Safety sciences role in pharmaceutical development
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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 functional objectives and responsibilities

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


Alignment of safety sciences activities with drug discovery development stages sds

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


Alignment of safety sciences activities with drug discovery development stages ld

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


Alignment of safety sciences activities with drug discovery development stages cs

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


Alignment of safety sciences activities with drug discovery development stages can to fih

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


Alignment of safety sciences activities with drug discovery development stages poc

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


Alignment of safety sciences activities with drug discovery development stages fd

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


Alignment of safety sciences activities with drug discovery development stages registration

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


Lj safety sciences toolbox under development
LJ Safety Sciences Toolbox (*under development)

1

2


Biological properties evaluated in a safety assessment
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
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


Studies conducted during human clinical trials
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


Studies conducted during clinical trials continued
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)


Studies conducted post marketing approval
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


Risk management1

Aspirin:

GI: emesis,Hemorrhage

Hematology: Thrombocytopenia, hyperglycemia, Increase PT

CNS: Convulsions, seizures

Respiration: Rate increased

Fatalities: yes

Risk Management


Risk management2

Caffeine:

GI: Emesis, loss of appetite

CNS: Tremors, convulsions, chills, flushing

CV: Tachycardia, arrythmias

Reproduction: Teratogenic

Risk Management


Parameters evaluated in safety studies
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…


Parameters evaluated in safety studies1
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…


Parameters evaluated in safety studies2
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…


Parameters evaluated in safety studies3
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


Parameters evaluated in embryo fetal development studies
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


Parameters evaluated in fertility early embryonic development studies
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


Parameters evaluated in pre and post natal development studies
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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