1. Science Board Update on FDA Cross-Cutting Initiatives Dr. Janet Woodcock November 4, 2005

2. Overview Critical Path Initiative See the Critical Path Web page at http://www.fda.gov/oc/initiatives/criticalpath Pharmacogenomics Efforts CGMPs for the 21 st Century

3. Critical Path Initiative — Making Progress First Critical Path Report, March 2004 – Comments to the Docket until July 30, 2005 Extensive outreach activities with industry, academia, agency scientists, other parties to identify specific opportunities (e.g., Imaging meeting, May 2005; http://www.fda.gov/cder/regulatory/medImaging/default.htm; ECG warehouse workshop, October 2005) http://www.fda.gov/cder/regulatory/medImaging/default.htm Second report (list of 70+ specific opportunities) in final clearance, will be out soon Third report under development: projects FDA is taking on

4. Examples of Current FDA CP Activities Interagency Oncology Task Force (with NCI) – Joint fellowship program – IT support for clinical trial automation – Joint research projects NCI/CMS biomarker qualification projects for specific cancers Freestanding/academic (e.g. C-Path Institute) Academic/industry (e.g., UCSF, Duke University) FDA-partner CRADAs

5. Examples of Current FDA CP Activities (cont.) Guidance development Pharmacogenomic Data Submissions guidance (final issued March 2005) Exploratory IND Studies (draft issued April 14) Guidance clarifying CGMPs for phase 1 studies (draft expected soon) Planning workshop on rapid microbial testing Drug and pharmacogenomic test co-development draft guidance being prepared

6. Examples of Ongoing FDA CP Activities (cont.) Bioinformatics (also supports e-health) – SPL/DailyMed (October 30, 2005) – Case report forms, voluntary standardization – ECG digital warehouse – Standards development (e.g., HL7, CDISC) – Standards to support clinical trials Pharmacogenomics initiative BiMo Initiative

7. Critical Path — Next Steps Publish Critical Path Opportunities List Publish report on projects FDA is engaged in Further develop consortia – Some as umbrella organization – Others around specific projects Continue with CP plan – try to gather a few more resources to accomplish work

8. Pharmacogenomics (PG) Initiative Final guidance issued March 2005 Agency-wide PG review group is up and running First voluntary submission received in March 2004, almost 20 since then Positive feedback from sponsors – Sponsors appreciate opportunity for open, informal data exchange and discussion, in formal feedback, rank VGDS meetings a 4 out of 5, with regulatory aspect being viewed more important/helpful than scientific impact See the PG Web page at http://www.fda.gov/cder/genomics/IPRG.htm

9. Pharmacogenomics (PG) at FDA Framework provided by “Guidance for Industry: Pharmacogenomic Data Submissions” – clarifies what type of genomic data needs to be submitted to FDA and when Guidance introduces two novel tools: – VGDS: Voluntary Genomic Data Submissions Submission of exploratory genomic data, usually not required to be submitted to IND Not used for regulatory decision making – IPRG: Interdisciplinary Pharmacogenomics Review Group First FDA-wide review group – representatives from all Centers Responsible for review of VGDS New policy and guidance development related to PG New genomics portal: www.fda.gov/cder/genomics

10. PG at FDA: VGDS Milestones March ’04: First VGDS May ’04: Genomics Group started operation in OCPB July ’04: First IPRG – Sponsor meeting March ’05: Final PG Guidance released March ’05: Genomics website goes live May ’05: First joint VGDS meeting with EMEA October ’05: Genomic Biomarker workshop October ’05: First large-scale toxicogenomics VGDS November ’05: PG to be discussed at ICH December ’05: ~20 voluntary submissions received

11. PG at FDA: Impact of VGDS Exposure to cutting-edge genomic data, otherwise not accessible to review at FDA Provides opportunity for scientific exchange of information without immediate regulatory impact, i.e. – Strategies for biomarker qualification – Biological interpretation of data – Clinical trial designs incorporating PG data – Data evaluation and interpretation: tools, strategies – Drug-test co-development Facilitates new policy and guidance development Redacted data sets used for reviewer training Very positive feedback from sponsors: several have submitted more than 1 VGDS already, follow-on submissions to be received

12. PG Initiative — Some Lessons Learned Early communication with sponsors is crucial Standards are needed (e.g. HL7, CDISC, others) Education is ongoing – Creation of FDA/CDER course on pharmacogenomics – Rotations in Genomics Group to expose reviewers to genomic data sets ICH conference next week in Chicago – FDA presentation on key points from pharmacogenomic data submissions

13. PG at FDA: Future VGDS goes global: – First joint meeting with EMEA held, two more scheduled – MOU with EMEA created – ICH meeting next week in Chicago, IL VGDS  VXDS: expansion into other eXploratory -omics fields (i.e. proteomics, metabolomics) VGDS  RGDS: VGDS program helped us to become well prepared to review complex Required PG data sets VGDS program continues to be used as a platform for information exchange for research conducted via different mechanisms, i.e. CRADAs, consortia, PPP, …

14. FDA Approval of PG Tests Roche Molecular Systems AmpliChip CYP450 (CYP2C19) (1/05) Roche Molecular Systems AmpliChip CYP450 (CYP2D6) (12/04) Invader* UGT1A1 Molecular Assay (UDP- glucuronoslytransferase) [use with irinotecan dosing] (8/05)

15. Pharmacogenomics at FDA’s National Center for Toxicologic Research Publication of multiple scientific papers on toxicogenomics Papers on bioinformatics approaches to analysis of microarray data Creation of Array Track Software and Database to assist FDA analysis of submitted pharmacogenomic data: excellent tool for this project

16. ArrayTrack An integrated solution for microarray data management, analysis and interpretation Review tool for FDA pharmacogenomics data submission – Training course is provided to the FDA reviewers every two months – At present, ~60 reviewers has been trained Freely available to public ( http://edkb.fda.gov/webstart/arraytrack ) http://edkb.fda.gov/webstart/arraytrack Users at big Pharma, academic and government institutions; U.S., Europe & Asia

17. The MAQC Project: Establishing QC Metrics and Thresholds for Microarray Quality Control http://edkb.fda.gov/MAQC /

18. The MAQC Project The U.S. FDA is promoting the use of omics technologies (e.g., microarrays) in medical product development and personalized medicine. Cross-lab/platform comparability is achievable and a prerequisite to move microarrays from a research tool to clinical practices. Quality control of bench experiments and guidance for data analysis are two fundamental challenges. Overall quality of microarray data are of concern for regulatory review of PG/TG data submissions.

19. The MAQC Project Microarray manufacturers should develop SOPs for controling the quality of individual steps and ensure the robustness of the technology. The merits of various data analysis methods should be critically evaluated. Biological interpretation of microarray results should be based on reliable data and appropriate analysis procedures. The U.S. FDA is working closely with the microarray community under the MAQC project to develop appropriate QC metrics and thresholds for assessing the overall performance of the microarray technology by establishing reference RNA samples and reference datasets.

20. Two Challenges Facing the Microarray Community To ensure experimental proficiency of individual laboratories To objectively assess the merits of various data analysis methods

21. Because there is a lack of: Calibrated RNA samples Reliable benchmark datasets Metrics/Thresholds for assessing the performance achievable on microarray platforms Thorough and independent validation Guidelines for microarray QC and data analysis

22. Pharmaceutical CGMPs for the 21st Century—A Risk Based Approach Large effort begun in 2002 to modernize FDA’s regulation of pharmaceutical quality for human and animal drugs and select biological products (e.g., vaccines) – Effort prompted many projects; see report on the effort at http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm Released 7 guidances on a variety of topics related to risk-based approaches to the regulation of pharmaceutical manufacturing. Goal was to enhance consistency and coordination of FDA’s drug quality regulatory programs Established and chartered a Council on Pharmaceutical Quality, a subcommittee to the FDA Management Council

23. CGMPs (cont.) Introduced process analytical technologies (PAT) via guidance (With ASTM International) established a Technical Committee E55 on Pharmaceutical Application of Process Analytical Technology to focus on process monitoring and control rather than testing Issued Aseptic Processing Guidance, which ensures operational and raw material inputs are predictable based on adequate controls.

24. CGMP (cont.) Issued guidance on Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice — a comprehensive quality systems model manufacturers can use Issued draft guidance on Comparability Protocols — explains how changes can be made in manufacturing without prior approval from the Agency

25. CGMP (cont.) Issued Part 11 guidance, which removed many barriers to scientific and technological advances and encourages use of risk-based approaches to managing computer systems Introduced risk-based approach for FDA (domestic) manufacturing site inspections — goal is to achieve greatest public health impact — Industry estimates that this guidance could save hundreds of millions of dollars that would have been wasted on unneeded changes to IT systems.

26. CGMP — State-of-the-Art Regulation CDER is shifting its CMC review system to a new risk-based pharmaceutical quality assessment system. Office of Generic Drugs is implementing a question-based review system. — These systems should reduce the need to submit manufacturing supplements and increase first-cycle approval of new drug applications, making drug products available to patients in a more timely manner.

27. CGMP — Agency Consistency and Coordination Increasing collaboration with international health and regulatory partners Adopted a Quality Systems Model for Agency Operations — defines the essential quality elements to consider Implemented a process for resolving scientific and technical disputes arising from CGMP inspections, which has been highly praised by industry Established a Pharmaceutical Inspectorate — a staff of highly trained individuals within ORA who devote most of their time to conducting complex and high-risk inspections that are most dependent on the enhanced technical expertise that they have acquired; 70 investigators have been trained so far. Revised regulatory procedures for determining when to issue warning letters in response to noncompliance with CGMP requirements

28. CGMP Recent Accomplishments/Future Plans Submitted PIC/S (Pharmaceutical Inspection Cooperation Scheme) Application (September 16, 2005) Participated in several ICH quality topics — Q8 (Quality by Design), Q9 (Risk Management), Q10 (Quality Systems) Reconfiguring working groups to align with the next steps of the initiative Continuing ongoing efforts to evaluate, revise, and refine the risk-based inspection model Plan to implement “Quality by Design” (pharmaceutical development) — may ultimately reduce the regulatory burden

29. CGMP — Future Plans (cont.) Re-evaluating current regulations for consistency with CGMP effort Establishing a Pharmaceutical Quality Standards working group to determine how to improve collaboration with standards organizations Certifying additional staff for the Pharmaceutical Inspectorate Enhancing interactions between the field and Center compliance and review staff Implementing new application and review standards and practices