DRUG DEVELOPMENT A view on the process from the idea to the registered pharmaceutical

1. 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

2. Organisation of the presentation I. DISCOVERY Identification of target and resource

3. Organisation of the presentation II. HIT GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

4. Organisation of the presentation III. LEAD GENERATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

5. Organisation of the presentation IV. CLINICAL DEVELOPMENT Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

6. Organisation of the presentation V. POST REGISTRATION Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

7. I. DISCOVERY Identification of target and resource

8. 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 ?

9. 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

10. 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.

11. I. DISCOVERY Resourceidentification - Alpinia Institute Natural organisms, in particularplants - 52%ofthedrugsapproved in the U.S. from 1981-2002 werenaturalproductsorderivedfromthem(2). - 26plant baseddrugswereapprovedduring 2000-2006, includingnovel-molecularbaseddrugs (3). - In thefuturemulticomponentbotanicaltherapeuticswill experience an increasinginterest in biomedicine (4). Medicinalplantscontinuetoplay a significantroleas a resourceforthediscoveryofnoveldrugs (1) 2) Newman, J Nat Pr 2002. 3) Saklani & Kutty, Drug Disc Today 2008. 4) Schmidt et al., Nature Chem Biol 2007.

12. 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

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

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

15. 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

16. 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

17. 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

18. 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

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

20. 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 clinicalstudyreports Module 5: Clinical studyreports

21. 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

22. II. HIT GENERATION A) RESEARCH AND DEVELOPMENT Working with cell cultures Medium and culture flasks for cell cultures. Medium for cell cultures is pipetted into a culture flask. Cells are kept in liquid nitrogen. 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.

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

24. III. LEAD GENERATION A) RESEARCH AND DEVELOPMENT Preclinical development In vivo testingAnimal 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)

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

26. 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

27. 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

28. 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 studyreports

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

30. 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 anIndependent Ethics Commitee (IEC).

31. 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 Example: Dose titration - first application in humans toxic Dosage (mg) therapeutic subtherapeutic Treatment groups

32. 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.

33. 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.

34. 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

35. 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

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

37. 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

38. 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

39. 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

40. Thank you for your attention !