CDER IND/NDA Reviews Guidance, The Common Technical Document and Good Review Practice

1. CDER IND/NDA ReviewsGuidance, The Common Technical Document and Good Review Practice John K. Leighton, Ph.D., DABT CDER/FDA

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

3. Review Team Project Managers Medical Officers Pharmacologists/Toxicologists Chemists Pharmacokineticists Statisticians

4. Nonclinical Studies • Pharmacodynamics/Pharmacology • Pharmacokinetics • Safety pharmacology • Toxicology • Genetic toxicity • Reproductive toxicity • Carcinogenicity

5. Goals of Nonclinical IND Studies • Identify starting dose • Identify organ toxicities and reversibility • Guide dosing regimens and escalation schemes

6. 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.

7. 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.

8. 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?

9. 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

10. 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 • FDA Guidance • Draft (for comment purposes only) • Final • http://www.fda.gov/cder/guidance/index.htm

11. IND format Start dose selection Acute toxicity testing Electronic NDA submission Carcinogenicity Genetic toxicity Reproductive toxicity Photosafety testing Immunotoxicology Biotechnology FDA/ICH Guidance Topics

12. 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.

13. 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

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

15. 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.