Larry Lesko, director of the Office of Clinical Pharmacology at the Center for Drug Evaluation and Research with the Federal Drug Administration, begins his talk by making the FDA’s commitment to personalized medicine as a public health agency. He touched on the future focus of improving drug safety and its role in future healthcare policy, citing the FDA Amendments Act of 2007. Lesko explained that the dual mission at hand is to foster innovation and promote new initiatives under a critical path while developing and clearly articulating the standards for drugs and diagnostics. The organization takes a lifecycle approach to evidence to inform and support decisions—this goes for previous drugs and new drug development. Moving forward, what else needs to be done? Lesko explained that ways to consensus on evidence are needed to support new drug approvals and relabeling of older drugs. He also believes that the FDA needs to develop more unambiguous drug product labels to enable actionable medical decisions and improve communication between CDER and CDRH on co-development and companion diagnostics.

1. PGx in Clinical Medicine: What Is FDA Doing to Facilitate the Movement Personalized Health Care National ConferenceThe Ohio State UniversityColumbus, OhioOctober 2, 2009 Lawrence J. Lesko, Ph.D., F.C.P. Office of Clinical Pharmacology Center for Drug Evaluation and Research Food and Drug Administration Silver Spring, Maryland

2. One emerging opportunity is the area of personalized medicine in which the agency should work with scientific leaders on novel approaches to treating illness .M.A. Hamburg and J.M. SharfsteinNEJM, June 11, 2009 FDA As A Public Health Agency Is Committed to Personalized Medicine

3. Number of Innovative Drugs Approved: Approvals in 2007 Lowest in 15 Years Nature Reviews Drug Discovery, February 2008

4. Improving Drug Safety Will Continue to Be a Major Focus of Public Health Policy Safety includes Preventing or reducing the probability of AEs Includes inability to respond to a drug Safety First and Sentinel Initiative FDA Amendments Act (2007) Post-marketing requirements (vs commitments) Post-marketing active surveillance systems REMS requirements for higher risk drugs Empowers requests to update labels

6. Growth in Reviews of Regulatory Submissions With Genomic Information

7. Guidance Outlining the Quantity and Quality of Evidence to Support Various Effectiveness Claims “In certain cases, effectiveness of a new product may be adequately demonstrated without additional adequate and well-controlled clinical efficacy trials. This is because other types of data provide a way to apply known effectiveness to a new population, a different dose or a different dosage form.” http://www.fda.gov/ohrms/dockets/98fr/971oogdl.pdf

8. Examples of Difference in Evidence Standards: The Question and Prior Knowledge 1. More than 90% of generic drugs are approved on bioequivalence studies in healthy volunteers 2. 57% of all new pediatric label approvals are based on PK and safety studies 3. Virtually all dosing adjustments for patients with renal impairment are based on PK studies 4. Trileptal was approved for monotherapyof partial seizures in children 4 to 16 yr based on M/S

9. Hierarchy of Evidence to Support Efficacy and Safety Claims in PGx Highest quality and quantity of evidence To identify “responder” and select drug (efficacy PGx) To identify “non-responder” and exclude from treatment To identify “at-risk” patient for likelihood to have serious AE (safety PGx) To improve precision of dose selection To elucidate specific genetic sources of variability in PK and/or PD To explore hypothesis-free metabolism and transporter gene association with PK Lowest quality and quantity of evidence

10. Examples of Hierarchy Used in Regulatory Decisions KRAS-testing to exclude non-responders to panitumamab Tropism test for CCR5 virus for maraviroc (efficacy PGx) HLA-B*1502 and SJS with CBZ (safety PGx) CYP2D6-guided dosing of tetrabenazine Association of irinotecan PK variability with common variants of ABCs, CYP3A4, CYP3A5 and UGT1A9 DMET chip with 1936 genetic variations in 225 genes

11. Relabeling of Previously Approved Drugs

12. Regulatory Decision on Retrospective Analyses of Banked Samples Cetuximab and panitumamab approved in 2004 and 2006 for patients with colorectal cancer Sponsor presented retrospective data on genetic testing for somatic mutations in the KRAS gene Tumors from patients with colorectal cancer enrolled in 7 clinical trials of the two drugs Retrospective subgroup analyses showed patients with mutated KRAS genes failed to respond FDA updated indication and usage sections of labels of both drugs ODAC, December 16, 2008

13. Critical Evidence to Support the KRAS Biomarker Hypothesis for EGFRI 1. Biological plausibility: downstream effects of blocking EGFR signaling not efficient with mutant KRAS activation 2. Consistent differences in objective response between WT and MT KRAS in 6 pooled single arm studies (replication) 3. High ascertainment rate of ~90% tumor samples from AWC studies (bias) 4. Prespecified statistical plan for data collection and retrospective analysis 5. Practical PCR test for KRAS mutations was analytically valid – sensitivity (95%) and specificity (100%)

14. Class Labeling Change Indication and Usage (Colorectal Cancer)Retrospective subset analysis of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13. The use of these drugs are not recommended for the treatment of colorectal cancer patients with these mutations [See Clinical Studies and Clinical Pharmacology]

15. PGx of Clopidegrel and CV Events in 1477 Patients with ACS esterases CYP1A2, 2C19, 2B6 CYP3A4/5, 2C19, 2C9, 2B6 (inactive) (active) Mega, NEJM, 2009

17. Phenotype and genotype distribution in populations

18. Effect of genotype on active metabolite exposure

19. Antiplatelet response between IMs and PMs

20. Genotype-linked CV event rates or stent thrombosis l

21. PGx testing can identify genotypes

22. Omits recommendation of optimal doses for PMs

23. New advice on PPI inhibition of CYP2C19http://www.genomeweb.com/dxpgx/fda-updates-plavix-label-pgx-data-does-not-provide-dosing-recommendations

24. Summary: PGx Is Not Qualitatively Different Than Current Clinical Practice Actions:Select DrugSelect Dose PredictableResponse Observations Molecular Tests

25. What Else Needs to Be Done? Ways to consensus on evidence needed to support new drug approvals and relabeling of older drug Develop more unambiguous drug product labels to enable actionable medical decisions Improve communication between CDER and CDRH on co-development and companion diagnostics