Science BoardUpdate on FDA Cross-Cutting

Initiatives

Dr. Janet Woodcock

November 4, 2005

Overview

Critical Path InitiativeSee the Critical Path Web page at

http://www.fda.gov/oc/initiatives/criticalpath

Pharmacogenomics Efforts CGMPs for the 21st Century

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)

Second report (list of 70+ specific opportunities) in final clearance, will be out soon

Third report under development: projects FDA is taking on

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

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draft guidance being prepared

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

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

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

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

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

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

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

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, …

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)

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

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)

Users at big Pharma, academic and government institutions; U.S., Europe & Asia

The MAQC Project: Establishing QC Metrics and Thresholds for Microarray Quality Control

http://edkb.fda.gov/MAQC/

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.

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.

Two ChallengesFacing the Microarray Community

• To ensure experimental proficiency of individual laboratories

• To objectively assess the merits of various data analysis methods

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

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

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

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.

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

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.

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.

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

CGMPRecent 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

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