DRUG DEVELOPMENT

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

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.Combinatorial chemistry . primary and secondary screening .Ethnobiological approach: Traditional use of natural organisms for medicines .Structure-based drug design Methods for drug discovery: .Natural organisms (plants. animals) . bacteria. fungi. DISCOVERY Resource identification Potential resources for novel drugs: .High throughput screening of random samples (HTS): Including screen development.

Life Sci 2005.Alpinia Institute Natural organisms. DISCOVERY Resource identification . . 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.I.

In the future multicomponent botanical therapeutics will experience an increasing 2) Newman.I. . Drug Disc Today 2008. J Nat Pr 2002. in particular plants Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs (1) . were natural products or derived from .26 plant based drugs were approved during 20002006.52% of the drugs approved in the U.S. from 19812002 them (2). 3) Saklani & Kutty. including novel-molecular based drugs (3). DISCOVERY Resource identification . . interest biomedicine (4). 4) Schmidt et al.Alpinia Institute Natural organisms. Nature Chemin Biol 2007..

Preselection of potentially active resources .Historical texts (e. documented traditional healers‘ experience) .Alpinia Institute Ethnobotanical approach Systematic screening of: . DISCOVERY Method of drug discovery . ancient botanico-medicinal manuscripts) Advantages: .Published literature on traditional medicinal plant use (e.Promising safety profile (age-long experience) .g.g.I.Cost-efficient and comparatively fast .

II. HIT GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation .

hard capsules Liquid extract. drops. ointments Encapsulatable mass Soft capsules .II. tincture Liquids. HIT GENERATION A) RESEARCH AND DEVELOPMENT Process development – in phytopharmacy Herbal raw material Extraction solvent Extract ion Miscella (Liquid raw extract) Dry extract Tablets.

Patent draft .Pharmacology .Dosage form Establish: marker) .II.Active substance (in phytopharmacy: native extract) .Mode of action Prepare: .Physico-chemical profile (active compounds. HIT GENERATION A) RESEARCH AND DEVELOPMENT Development of the test substance Define: . Investigate: .

consumables Herbal raw material .Quality variations .Established market product ? . HIT GENERATION B) QUALITY CONTROL AND PRODUCTION Raw material supply Availability of raw materials.Biodiversity regulations .Continuous availability Pay attention to: .Existing patent and intellectual property rights .Contract cultivation ? .II.Sustainable cultivation / harvesting .Wild harvesting ? . excipients.

solubility Identification: microscopy. HIT GENERATION B) QUALITY CONTROL AND PRODUCTION Identity test.Herbal raw materials Organisation of a monograph Definition: chemical characterisation Characters: appearance. physico-chemical tests Tests: qualitative analysis Assay: quantitative analysis Impurities: chemical or microbiological impurities .II.Chemical substances . controls Monographs in pharmacopoeias for: .

8 30 90 4 3 9 7 2 m AU 2 50 250 2 00 200 1 50 150 1 00 100 50 50 0 0 0 2 4 6 8 10 12 14 Minut es 16 18 20 22 24 26 28 m AU 3 00 . HIT GENERATION B) QUALITY CONTROL AND PRODUCTION In house controls Two standard analytical methods in phytopharmacy: .II.TLC = Thin layer chromatography . C 0 1 con tr o l Retenti on Ti m e Area 300 1 4 . E12.HPLC = High performance liquid chromatography D AD -C H 1 218 n m C N 002.

Module 1: Information Structure of the CTD Module 2: Summaries Module 3: Module 4: Quality Non clinical study reports Module 5: Clinical study reports . *ICH: International Japan.II. USA) conference for harmonisation of technical requirements for registration of pharmaceuticals for human use. 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.

HIT GENERATION C) MARKETING AUTHORISATION PROCESS CTD documentation Prepare Module 3: Quality .Monograph .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.Specification .

II.Isolated tissue assays (e.g.g. HIT GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development In vitro profiling: . cancer cell lines) .Cell culture assays (e. enzyme activity assays) .Biochemical assays (e.or cell cultures .g. mucosa model) In vitro toxicology: Investigate potential toxic effects in bacteria.

II. Medium and culture flasks for cell cultures. . Medium for cell cultures is pipetted into a culture flask. HIT GENERATION A) RESEARCH AND DEVELOPMENT Working with cell cultures Cells are kept in liquid nitrogen. Cultivation of cell cultures in petri-dishes or cell plates with the addition of test substances. Changes of the cultivated cells are evaluated under the micro-scope after the addition of a test substance.

III. LEAD GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation .

Behaviour and reaction .III.Physiology . LEAD GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development In vivo testing Animal model (mouse or rat) Drug action: . number and kind of animals used) .Histopathology Toxicology: - Acute toxicity Subchronic toxicity Tissue specific toxicity Tolerability Consider ethical aspects (e.g.

Excretion What does the body to Pharmacodynamic studies What does the drug to the body ? Investigate: .Drug action .Distribution .III.Absorption .Physiological effects .Liberation .Metabolism .Relationship between drug concentration and . LEAD GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development (continued) Pharmacokinetic studies the drug ? Investigate: .

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. humidity and exposure time . 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.

III. LEAD GENERATION C) MARKETING AUTHORISATION PROCESS CTD documentation Continue Module 3: Quality - Validation report Stability report Manufacturing protocol Development report (on going) Prepare Module 4: Non clinical study reports Module 3: Quality Module 1: Information Module 2: Summaries Module 4: Module 5: Non Clinical clinical study study reports reports .

IV. CLINICAL DEVELOPMENT Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation .

Respect freedom of decision of volunteers . CLINICAL DEVELOPMENT A) RESEARCH AND DEVELOPMENT Clinical development – “Linking bench to bedside” Clinical drug studies – Research in humans Subject to ethical concern: . .IV.Involve a substantiated risk-benefit assessment The realisation of a clinical drug study has to be approved by an Independent Ethics Commitee (IEC).Qualify to increase existing knowledge .

IV.first application in humans .Pharmacodynamics Dosage (mg) toxic therapeut ic subtherape utic Treatment groups .Pharmacokinetics . CLINICAL DEVELOPMENT A) RESEARCH AND DEVELOPMENT Clinical development – “Linking bench to bedside” Phase I studies 20 to 30 healthy volunteers Investigate: Example: Dose titration .Safety and tolerability .

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.

CLINICAL DEVELOPMENT A) RESEARCH AND DEVELOPMENT 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. .

Prepare complete batch release documentation .Define sample shipment logistics Quality control . CLINICAL DEVELOPMENT B) QUALITY CONTROL AND PRODUCTION Clinical samples Production I.Provide appropriate sample quantities (Phase . II.IV.Define short and long term storage of samples GMP and GLP environments . III) .

Submit the completed CTD .Compile the whole CTD Module 3: Module 4: Quality Non clinical study Regulatory Authorities reports Module 5: Clinical study reports .IV.Prepare Modules: Module 1: Information 1: Administrative information 2: CTD summaries Module 2: 5: Clinical study reports Summaries .File a New Drug Application with EMEA (Europe) or FDA (USA) . CLINICAL DEVELOPMENT C) MARKETING AUTHORISATION PROCESS CTD documentation .

V. POST REGISTRATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation .

g. 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: .: The worldwide use of the approved drug might lead to the occurrence of very rare side effects. dosage. Reason for expanded epidemiologic studies .Combination with other drugs .Expanded benefit-risk-profile .V. application) E.g.Optimization (e.

Controls acc. POST REGISTRATION B) PRODUCTION & QC / C) MARKETING AUTHORISATION Production and quality control Manufacture. to the established batch release process GMP and GLP environments Marketing authorisation process Approval Authorities .Drug is approved for marketing by the .V.Manufacturing of the product .