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A view on the process from the idea to the registered pharmaceutical
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
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Organisation of the presentation
I. DISCOVERY Identification of target and resource
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Organisation of the presentation
II. HIT GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Organisation of the presentation
III. LEAD GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Organisation of the presentation
IV. CLINICAL DEVELOPMENT Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Organisation of the presentation
V. POST REGISTRATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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I. DISCOVERY Identification of target and resource
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Target identification - Area of interest in terms of drug indication ?
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 ?
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Resource identification Potential resources for novel drugs:
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
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Resource identification - Alpinia Institute
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.
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Resource identification - Alpinia Institute
I. DISCOVERY Resource identification - Alpinia Institute Natural organisms, in particular plants - 52% of the drugs approved in the U.S. from were natural products or derived from them (2). - 26 plant based drugs were approved during , including novel-molecular based drugs (3). - In the future multicomponent botanical therapeutics will experience an increasing interest in biomedicine (4). Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs (1) 2) Newman, J Nat Pr ) Saklani & Kutty, Drug Disc Today ) Schmidt et al., Nature Chem Biol 2007.
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Method of drug discovery - Alpinia Institute Ethnobotanical approach
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
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II. HIT GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Process development – in phytopharmacy
II. HIT GENERATION A) RESEARCH AND DEVELOPMENT Process development – in phytopharmacy Herbal raw material Extraction solvent Extraction Miscella (Liquid raw extract) Encapsulatable mass Dry extract Liquid extract, tincture Soft capsules Liquids, drops, ointments Tablets, hard capsules
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Development of the test substance
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
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Availability of raw materials, excipients, consumables
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
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Identity test, controls Monographs in pharmacopoeias for:
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
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Two standard analytical methods in phytopharmacy:
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
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Common Technical Document:
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) Module 1: Information Module 2: Summaries Module 3: Quality Module 4: Non clinical study reports Module 5: Clinical study reports Structure of the CTD *ICH: International conference for harmonisation of technical requirements for registration of pharmaceuticals for human use.
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Prepare Module 3: Quality
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
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Preclinical development In vitro profiling:
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
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Working with 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. Medium for cell cultures is pipetted into a culture flask. Changes of the cultivated cells are evaluated under the micro-scope after the addition of a test substance. Cultivation of cell cultures in petri-dishes or cell plates with the addition of test substances.
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III. LEAD GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Preclinical development In vivo testing Animal model (mouse or rat)
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)
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Preclinical development (continued)
III. LEAD GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development (continued) Pharmacokinetic studies What does the body to the drug ? Investigate: - Liberation - Absorption - Distribution - Metabolism - Excretion Pharmacodynamic studies What does the drug to the body ? Investigate: - Physiological effects - Drug action - Relationship between drug concentration and effect
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Preclinical development (continued) Patent policy
III. LEAD GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development (continued) Patent policy Explore the related patent environment: Develop a patent strategy: Database of the European Patent Office (espacencet) Rationale Possibilities - Desired strength - Costs
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Scaling up from laboratory to production size GMP and GLP environments
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
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Continue Module 3: Quality
III. LEAD GENERATION C) MARKETING AUTHORISATION PROCESS CTD documentation Continue Module 3: Quality Prepare Module 4: Non clinical study reports Validation report Stability report Manufacturing protocol Development report (on going) Module 1: Information Module 2: Summaries Module 3: Quality Module 4: Non clinical study reports Module 5: Clinical study reports
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IV. CLINICAL DEVELOPMENT
Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Clinical development – “Linking bench to bedside”
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).
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Clinical development – “Linking bench to bedside”
IV. CLINICAL DEVELOPMENT A) RESEARCH AND DEVELOPMENT Clinical development – “Linking bench to bedside” Phase I studies 20 to 30 healthy volunteers Investigate: - Safety and tolerability - Pharmacokinetics - Pharmacodynamics Treatment groups toxic therapeutic subtherapeutic Dosage (mg) Example: Dose titration - first application in humans
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Clinical development – “Linking bench to bedside” (continued)
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.
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Clinical development – “Linking bench to bedside” (continued)
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.
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Production - Provide appropriate sample quantities (Phase I, II, III)
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
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1: Administrative information 2: CTD summaries
IV. CLINICAL DEVELOPMENT C) MARKETING AUTHORISATION PROCESS CTD documentation - Prepare Modules: 1: Administrative information 2: CTD summaries 5: Clinical study reports - Compile the whole CTD Regulatory Authorities - Submit the completed CTD - File a New Drug Application with EMEA (Europe) or FDA (USA) Module 1: Information Module 2: Summaries Module 3: Quality Module 4: Non clinical study reports Module 5: Clinical study reports
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V. POST REGISTRATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation
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Clinical development after marketing
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
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Production and quality control
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
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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
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Thank you for your attention !
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