Toxicology in Drug Development

Types of Toxicology Studies Recommended

• General Toxicology
– acute and repeat dose toxicology studies
• Special Toxicology Studies
– local irritation studies, e.g., site specific, ocular
– hypersensitivity studies for inhalation and dermal drug products
• Reproductive and Developmental Toxicology Studies
– male and female fertility
– embryonic and fetal development
– post-natal reproductive and developmental effects
 Impact of Nonclinical Studies on Drug Development

• Setting Initial Doses in Humans

• Identification of Possible Adverse Effects
• Identification of Reversible vs Irreversible Effects
• Identification of Useful Biomarkers for Monitoring Toxicity
during Clinical Trials
• Drug Labeling
 Drug Development Process

PRELEAD IND NDA

Investigational New Drug New Drug Application

Research
“Discovery”

Development
 Toxicology Testing Process
PRELEAD IND NDA/BLA

Discovery

Development

Nonclinical tox studies in animals

P1 P2 P3
Clinical trials
 What are Phase 1, 2, and 3 Trials?

Phase 1: Phase 2:
 Safety and pharmacokinetics  Efficacy and safety
 Generally 20 to 80 subjects
 Usually no more than
 Closely controlled
several hundred subjects
 Closely controlled

Phase 3:
 Efficacy and safety
 Several hundred to several
thousand subjects
 Controlled and uncontrolled
 Nonclinical Information Flow
In vitro/Animal Models Application Trial
• Hypothesis testing • Potential for effect
• Mechanism of • Toxicity profile
action • Dose/regimen
• Safety assessment • Route of administration
• Develop surrogate
markers
• ADME/PK

J. Lipani, 1998
 Contract Research Organizations
• Formulation/Manufacture/Fill and Finish
• Metabolism/distribution (ADME/PK)
• In vitro
– Activity/high throughput screening
– Toxicity (non-GLP and GLP)
• In vivo
– Research
– Model development
– Proof of concept/efficacy
– Development
– GLP toxicology testing for regulatory submission
 Good Laboratory Practice (GLP) for Nonclinical
Laboratory Studies

• 21 CFR Part 58
• Regulatory guidelines for conduct of toxicology (safety)
studies in support of regulatory submission
• Guidelines “intended to assure the quality and integrity of the
safety data…”
 Types of Nonclinical Studies Reviewed by FDA

• Basic pharmacology

– primary and secondary mechanisms of action

– nonclinical efficacy studies

• Safety pharmacology

• Pharmacokinetics

• Toxicology

• Genotoxicology

• Carcinogenicity
 What Does FDA Expect from Nonclinical Studies?

• Pharmacology
– proposed mechanism of action
– identification of secondary pharmacologic effects
– Proof of Concept studies for serious indications
• Safety Pharmacology
– effects on neurological, cardiovascular, pulmonary,
renal, and gastrointestinal systems
– abuse liability
 What Does FDA Expect from Nonclinical Studies?

• Pharmacokinetics
– comparison of ADME in species used for toxicology
studies
– identification of bioaccumulation potential
– identification of potential differences in gender
– generation of PK parameters, e.g., Cmax, Tmax,
AUC(o-inf.), half life
 What Does FDA Expect
in General Toxicology Studies?

• Acute and repeat toxicology studies in two species

• Duration of repeat dose nonclinical studies should be at least

equal or greater than the duration of the proposed clinical study

• A control and at least 3 drug concentrations

– identification of the NOAEL and MTD

– identify shape of the dose-response curve

• Doses/systemic exposure should exceed clinical dose/exposure

 What Does FDA Expect
in General Toxicology Studies?

• Formulation should be the same as the clinical formulation

• Route of exposure:

– should be the same as clinical route

– additional routes of exposure may be needed to achieve systemic toxicity

• Histopathology examination of all animals and standard tissues

• Lymphoproliferative tissues should be assessed for unintended effects on the

immune system

• Toxicokinetic information
 Timing of Nonclinical Studies - Phase 1
• Prior to “First Time in Humans”
– safety pharmacology
– pharmacokinetics/toxicokinetics (exposure data)
– single dose toxicity studies in 2 mammalian species
– expanded acute or repeat dose toxicity studies in a rodent
and a nonrodent
– local tolerance
– in vitro evaluation of mutations and chromosomal damage
– hypersensitivity for inhaled and dermal drugs
– teratogenicity studies
 Timing of Nonclinical Studies - Phase 1/2

• Phase 1-2 Clinical Trials

– repeat dose toxicity studies of appropriate length

• Phase 2 Clinical Trials

– complete genotoxicity assessment (in vivo and in vitro)
– repeat dose toxicity studies of appropriate length
 Timing of Nonclinical Studies - Phase 3

• Phase 3 Clinical Trials

– repeat dose toxicity studies of appropriate length
– male and female fertility
– post-natal development