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Safety Sciences Role in Pharmaceutical Development

Safety Sciences Role in Pharmaceutical Development. Discovery. FD. ED. ESD. SDS. LD. CS. Pre- Clinical. P-1. P-2. P-3. Safety Sciences Functional Objectives and Responsibilities. Stage Gates. R2D2. SAN. POP. LAN. CAN. NDA. IND. Documents Strategy SSLJ Responsibility.

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Safety Sciences Role in Pharmaceutical Development

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  1. Safety Sciences Role in Pharmaceutical Development

  2. Discovery FD ED ESD SDS LD CS Pre- Clinical P-1 P-2 P-3 Safety Sciences Functional Objectives and Responsibilities Stage Gates R2D2 SAN POP LAN CAN NDA IND Documents Strategy SSLJ Responsibility pCAN POP CAN Target/ Benchmark ETOSA,LBR TOT, TI TAL TAL+ In.Sci TAL+Path+In. Sci Path+ ECMT Rep.+General Tox+ In.Sci ECMT Rep + TAL

  3. ESD SDS CS Pre- Clinical P-1 P-3 Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (SDS) LD P-2 SDS R2D2 SAN POP LAN CAN NDA IND POP Mechanism- or target based liabilities Safety Sciences Objective Use model or protoype to detect fundamental risks Philosophy Focused in vitro assays or (limited) in vivo work in model; literature Capability

  4. ESD SDS CS Pre- Clinical P-1 P-3 P-2 LD R2D2 SAN POP LAN CAN NDA IND LAN Probablility-based adverse outcome screen Generic approach to reducing attrition by detecting patterns previously associated with adverse outcomes Toolbox Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (LD) LD Safety Sciences Objective Philosophy Capability

  5. ESD SDS CS Pre- Clinical P-1 P-3 CS CAN Issue Resolution (targeted) Targeted approach to integrate concentration- exposure relationships and past experience into candidate optimization Toolbox Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (CS) LD P-2 R2D2 SAN POP LAN CAN NDA IND Safety Sciences Objective Biological Properties Philosophy Capability

  6. ESD SDS CS Pre- Clinical P-1 P-3 P-2 R2D2 SAN POP LAN CAN NDA IND Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (CAN to FIH) LD CAN FIH Position for rapid FIH support and accurate bulk estimation; support introduction into humans Safety Sciences Objective Identify safe clinical starting doses and relevant biomarkers; Risk Manage Philosophy Studies Capability

  7. ESD SDS CS Pre- Clinical P-1 P-3 P-2 POC R2D2 SAN POP LAN CAN NDA IND Estimate human risk Minimize human risk until POC is shown and a reasonable risk-benefit comparison can be made Studies Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (POC) LD Safety Sciences Objective Philosophy Capability

  8. ESD SDS CS Pre- Clinical P-1 P-3 P-2 FD R2D2 SAN POP LAN CAN NDA IND Define human risk Definitive preclinical assessments of relevant human risks Studies Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (FD) LD Safety Sciences Objective Philosophy Capability

  9. Registration ESD SDS CS Pre- Clinical P-1 P-3 P-2 R2D2 SAN POP LAN CAN NDA IND Obtain approval and appropriate label descriptions Communicate risks clearly and unambiguously; provide guidance for detection of undesired effects Phase IV Studies Alignment of Safety Sciences Activities with Drug Discovery/ Development Stages (Registration) LD Safety Sciences Objective Philosophy Capability

  10. LJ Safety Sciences Toolbox (*under development) 1 2

  11. Biological Properties Evaluated in a Safety Assessment • Acute Toxicity • Cumulative/ Chronic Toxicity • Teratogenicity • Reproductive Toxicity • Genotoxicity • Local Effects • Carcinogenicity • Pharmacology

  12. Studies Conducted During the Pre-Clinical Phase • GenotoxicityBacterial Reverse Mutation & Chromsomsal Aberration • Safety PharmacologyCV/Respiratory & Behavior • Acute Toxicity1 rodent and 1 non-rodent species (may be part of repeated-dose study) • Cumulative Toxicity 1 Rodent and 1 non-rodent Species • < 2 Weeks in humans: 2 Weeks in Tox Studies • Up to 1 Month: 1 Month • Up to 3 Months: 3 Months • Up to 6 Months: 6 Months • > 6 Months: 6 Months Rodent + 9 (12) Months Non-Rodent

  13. Studies Conducted During Human Clinical Trials • Phase II (Therapeutic Exploratory) • Cumulative/Repeat dose Same as Phase I for all Regulatory Agencies Schedule-Dependent up to 6 Months • Embryo-Fetal Development (2 Species) • Reproductive Tox • GenotoxicityAdditional mammalian mutation/in vivo clastogenicity

  14. Studies Conducted During Clinical Trials Continued • Phase III (Therapeutic Confirmatory)/Pre-NDA • Complete Reproductive Toxicity Studies • EU and Japan Trials/Marketing Up to 3 Months: 6 Months Rodent + 3 Months Non-Rodent Greater than 6 Months: 6 Months Rodent + 9 (12) Months Non-Rodent • Support CMC/EU Notification • Begin Carcinogenicity Studies (2 Species) • Complete Safety Pharmacology • Specialized Safety (aged, pediatrics, metabolites)

  15. Studies Conducted Post Marketing Approval Phase IV • Post Marketing Studies • Clinical studies to extend claims or usage of new patient population or indication • To demonstrate manufacturing changes • To validate surrogate clinical endpoints required in cases of accelerated approval

  16. Compound A: GI: emesis,Hemorrhage Hematology: Thrombocytopenia, hyperglycemia, Increase PT CNS: Convulsions, seizures Respiration: Rate increased Fatalities: yes Would you advance this compound into Phase 1 healthy volunteers? Compound B: GI: Emesis, loss of appetite CNS: Tremors, convulsions, chills, flushing CV: Tachycardia, arrythmias Reproduction: Teratogenic Would you advance this compound into Phase 1 healthy volunteers? Risk Management

  17. Aspirin: GI: emesis,Hemorrhage Hematology: Thrombocytopenia, hyperglycemia, Increase PT CNS: Convulsions, seizures Respiration: Rate increased Fatalities: yes Risk Management

  18. Caffeine: GI: Emesis, loss of appetite CNS: Tremors, convulsions, chills, flushing CV: Tachycardia, arrythmias Reproduction: Teratogenic Risk Management

  19. Parameters Evaluated in Safety studies • Clinical Observations: General condition and behavior, Food consumption, Body weights, Ophthalmology, Mortalities • Clinical Chemistry: AST ALT Alk Phos sodium potassium calcium total protein globulin chloride albumin total cholesterol BUN triglycerides A/G ratio creatinine glucose GGT total bilirubin Continued…

  20. Parameters Evaluated in Safety studies • Hematology: Hemoglobin (Hg) conc. RBC HCT RBC volume RBC Hg reticulocytes WBC (total & Differential) platelet count prothrombin time aPTT platelet volume bone marrow smears • Urinalysis: Specific gravity volume bilirubin pH Protein sediment glucose ketones Continued…

  21. Parameters Evaluated in Safety studies • Necropsy: • Gross evaluation • Organ weights • Microscopic (see list below) List of organs/tissues evaluated Gross lesions Kidney Urinary bladder Liver Pancreas Salivary gland Heart Aorta Skin/adnexa Mammary gland Tongue Trachea Continued…

  22. Parameters Evaluated in Safety studies List of organs/tissues evaluated Lung Spleen Thymus Lymph nodes Thyroid Parathyroid Adrenal Pituitary Testis Epididymis Prostate Seminal vesicle Ovary Cervix Uterus Vagina Esophagus Stomach Duodenum Jejunum Ileum Cecum Colon Brain Spinal cord Eye Bone (sternum) Nerve (peripheral) Joint Bone Marrow Optic nerve Oviduct Ureter GALT Larynx Turbinates

  23. Parameters Evaluated in Embryo-Fetal Development studies • Clinical Observations: General condition and behavior, Food consumption, Body weights, Mortalities • Laparotomy • Dams: Gravid uterine wt. Corpora lutea Implantation sites Early/late resorptions Dead/live fetuses Placenta • Fetus: Body wt. Sex external Internal Skeletal

  24. Parameters Evaluated in Fertility & Early Embryonic Development studies • Clinical Observations: General condition and behavior, Food consumption, Body weights, Estrus cycle, Mortalities • Females Corpora lutea Implantation sites Abortions Premature deliveries • Males Sperm count and motility from epididymis and vas deferens

  25. Parameters Evaluated in Pre- and Post-Natal Development studies • F0-Clinical Observations: General condition and behavior, Food consumption, Body weights, Lactation, Mortalities • F0 females: Implantation sites and Gross necropsy • F1: Pup weights, Appearance, Behavior, external/oral cavity abnormalities, visual integrity, sexual maturity, Locomotor activity, Startle response, Water maze, Passive avoidance and FOB • F1 Breeding: Estrus cycle, implantation sites and viable fetuses • F2: Pup weights, number and sexing and external/oral abnormalities

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