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  1. Overview of Regulatory Toxicology BrAPP Cardiff – Module 1 September 2012 Mike Kelly

  2. The roles of Safety Assessment. Fulfilling Regulatory and Statutory obligations • Providing reassurance for conduct of clinical trials • Safety information for marketing applications • Support for marketed products • Candidate compound selection & rejection • Worker and Environmental protection

  3. REGULATORY TOXICOLOGY: NON-CLINICAL SAFETY ASSESSMENT Supporting Clinical Development: Provide reassurance & build confidence to proceed ‘Post marketing’ Regulatory Approval Healthy volunteers Volunteer Patients Workplace & Environment

  4. PHARMACOLOGY TOXICOLOGY Pre-Clinical Development - The Questions DOES IT WORK ? IS IT SAFE May be related or unrelated The two fundamental questions for drug development and use

  5. NON-CLINICAL SAFETY ASSESSMENT Job #1 ...... “DETECTING THE HAZARDS”

  6. “. . . . Aspects of a Safety Assessment. . . . “ ONE DOSE LIFETIME USE Reproduction Chronic Effects Acute Responses Development Genetic damage? Carcinogenicity?

  7. TOXICOLOGY - WHAT do we examine? PARAMETER/PROCESS EXPERIMENTS “Safety Pharmacology” Behaviour, Function, Physiology, Behaviour, Function, Physiology, Clinical biochemistry, pathology “General Toxicology” “Genetic Toxicology and Carcinogenicity” Mutation, Chromosomal changes, Non-genotoxic carcinogens Fertility, pregnancy, Fetal, peri/post-natal “Reproductive Toxicology”

  8. How are we doing………….? Concordance of Toxicity of Pharmaceutical in Humans and in Animals International Life Sciences Institute Workshop - April 1999 (ILSI) [Regulatory Toxicology and Pharmacology 32:56-67 (2000)]

  9. Concordance of Toxicity of Pharmaceutical in Humans and in Animals International Life Sciences Institute Workshop - April 1999 (ILSI) ex. Regulatory Toxicology and Pharmacology 32:56-67 (2000) • 12 Companies • 150 Compounds • 221 Human Toxicities (HT) • 47 Multiple Human Toxicities True positive concordance 71% for rodents & non-rodents 63% for non-rodents alone 43% for rodents alone Concordance Best Haematologic, Gastrointestinal, Cardiovascular HTs Least Cutaneous HT’s

  10. 79% predicted 63% predicted 64% predicted Success of animal studies in predicting human toxicities emerging during clinical trials ILSI survey - 2001

  11. 94% detection within 4-Weeks Duration of animal studies to predict human toxicities First time to detection in rodent or non-rodent (n=151)

  12. Analysis of Causes of Development Failure Kennedy, T. 1997, DDT 2:436-444 (Similar info in: Prentis, 1988, Br J Clin Pharm, 25:387-396) (* = 7% if exclude anti-infectives)

  13. NON-CLINICAL SAFETY ASSESSMENT Getting the Job done ... #1 “SOME PRACTICALITIES”

  14. PRE-CLINICAL SAFETY ASSESSMENT Collaborative process with many participants: TOXICOLOGY and other essential contributions . . . . . . • ‘Absorbtion, Distribution, Metabolism & Excretion’ • Pharmacology • Pharmacy, Synthetic & Analytical Chemistry • Quality Assurance • Clinical Pharmacology & Research

  15. PRE-CLINICAL SAFETY ASSESSMENT SOME OF THE PRACTICAL DETAILS • The ‘Test System’ • In vitro, in vivo, ex vivo, in silico • The ‘Test Material’ • The Dose • The Route

  16. PRAGMATISM Availability Cost Size Handlability Background knowledge SCIENCE Pharmacology Metabolism Pharmacokinetics Physiology SELECTION OF SPECIES AND….. May include: Mouse, Rat, Hamster, Rabbit, Dog, Pig, Marmoset, Cynomolgus monkey

  17. THE TEST MATERIAL All medicines contain more than the active drug ! • ACTIVE DRUG • Related substances • Process residues • Degradation products • Excipients • Other active materials • ‘Extractives’

  18. LOW DOSE small multiple of the therapeutic dose • HIGH DOSE limited by toxicity (or kinetics, pharmacology, pharmacy) • MID DOSE somewhere in between! Balance between definition of toxicologic profile with support for clinical studies THE DOSE? …..How much drug do we administer Guiding principles from....................... PHARMACOLOGY/TOXICOLOGY/KINETICS CLINICAL DOSE/EXPOSURE “....But mg swallowed does not equate to exposure ......”

  19. ESTIMATING DRUG EXPOSURE • 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 INITIALLY . . . . Estimates based on pharmacology and human kinetic modelling LATER . . . . . Exposures achieved in human volunteers & patients Don’t forget exposure to metabolites may also be important!

  20. Routes of Administration of test material ‘Usually to reflect the intended clinical route’ Oral Diet, intubation, tablets, capsules Intravenous Infusion, injection Inhalation Powders, aerosols Intranasal Subcutaneous Topical Creams, lotions, ointments Other local sites Determined by clinical use (Intraperitoneal) Rarely Non-clinical routes may be used to increase/maximise systemic exposure of compound, overcome local tolerability issues, to support special clinical investigations

  21. TOXICOLOGY - The Menu • Safety Pharmacology • Acute/Single dose • Repeat Dose • Genotoxicity • Oncogenicity • Reproductive & Developmental • Health and Safety • Environmental

  22. WHEN do we have to provide the information? CANDIDATE SELECTION TRIALS IN PATIENTS BEFORE FIRST DOSE TO MAN FOR MARKETING APPROVAL FORMAL SAFETY ASSESSMENT SCREENING GENETIC TOX SAFETY PHARM ACUTE TOXICITY 14-28 DAY STUDIES* (rodent + non-rodent ) 3-9 MONTH STUDIES (rodent + non-rodent ) REPRODUCTION & DEVELOPMENT H&S, ENVIRONMENT *Depending on trial design GENETIC TOX SAFETY PHARM RODENT: 4-DAYS Other ‘Specials’ Cytotoxicity S.A.R alerts CARCINOGENICITY DEVELOPMENT EXTRA STUDIES? Juvenile Toxicology Local tolerance Immunotoxicity Phototoxicity

  23. NON-CLINICAL SAFETY ASSESSMENT Getting the Job done .... #2 The studies to be conducted

  24. SAFETY PHARMACOLOGY(Undesirable pharmacodynamic changes) • CNS • Behavioural Effects • “Irwin-style” observational screen • Respiratory • Plethysmography • Cardiovascular function • Physical monitoring or Remote Telemetry • Electrophysiology • Cardiac ion channels, QT/’torsades’ ICH S7a and b guidelines

  25. “GENERAL TOXICOLOGY” STUDIES REPEAT DOSE TOXICOLOGY • TWO SPECIES, typically Rat and Dog • ~12 rodents, ~4 non-rodents /sex/ Gp • Control group and at least 3 drug-treated • Max 1000mg/kg • Typically by clinical route • 14 Days to 9 Months treatment • May Include ‘Recovery’ Post-treatment ICH S4a guideline - Chronic Tests

  26. ASSESSING TARGET ORGAN TOXICITY • Clinical observations: condition, behaviour, food intake, body weight • Functional measurements: ECG, Ophthalmoscopy • Clinical pathology: haematology, clinical biochemistry, urinalysis • Macropathology and organ weights • Micropathology 50+ tissues (nearly 5000 tissue specimens to examine) SUPPORTED BY TOXICOKINETICS

  27. REPRODUCTIVE & DEVELOPMENTAL TOXICOLOGY

  28. S5a S5b

  29. REPRODUCTIVE & DEVELOPMENTAL TOXICOLOGY KEY STAGES FOR EXAMINATION: THREE ROUTINE SCREENING STUDIES RAT RABBIT • Pre-mating to conception • Conception to implantation • Embryo-Fetal development - mid-pregnancy • Fetal development - late pregnancy • Birth to weaning • Weaning to Sexual Maturity 1 2 2 3 1 = Fertility; 2 = Embryofetal Development; 3 = Pre/post-natal

  30. Rat/rabbit embryo-fetal development study (treat females) F1 Organogenesis Parturition Lactation Mate Day 7 Kill dams Premating Mating Implantation (day 6) Kill Mate Kill pre-term Implantation Closure of hard palate Rat pre- and post-natal development study (treat females) ICH Guidelines - PREFERRED OPTIONS Rat fertility and early embryonic development study (treat male and/or female)

  31. GENOTOXICITY Tests to detect genetic damage directly or indirectly ENDPOINTS • Gene Mutation • Chromosomal damage • Recombinations • Changes in chromosome No. • Bacterial mutation assays • Mammalian cells In vitro (Mutation/clastogenicity - Mouse Lymphoma or CHO cells, Human Peripheral Lymphocytes) • Chromosome damage in vivo (Micronucleus test, Unscheduled DNA synthesis) Compounds which are positive in these tests MAY be human carcinogens or mutagens ICH S2(R) Guidelines

  32. Some other specialised areas of Safety Testing Immunotoxicology: European and US guidance • Tests for all drugs to be registered in Europe (July 2000) • either primary antibody response to T-cell dependent antigen or flow cytometry in combination with NK kill assay • For ‘immunoactive’ drugs add other special tests • FDA: a “Concern-based” approach focused on….. • Unintended immunosuppression and enhancement • Drugs to be used in patients with immuno-deficiency diseases • Hypersensitivity for respiratory and topical drugs

  33. Some other specialised areas of Safety Testing Photo-safety: European and US guidance Europe - Note for Guidance, June 2002 Hierachy of absorbance, in vitro, biodistribution (skin, eye), and clinical studies. plus, Photo-allergy and photo-carcinogenicity. 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 A PARTICULAR CONSIDERATION FOR TOPICAL, DERMATOLOGY MEDICINES

  34. CARCINOGENICITY “Given the complexity of the process of carcinogenesis, no single experimental approach can be expected to predict the carcinogenic potential of all pharmaceuticals for humans” • An expensive step in the dark! • Closely scrutinised in Regulatory Review • Data delivered late in development program ICH S1 guideline, July 1997

  35. CARCINOGENICITY LIFE-TIME STUDIES IN RATS AND MICE (18-24 MONTHS) • 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? Use of short term, transgenic mouse studies possible. Can replace or supplement mouse ‘lifetime’ study but careful justification required.

  36. CARCINOGENICITY • 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

  37. NON-CLINICAL SAFETY ASSESSMENT What does it all mean.....? “Determining the Risk”

  38. 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 From this we can make an estimate of ... No Effect Dose No Observable Effect Level (NOEL) No Observed Adverse Effect Level (NOAEL)

  39. EFFECTS • 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?

  40. Systemic Exposure and Safety Assessments Extent and Duration of Systemic Exposure (eg: 2, 10 and 50 mg/kg in rats) No Observed Adverse Effects at 2mg/kg Systemic Exposure ng/ml Hours post-dose

  41. Limit of human exposure Max. human Exposure Extent and Duration of Systemic Exposure (eg: 2, 10 and 50 mg/kg in rats. 20mg to Human) Systemic Exposure and Safety Assessments No Observed Adverse Effects at 2mg/kg Systemic Exposure Hours post-dose Maximum rat plasma concentration and duration of exposure to drug is ~2x that predicted/achieved in humans

  42. Systemic Exposure and Safety Assessments Daily Systemic Exposure (AUC 0-24hr) AUC 0-24hr Max. exposure in humans over 24 hours DAILY DOSE In the rat the maximum 24 hour exposure to drug is ~2x that predicted/achieved in humans

  43. PRE-CLINICAL SAFETY ASSESSMENT DETERMINING THE RISK Putting adverse effects into clinical perspective - Some considerations • 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)

  44. PRE-CLINICAL SAFETY ASSESSMENT 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 Data, Results and Opinions TO Safety Assessment for Ethical & Regulatory agencies.

  45. NON-CLINICAL SAFETY ASSESSMENT What may it enable us to do.... Toxicology and clinical trial durations

  46. NON-CLINICAL SAFETY ASSESSMENT CLINICAL TRIALS • Phase 1 • Phase 2 • Phase 3 • Phase 3b/4 Healthy volunteers (single or multiple doses) Volunteer patients (single or multiple doses). To define safety and dose range for efficacy trials Definitive safety & efficacy trials in patients Post- marketing - Product differentiation, new indications, combinations etc.

  47. REPEAT DOSE TOXICOLOGY DURATIONS - ICH M3

  48. What dose? • A fraction of the NOAEL based on..? • Administered dose (mg/kg, mg/ml) • local tolerance • Administered dose ‘scaled’ between species (mg/m2) • Starting dose FTIH, liver toxicity, GI “direct effects” • Maximum Systemic drug concentration (Cmax) • CNS, CV • 24 hour systemic exposure (AUC0-24) • Systemic organ toxicity

  49. MABEL EMEA/CHMP/SWP/28367/07 • 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