Masterstudiengang TOXIKOLOGIE

Transcription

1 Masterstudiengang TOXIKOLOGIE Kolloquium Toxikologie Präklinische Untersuchungsstrategien in der Europäischen Arzneimittelzulassung 21. Januar 2009 Rolf Baß, Berlin

2 Arzneimittelzulassung Gesetze (Europa, national) Technische Anweisungen (Antragsformate) Guidelines (Durchführung von Prüfungen) Akute Toxizität Chronische Toxizität etc. Guidelines (Schwangerschaft) Guidelines (klinische Prüfung) Scientific Rational (Strategie) 2

3 Arzneimittelgesetzgebung The testing Council Directive 75/318/EEC ( as amended): Introduction of Standards and protocols for the performance of tests and trials: protection of public health and facilitation of Free movement of goods within the EU Adoption of Uniform rules applicable to tests and trials and their assessment will provide same chances for all companies 3

4 Arzneimittelgesetzgebung ta bene: The relevant EU Legislation is now set out in Directive 2001/83/EC as amended by Commission Directive 2003/63/EC, thus incorporating the updated ANNEX I (previously Annex I to Directive 75/318/EC) on the Testing of medicinal products (as set forth in Art. 8( )(i) of this Directive): Q, S, E Standards and Protocols in respect of the testing of medicinal products for humans 4

5 Technische Anweisungen tice to Applicants tice to Marketing Authorisation Holders Common Technical Document (CTD) ectd 5

6 Guidelines afety.htm multi.htm guidelines/nonclinical.htm 6

7 Untersuchungsstrategien Von der präklinischen l art pour l art zur Koppelung an die klinische Zweckbestimmung des Arzneimittels Anforderungen für die Klinische Prüfung Anforderungen für die Marktzulassung Problemlösungen Spezielle Populationen und Situationen 7

8 Anforderungen und -möglichkeiten Safety Pharmacology Toxicokinetic and Pharmacokinetic Studies Acute Toxicity Studies Repeated Dose Toxicity Studies Clinical development Marketing Authorisation Studies Supporting the Estimation of the First Dose in Human Studies Supporting Exploratory Clinical Studies Microdose Single dose up to sub-therapeutic / intended therapeutic range Multiple dose Local Tolerance Studies Genotoxicity Studies Carcinogenicity Studies Reproduction Toxicity Studies Men Women not/ of child-bearing potential, pregnant women Paediatric populations Other Toxicity Studies, Immunotoxicity, Phototoxicity, Abuse Liability Fixed combinations ICH Topic M3 (R2) (CPMP/ICH/286/95) (draft July 2008) 8

9 RISK ASSESSMENT FOR THE USE IN HUMANS PRECLINICAL STUDIES Bridge of Interpretation CLINICAL STUDIES EFFICACY and SAFETY EFFICACY and SAFETY ANIMAL STUDIES ANIMAL STUDIES pharmacology toxicology pharmacokinetics biotransformation pharmacokinetics biotransformation tolerance NON-ANIMAL STUDY MODELS isolated organs tissues cells cell components micro-organisms NON-ANIMAL STUDY MODELS protein binding receptor analysis receptor binding biochemical mechanism of action protein binding receptor analysis receptor binding biochemical mechanism of action clinical pharmacology clinical in different phases monitoring of pharmacotherapy chemical structure physical and chemical properties basic flow of information feedback of information on planning and validation of 9

10 Development of Individual Testing Strategies Main features of risk As arising from planned clinical Potential risk Situation envisaged Type of study Group/type of persons Stage of illness Planned doose and duration Potential areas of risk (in humans) which have to be experimentally clarified Adverse reactions before during after CT s Basic principles To be considered Present state of knowledge on Ethical norms Appropriate testing strategy for risk assessment (in humans) and for every single step of medicinal products development Simulation of clinical situation Basic suitability of test system/study 10

11 Coordination Plan for Stepwise Progress rmal way (full application, new active substance) Initial preclinical and pharmacodynamic profiling for choice of substance Decision on development of medicinal product Special way (abridged application" e.g. new indications, new formulation) Feedback Initial preclinical, toxicological and kinetic Extended preclinical pharmacodynamic profiling Initial clinical (in humans) e.g. kinetics, pharmacodynamics, tolerance Extended preclinical toxicological and kinetic in selected suitable models Extended clinical (in humans) e.g. kinetics, pharmacodynamics, clinical Marketing Authorisation Application 11

12 Generic Principle of Flowchart Input Evaluation Decision Consequences All data available at a certain point in time Low (Further) not necessary or suspicion to Be clarified Certain necessary or High Scale of likelihood: Is there suspicion about A risk to be clarified? From Probability to Decision Decision on use (in humans) : conditions 12

13 Discussion about Single Dose Toxicity Testing Possible available Data to be taken Into consideration Likelihood Suspicion of an acute intoxication Type of toxicity study after single dose Low - structure - results from pharmacological no - mechanism of effect - dose planned for use in humans "Limit Tests" or rough determination of dose causing lethal or other adverse events - other data High Determination of exact dose-effect relationship (e.g. choice of species, escalating or single doses, confidence intervals in particular cases) 13

14 Discussion about Repeated Dose Toxicity Testing Possible available Data to be taken Into consideration Likelihood Suspicion of chronic intoxication Type of toxicity Study after Repeated dose Low - structure - single-dose toxicity no - pharmacodynamics - phamacokinetics - clinical ( pharmacokinetics, pharmacodynamics) - other data with individually justified - dose - duration - species - way of administration High 14

15 Discussion about Toxicity to Male Fertility Testing Possible available Data to be taken Into consideration Likelihood Suspicion adverse effect on male fertility Categorisation of adverse events on male fertility Planned duration of treatment in men Conditions of treatment in men Necessity of undertaking experimental Low short-term or long-term use - structure - pharmacokinetics (in humans) - toxicity after single and repeated dose reversible functional effects on neuroendocrine system short-term use (< 7 days) long-term use adverse events would be acceptable adverse events would NOT be - genotoxicity acceptable - short-term tests - pharmacokinetics (in animals) - pharmacology (in humans) - other data toxic morphological damage or unclear mechanism short-term or long-term use adverse events would be acceptable adverse events would NOT be High acceptable 15

16 Discussion about Toxicity to Female Fertility Testing Possible available Data to be taken Into consideration Likelihood Suspicion adverse effect on female fertility Categorisation of adverse events on female fertility Planned duration of treatment in women of child-bearing potential Conditions for use in women of child-bearing potential Necessity of undertaking experimental Low short-term or long-term use - structure - pharmacokinetics (in humans) - toxicity after single and repeated dose reversible functional effects on neuroendocrine system short-term use (< 7 days) long-term use adverse events would be acceptable adverse events would NOT be - genotoxicity acceptable - short-term tests - pharmacokinetics (in animals) - pharmacology (in humans) - other data toxic morphological damage or unclear mechanism short-term or long-term use adverse events would be acceptable adverse events would NOT be High acceptable 16

17 Discussion about Embryonal / Foetal Toxicity Testing Possible available Data to be taken Into consideration Likelihood Suspicion embryotoxic incl. teratogenic effects Conditions of treatment in humans Necessity of undertaking experimental Low - structure - pharmacokinetics (in humans) - toxicity after single and repeated dose use during pregnancy very unlikely - genotoxicity - short-term tests - pharmacokinetics (in animals) - pharmacology (in humans) - other data use during pregnancy planned or possible High 17

18 Discussion about Postnatal Development Toxicity Testing Possible available Data to be taken Into consideration Likelihood Suspicion peri-/post-natal toxic effects Conditions of treatment in humans Necessity of undertaking experimental Low - structure - pharmacokinetics (in humans) - toxicity after single and repeated dose use during pregnancy very unlikely, weaning or interruption of breastfeeding possible - genotoxicity - short-term tests - pharmacokinetics (in animals) - pharmacology (in humans) - other data use during pregnancy or breastfeeding planned or possible High 18

19 Discussion about Genotoxicity Testing Possible available Data to be taken Into consideration Likelihood genotoxic effects Suspicion Basic data Additional data Conditions of treatment in humans Decision on use in humans Low - structure - biotech product - pharmacodynamics - pharmacokinetics - metabolism - other data Option 1 core Battery in vitro Option 2 in vivo mechanistic High mutagenic risk acceptable 19

20 Discussion about Tumourigenicity Testing Possible available data to be taken into consideration Likelihood Suspicion of a tumorigenic effects Planned duration of treatment in humans Use in humans Necessity of undertaking experimental Low - structure short-term use - toxicity after single and repeated dose long-term clinical study (up to 6 months) - genotoxicity - short-term tests - pharmacokinetics (in animals) use clinical study and therapy (unlimited duration) - pharmacokinetics (in humans) - pharmacology (in humans) - other data short-term or long-term use tumourigenic potential would not be acceptable tumourigenic potential would be acceptable High 20

21 Discussion about Safety Pharmacology Testing Possible available data to be taken into consideration Likelihood of an adverse event Suspicion Type of safety pharmacological Low - structure - results from pharmacological no - mechanism of effect - results from toxicological - planned dose for use in humans - other data Vital systems: -CNS -Cardiovascular -Respiratory High 21

22 Discussion about Safety Pharmacology Testing Possible available data to be taken into consideration Likelihood Suspicion of a QT Interval Prolongation Type of ventricular Repolarisation Studies Low - structure - results from pharmacological no - mechanism of effect - results from toxicological - planned dose for use in humans - chemical/ pharmacological class In vitro herg In vivo ECG Follow up and Supplementary Studies High 22

23 Discussion about Juvenile Animals Testing Possible available data to be taken into consideration Likelihood of an adverse effect Suspicion Juvenile Animal results from clinical and non-clinical : - Clinical: paediatric specs; class effects; ADME; adult ADR s Pre-clinical: mechanism of action; target; results from pre- /postnatal Low High Study in one species or modified pre-and postnatal development study Studies in two species 23

24 Summary and Conclusions Strategy for Testing: case by case Strategy for Testing: discussion based on use of flow-charts Strategy for Testing: re-iterative process (taking into due consideration the increase in knowledge over time) Strategy for Testing: based on judgment of probabilities Strategy for Testing: further support from ICH- Guideline 24