1. The process of drug development

2. Drug development 0,8 – 1 mld. USD

3. Sources for new drus Modification of known function New characteristics of „old“ drugs – E.g. Thalidomide Natural structures – plants, bacteria Target synthesis – In silico - from knowledge of receptor site – Computer assisted - QSAR

4. Preclinical development

5. predict the efficacy and toxicity of drugs that are candidates for clinical use - GLP. Drug discovery and synthesis – 10000 and more compounds Pharmacology testing – tests for effect selection including general effects - e.g. autonomic, cardiovascular, central nervous system, so called “secondary pharmacology“ – toxicity acute, chronic, special (dermatologic, reproduction, mutagenesis, cartinogenesis) – pharmacokinetics

6. Toxicity testing Acute – the estimated lethal dose (LD50) is usually evaluated in rodents Chronic – dose selection based on acute toxicity data, – 3-4 dose levels are selected and administered daily for certain periods to two species one rodent (usually rat) and one nonrodent (usually dog). – The doses selected are intended to include: a „no effect“ dose level, low dose, mild dose and of a top dose at which fatalities will occur It is essential to include a placebo dose group.

7. Chronic toxicity Duration of chronic studies: – if up to 3 doses are to be given to human: the results of 14 days´ should be provided – for repeat dosing up to 10 days in human: animal toxicity testing for 28 days is needed. – if longer duration of therapy is suggested then 6 or 12 month toxicity should be available. In vivo testing – biochemical, – hematological and – urinalysis profiles are performed – as well as physical examination, – blood samples are taken for measurement of – concentrations of the drugs. – some animals are killed, and a full histopathological – examination is performed on all organs.

8. Specific Organ toxicity Genotoxicity Mutageneicity Reproductive toxicity – 2 species, 1 nonrodent Local toxicity (skin, conjuctival…) Fototoxicity Cardiotoxicity - QT interval

9. Pharmacokinetics Method development In vivo/in vitro Plasma profile, bile, urine, stool + tissue distribution

10. Clinical testing Design – subjects (healthy volunteers or patients) – randomization – inclusion/exclusion criteria – controls: placebo or a reference drug – double-blind design – Crossover ethics committees tasks: to protect the subjects of research to preserve their rights, to provide public reassurance Phase I - Phase II - Phase III

11. Phase I First time in humans goals: safety evaluation assessment of PK/PD in healthy subjects These individuals volunteer to be given the drug under strictly controlled, hospitalized, expert medical supervision Exception – cytostatic in terminally ill cancer patients 50-100 subjects in total

12. Phase II First time in patients – specific indication goals: – safety and efficacy evidence – identification of the dose range for phase III trial – well controlled with narrowly defined patients population design: – single or multicenter trials – usually double blind, randomized and often placebo controlled 100-150 patients in total

13. Phase III Controlled goals: – efficacy and safety evidence – information on overall benefit/risk – collection of data on a large patient population with indication design: – large multicenter – controlled by a placebo or reference drug – cross-over, parallel groups – usually bouble-blind 1000-5000 patients in total

14. Regulatory approval-product license Formal application to the Licensing Authority – Huge documentation Marketing approval – general – all doctors – granted subject to certain limitations restriction to hospital practice only, restriction in indications for use or a requirement to monitor in a specified number of patients.

15. Postmarketing surveillance: Phase IV prospective trials performed after marketing approval To evaluate: – new formulations – dosage requirements – drug interactions – detection of previously unrecognized unwanted events > 30 000 patients – detection of infrequent events

16. Generic drugs Copy of original new drug – By other pharmaceutical company - generic producer once the patent life of a new drug has expired – anyone may manufacture and sell their version of the drug – 5 years. generic drug – producer has only to demonstrate bioequivalence to the standard formulation – brand name. the plasma concentration-time curves must be sufficiently similar – 80 – 125 % Proprietary (trade) and non-proprietary (generic) names