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 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

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


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


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


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


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


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


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


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)

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

  • 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

  • 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

  • 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

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


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

Risk Management


Parameters Evaluated in Safety studies

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

  • Clinical Chemistry:

    ASTALTAlk Phos

    sodiumpotassiumcalcium

    total proteinglobulinchloride

    albumintotal cholesterolBUN

    triglyceridesA/G ratiocreatinine

    glucoseGGTtotal bilirubin

    Continued…


Parameters Evaluated in Safety studies

  • Hematology:

    Hemoglobin (Hg) conc.RBCHCT

    RBC volumeRBC Hgreticulocytes

    WBC (total & Differential)platelet countprothrombin time

    aPTTplatelet volume bone marrow smears

  • Urinalysis:

    Specific gravityvolumebilirubinpH

    Proteinsedimentglucoseketones

    Continued…


Parameters Evaluated in Safety studies

  • Necropsy:

    • Gross evaluation

    • Organ weights

    • Microscopic (see list below)

      List of organs/tissues evaluated

      Gross lesionsKidneyUrinary bladder

      LiverPancreasSalivary gland

      HeartAortaSkin/adnexa

      Mammary glandTongueTrachea

      Continued…


Parameters Evaluated in Safety studies

List of organs/tissues evaluated

LungSpleenThymusLymph nodes

ThyroidParathyroidAdrenalPituitary

TestisEpididymisProstateSeminal vesicle

OvaryCervixUterusVagina

EsophagusStomachDuodenumJejunum

IleumCecumColonBrain

Spinal cordEyeBone (sternum)Nerve (peripheral)

JointBone MarrowOptic nerveOviduct

UreterGALTLarynxTurbinates


Parameters Evaluated in Embryo-Fetal Development studies

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

  • Laparotomy

    • Dams:

      Gravid uterine wt.Corpora luteaImplantation sites

      Early/late resorptionsDead/live fetuses

      Placenta

    • Fetus:

      Body wt.Sexexternal

      InternalSkeletal


Parameters Evaluated in Fertility & Early Embryonic Development studies

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

  • Females

    Corpora luteaImplantation sites

    AbortionsPremature deliveries

  • Males

    Sperm 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


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