FDA Expectations for Toxicology Support of Clinical Trials ...

FDA Expectations for Toxicology Support

of Clinical Trials and Marketing

Tacey E.K. White, PhD

Director of Operations and Senior Consultant

Nonclinical Toxicology

Aclairo Pharmaceutical Development Group, Inc.

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Outline

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Relevant ICH Guidelines

Standard Development ¨C Small Molecules

Cancer Indications

Biologics - CDER

Biologics and Novel Therapeutics - CBER

Pediatric Indications ¨C time permitting

FDA Follows ICH Guidelines

? ICH M3(R2) - Guidance on nonclinical safety studies for the

conduct of human clinical trials and marketing authorization for

pharmaceuticals - Step 4

¨C Describes the timing of all nonclinical studies needed to support

each phase of clinical development and marketing

? ICH S9 ¨C Nonclinical Evaluation for Anticancer Pharmaceuticals

¨C Describes specific considerations for oncology products

? ICH S6 (R1) - Preclinical Safety Evaluation of BiotechnologyDerived Pharmaceuticals - Addendum (R1): Step 4

¨C Describes additional considerations for Biologics - CDER

Drug Development Phases

Discovery

Non-Clinical ¨C Toxicology, Safety Pharm, DMPK

Genetic Tox

Repeat Dose Tox

Safety Pharmacology

Ames Test

Mouse Lymphoma

In vivo Micronucleus

28 Day rodent

28 Day non-rodent

Rat Irwin ¨C neurobehavior

Rat Respiratory

Non-rodent cardiovascular

in vitro hERG assay

IND

FTIH

[WOCBP]

Phase I

Healthy volunteers

Phase IIa / IIb

Patients, Dose-ranging

Phase III

Patients, Definitive

Sub-chronic Tox

Chronic Tox

Carcinogenicity

3-month rodent

3-month non-rodent

6 - month rodent

9 - month non-rodent

2-year rat

2-year mouse

ReproTox

ReproTox

ReproTox

EFD - rodent

EFD - non-rodent

Male Fertility - rodent

Female Fertility - rodent

Pre-/postnatal development

- rodent

IND = Investigational New Drug application ¨C permission to dose people

NDA = New Drug Application ¨C permission to market drug

BLA = New Biologics Application ¨C permission to market biologic

NDA

BLA

Standard Duration of Nonclinical Toxicity Studies to

Support Clinical Trials (ICH M3(R2))

Max Clinical

Trial Duration

Pivotal (Definitive) Toxicology Study

Duration

Rodents

Non-rodents

¡Ü2 Weeks

2 weeks

2 weeks

2 Weeks to 6 Months

Same as clinical trial

Same as clinical trial

Greater than 6 Months

6 months

9 months (6 in EU)

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