Safety Sciences Role in Pharmaceutical Development

Safety Sciences Role in Pharmaceutical Development

Discovery

NDAR2D2SAN POP LAN CANIND

P-3ESD SDS CS Pre-Clinical

P-1 P-2

FDED

Documents

Strategy

SSLJResponsibility

StageGates

TAL TAL+ In.Sci

TAL+Path+In. Sci

pCANCAN

Path+ECMT Rep.

+General Tox+In.Sci

POP

ECMT Rep + TAL

Target/Benchmark

ETOSA,LBR

TOT,TI

Safety Sciences Functional Objectives and Responsibilities

LD

Alignment of Safety Sciences Activities with Drug Discovery/

Development Stages (SDS)



P-1 P-2

Safety Sciences Objective

Philosophy

Capability

SDS

POPMechanism- or target based liabilities

Use model or protoype to detect fundamental risks

Focused in vitro assays or (limited) in vivo work in model; literature

LD


Development Stages (LD)



P-1 P-2


Philosophy

Capability

LDLD

LANProbablility-based adverse outcome screen

Generic approach to reducing attrition by detecting patterns previously associated with adverse outcomes

Toolbox


Development Stages (CS)



P-1 P-2


Philosophy

Capability

LD

CS

CAN

Issue Resolution (targeted)

Targeted approach to integrate concentration- exposure relationships and past experience into candidate optimization

Toolbox

Biological Properties



P-1 P-2


Philosophy

Capability

LD

FIHCAN

Position for rapid FIH support and accurate bulk estimation; support introduction into humans

Identify safe clinical starting doses and relevant biomarkers; Risk Manage

Studies


Development Stages (CAN to FIH)


Development Stages (POC)



P-1 P-2


Philosophy

Capability

LD

POC

Estimate human risk

Minimize human risk until POC is shown and a reasonable risk-benefit comparison can be made

Studies


Development Stages (FD)



P-1 P-2


Philosophy

Capability

LDFD

Define human risk

Definitive preclinical assessments of relevant human risks

Studies


Development Stages (Registration)



P-1 P-2


Philosophy

Capability

LD

Obtain approval and appropriate label descriptions

Registration

Communicate risks clearly and unambiguously; provide guidance for detection of undesired effects

Phase IV Studies

Function Assay/Tool Utility StageGene Tox DEREK Rank Order SDS, LD, CS

Ames Decision Making SDS, LD, CS

In vitro Micronucleus Decision Making SDS, LD, CS

CV/Safety Pharm Cerep Rank Order LD, CS

HERG Decision Making LD, CS

Purkinje Decision Making CS

Telemetry* Decision Making CS

Safety of Target Antisense*, Trasgenics, Abs, Reporter*

Decision Making SDS

Target Organ/Safety Margin

Gene Expression (eg. arrays, PCR)

Rank Order LD, CS

Protein Modulation Rank Order LD, CS

In Vitro Cytotoxicity Rank Order LD, CS

In Vivo assays (eg. RF, LBRs, PK/Discovery studies)

Rank Order, Decision Making

CS

Metabonomics* Rank Order CS

LJ Safety Sciences Toolbox (*under development)

1 2

Biological Properties Evaluated in a Safety Assessment

• Acute Toxicity• Cumulative/ Chronic Toxicity• Teratogenicity• Reproductive Toxicity• Genotoxicity• Local Effects• Carcinogenicity• Pharmacology

Studies Conducted During the Pre-Clinical Phase

• Genotoxicity Bacterial Reverse Mutation & Chromsomsal Aberration

• Safety Pharmacology CV/Respiratory & Behavior

• Acute Toxicity 1 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

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– Genotoxicity Additional mammalian mutation/in vivo

clastogenicity

Studies Conducted During Clinical Trials Continued

• Phase III (Therapeutic Confirmatory)/Pre-NDA– Complete Reproductive Toxicity Studies

– EU and Japan Trials/MarketingUp 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)

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

Risk Management

• 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

• Aspirin:GI: emesis,Hemorrhage

Hematology: Thrombocytopenia, hyperglycemia, Increase PT

CNS: Convulsions, seizures

Respiration: Rate increased

Fatalities: yes

Risk Management

• Caffeine:GI: Emesis, loss of appetite

CNS: Tremors, convulsions, chills, flushing

CV: Tachycardia, arrythmias

Reproduction: Teratogenic

Parameters Evaluated in Safety studies

• Clinical Observations: General condition and behavior, Food consumption, Body weights, Ophthalmology, Mortalities

• Clinical Chemistry:AST ALT Alk Phossodium potassium calciumtotal protein globulin chloridealbumin total cholesterol BUNtriglycerides A/G ratio creatinineglucose GGT total bilirubin

Continued…


• 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…


• 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 TracheaContinued…


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

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 sitesEarly/late resorptions Dead/live fetusesPlacenta– Fetus:Body wt. Sex externalInternal Skeletal

Parameters Evaluated in Fertility & Early Embryonic

Development studies• Clinical Observations: General condition and behavior,

Food consumption, Body weights, Estrus cycle, Mortalities

• FemalesCorpora lutea Implantation sites

Abortions Premature deliveries

• MalesSperm count and motility from epididymis and vas deferens

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