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  1. Non-clinical Safety Studies: What is required and when, for effective support of clinical trials Mike Kelly

  2. ACTIVE DRUG Related substances Process residues Degradation products Excipients Other active materials ‘Extractives’ Points to consider 1:- the test material All medicines contain more than the active drug !

  3. Points to consider 2:- the process • Toxicology is a collaborative process • ‘Absorption, Distribution, Metabolism & Excretion’ • Pharmacology • Pharmacy, Synthetic & Analytical Chemistry • Quality Assurance • Clinical Pharmacology & Research

  4. TOXICOLOGY - What do we examine? • Behaviour, Function, Physiology • Safety Pharmacology • Mutation, Chromosomal changes, Non-genotoxic carcinogens • Genetic Toxicology and Carcinogenicity • Behaviour, Function, Physiology, Clinical biochemistry, pathology • General Toxicology • Fertility, pregnancy, Fetal, peri/post-natal • Reproductive Toxicology

  5. Typical Development Process: Phases and Decision Points FTIH to PoC (Phase 2) (18 months) PoC to Commit to Phase 3 (9 months) Candidate Selection to FTIM (9 months) Lead to Candidate (24 months) Lifecycle Management (?) Phase 3 (?) File & Launch (?) Candidate Selection Agree Proof of Concept & Commit to Development Launch FTIH • FTIH = First time in humans (Initially single doses, then for several days) • Phase 2 = Limited patient trials (Defining the appropriate doses for efficacy & safety) • PoC = Proof of Concept (Is the drug likely to work!) • Phase 3 = Full-scale patient trials

  6. Non-Clinical Activities Lead to Candidate(Selecting a promising molecule: Unregulated, non-GLP compliant) Lead -12 months -6 months Candidate Selection Genotox (in silico SAR) Contingency for specific screens (teratogenicity, cytotoxicity, mutagenicity, HERG) or biomarkers Based on prior knowledge Formulation and species for GLP studies Rat 7-Day screen Mammalian genotoxicity (in vitro) Bacterial mutagenicity screen SAFETY ASSESSMENT Intellectual input: Early leads and target liability assessment Rat CV Safety Pharm Start synth 28 day tox and FTIH supplies Supply of ~50-100g compound from Med Chem Synth ~500g, dose ranging studies “CHEMISTRY” Assistance with formulations for animal models Prelim form. For Tox and FTIH studies “PHARMACY” Assay development, preliminary metabolism studies support for Tox and Pharmacy Kinetics & Metabolism

  7. Safety Assessment at Phase 1 • Provide sufficient safety data to support dosing at the required phase • Phase 1: • No clinical data • Low dose • Careful escalation • Small numbers

  8. Genotoxicity: Tests to detect genetic damage • Gene Mutation (substitution, insertion/deletion, frame shift) • Bacterial mutation assays • Ames • Mammalian cells In vitro • Selective colony forming assays: Mouse Lymphoma (TK±) or CHO cells (HGPRT) • DNA damage/repair (in vivo or in vitro) • Unscheduled DNA synthesis (UDS) • Comet assay • DNA adducts (in vivo or in vitro) • P32 post-labeling • Chromosomal damage, recombination, aneuploidy • Clastogenicity assay in vitro • Chromosome aberration assay: Human lymphocytes, CHO cells • Selective colony forming assay: Mouse Lymphoma (TK±) • Clastogenicity assay in vivo • Rodent bone marrow micronucleus assay • Chromosome aberration assay: Bone marrow ICH S2a & b Guidelines

  9. Safety Pharmacology (Secondary or General Pharmacology) • Behavioural Effects (CNS) • “Irwin-style” observational screen (rat) • Respiratory • Plethysmography (rat) • Cardiovascular function • Anaesthetised/conscious rodent or non-rodent; • Physical monitoring (multi-lead ECG) or Remote Telemetry • Electrophysiology • Cardiac ion channels, QT prolongation (torsades) • Major Organ Function • Renal, GI ICH S7a and b guidelines

  10. Repeat Dose Toxicology • Two species; rodent and non-rodent, typically rat and dog (mouse, hamster, monkey, pig) • ~12 rodents, ~4 non-rodents /sex/group • Control group and at least 3 drug-treated • Max usually 1000mg/kg non-rodent, 1000mg/kg rodent • Maximum feasible, 50x clinical AUC • Typically by clinical route • May Include treatment-free ‘recovery animals’ (control and high dose) • Duration dependent on the proposed exposure in clinical trials ICH S4 and M3 guidelines

  11. Human Single Dose Up to 2 weeks > 6 Months Non-Clinical 2 Weeks 2-4 Weeks Match duration of clinical exposure Chronic Studies* Repeat Dose Toxicology- ICH M3 * = Rodent 6 months, Non-rodent 9-12 Months

  12. Support of exploratory trials

  13. Support of exploratory trials

  14. Support of exploratory trials

  15. The clinical dose • A fraction of the NOAEL based on..? • Administered dose • Administered dose ‘scaled’ between species (mg/m2) • Maximum Systemic drug concentration (Cmax) • 24 hour systemic drug ‘load’ (AUC0-24) • Average concentration over 24 hours • Minimal Anticipated Biological Effect Level (MABEL) Based on.. • Receptor binding/occupancy in vitro/in vivo • Concentration response curves • Exposure at pharmacological doses ICH M3 (revision 2) EMEA guidance: Guideline On Strategies to Identify and Mitigate Risks for First-in-Human Clinical trials with Investigational Medicinal Products FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers

  16. Say hello to MABEL • Mode • Is the mode of action novel? • Is the mode of action pleiotropic? • Weird (steep, U shaped, Non-linear) dose response? • Target • Structure, function, distribution (particularly immune), cell specificity, disease specificity, expression, regulation and downstream effects, polymorphisms • Relevance of preclinical species EMEA/CHMP/SWP/28367/07

  17. Starting dose based on pharmcodynamics • Minimal Anticipated Biological Effect Level • Based on i) target binding and receptor occupancy studies in vitro in target cells from human and the relevant animal species; ii) concentration-response curves in vitro in target cells from human and the relevant animal species and dose/exposure-response in vivo in the relevant animal species. iii) exposures at pharmacological doses in the relevant animal species.

  18. Non-Clinical Activities Candidate to First Time in Humans (FTIH) Candidate Selection -3 months -6 months FTIH GLP Genetic Tox Ames Test Mouse Lymphoma Micronucleus SAFETY ASSESSMENT Safety Pharmacology Rat Irwin study Rat Respiratory Non-rodent CV hERG Output: Summaries for IND/CIB Health & Safety, Eco-Tox. Studies (with Occupational. Health Group) Final Reports for IND Dose ranging in rats (if required) Initial Repeat dose Tox 28 day rodent 28-Day Non-rodent Dose ranging non-rodent Define long term MANUFACTURING process Toxicokinetics & ID major circulating metabolites ALL STUDIES GLP, REGULATORY GUIDELINE, COMPLIANT FROM HERE…….

  19. Safety Assessment at Phase 2 • Provide sufficient safety data to support dosing at the required phase • Phase 2: • First patient trial • Pharmacologically active dose • First exposure of WCBP • Extended duration • Extended duration toxicity data available • Safety margin based on human exposure data

  20. Reproductive & Developmental Toxicology 1 2 3 • Key stages for examination: three routine screening studies Pre-mating to conception Conception to implantation Embryo-Fetal development - mid-pregnancy Fetal development - late pregnancy Birth to weaning Weaning to Sexual Maturity 2 RABBIT RAT 1 = Fertility and early development; 2 = Embryofetal Development; 3 = Pre/post-natal ICH S5a and S5b

  21. ICH Guidelines - Preferred Options Rat/rabbit embryo-fetal development study (treat females) Organogenesis Premating Mating Implantation (day 6) Kill Mate Kill pre-term Implantation Closure of hard palate Rat fertility and early embryonic development study (treat male and/or female)

  22. Non-Clinical ActivitiesFTIH to ‘Proof of Concept’ (PoC) FTIH +6 months End Phase (+9 months) POC (+18 Months) Additional Repeat Dose: 3/6 month tox studies (rodent & non-rodent) possible enabler Rat EFD Study Pre-Onco Studies [4 yrs.before NDA/MAA] Initiate Program of Investigative studies as required. Tox. support for human bioavailability study Rabbit dose range Rabbit EFD Additional Enviro. Safety studies (with Occ. Health Group) REPRODUCTIVE TOXICOLOGY To enable later clinical work? Prepare drug supply 9/12 month Tox.& Carc studies. Needs to be like ‘Final’ manufactured drug

  23. Safety Assessment at Phase 3 • Provide sufficient safety data to support dosing at the required phase • Phase 3: • Long-term large-scale patient trial • Pharmacologically active dose • Extended duration toxicity data available • Safety margin based on human exposure data

  24. Additional studies required for Phase 3 and Launch • Before Phase 3 • Appropriate duration of tox: • 6 month rodent • 9 month non-rodent • Fertility • Immunotoxicology • Before and during Phase 3 • Juvenile studies • Investigative • Phototox • Carcinogenicity • Pre and post-natal

  25. Final preclinical studies F1 Parturition Lactation Mate Day 7 Kill dams Rat pre- and post-natal development study (treat females) • Carcinogenicity • Usually the oral route - diet or gavage • Choose dose to avoid excessive mortality • Increased incidence of tumours? • Changes in onset time of tumours? • Changes in tumour profiles?

  26. Carcinogenicity studies • Many background tumours • Need a reliable concurrent database • Extensive statistical evaluation • Pathology issues - diagnostic criteria • Significance of non-genotoxic neoplasia? • Need good systemic exposure data

  27. Final preclinical studies • Photo-safety: European and US guidance • Europe - Note for Guidance, June 2002 • Hierachy of absorbance, in vitro, biodistribution (skin, eye), and clinical studies. Photo-allergy and photo-carcinogenicity also mentioned. CPMP/SWP/398/01 • FDA - Guidance for Industry “Photosafety Testing”, January 2000 • Similar step-wise approach to assessments http://www.fda.gov/cder/guidance/3281dft.pdf • Paediatric populations • All reproduction studies, standard battery of genotoxicity tests, and appropriate repeat dose toxicity studies. and • Adult human data on a case by case basis • Studies in juvenile animals if previous data are considered insufficient or if known risks

  28. Non-Clinical ActivitiesProof of Concept to Launch Filing with Reg. Agencies Phase 2 (cont) Commit Phase 3 Launch CHRONIC: Non-rodent 9 Month Juvenile Tox studies if req. CHRONIC: Rat 6 month (if not done before) Respond to Reg. Questions Compilation of NDA/MAA REPRO: Rat Pre/post Natal Rat male and female fertility Rat & Mouse Onco studies (3 yrs pre-file) Other supporting studies - bridging, combo, new routes, regional requirements, investigative tox.

  29. Risk Assessment What does it all mean?

  30. Study Results And Observations • In an ideal world a Study might give you : • Dose(s) that produce no effects • Dose(s) that produce acceptable effects • Dose(s) that produce overt toxicity No Observable Effect Level (NOEL) No Observed Adverse Effect Level (NOAEL)

  31. Effects and interpretation • Are there margins of safety for humans ? • Changes may be toxicologic • Changes may be pharmacologic • What do the changes mean? • Species idiosyncrasies • Can potential changes be monitored in man?

  32. Effects and interpretation • relevance to humans • Thyroid hypertrophy after metabolic induction • Peroxisome proliferation in rodent liver • Rodent forestomach changes • relevance to clinical dose & regime • Duration of treatment (migraine, acute use vs. 12-month tox?) • Massive exposure margins, local tolerance issues (iv/po) • risk:benefit for indication • Cardiac QT interval with ‘hayfever’ drugs vs anti-psychotics • Unmet medical need (IBS - Lotronex), Rheumatology - DMARD’s • Hepatotoxicity with troglitazone (newer safer agents developed)

  33. Putting the observations into a clinical perspective • THE DOCUMENTS AND SUBMISSIONS • Clinical Investigators Brochure (CIB) • Clinical Trials Application (CTA) • Investigational New Drug Application (IND) • New Drug Application (NDA) • Marketing Approval Application (MAA) • Labels and Package Inserts

  34. SUPPORT AFTER MARKETING NEW FORMULATIONS NEW INDICATIONS NEW SYNTHETIC ROUTES NEW IMPURITIES NEW TECHNOLOGY LICENCE REVIEWS Digoxin (Lenoxin)

  35. NON-CLINICAL SAFETY ASSESSMENT • Assure ourselves it is safe and ethical to proceed • Fulfil Regulations • Understand the activities of the compound • Support our marketed products • Protect the user • Protect the workers