development of a new medicinal product · directive 2001/20/ec. clinical trials phase i trials are...
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Development of a new
medicinal product
as. MUDr. Martin Votava, PhD.
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Development and registration of a medicinal product
Costs of development: 800 mil USD
Time to develop: 10 years
Successfulness: 0,005% - 0,001%
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Development of a new medicinal
product
IND NDA
Chemical synthesis and development of pharmaceutical form
Preclinical models
Development of
methods
Preclinical PK
aand PD
Dose
Escalation a
iniciální PK
„Proof of
Concept“ a „Dose
Finding“
Velké studie
účinnosti
Phase I Phase II Phase III
Preclinical development Clinical development
PK/PD studie u speciálních populací
N=10-100 N=100-1000 N>1000
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Choice of chemical entity(n=10000)
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New chemical entity
• modification of chemical structure of a known medicinal product
• use of natural compounds
• use of new features of known active substances
• drug design – targeted synthesis of new chemical entities
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Preclinical development(n = 100-1000)
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Aims of preclinical
development
• To identify potential adverse drug reactions– Target toxicity organs– Reversibility of changes
• PK profile• PD effect
– „Proof of Principle“
• To establish safety administration in humans– Safe and effective starting dose in humans– To establish main monitoring parameters during clinical
studies
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Preclinical safety studies
• Safety pharmacology
• Toxicokinetics & pharmacokinetics
• Acute toxicity
• Chronic toxicity
• Special toxicity studies – Carcinogenicity
– Mutagenicity
– Genotoxicity
– Phototoxicity
– Local tolerance
– Reproductive toxicity
– Oculotoxicity etc…
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Safety pharmacology
• Influence of the drug on the specific organ systems– Cardiovascular (QT interval…)– CNS (convulsion, sedation atd.)– Respiratory system
• Results before first administration to human
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Toxicokinetics & pharmacokinetics
• Analytical method
• Preclinical PK/PD efficacy and safety
• Testing of pharmaceutical form
• Testing of different doses and dosing schedules
• ADME in different species
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Preclinical toxicity
• GLP studies
• Use of intended dosing schedule, pharmaceutical form
• Studies of acute toxicity in two mammals species before the first administration in human– Rats and dogs for small moleculs
– Primates for biologicals
• Studies of chronic toxicity requirements– 3-months for administartion < 3 months in humans
– 6-months for administartion > 6 months in humans
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Special toxicity studies
– Carcinogenicity
– Mutagenicity
– Genotoxicity
– Phototoxicity
– Local tolerance
– Reproductive toxicity
– Oculotoxicity etc…
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Clinical trials(n = 10 - 100)
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Clinical trial
any systematic evaluation of a drug effect in humans for the purpose:
– 1. to evaluate clinical pharmacological or any other pharmacodynamic properties
– 2. to evaluate adverse reactions
– 3. to evaluate pharmacokinetic parameters
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Good clinical practice
• Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects.
Directive 2001/20/EC
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Clinical trials
Phase I trials are the first stage of testing in human subjects.
Phase II trials are designed to confirm „proof of principle“ concept in the target groups of patients Phase IIA is specifically designed to assess dosing requirements
Phase IIB is specifically designed to study efficacy
Phase III trials are large confirmatory clinical trials, basis for marketing authorization of a drug
Phase IV - Post Marketing Surveillance Trials
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Clinical studies
• Controlled
• Randomised
• Blinded
• Multicentre
• GCP, Informed consent
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Research activities in CZ
• Basic research
• Pharmaceutical development
• Preclinical tests
• Clinical studies
• Postmarketing studies
• No commercial research centers
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Patent protection
Marketing authorization
Life-cycle of a medicinal product
Reseach and development
SPC
Patent registration
Data exclusivity
Application formarketing
authorization ofa generic product
Market access of a generic product
Price andreimbursement
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Marketing authorization(n = 1)
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Marketing authorization
• National
• Mutual recognition procedure
• Decentralised procedure
• Centralised procedure
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Prices and reimbursement(n=0 ?)
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Prices and reimbursement
• Efficacy• Effectiveness• Efficiency
• Public interest• Cost-effectiveness
• Innovative therapy• Therapeutic guidelines• Impact of health outcomes
• Price for QALY
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Patent protection of medicinal products
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Patent law
• Different in every state
• Applies not only for new chemical substances, but also for:– chemical process
– pharmaceutical form
– new use of old molecules
– manufacturing steps
– etc...
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Evropean patent
• based on one application form to EPO
• But not valid for the whole EU area, but its multiple national patent
• need of validation in each member state → translations → relatively high costs
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Questions??