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

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

I. DISCOVERY

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.

Resource identification - Alpinia Institute

Natural organisms, in particular plants

- 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).

I. DISCOVERY

Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs (1)

2) Newman, J Nat Pr 2002. 3) Saklani & Kutty, Drug Disc Today 2008. 4) Schmidt et al., Nature Chem Biol 2007.

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

I. DISCOVERY

II. HIT GENERATION

Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

Process development – in phytopharmacy

Herbal raw material Extraction solvent

Extraction

Miscella (Liquid raw extract)

Encapsulatable massDry extract Liquid extract, tincture

Soft capsulesLiquids, drops, ointments

Tablets, hard capsules

II. HIT GENERATIONA) 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 GENERATIONA) RESEARCH AND DEVELOPMENT

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 GENERATIONB) QUALITY CONTROL AND PRODUCTION

Identity test, controls

Monographs in pharmacopoeias for: - Chemical substances- Herbal raw materials

Organisation of a monographDefinition: chemical characterisationCharacters: appearance, solubilityIdentification: microscopy, physico-chemical testsTests: qualitative analysisAssay: quantitative analysisImpurities: chemical or microbiological impurities

II. HIT GENERATIONB) QUALITY CONTROL AND PRODUCTION

In house controls

Two standard analytical methods in phytopharmacy:

- TLC = Thin layer chromatography

- HPLC = High performance liquid chromatography

II. HIT GENERATIONB) QUALITY CONTROL AND PRODUCTION

Minutes

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

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DAD-CH1 218 nmCN002.E12.C01 control

Retention TimeArea

CTD documentation

II. HIT GENERATIONC) MARKETING AUTHORISATION PROCESS

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.

CTD documentation

Prepare Module 3: Quality

- Monograph- Specification- Development report (on going)

II. HIT GENERATIONC) MARKETING AUTHORISATION PROCESS

Module 1:Information

Module 2:Summaries

Module 3:Quality

Module 4:Non clinical study reports

Module 5:Clinical study reports

II. HIT GENERATIONA) 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 GENERATIONA) 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.

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

III. LEAD GENERATIONA) 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 GENERATIONA) 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

III. LEAD GENERATIONA) 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

III. LEAD GENERATIONB) 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 GENERATIONC) 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

IV. CLINICAL DEVELOPMENT

Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

IV. CLINICAL DEVELOPMENTA) 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).

IV. CLINICAL DEVELOPMENTA) 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

Dos

age

(mg)

Example: Dose titration - first application in humans

IV. CLINICAL DEVELOPMENTA) 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 DEVELOPMENTA) 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. CLINICAL DEVELOPMENTB) 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 DEVELOPMENTC) 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

V. POST REGISTRATION

Perspectives: A) Research and Development B) Quality Control and Production C) Marketing Authorisation

V. POST REGISTRATIONA) 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 REGISTRATIONB) 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. DISCOVERYIdentify target and resource

II. HIT GENERATIONDevelop process and test substance Conduct in vitro testing

III. LEAD GENERATIONConduct in vivo testingPharmacokinetic and pharmacodynamic studies

IV. CLINICAL DEVELOPMENTHuman trials – Phase I, II, III

V. POST REGISTRATIONHuman trials – Phase IV

Thank you for your attention !