Science Board Update on FDA Cross-Cutting Initiatives

1
Science BoardUpdate 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 21st 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/regulat
  ory/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

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  draft guidance being prepared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/gen
  omics/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 FDAs 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/we
  bstart/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 ChallengesFacing 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 CenturyA Risk
Based Approach

• Large effort begun in 2002 to modernize FDAs
  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
  FDAs 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
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

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