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CDER IND/NDA ReviewsGuidance,
The Common Technical Document and Good Review
Practice
John K. Leighton, Ph.D., DABT
CDER/FDA
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Overview
• Current IND/NDA review process• FDA/ICH guidance• Common Technical Document• CDER Pharmacology Good Review Practice
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Review Team
Project ManagersMedical OfficersPharmacologists/ToxicologistsChemistsPharmacokineticistsStatisticians
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Nonclinical Studies
• Pharmacodynamics/Pharmacology• Pharmacokinetics• Safety pharmacology• Toxicology• Genetic toxicity• Reproductive toxicity• Carcinogenicity
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Goals of Nonclinical IND Studies
• Identify starting dose• Identify organ toxicities and reversibility• Guide dosing regimens and escalation
schemes
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Pharmacology Studies
• Pharmacological activity determined in nonclinical studies is generally of low relevance to safety (IND) and efficacy (NDA) decisions.
• Summary report,without individual animal records or individual study results, usually suffices.
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Toxicology Study Design
• Pivotal for safety/start dose decision.• Toxicology studies should mimic the
schedule, duration, formulation, and route as that proposed for the clinical trial.
• Conform to standard toxicology protocols.• Conduct according to GLP.
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Initial IND Development
• Integrated pharmacology/toxicology summary.
• Full tabulation of each toxicology study to support safety of proposed trial.
• Pharmacogenomic data: – Start dose selection?– Choice of relevant species?– Identify biomarkers?
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IND/NDA Stage• Long-term toxicology studies• Genetic toxicology panel completed• Reproductive toxicology• Carcinogenicity studies (if necessary)
• Pharmacogenomic data:– Decrease study length?– Improve assessment of organ toxicity?– Provide mechanistic explanation of toxicity?
Not replace standard assessment
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GuidanceFDA/ICH
• Represent current thinking of the Agency.• Recommendations/not requirements.• FDA Guidance
– Draft (for comment purposes only)– Final
• http://www.fda.gov/cder/guidance/index.htm
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FDA/ICH Guidance Topics
• IND format• Start dose selection• Acute toxicity testing• Electronic NDA
submission
• Carcinogenicity• Genetic toxicity• Reproductive toxicity• Photosafety testing• Immunotoxicology• Biotechnology
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The Common Technical Document
• Guidance describing harmonized format for technical documentation for registration in all three regions.– Modules 2-5 common to all regions– Reduces time and resources used to compile
registration documentation
• Use with other ICH and Agency guidance.• Allows for regional specific summaries.
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Good Review Practice
• Guidance for Reviewers: Pharmacology/Toxicology Review Format
• Internal review format for IND and NDA primary reviews
• Purpose– standardization of reviews across divisions– ensure that important information is captured– allows for continued assessment of IND
• Consistent with ICH CTD• http://www.fda.gov/cder/guidance/4120fnl.pdf
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Good Review PracticeGeneral Toxicology Study
Results: MortalityClinical SignsBody WeightsFood ConsumptionOphthalmoscopyElectrocardiography
HematologyClinical ChemistryUrinalysisOrgan WeightsGross PathologyHistopathologyToxicokinetics
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SUMMARY
• Different submission format for pivotal safety data.• Good review practices for evaluation of data;
provides consistency among review divisions and transparency. GRP will need to consider interdiscliplinary review of pharmacogenomic data.
• Pharmacogenomics may play an important role in safety assessment in future INDs and NDAs.