1. European Patients’ Academy on Therapeutic Innovation Non-clinical development

2. European Patients’ Academy on Therapeutic Innovation  Once a lead molecule (candidate compound) is identified, non-clinical development begins. Non-clinical studies seek to answer the following questions:  Does it work? (Efficacy assessment)  How can it be delivered and how does the body react? (ADME profiling)  Is it safe? (Toxicology/safety, pharmacology assessment)  Is the manufacturing process viable and controllable? (CMC activities)  Non-clinical development studies and activities continue throughout the life-cycle of the product. 2 Objectives of non-clinical development

3. European Patients’ Academy on Therapeutic Innovation  The non-clinical development of a medicine is complex and regulatory-driven.  The non-clinical development phase primarily aims to  identify which candidate compound has the greatest probability of success  assess its safety, and  build a solid scientific foundation before transition to the clinical development phase, i.e. Phase I (first-in-human) 3 Non-clinical developement definition and background

4. European Patients’ Academy on Therapeutic Innovation  During the non-clinical development phase:  the intellectual property rights of the candidate compound are registered (patented), and  availability of the medicinal product for clinical trials is prepared -synthesis and production of an appropriate amount of medicine for pre-clinical and clinical testing Background activities during non- clinical development

5. European Patients’ Academy on Therapeutic Innovation  Information obtained in non-clinical studies is needed in specific situations for decisions:  on clinical trials,  on marketing authorization applications, and  on post-marketing or monitoring studies.  Non-clinical information is also used  to determine first-in-human doses of the compound (based on pharmacology and toxicology data)  in clinical studies specific on heart function, and  in safety monitoring in different systems (liver, central nervous system, renal, etc.) 5 Why are non-clinical studies needed?

6. European Patients’ Academy on Therapeutic Innovation

7. European Patients’ Academy on Therapeutic Innovation  In-vitro (Latin for ‘within the glass’)  performing a procedure in a controlled environment outside of a living organism; for example, using hepatocyte cultures (cells from the liver) for metabolism studies.  In-vivo (Latin for ‘within the living’)  experimentation using a whole, living organism as opposed to tissues or cells; for example, in animals or plants.  In-silico  an expression meaning ‘performed on computer or via computer simulation’; for example, predicting the toxicology profile of a product using its chemical structure with data-based approaches. 7 Types of non-clinical studies (1)

8. European Patients’ Academy on Therapeutic Innovation  In vivo studies (e.g. Animal models)  Pharmacodynamics (effects of medicine on organism)  Pharmacokinetics (effects of organism on medicine)  Toxicity (toxicology)  Effects on pregnancy and fertility  Carcinogenicity  In vitro studies (e.g. Cell lines of a tumor)  Carcinogenicity 8 Types of non-clinical studies (2)

9. European Patients’ Academy on Therapeutic Innovation  In Silico (e.g. Computer models)  Pharmacogenomics  Effects on biomarkers  Development of the compound 9 Types of non-clinical studies (3)

10. European Patients’ Academy on Therapeutic Innovation  Pharmacodynamics studies  Aim to study how the medicine acts on the body (mode of action (MOA)). Includes gathering information on the pharmacology of the medicine (the study of specific effects on organs, for instance the heart).  Pharmacokinetic studies  Aim to study the effects of the body on the medicine  ADME: A (absorption), D (distribution), M (metabolism), E (excretion)  Toxicokinetics of the medicine – is the product toxic? 10 Types of non-clinical studies (4)

11. European Patients’ Academy on Therapeutic Innovation  Toxicology studies aim to address the toxicity of the compound in different scenarios:  Single-dose toxicity  Repeated-dose toxicity  Genotoxicity (will the product alter the genetic profile, interfering with DNA or chromosomes?)  Carcinogenicity (will the product cause cancer?)  Development and reproductive toxicity (DART) 11 Types of non-clinical studies (4)

12. European Patients’ Academy on Therapeutic Innovation  Before non-clinical studies can begin, an adequate amount of the active ingredient (AI) must be produced.  Non-clinical studies usually require quantities of the AI in milligrams or grams; later stages of the development process will require a scale-up process to produce kilograms of the AI  In order for studies to meet Good Laboratory Practice (GLP) guidelines, the batches of AI must be qualified and produced according to Good Manufacturing Practice (GMP) guidelines.  Chemistry, Manufacturing, Control (CMC) are key aspects during non-clinical development. 12 Development of the compound for its use in development (1)

13. European Patients’ Academy on Therapeutic Innovation  Formulation for non-clinical development studies  Determining the dosing system and method of application of the active ingredient based on product properties and type of animal model.  Detailed physico-chemical characterisation  Stability testing and impurity analysis  Development and validation of methods to quantify the active substance in body fluids (e.g. blood, plasma, urine) in pharmacokinetic and toxicokinetic studies  Development of a prototype for the clinical formulation 13 Key CMC steps during non-clinical development

14. European Patients’ Academy on Therapeutic Innovation  Discovery of target organ toxicity  For example, if a compound is hepatotoxic (toxic for the liver) in an animal  Identification of poor pharmacokinetic properties  For example, if a product is poorly absorbed, if it accumulates, or if it generates toxic metabolites.  ADME studies are performed to optimize selection of successful product candidates 14 Non-clinical outcomes that can halt development

15. European Patients’ Academy on Therapeutic Innovation  On ethical grounds, the Declaration of Helsinki states the acceptability of using animals as models of risk assessment for man when these models can mimic human diseases.  Questions that must be addressed:  How relevant are non-clinical (animal) models for the human situation?  Were the non-clinical signs and pathologies sufficiently studied within the context of the proposed human use of the novel medicine? 15 Use of animals in medicines research & development (1)

16. European Patients’ Academy on Therapeutic Innovation  How to align expectations from animal information to the information provided by clinical studies in healthy volunteers and patients?  Can alternative tests be used?  Further resources regarding the importance of animal testing:  http://www.animalresearchcures.org/ http://www.animalresearchcures.org/  http://www.animalethics.org.au/legislation/international http://www.animalethics.org.au/legislation/international  Experience of patients: http://www.smh.com.au/world/i-would- have-been-dead-at-nine-caterina-simonsen-in-hospital-after- backlash-over-defence-of-animal-testing-20131230-hv75n.html 16 Use of animals in medicines research & development (2)

17. European Patients’ Academy on Therapeutic Innovation  The selection process of an animal species is based on the similarities between the animal species and humans in aspects such as:  pharmacodynamics (safety pharmacology),  pharmacokinetics, and  physiology and pathophysiology of the species compared: -Healthy animals can be used -As well as specific animal disease models 17 Selecting the appropriate animal model (1)

18. European Patients’ Academy on Therapeutic Innovation  Some examples of animal models include:  rat (osteoporosis, inflammatory diseases, diabetes, obesity, cardiovascular dysfunctions, neurodegenerative diseases, cancers),  monkey (osteoporosis, inflammatory diseases),  pig (cardiovascular dysfunctions such as hypertension), and  mouse (cancers and some genetic diseases) 18 Selecting the appropriate animal model (2)

19. European Patients’ Academy on Therapeutic Innovation The extent and scope of the non-clinical development programme before, during and after clinical trials is determined according to the following factors:  type of medicinal product,  type and severity of the disease,  population intended to treat,  clinical trial phase (Phase I, II, III and post-marketing Phase IV), and  anticipated dose and duration of the treatment duration in humans. 19 Extent of non-clinical testing

20. European Patients’ Academy on Therapeutic Innovation  The table on the following slide shows the standard non- clinical information needed before clinical testing (Phase I trials) can begin.  The duration of repeated dose toxicity studies depends on the duration of the clinical trial. 20 Toxicity studies required before clinical testing (1)

21. European Patients’ Academy on Therapeutic Innovation Toxicity studies required before clinical testing (2)

22. European Patients’ Academy on Therapeutic Innovation

23. European Patients’ Academy on Therapeutic Innovation  Local tolerance studies  Genotoxicity studies:  Assessment of gene mutation  Assessment for chromosomal damage in mammalian systems  If positive findings are observed in genotoxicity tests, additional testing must be considered. 23 Types of toxicity studies (1)

24. European Patients’ Academy on Therapeutic Innovation  Carcinogenicity studies  For medicines indicated for serious diseases in adults or paediatric patients, carcinogenicity testing may be concluded post-approval based on the assumption that early access to the medicines for patients outweighs the possible risk, but the sooner these can be carried out the better.  Reproduction toxicity studies 24 Type of toxicity studies (1)

25. European Patients’ Academy on Therapeutic Innovation  Some important factors to consider when the first-in- human dose is established include:  All relevant nonclinical data -pharmacological dose response studies, -pharmacological/toxicological profile, and -pharmacokinetics studies  Particular aspects of the candidate compound, and  Clinical Study design 25 How to choose the first-in-human dose (1)

26. European Patients’ Academy on Therapeutic Innovation  The No Observed Adverse Effect Level (NOAEL) is most important  NOAEL level is the level of exposure at which there is no significant increase in the frequency or severity of any adverse effects.  In the case of many biotechnology-derived medicines (biological medicines), and when risk factors have been identified, the first human dose is established using the Minimal-Anticipated-Biological-Effect-Level (MABEL). 26 How to choose the first-in-human dose (2)