1 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
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/ ToxicologyNonclinical Development
A compound is tested in cell cultures and whole animals in order to make educated guesses about how it should be used in people. Pharmacology Studies (efficacy,
mechanism) Toxicology Studies (safety) Pharmacokinetic studies (ADME)
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Pharmacology Studies 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 Studies Review the nonclinical (animal)
studies to: 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 (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)
While risks for humans cannot be eliminated, they may be anticipated, ameliorated, and/or avoided
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Common Types of Toxicity Studies
General Toxicity (repeat dose), can have incorporated in it: Safety Pharmacology TK
Genotoxicity (later in the development unless disease-free subjects are entered)
Reproductive Toxicity (later in the development)
Carcinogenicity (for disease-free subjects; later in the development)
Immunotoxicity (occasionally required)
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Pharmacokinetic (ADME) Studies 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)
Line listed data Interpretation of the data- The
output is “information”, not report
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Interpretation of the data Integration of intra-species findings
Clinical signs, clinical pathology, histopath... Exaggerated pharmacologic effect? Intended
or toxic effects? Cross-species extrapolation
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
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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Plan in AdvanceEstimated Costs of Toxicology Studies
Anticancer Drug Development Guide; BA Teicher and PA Andrews
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User Fee
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.htmhttp://www.fda.gov/cder/about/smallbiz/pdufa.htmhttp://www.fda.gov/orphan/faq/index.htm
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ResourcesGuidances and Guidelines: ICH- http://www.fda.gov/cder/guidance/index.htm
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)
Articles/Books (regulatory + technical )
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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