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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

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Drug development 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


Drug development a view on the process from the idea to the registered pharmaceutical

Organisation of the presentation

I. DISCOVERY

Identification of target and resource


Drug development a view on the process from the idea to the registered pharmaceutical

Organisation of the presentation

II. HIT GENERATION

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

Organisation of the presentation

III. LEAD GENERATION

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

Organisation of the presentation

IV. CLINICAL DEVELOPMENT

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

Organisation of the presentation

V. POST REGISTRATION

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

I. DISCOVERY

Identification of target and resource


Drug development a view on the process from the idea to the registered pharmaceutical

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 ?


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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.


Drug development a view on the process from the idea to the registered pharmaceutical

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.


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

II. HIT GENERATION

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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.


Drug development a view on the process from the idea to the registered pharmaceutical

III. LEAD GENERATION

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

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)


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

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


Drug development a view on the process from the idea to the registered pharmaceutical

IV. CLINICAL DEVELOPMENT

Perspectives: A) Research and Development

B) Quality Control and Production

C) Marketing Authorisation


Drug development a view on the process from the idea to the registered pharmaceutical

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).


Drug development a view on the process from the idea to the registered pharmaceutical

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Clinical development – “Linking bench to bedside”

Phase I studies20 to 30 healthy volunteers

Investigate:- Safety and tolerability

- Pharmacokinetics

- Pharmacodynamics

Example:

Dose titration - first application in humans

toxic

Dosage (mg)

therapeutic

subtherapeutic

Treatment groups


Drug development a view on the process from the idea to the registered pharmaceutical

IV. CLINICAL DEVELOPMENT

A) RESEARCH AND DEVELOPMENT

Clinical development – “Linking bench to bedside” (continued)

Phase II studies100 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.


Drug development a view on the process from the idea to the registered pharmaceutical

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.


Drug development a view on the process from the idea to the registered pharmaceutical

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


  • Drug development a view on the process from the idea to the registered pharmaceutical

    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


    Drug development a view on the process from the idea to the registered pharmaceutical

    V. POST REGISTRATION

    Perspectives: A) Research and Development

    B) Quality Control and Production

    C) Marketing Authorisation


    Drug development a view on the process from the idea to the registered pharmaceutical

    V. POST REGISTRATION

    A) RESEARCH AND DEVELOPMENT

    Clinical development after marketing

    Phase IV studiesPost 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


    Drug development a view on the process from the idea to the registered pharmaceutical

    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


    Drug development a view on the process from the idea to the registered pharmaceutical

    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


    Drug development a view on the process from the idea to the registered pharmaceutical

    Thank you for your attention !


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