DIA Workshop on The Regulation of Biotechnology: Product Development for the New Millennium

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DIA Workshop on The Regulation of
BiotechnologyProduct Development for the New
Millennium

• Kathryn C. Zoon, Ph.D.
• CBER, FDA
• February 1, 1999

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BIOLOGICAL PRODUCTSREGULATED BY CBER
Vaccines
Allergenic Extracts
Blood Derivatives
Monoclonal Antibodies
BloodComponents
Biotech DerivedTherapeutics
Whole Blood
SomaticCell GeneTherapy
in Vitro Diagnostics
Tissues
Xenotransplantation
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Forces Shaping Biotechnology Products in the 21st
Century

• New Discovery Research and Technology
• Demand for New Biotech Products and Faster Access
• Global Market International Harmonization and
  Competition

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Forces Shaping Biotechnology Products in the 21st
Century

• Changing Health Care Environment
• Mergers. Reorganizations, Process
• Changes
• New Laws
• Safety and Ethical Issues

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Regulation of Biological ProductsBased on Sound
Science, Law and Public Health Impact
Review
Research
Surveillance
Policy
Compliance
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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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Organizational Update

• Office of Compliance and Biologics Quality
  Director Steven Masiello
• Office of Vaccines Research and Review Acting
  Director Dr. Bill Egan

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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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CBER Biotech INDs/IDEs Received FY 86-98Compared
to Total
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CBER Product License Applications ReceivedFY95-98
Other includes Non-Biotech Vaccines,
Therapeutics, Allergenics and In Vitro
Diagnostics Data as of 30 September 1998
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CBER User Fee Review PerformanceLicense
Applications and Supplements of First Actions
Within GoalBy Cohort Fiscal Year 1993-1997
PDUFA Performance Goals FY93-9455,
FY9570, FY9680, FY9790 (Indicated by Red
Lines)
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CBER Review Performance FY 98 Cohort of User Fee
Applications
APApproved, RTFRefuse To file, UNUnacceptable
For Filing, WFWithdrawn Before Filing Data as
of 31 Dec 98/excludes corporate entity changes
and mergers (08)RIMS1/21/99
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PDUFA Performance Goals NDAs, BLAs, Eff. Supps
Standard

• FY 99

• 30 in 10 months
• 90 in 12 months

Priority

• FY 99

• 90 in 6 months

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PDUFA Performance GoalsFY 99
Protocol Assessments

• 60 in 45 days

• 90 in 30 days

Clinical Hold Responses
Major Dispute Resolution

• 70 in 30 days

Manufacturing Supplements Prior
Approval No Prior Approval

• 30 in 4 months

90 in 6 months

• 90 in 6 months

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Meeting Types

• Type A - Necessary for proceeding w/ development
  (30 Calendar days)
• Type B - Pre IND, End of Phase 1 or Phase 2/Pre
  Phase 3, Pre-NDA/BLA (60 Calendar days)
• Type C - All other meetings (75 Calendar days)

Meeting Management Goals Response to
Meeting Requests / Scheduling Meetings
FY 99 70 in 14 Days
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of PLA Approvals
7 6
6 14 3


FY99 Data includes 1 Oct 98 - 31 Dec 98
(18)RIMS1/21/99
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2 4
4 9
2
of PLA Approvals

FY99 Data includes 1 Oct 98 - 31 Dec 98
(17)RIMS1/21/99
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Recent Biotech 1st Time Approvals

• Interferon alfacon-1
• (Infergen)
• Daclizumab
• (Zenapax)
• Becaplermin
• (Regranex)
• Palivizumab
• (Synagis)

• Treatment of Chronic
• Hepatitis C
• Prophylaxis of acute renal
• allograft rejection
• Treatment of diabetic
• ulcers
• Prophylaxis of serious lower
  respiratory tract disease, caused by RSV

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Recent Biotech 1st Time Approvals

• Trastuzumab
• (Herceptin)
• Infliximab
• (Remicade)
• Enbrel
• (Entanercept)

• Treatment of patient with metastatic breast
  cancer whose tumors overexpress the HER2 protein.
  (Fast Track)
• Treatment of moderately to severely active
  Crohns disease for the reduction of the signs
  and symptoms in patients who have an inadequate
  response to conventional therapies.
• Treatment of Rheumatoid Arthritis (Fast Track)

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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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CBER 2004Strategic Goals

• A high-quality regulatory process which is
  managed and integrated from discovery through
  post marketing
• A high quality research program which contributes
  directly to the regulatory mission
• A high quality and diverse work force
• Interactive information systems which are
  integral to all CBER activities
• Leveraged resources

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Goal A high-quality Regulatory Process which is
managed and integrated from discovery through
post-marketing

• Strategies
• Apply the concepts of managed review to the
  entire regulatory process
• Continually improve the regulatory process
• Assure an accountable management that promotes
  teamwork at all staff levels

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Project Plan

• Develop a business model of CBERs regulatory
  process - DONE
• Identify weaknesses/bottlenecks in the current
  regulatory process - DONE
• Propose and evaluate solutions to overcome these
  weaknesses/bottlenecks - DONE
• Design a new, streamlined Managed Review Process
  (MRP) - DONE
• Identify performance goals in order to expand the
  MRP (in Progress)

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Implementation

• Phase I
• Pre-submission
• Investigational
• Coordinate Public Health Based Research
• Phase II
• Applications/Supplements (Marketing submissions)
• Phase III
• Post Marketing
• Cross cutting

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Pilot of Phase I

• Will begin March, 1999
• Includes entire Center
• Continuous feedback
• Evaluate and refine
• Implement

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EstablishCBER Coordinating Committees(in
progress)

• Expert committees in various areas of policy
  development
• Establish policy and procedures
• Manage subcommittees
• Resolve disputes
• Information management and medical

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Active CBER Coordinating Committees

• Information Management (IMCC)
• Regulatory Management (RMCC)
• Medical Policy (MPCC)
• Training (TCC)

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Goal Interactive information systems are
integral to all CBER activities

• Strategies
• Fully integrate information systems to support a
  seamless regulatory process
• Support the development and use of interactive
  databases
• Capitalize on information related initiatives
  outside of CBER

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Significant Accomplishments in Information
Technology

• Desktop Standardization
• Electronic Submissions - BLAs, INDs
• Document Management Technology
• Regulatory Management System
• Electronic Lot Release (note 26 reduction in
  Review Days)

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Electronic Submissions

• Update IM Infrastructure
• Electronic INDs, NDAs, BLAs
• Final Guidance for Industry Publishing February
  ,1999
• Providing Regulatory Submissions in
  Electronic
• Format - General Considerations
• Companion Guidance for BLA under revision
• Paperless by 2002

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SPONSOR- Application Review- Application Status
MODEL

AGENCY- Application Review- Application Status
Communication with Field Offices
CBER/CDER Standards/Guidance
EDR
EDI Gateway
Online Review
Databases Documentum
Results
Format Text/Data/Image
Format Text/Data/Image
CD-Rom 3.5 Floppy DLT
Information Document Tracking Scientific
Databases
Technical Infrastructure, Technical Support,
Training
Action Letters
Future
Electronic Regulatory Submission and Review
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Goal A high quality research program which
contributes directly to the regulatory mission

• Strategies
• Develop and implement performance, promotion, and
  retention systems which better reflect the
  scientists contributions to CBERs regulatory
  mission
• Develop and implement a CBER-coordinated model of
  research that is driven by regulatory need
• Foster excellence in regulatory research

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Impact of Research
Pre-IND
Phase 1,2
Phase 3
Phase 4


Change in Policy Labeling Changes Methods
Policy Statements Risk Assessment Consensus
Policy
Policy Statements Testing Consensus Dev.
Risk Assessment
Change in Policy Standards Methods
Program Output
Predicted or Demonstrated Benefit for Industry
Outcome Measures
Decreased Testing Enhanced Safety Decreased
Time Clinical Holds Economic Cost
Cost of Changes Relief of Testing Review
Supplements Economic Cost
New products Decreased time Economic cost
Clinical Holds Time for OS Review Impact of
Phase 1 Education
Predicted or Demonstrated Benefit for the Public
Health

• Reduction/Elimination of specific diseases

• Increased margin of safety of products

• Reduced cost to consumers of products

• More rapid availability of products

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Investigational New Drug (IND)
Ensure safety of xenotransplantation clinical
trials

• Research Category
• Test methods for detection of porcine endogenous
  retrovirus
• Safety of porcine xenografts and other porcine
  products
• Research Program Output
• Provide methodology for detection of porcine
  endogenous retrovirus (PERV)
• Provide preclinical in vitro data on infectivity
  of PERV
• Develop guidance to industry on testing for PERV
  in xenograft products and in patients who receive
  this treatment

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Investigational New Drug (IND)
Ensure safety of xenotransplantation clinical
trials

• Outcome Measure for Industry and Public Health
• Decreased time in development of methods for
  detection of PERV
• Enhanced safety of porcine xenografts by
  accumulating data on activation and infectivity
  of PERV
• Identification of a public safety issue related
  to the presence of retroviruses

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External Review of CBER Research

• Evaluation of the Centers entire research
  program down to the Division level
• Not intended to be an in-depth review of
  individual independent investigators and their
  targeted research at the Laboratory level

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External Review of CBER Research

• First objective, obtain recommendations which
  will provide us assistance in making decisions on
  prioritization and resource allocation among our
  research programs, as a consequence of loss of
  PDUFA funds and shrinkage of the Agencys budget
• Second objective, provide validation and
  participation in the implementation of a proposed
  model for coordinated research at CBER, part of
  our Strategic Plan

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External View of CBER Research

• Leslie Benet, Chair, Subcommittee for External
  Review of CBER Research, 2/98
• To do good review in this rapidly expanding,
  cutting-edge field, youve got to understand the
  science. And you can only understand the science
  by having the experience. Thats why I
  personally believe its important to combine
  research and review.
• (Bruce Agnew, Science, 279, 976-77, 13 February
  1998)

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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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Reinventing GovernmentSelected Accomplishments

• Changes To An Approved Application-Final Rule
  (July, 1997)
• Development of a Harmonized Application
  Form-Published (July, 1997)
• Elimination of the ELA Requirement for Specified
  Biotechnology Products-Final Rule (May, 1996)
• Elimination of Lot Release for Specified
  Biotechnology Products-FR Notice (December, 1995)
• Licensure of Pilot Plants-Guidance (July, 1995)

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FDA Modernization Act of 1997(FDAMA)

• Signed into law November 21, 1997
• Amends the Food, Drug Cosmetic Act
• Amends the Public Health Service Act
• Renews the Prescription Drug User Fee Program
  with amendments (PDUFA 2)
• Effective 90 days after enactment unless
  otherwise specified

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CBER LEAD IN FDAMA REGULATION/GUIDANCE INITIATIVES

• RADIOPHARMACEUTICALS - New requirements for
  review of Radiopharmaceuticals Proposed Rule
  (5/20/98)
• POSTMARKETING STUDIES - revise 314 and 601 to
  require annual progress reports
• FAST TRACK - policies and procedures on fast
  track products Final Guidance (11/19/98)
• BIOLOGICS MODERNIZATION - regulations for BLAs
  Proposed Rule (7/31/98)

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FAST TRACK PRODUCTSSection 112

• Designed to
• Expedite development and review
• Product request for designation Serious and life
  threatening / Potential to address unmet need
• Review of portions of incomplete applications
• Expedited withdrawal
• Disseminate to physicians and others a
  description of the provisions applicable to fast
  track products
• Guidance within 1 year

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Process for Designation

• Timing of the submission - Anytime concurrently
  with or after the IND
• Amendment to the IND
• Discussion and supporting documentation

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FDA Response

• Designation letter
• Non-designation letter
• 60 day response time

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Continued Designation

• No longer demonstrates the potential to fulfill
  an unmet medical need
• No longer being studied in such a manner
• Discussions during development
• Agency may send a letter indicating it no longer
  meets the criteria

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Fast Track Programs

• Meetings
• Written correspondence
• Review programs
• Priority review
• Rolling review
• Accelerated approval

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Rolling Review

• Schedule for portions
• Clinical trials are nearing completion or have
  been completed
• Continues to meet Fast Track criteria
• Preliminary evaluation of clinical data supports
  that the product may be effective
• FDA should agree

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Rolling Review (contd)

• User Fee submitted
• Pre BLA/NDA meeting
• FDA will respond by letter
• Changes to agreement should also be in writing
• Generally only complete sections (i.e..
  toxicology, clinical, CMC)

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Accelerated Approval

• Accelerated approval regulations 21 CFR 601.40-45
• Approval based on a surrogate reasonably likely
  to predict clinical benefit
• Clinical endpoints other than survival or
  irreversible morbidity
• Conditional as listed in the regulations

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Conditions of Approval

• Phase 4 confirmatory studies
• Submission of promotional labeling 30 days prior
  to dissemination
• Expedited withdrawal procedures
• Sponsor fails to conduct studies
• Studies fail to confirm benefit
• Promotional labeling is false or misleading
• Other evidence shows the product is not safe or
  effective

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BIOLOGICS MODERNIZATIONSection 123

• Amends Section 351 of the PHS Act to provide for
  BLA and Biologics license which codifies the REGO
  initiative
• Clarifies that the FD C Act applies to
  biologics
• Requires the facility to be available for
  inspection and standards must be met
• Retains safe, pure and potent language

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BLA Regulations Proposed Rule

• Eliminates all references to
• establishment and products license applications
• establishment and product licenses
• Requires submission of a Biologics License
  Application
• Uses the form FDA 356h
• Harmonizes application procedures
• Updates the format of certain regulations

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Administrative Issues

• Approval letter will be functional equivalent of
  the license
• No physical certificate
• Listing of all manufacturing locations in the BLA
• Multiple products in some BLAs

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Deemed Biologics Licenses

• Existing Product and Establishment License
  holders
• Upon effective date
• Will be considered to have Biologics Licenses
• No submissions necessary to FDA
• Portions of the PLA/ELA will constitute the BLA

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Implementation of the 356h

• Currently using 356h
• Specified products
• Autologous somatic cell therapy
• Start to use 356h
• When FINAL CMC documents issue
• FR notice will advise applicants

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Transition Grace Period

• Ten months after the effective date of the final
  rule
• All applicants should use the BLA/356h
• During the ten months
• PLAs and ELAs will be accepted
• BLAs will be accepted
• All information in 356h needed
• Administratively handled as BLAs

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Issuance of Biologics License

• Began February 19, 1998
• Regardless of application type submitted

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TEAM BIOLOGICS

• A plan for Reinventing FDAs Ability to Optimize
  Compliance of Regulated Biologics Industries
• Joint effort of CBER and the Office of
  Regulatory Affairs
• Capitalize on diverse skills and knowledge
• Focus on inspectional and compliance issues

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TEAM BIOLOGICS (cont)

• Transfer of lead responsibility for biennial
  inspections
• Reduce inconsistency
• Cadre of specialized biologics inspectors
• Inspections will include
• Lead investigator
• CBER staff
• Specialized training

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Team BiologicsExpansion Plans

• Fractionated products - October, 1997
• Licensed In-vitro diagnostics - April, 1998
• Biotechnology and allergenic products - October,
  1998
• Vaccines and all other products - October, 1999

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Other Reinvention Initiatives

• Tissue Action Plan
• Xenotransplantation Action Plan
• Blood Action Plan
• Device Action Plan

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CBER PrioritiesFY99

• Implement FDA Reform
• Meet or exceed the PDUFA FY 99 performance
  standards for reviewing applications for which
  fees are paid.
• Take whatever actions are necessary to assure the
  safety of, and public confidence in, the Nations
  blood supply.

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CBER PrioritiesFY99

• Facilitate the development and approval of
  significant vaccine, blood and therapeutic
  product advances through review, policy
  formulation, regulation development, guidance
  issuance to industry, workshops and meetings.
• Pursue excellence in research that is directly
  targeted to the evaluation and regulation of
  biological products

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CBER PrioritiesFY99

• Improve automated system support for the review
  and evaluation of biological products.
• Continue to support efforts for a high quality,
  diverse workforce.

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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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International HarmonizationPriorities

• International Conference on Harmonization
• World Health Organization
• National Institute of Biological Standards and
  Controls

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CBER UPDATE

• Organizational Update
• CBER Workload and Performance
• Strategic Plan Update
• Reinvention Initiatives
• International Harmonization
• Challenges

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Challenges for the 21st Century for
Biotechnology-Derived Products

• New Technology
• Safety of Biological Products
• Ethical Issues
• Access to Biotechnological Products
• Harmonization of Regulatory Standards
• Global Competition
• Partnerships

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• Request documents through the internet!
• Send E-MAIL to
• CBER_INFO_at_A1.CBER.FDA.GOV
• For a list of Documents
• DOC_LIST_at_A1.CBER.FDA.GOV
• To visit CBERs Home page
• www.fda.gov/cber