Once a lead molecule candidate compound is identified nonclinical development begins Nonclinical studies seek to answer the following questions Does it work E fficacy assessment How can it be delivered and how does the body react ID: 1012199
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1. Non-clinical development
2. 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.2Objectives of non-clinical development
3. 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, andbuild a solid scientific foundation before transition to the clinical development phase, i.e. Phase I (first-in-human)3Non-clinical developement definition and background
4. During the non-clinical development phase: the intellectual property rights of the candidate compound are registered (patented), andavailability of the medicinal product for clinical trials is preparedsynthesis and production of an appropriate amount of medicine for pre-clinical and clinical testingBackground activities during non-clinical development
5. Information obtained in non-clinical studies is needed in specific situations for decisions:on clinical trials,on marketing authorization applications, andon post-marketing or monitoring studies.Non-clinical information is also usedto determine first-in-human doses of the compound (based on pharmacology and toxicology data)in clinical studies specific on heart function, andin safety monitoring in different systems (liver, central nervous system, renal, etc.)5Why are non-clinical studies needed?
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7. 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.7Types of non-clinical studies (1)
8. 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 fertilityCarcinogenicityIn vitro studies (e.g. Cell lines of a tumor)Carcinogenicity8Types of non-clinical studies (2)
9. In Silico (e.g. Computer models)PharmacogenomicsEffects on biomarkersDevelopment of the compound9Types of non-clinical studies (3)
10. Pharmacodynamics studiesAim 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 studiesAim 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?10Types of non-clinical studies (4)
11. Toxicology studies aim to address the toxicity of the compound in different scenarios:Single-dose toxicityRepeated-dose toxicityGenotoxicity (will the product alter the genetic profile, interfering with DNA or chromosomes?)Carcinogenicity (will the product cause cancer?)Development and reproductive toxicity (DART)11Types of non-clinical studies (4)
12. 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 AIIn 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. 12Development of the compound for its use in development (1)
13. Formulation for non-clinical development studiesDetermining the dosing system and method of application of the active ingredient based on product properties and type of animal model.Detailed physico-chemical characterisationStability testing and impurity analysisDevelopment and validation of methods to quantify the active substance in body fluids (e.g. blood, plasma, urine) in pharmacokinetic and toxicokinetic studiesDevelopment of a prototype for the clinical formulation13Key CMC steps during non-clinical development
14. Discovery of target organ toxicityFor example, if a compound is hepatotoxic (toxic for the liver) in an animalIdentification of poor pharmacokinetic propertiesFor 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 candidates14Non-clinical outcomes that can halt development
15. 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?15Use of animals in medicines research & development (1)
16. 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.animalethics.org.au/legislation/internationalExperience 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.html16Use of animals in medicines research & development (2)
17. 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, andphysiology and pathophysiology of the species compared:Healthy animals can be usedAs well as specific animal disease models17Selecting the appropriate animal model (1)
18. 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), andmouse (cancers and some genetic diseases)18Selecting the appropriate animal model (2)
19. 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), andanticipated dose and duration of the treatment duration in humans.19Extent of non-clinical testing
20. 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.20Toxicity studies required before clinical testing (1)
21. Toxicity studies required before clinical testing (2)Type of studyAim of studySafety pharmacology core studiesAssessing effects on cardiovascular, respiratory, and central nervous systems (CNS). Primary pharmacodynamics studiesIn vivo and/or in vitro studies, assessing mode of action/effects of candidate compound on the target.Pharmacokinetics and toxicokinetics studiesData gathered during in vitro studies on metabolic and blood protein binding data for animals and humans. Systemic exposure data from toxicology studies.Acute toxicity studiesSingle-dose toxicity studies in two mammalian species – but can be completed during studies that define a maximum tolerated dose in the species used for toxicity testing.Repeated-dose toxicity studiesVary in length according to duration, therapeutic indication and scope of the proposed clinical programme. Minimum duration for two weeks in two species (one of which is not a rodent).Other studies of concern For instance, investigation into phototoxicity (causing a reaction of the skin when exposed to light)
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23. Local tolerance studiesGenotoxicity studies: Assessment of gene mutationAssessment for chromosomal damage in mammalian systemsIf positive findings are observed in genotoxicity tests, additional testing must be considered.23Types of toxicity studies (1)
24. 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 studies24Type of toxicity studies (1)
25. Some important factors to consider when the first-in-human dose is established include:All relevant nonclinical datapharmacological dose response studies,pharmacological/toxicological profile, andpharmacokinetics studiesParticular aspects of the candidate compound, andClinical Study design25How to choose the first-in-human dose (1)
26. The No Observed Adverse Effect Level (NOAEL) is most importantNOAEL 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). 26How to choose the first-in-human dose (2)