CDER IND/NDA ReviewsGuidance,

The Common Technical Document and Good Review

Practice

John K. Leighton, Ph.D., DABT

CDER/FDA

Overview

• Current IND/NDA review process• FDA/ICH guidance• Common Technical Document• CDER Pharmacology Good Review Practice

Review Team

Project ManagersMedical OfficersPharmacologists/ToxicologistsChemistsPharmacokineticistsStatisticians

Nonclinical Studies

• Pharmacodynamics/Pharmacology• Pharmacokinetics• Safety pharmacology• Toxicology• Genetic toxicity• Reproductive toxicity• Carcinogenicity

Goals of Nonclinical IND Studies

• Identify starting dose• Identify organ toxicities and reversibility• Guide dosing regimens and escalation

schemes

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.

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.

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?

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

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– Draft (for comment purposes only)– Final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

FDA/ICH Guidance Topics

• IND format• Start dose selection• Acute toxicity testing• Electronic NDA

submission

• Carcinogenicity• Genetic toxicity• Reproductive toxicity• Photosafety testing• Immunotoxicology• Biotechnology

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.

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

Good Review PracticeGeneral Toxicology Study

Results: MortalityClinical SignsBody WeightsFood ConsumptionOphthalmoscopyElectrocardiography

HematologyClinical ChemistryUrinalysisOrgan WeightsGross PathologyHistopathologyToxicokinetics

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.