CDER INDNDA Reviews Guidance The Common Technical Document

CDER IND/NDA Reviews Guidance, 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 Managers Medical Officers Pharmacologists/Toxicologists Chemists Pharmacokineticists Statisticians

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

Guidance FDA/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 • FDA Guidance – Draft (for comment purposes only) – Final • http: //www.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/4120 fnl. pdf

Good Review Practice General Toxicology Study Results: Mortality Clinical Signs Body Weights Food Consumption Ophthalmoscopy Electrocardiography Hematology Clinical Chemistry Urinalysis Organ Weights Gross Pathology Histopathology Toxicokinetics

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.