEVELOPMENT
A view on the process from the idea to the registered
pharmaceutical
Dr. Matthias Kreuter
Head of Alpinia Laudanum Institute of Phytopharmaceutical Sciences AG
Walenstadt, Switzerland
Organisation of the presentation
I. DISCOVERY
Identification of target and resource
Organisation of the presentation
II. HIT GENERATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
Organisation of the presentation
III. LEAD GENERATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
Organisation of the presentation
IV. CLINICAL DEVELOPMENT
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
Organisation of the presentation
V. POST REGISTRATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
I. DISCOVERY
Identification of target and resource
I. DISCOVERY
Target identification
- Area of interest in terms of drug indication ?
- Relevant cellular or molecular targets ?
- Appropriate assays – established or to be developed ?
- Available relevant literature ?
- Patent situation in the target area ?
I. DISCOVERY
Resource identification
Potential resources for novel drugs:
- Natural organisms (plants, fungi, bacteria, animals)
- Combinatorial chemistry
- Structure-based drug design
Methods for drug discovery:
- High throughput screening of random samples (HTS):
Including screen development, primary and secondary screening
- Ethnobiological approach:
Traditional use of natural organisms for medicines
I. DISCOVERY
Resource identification - Alpinia Institute
Natural organisms, in particular plants
Medicinal plants continue to play a significant role
as a resource for the discovery of novel drugs (1)
1) Balunas and Koinghorn, Life Sci 2005.
I. DISCOVERY
Resource identification - Alpinia Institute
Natural organisms, in particular plants
Medicinal plants continue to play a significant role
as a resource for the discovery of novel drugs (1)
- 52% of the drugs approved in the U.S. from 1981-2002
were natural products or derived from them (2).
- 26 plant based drugs were approved during 2000-2006,
including novel-molecular based drugs (3).
- In the future multicomponent botanical therapeutics will
experience an increasing interest in biomedicine (4).
2) Newman, J Nat Pr 2002. 3) Saklani & Kutty, Drug Disc Today 2008. 4) Schmidt et al., Nature Chem Biol 2007.
I. DISCOVERY
Method of drug discovery - Alpinia Institute
Ethnobotanical approach
Systematic screening of:
- Published literature on traditional medicinal plant use
(e.g. documented traditional healers‘ experience)
- Historical texts
(e.g. ancient botanico-medicinal manuscripts)
Advantages:
- Preselection of potentially active resources
- Promising safety profile (age-long experience)
- Cost-efficient and comparatively fast
II. HIT GENERATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT
Process development – in phytopharmacy
Herbal raw material
Extraction solvent
Extraction
Miscella (Liquid raw extract)
Dry extract
Tablets,
hard capsules
Liquid extract, tincture
Liquids, drops,
ointments
Encapsulatable mass
Soft capsules
II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT
Development of the test substance
Define:
- Active substance (in phytopharmacy: native extract)
- Dosage form
Establish:
- Physico-chemical profile (active compounds, marker)
Investigate:
- Pharmacology
- Mode of action
Prepare:
- Patent draft
II. HIT GENERATION
B) QUALITY CONTROL AND PRODUCTION
Raw material supply
Availability of raw materials, excipients, consumables
Herbal raw material
- Established market product ?
- Contract cultivation ?
- Wild harvesting ?
Pay attention to:
- Continuous availability
- Quality variations
- Sustainable cultivation / harvesting
- Biodiversity regulations
- Existing patent and intellectual property rights
II. HIT GENERATION
B) QUALITY CONTROL AND PRODUCTION
Identity test, controls
Monographs in pharmacopoeias for:
- Chemical substances
- Herbal raw materials
Organisation of a monograph
Definition:
chemical characterisation
Characters:
appearance, solubility
Identification:
microscopy, physico-chemical tests
Tests:
qualitative analysis
Assay:
quantitative analysis
Impurities:
chemical or microbiological impurities
II. HIT GENERATION
B) QUALITY CONTROL AND PRODUCTION
In house controls
Two standard analytical methods in phytopharmacy:
- TLC = Thin layer chromatography
- HPLC = High performance liquid chromatography
DAD-CH1 218 nm
CN002.E12.C01 control
Retenti on T i m e
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II. HIT GENERATION
C) MARKETING AUTHORISATION PROCESS
CTD documentation
Common Technical Document:
Harmonised format for applications for
preparing marketing authorisation in the
three ICH* regions (Europe, Japan, USA)
*ICH: International conference
for harmonisation of technical
requirements for registration of
pharmaceuticals for human use.
Structure of the CTD
Module 1:
Information
Module 2:
Summaries
Module 3:
Quality
Module 4:
Non clinical
study reports
Module 5:
Clinical
study reports
II. HIT GENERATION
C) MARKETING AUTHORISATION PROCESS
CTD documentation
Prepare Module 3: Quality
- Monograph
- Specification
- Development report (on going)
Module 1:
Information
Module 2:
Summaries
Module 3:
Quality
Module 4:
Non clinical
study reports
Module 5:
Clinical
study reports
II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT
Preclinical development
In vitro profiling:
- Biochemical assays (e.g. enzyme activity assays)
- Cell culture assays (e.g. cancer cell lines)
- Isolated tissue assays (e.g. mucosa model)
In vitro toxicology:
Investigate potential toxic effects
in bacteria- or cell cultures
II. HIT GENERATION
A) RESEARCH AND DEVELOPMENT
Working with cell cultures
Cells are kept in liquid nitrogen.
Medium and culture flasks for cell
cultures.
Changes of the cultivated cells
are evaluated under the microscope after the addition of a test
substance.
Cultivation of cell cultures in
petri-dishes or cell plates with
the addition of test substances.
Medium for cell cultures is
pipetted into a culture flask.
III. LEAD GENERATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
III. LEAD GENERATION
A) RESEARCH AND DEVELOPMENT
Preclinical development
In vivo testing
Animal model (mouse or rat)
Drug action:
- Behaviour and reaction
- Physiology
- Histopathology
Toxicology:
- Acute toxicity
- Subchronic toxicity
- Tissue specific toxicity
- Tolerability
Consider ethical aspects (e.g. number and kind of animals used)
III. LEAD GENERATION
A) RESEARCH AND DEVELOPMENT
Preclinical development (continued)
Pharmacokinetic studies
Investigate:
- Liberation
- Absorption
- Distribution
- Metabolism
- Excretion
What does the body to the drug ?
Pharmacodynamic studies
What does the drug to the body ?
Investigate:
- Physiological effects
- Drug action
- Relationship between drug concentration and effect
III. LEAD GENERATION
A) RESEARCH AND DEVELOPMENT
Preclinical development (continued)
Patent policy
Explore the related patent environment:
Database of the European Patent Office (espacencet)
Develop a patent strategy:
- Rationale
- Possibilities
- Desired strength
- Costs
III. LEAD GENERATION
B) QUALITY CONTROL AND PRODUCTION
Scaling up
Scaling up from laboratory to production size
GMP and GLP environments
Validation
Conduct a process validation including various batch sizes
Stability testing
Conduct a stability test under different conditions of temperature, humidity
and exposure time
III. LEAD GENERATION
C) MARKETING AUTHORISATION PROCESS
CTD documentation
Continue Module 3: Quality
- Validation report
- Stability report
- Manufacturing protocol
- Development report (on going)
Module 1:
Information
Module 2:
Summaries
Prepare Module 4: Non clinical
study reports
Module 3:
Quality
Module 4:
Non clinical
study reports
Module 5:
Clinical
study reports
IV. CLINICAL DEVELOPMENT
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
IV. CLINICAL DEVELOPMENT
A) RESEARCH AND DEVELOPMENT
Clinical development – “Linking bench to bedside”
Clinical drug studies – Research in humans
Subject to ethical concern:
- Qualify to increase existing knowledge
- Respect freedom of decision of volunteers
- Involve a substantiated risk-benefit assessment
The realisation of a clinical drug study has to be approved by an
Independent Ethics Commitee (IEC).
IV. CLINICAL DEVELOPMENT
A) RESEARCH AND DEVELOPMENT
Clinical development – “Linking bench to bedside”
Phase I studies
20 to 30 healthy volunteers
Investigate:
Example:
Dose titration - first application in humans
- Safety and tolerability
- Pharmacokinetics
- Pharmacodynamics
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Treatment groups
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IV. CLINICAL DEVELOPMENT
A) RESEARCH AND DEVELOPMENT
Clinical development – “Linking bench to bedside” (continued)
Phase II studies
100 to 500 patient volunteers
Investigate:
- Safety and tolerability
- Pharmacokinetics
- Pharmacodynamics
- Efficiency
- Dosage to effect relationship
Study design:
- Dosage comparison
Antitumor drugs: Combination of Phase I and II at an early stage of drug
development is possible.
IV. CLINICAL DEVELOPMENT
A) RESEARCH AND DEVELOPMENT
Clinical development – “Linking bench to bedside” (continued)
Phase III studies:
Up to 1000 or more patient volunteers
Monitor reaction to long term drug use.
Study design:
- Comparison to placebo or to standard therapy
- Multicentre and multinational trials
Overall aim of Phase III: Risk-benefit evaluation
Phase III studies are “pivotal studies” = outcome is crucial for the decision
taking of the regulatory authorities.
IV. CLINICAL DEVELOPMENT
B) QUALITY CONTROL AND PRODUCTION
Clinical samples
Production
- Provide appropriate sample quantities (Phase I, II, III)
- Define sample shipment logistics
Quality control
- Prepare complete batch release documentation
- Define short and long term storage of samples
GMP and GLP environments
IV. CLINICAL DEVELOPMENT
C) MARKETING AUTHORISATION PROCESS
CTD documentation
- Prepare Modules:
1: Administrative information
2: CTD summaries
5: Clinical study reports
Module 1:
Information
Module 2:
Summaries
- Compile the whole CTD
Module 3:
Quality
Regulatory Authorities
Module 4:
Non clinical
study reports
Module 5:
Clinical
study reports
- Submit the completed CTD
- File a New Drug Application with EMEA (Europe) or FDA (USA)
V. POST REGISTRATION
Perspectives:
A) Research and Development
B) Quality Control and Production
C) Marketing Authorisation
V. POST REGISTRATION
A) RESEARCH AND DEVELOPMENT
Clinical development after marketing
Phase IV studies
Post marketing testing
Investigate specific questions within the frame of the approved indication:
- Expanded benefit-risk-profile
- Combination with other drugs
- Optimization (e.g. dosage, application)
E.g.: The worldwide use of the approved drug might lead to the occurrence of
very rare side effects.
Reason for expanded epidemiologic studies
V. POST REGISTRATION
B) PRODUCTION & QC / C) MARKETING AUTHORISATION
Production and quality control
Manufacture
- Manufacturing of the product
- Controls acc. to the established batch release process
GMP and GLP environments
Marketing authorisation process
Approval
- Drug is approved for marketing by the Authorities
Summary
I. DISCOVERY
Identify target and resource
II. HIT GENERATION
Develop process and test substance
Conduct in vitro testing
III. LEAD GENERATION
Conduct in vivo testing
Pharmacokinetic and pharmacodynamic studies
IV. CLINICAL DEVELOPMENT
Human trials – Phase I, II, III
V. POST REGISTRATION
Human trials – Phase IV
Thank you for your attention !