Pharmacology/Toxicology
information to submit an IND
for an anticancer drug
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This presentation is not an official
FDA guidance or policy statement.
No official support or endorsement
by the FDA is intended or should
be inferred
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Disciplines involved in the review process
of applications for oncology drug products
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Project Manager (to coordinate meetings,
respond to sponsors, provide regulatory
insights)
Pharmacology/Toxicology
Chemistry
Medical
Clinical Pharmacology
Biostatistics (usually not at the initial IND
stage)
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Pharmacology/ Toxicology
Nonclinical Development
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A compound is tested in cell cultures and
whole animals in order to make educated
guesses about how it should be used in
people.
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Pharmacology Studies (efficacy, mechanism)
Toxicology Studies (safety)
Pharmacokinetic studies (ADME)
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Pharmacology Studies
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Used to evaluate desirable effects, but
may give additional insight into toxicity
Exact mechanism of action may never be
determined
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Toxicology: The search for the
unexpected
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Toxicology Studies
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Review the nonclinical (animal) studies to:
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estimate the safe starting dose for clinical
studies
assess toxic effects with respect to target
organs; therefore, potential organ
toxicities to be monitored in the clinical
studies
assess potential reversibility
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Toxicology Studies
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(cont’d)
assess dose dependence
assess relationship to exposure
assess hazards that cannot be evaluated
in clinical trials (e.g. carcinogenicity and
teratogenicity)
To identify hazards and estimate
the relatively safe starting dose
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Toxicology Studies (cont’d)
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While risks for humans cannot be
eliminated, they may be anticipated,
ameliorated, and/or avoided
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Common Types of Toxicity
Studies
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General Toxicity (repeat dose), can have
incorporated in it:
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Safety Pharmacology
TK
Genotoxicity (later in the development unless
disease-free subjects are entered)
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Reproductive Toxicity (later in the development)
Carcinogenicity (for disease-free subjects; later in
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Immunotoxicity (occasionally required)
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the development)
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Pharmacokinetic (ADME)
Studies
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Not required, but strongly encouraged
Assists the interspecies comparison of
toxicity and extrapolation to humans
May suggest modifications in the intended
dose, route or schedule for the clinical trial
Can contribute to optimal dose escalation in
early clinical studies
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Nonclinical Information
(Item 8 of the IND)
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Line listed data
Interpretation of the data- The
output is “information”, not report
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Interpretation of the data
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Integration of intra-species findings
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Clinical signs, clinical pathology, histopath...
Exaggerated pharmacologic effect? Intended or
toxic effects?
Cross-species extrapolation
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Allow educated guesses about the implications of
nonclinical findings for human
Are findings consistent across species?
Correlate toxic doses with exposure
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Estimation of the
starting dose in
cancer patients
http://www.fda.gov/cder/cancer/docs
/doseflow.pdf
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Good Laboratory Practices (GLP)
21CFR 58
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The purpose of the GLPs is to assure
the quality and integrity of the
nonclinical safety data submitted to the
regulatory agency
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Good Laboratory Practices (GLP)
http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr58_00.html
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Plan in Advance
Estimated Costs of Toxicology Studies
Anticancer Drug Development Guide; BA Teicher and PA Andrews
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Example of Poor Planning!
Acknowledge that planning is a dynamic process
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User Fee
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No IND fee
NDA user fee is waived for Small Business
(<500 employees) for the 1st human drug
application that a small business or its
affiliate submits for review.
http://www.fda.gov/cder/about/smallbiz/Econonic.htm
http://www.fda.gov/cder/about/smallbiz/pdufa.htm
http://www.fda.gov/orphan/faq/index.htm
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Resources
Guidances and Guidelines:
 ICH- http://www.fda.gov/cder/guidance/index.htm
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S1 Carcinogenicity
S2 Genetic toxicity
S3 Toxicokinetics
S4 Duration of Chronic Toxicity Testing
S5 Reproductive toxicity
S6 Biotechnology
S7 Safety Pharmacology
M3 Nonclinical Safety Studies for the conduct of
Human Clinical Trials
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Resources
(cont’d)
CFSAN Redbook:
http://www.cfsan.fda.gov/~redbook/redtoca.html
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Resources
(cont’d)
Articles/Books (regulatory + technical )
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DeGeorge et al.: “Regulatory considerations
for preclinical development of anticancer
drugs”. Cancer Chemother Pharmacol 1998,
41: 173-185
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Resources
(cont’d)
• Diehl et al: “A good practice guide to the
administration of substances and removal of
blood, including routes and volumes”- Journal
of Applied Toxicology 2001, 21: 15-23
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