1. CDER IND/NDA Reviews Guidance, 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. 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 FDA Guidance –Draft (for comment purposes only) –Final http://www.fda.gov/cder/guidance/index.htm

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

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 Practice General 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.