CBER%20510(k)%20Issues

1
CBER 510(k) Issues

• Sheryl A. Kochman, MT(ASCP)
• Chief, Devices Review Branch
• DBA/OBRR/CBER
• IVD Roundtable OIVD Workshop April 23, 2003

2
Why does CBER review devices?

• Jurisdiction for medical device review is
  governed by the FDA Intercenter Agreement between
  the Center for Biologics Evaluation and Research
  (CBER) and the Center for Devices and
  Radiological Health (CDRH) (October 31, 1991)
• Available at
• http//www.fda.gov/cber/dap/devpubs.htm

3
Intercenter Agreement Between CBER and CDRH
(October 31, 1991)

• CBER will have the lead responsibility for
  regulating medical devices used or indicated for
  the collection, processing, testing, storage, or
  administration of biological products (including
  blood products, blood components, or analogous
  products), and will use authorities under the
  Public Health Service Act (PHS Act) and the FDC
  Act, as well as any other authorities delegated
  to it, as appropriate.

4
Intercenter Agreement (cont) In vitro tests
which are required for blood donor screening and
related blood banking practices (such as donor
re-entry) are licensed under the PHS Act

• Immunohematology Reagents
• Blood Grouping Reagents
• Reagent Red Blood Cells
• Antihuman Globulins
• Limulus amebocyte lysate (LAL)

• Blood Borne pathogen tests
• HIV 1/2
• HIV Ag
• HBsAg
• HB core
• HCV
• HTLV I/II
• examples only, not a complete list

5
Intercenter Agreement (cont)

• CBER also has the responsibility for regulating
  all in vitro diagnostic tests and any other
  medical devices intended for use for human
  immunodeficiency virus, type 1 (HIV 1) and type 2
  (HIV 2) and other retroviruses.
• These devices, including but not limited to
  collection devices, specimen containers, test kit
  components or support materials and those used or
  indicated for the inactivation of these viruses,
  will be regulated by CBER under the Medical
  Device Authorities (MDA).

6
What devices does CBER review ?

• Medical devices that are dedicated systems
  intended for use in collection, processing, or
  administration of a licensed biological or
  analogous product
• Includes
• Apheresis machines ? Blood Warmers
• Filters ? Plasma Thawers
• Refrigerators ? Stem Cell Concentrator
• Excludes
• Administration sets
• Therapeutic devices
• Dialysis machines
• Intraoperative blood salvage devices
• As stated in the Intercenter Agreement

7
Devices Reviewed at CBER (cont)

• Certain In Vitro Reagents
• Those intended for use in the processing of
  licensed biologicals and analogous products
• Lectins
• Protectins
• Bovine albumin potentiating media
• Leukocyte typing sera or other medical devices
  intended for use in the determination of tissue
  type
• Quality assurance reagents intended for use in
  conjunction with a licensed biological reagents
  or in vitro tests

8
Devices Reviewed at CBER (cont)

• Medical devices other than reagents intended for
  use in the preparation of, in conjunction with,
  or for the quality assurance of a blood bank
  related licensed biological product or practice.
• Clinical laboratory devices with separate blood
  bank claims
• Software programs for data management in a blood
  establishment
• Dosimeters and thermal indicators
• Microwave ovens used for thawing blood products

9
Devices Reviewed at CBER (cont)

• See also
• 21 CFR 864.9050 through 864.9875
• List of Devices Regulated by CBER
• http//www.fda.gov/cber/dap/devlst.htm
• KSS/Blood Banking supplies consists of a wide
  variety of devices, some of which are
• Blood temperature indicator
• Tube stripper
• Isotonic saline labeled for BB use
• Blood irradiation label
• Blood component separator

10
Devices Reviewed at CBER (cont)

• ZZZ/Unclassified was used for devices for which a
  firm could identify a predicate, and therefore
  could submit a 510(k) but which had not been
  formally classified. This group also contains a
  wide variety of devices, such as
• HLA reagents
• CMV test kits
• Instrument software
• Syphilis tests
• Platelet antigen/antibody tests
• Leukocyte removal filters

11
What kinds of premarket device submissions does
CBER review ?

• Everything that CDRH does
• But fewer of them
• INDs and BLAs

12
Special Situations for IVDs

• For diagnostic use only (except HIV and
  retroviruses), CDRH regulates under MDA
• HIV and other retrovirus diagnostics regulated by
  CBER under MDA
• For blood donor screening, CBER regulates under
  MDA, i.e., 510(k)
• CMV
• As stated in the Intercenter Agreement

13
Special Situations for IVDs (cont)

• For diagnostic use AND blood donor screening,
  CDRH is lead Center with each center reviewing
  their respective data sets under MDA
• CMV
• Required for use in blood donor testing, CBER
  regulates under the PHS Act
• Blood borne pathogen tests (IND/BLA)
• Syphilis is an exception (reviewed under 510(k))
• Immunohematology reagents (BLA)

14
What are some of the public health issues that
are unique to CBER ?

• Ensuring safety and efficacy of biological
  therapeutic products
• Management of those products
• Recalls
• Management of donors
• Temporary deferral and subsequent re-entry
• Permanent deferral
• Counseling
• Rapid response to emerging infectious agents
• TSEs
• West Nile Virus
• SARS

15
What are some of the outside groups CBER deals
with ?

• Significant outside interactions with
• Blood Products Advisory Committee
• Advisory Committee on Blood Safety and
  Availability
• PHS Blood
• FDA, CDC, NIH, DOD
• Congress
• Public perception of blood safety
• Patient advocacy groups

16
Scope of the Blood Industry

• Whole Blood
• 13.9 million units collected/yr
• 18 million components
• 8 million donors
• 3000 registered facilities
• 3.5 million recipients

• Source Plasma
• 12 million units collected/yr
• Manufactured into 35 different plasma derivative
  products
• 1 million donors
• 80 licensed establishments

17
What are some of the review issues that are
important to CBER ?

• Detection and identification of disease in a
  population of normal, healthy adults
• Versus
• Diagnosis of disease in a patient showing
  signs and symptoms of disease
• Requires higher numbers of clinical trial
  samples to assure statistical significance

18
What are some of the review issues that are
important to CBER ?

• Many of our products are Combination Products
  because they are linked by their labeling, i.e.,
  a system
• Licensed reagent(s) (biologicals)
• Accessory reagents (devices)
• Accessory instruments (devices)
• Accessory software (devices)
• Ancillary goods (devices)
• Pipettes
• Tubes
• Micro-well plates
• Others are combination products because of their
  packaging
• Therapeutic biological in a syringe

19
What are some of the procedural issues that are
different at CBER ?

• We currently do not respond by e-mail to incoming
  e-mails that contain proprietary or confidential
  information but are working on a secure e-mail
  system to allow us to do so.
• We have different submission binding and filing
  formats.
• Please see SOPPs 8007 and 8110 at
• http//www.fda.gov/cber/regsopp/regsopp.htm
• We have a different address
• FDA/CBER
• Document Control Center, HFM-99, Suite 200N
• 1401 Rockville Pike
• Rockville, MD 20852-1448
• We usually need more than one copy please send
  at least two or call ahead and ask.

20
Recent CBER Process Changes (To Enhance the
Review Process)

• New priority courier service for regulatory
  documents
• New bar-coded tracking of regulatory documents
• Close collaboration with CDRH
• Least Burdensome training
• Active problem solving during first cycle, not
  just problem finding
• Down delegation to Division Directors

21
Recent CBER Process Changes (cont)

• Where possible, use CDRH policies
• Set internal goals in parallel with CDRH
• ex. 60 day response for 510(k) IVD submissions
• Increased pre-submission meetings
• Device subcommittee of RMCC

22
Is everything unique or different at CBER ?

• ABSOLUTELY NOT !
• We are subject to the same Congressional mandates
  as CDRH
• FDAMA
• MDUFMA
• We support the use of pre-submittal (Pre-IDE)
  meetings
• CBER SOPP 8101.1 http//www.fda.gov/cber/regsopp/8
  1011.htm
• We utilize
• Standards guidances
• Scientific workshops
• Advisory committee recommendations

23
How Do I Find a Predicate ?

• Go to CBERs web site for list of cleared devices
  1st
• 510(k) Blood Establishment Computer Software
• http//www.fda.gov/cber/products/510ksoft.htm
  
• Substantially Equivalent 510(k) Device
  Information
• http//www.fda.gov/cber/efoi/510k.htm
• 510(k) Device Applications (Cleared Since 1996)
• http//www.fda.gov/cber/dap/510kman.htm
• If you cant find one on ours, try CDRHs website

24
What about guidance documents ?

• Most general CDRH guidances are applicable
• Federal Register - FDA Modernization Act of 1997
  List of Documents Issued by the FDA That Apply to
  Medical Devices Regulated by CBER - 4/26/1999
• Several CBER-specific guidances exist.
• The following are available at
• http//www.fda.gov/cber/dap/devpubs.htm
• Federal Register - Medical Devices Hematology
  and Pathology Devices Reclassification of
  Automated Blood Cell Separator Device Operating
  by Filtration Principle from Class III to Class
  II Final rule - 2/28/2003

25
CBER-specific guidances

• Draft Guidance for Industry Premarket
  Notifications 510(k)s for In Vitro HIV Drug
  Resistance Genotype Assays Special Controls -
  8/28/2001
• Draft Guidance for FDA Reviewers Premarket
  Notification Submissions for Automated Testing
  Instruments Used in Blood Establishments -
  8/3/2001
• Guidance for FDA Reviewers Premarket
  Notification Submissions for Blood and Plasma
  Warmers - 7/19/2001
• Guidance for FDA Reviewers Premarket
  Notification Submissions for Transfer Sets
  (Excluding Sterile Connecting Devices) -
  7/19/2001

26
CBER-specific guidances (cont)

• Guidance for FDA Reviewers Premarket
  Notification Submissions for Empty Containers for
  the Collection and Processing of Blood and Blood
  Components - 7/19/2001
• Draft Guidance for Industry Clinical Development
  Programs for Drugs, Devices, and Biological
  Products Intended for the Treatment of
  Osteoarthritis (OA) 7/15/1999
• Guidance for Industry Clinical Development
  Programs for Drugs, Devices, and Biological
  Products for the Treatment of Rheumatoid
  Arthritis 2/17/1999

27
CBER-specific guidances (cont)

• These CBER-specific guidances are available at
  http//www.fda.gov/cber/blood/bldguid.htm
• Guidance for Industry In the Manufacture and
  Clinical Evaluation of In Vitro Tests to Detect
  Nucleic Acid Sequences of Human Immunodeficiency
  Viruses Types 1 and 2 - 12/14/1999
• Draft Guidance for Industry Application of
  Current Statutory Authority to Nucleic Acid
  Testing of Pooled Plasma- 11/26/1999

28
CBER-specific guidances (cont)

• Draft Guidance for Industry In the Manufacture
  and Clinical Evaluation of In Vitro Tests to
  Detect Nucleic Acid Sequences of Human
  Immunodeficiency Virus Type 1 - 7/10/1998
• Guidance for Industry - The Sourcing and
  Processing of Gelatin to Reduce the Potential
  Risk Posed by Bovine Spongiform Encephalopathy
  (BSE) in FDA-Regulated Products for Human Use -
  10/07/1997
• Reviewer Guidance for a Premarket Notification
  Submission for Blood Establishment Computer
  Software - 1/13/1997

29
CBER-specific guidances (cont)

• Draft Guideline for the Validation of Blood
  Establishment Computer Systems - 9/28/1993
• Draft Points to Consider in the Manufacture and
  Clinical Evaluation of In Vitro Tests to Detect
  Antibodies to the Human Immunodeficiency Virus
  Type 1 - 8/8/1989

30
Contacting CBER About Submissions

• For pre-submission help
• Contact the person identified in the slides that
  follow based on the device you wish to discuss
• If you cannot decide who to contact, contact the
  Center Ombudsman, Dr. Sheryl L. Lard-Whiteford
• For post-submission help
• Contact your RPM first (see acknowledgement
  letter)
• The RPM can set up conference call or meeting
  with the review team
• Contact Division management
• Contact Office management (Dr. Mary Beth Jacobs
  for OBRR)
• Contact the Center Ombudsman

31
How to Contact CBER for Information

• Contact the Office of Communication, Training
  Manufacturers Assistance at
• Phone [phone] or 800-835-4709
• E-mail MATT_at_CBER.FDA.GOV
• Web site http//www.fda.gov/cber/pubinquir
  e.htm
• See our current organization charts and lists at
• http//intranet.fda.gov/cber/admin/orgcht.htm
• Visit our web site http//www.fda.gov/cber/
• Guidance http//www.fda.gov/cber/dap/devpubs.htm

32
CBER Office of the Director

• Jesse L. Goodman, M.D., M.P.H., Center Director,
• Previously Deputy for Medicine
• Spokesperson on West Nile Virus
• Mark A. Elengold, Deputy Director for Operations
• Robert A. Yetter, Ph.D., Associate Director for
  Review Management
• Diane Maloney, J.D., Associate Director for
  Policy
• Sheryl L. Lard-Whiteford, Ph.D., Associate
  Director for Quality Assurance and CBER
  Ombudsman

33
Office of Blood Research Review

• Jay S. Epstein, M.D., Director
• Richard M. Lewis, Ph.D., Deputy Director
• Mark J. Weinstein, Ph.D., Associate Deputy
  Director
• John S. Finlayson, Ph.D., Associate Director for
  Science
• Mary Elizabeth Jacobs, Ph.D., Associate Director
  for Regulatory Affairs
• Edward Tabor, Ph.D., Associate Director for
  Medical Affairs
• Linda A. Smallwood, Ph.D., Associate Director
  for Policy (BPAC contact)

34
Division of Blood Applications

• Alan E. Williams, Ph.D., Director
• Elizabeth G. Callaghan, Deputy Director
• Sayah Nedjar, Ph.D., Chief, Regulatory Program
  Management Branch
• Sheryl A. Kochman, Chief, Devices Review Branch
  
• Elizabeth G. Callaghan, Chief (Acting) Blood and
  Plasma Branch

35
Division of Emerging Transfusion Transmitted
Diseases

• Hira L. Nakhasi, Ph.D., Director
• Paul A. Mied, Ph.D., Deputy Director
• Indira K. Hewlett, Ph.D., Chief, Laboratory of
  Molecular Biology
• Gerardo Kaplan, Ph.D., Chief, Laboratory of
  Hepatitis Related Emerging Agents
• David Asher, M.D., Chief, Laboratory of
  Bacterial, Parasitic, Unconventional Agents

36
Division of Hematology

• Basil (Dov) Golding, M.D., Director (Acting)
• Andrew Chang, Ph.D., Deputy Director (Acting)
• Jaro Vostal, M.D., Ph.D., Chief (Acting),
  Laboratory of Cellular Hemostasis
• Dorothy E. Scott, M.D., Chief (Acting),
  Laboratory of Cellular Hematology
• Andrew Chang, Ph.D., Chief (Acting), Laboratory
  of Hemostasis
• Toby A. Silverman, M.D., Chief, Clinical
  Review Branch

37
Office of Vaccines Research Review

• Karen Midthun, M.D., Director
• William M. Egan, Ph.D., Deputy Director
• Norman W. Baylor, Ph.D., Associate Director for
  Regulatory Policy
• Richard I. Walker, Ph.D., Director Division of
  Bacterial, Parasitic Allergenic Products
• Jerry P. Weir, Ph.D., Director, Division of Viral
  Products
• Karen L. Goldenthal, M.D., Division of Vaccines
  Related Products Applications

38
Office of Cellular, Tissue,
Gene Therapies

• Philip D. Noguchi, M.D., Director (Acting)
• Joyce L. Frey-Vasconcells, Ph.D., Deputy Director
  (Acting)
• Andrea Wright, Regulatory Management Staff
• Raj K. Puri, M.D., Ph.D., Director (Acting),
  Division of Cellular Gene Therapies
• Cynthia A. Rask, M.D., Director (Acting),
  Division of Clinical Evaluation
  Pharmacology/Toxicology
• Ruth Solomon, M.D., Director (Acting),
  Division of Human Tissues

39
Who Does What ?

• Office of Blood Research Review (OBRR)
• Division of Blood Applications (DBA)
• Devices Review Branch
• Immunohematology/HLA reagents, controls,
  instruments, and accessories
• Blood Establishment Computer Software (BECS)
• Meeting requests for the above
• Call Sheryl Kochman or staff at 301-827-3503

40
Who Does What ?

• Office of Blood Research Review (OBRR)(cont)
• Division of Blood Applications (DBA)(cont)
• Regulatory Project Management Branch
• Blood collection, mixing, weighing, storage
  systems
• Management and tracking of the reviews
• Meeting requests for all OBRR (except DRB)
  submissions
• Call Dr. Sayah Nedjar or staff at 301-827-5307

41
Who Does What ?

• Office of Blood Research Review (OBRR) (cont)
• Division of Emerging Transfusion Transmitted
  Diseases (DETTD)
• Blood borne pathogen reagents, kits, instruments
• HIV diagnostics, viral load test kits
• West Nile Virus
• TSEs
• Call Dr. Sayah Nedjar or staff at 301-827-5307

42
Who Does What ?

• Office of Blood Research Review (OBRR) (cont)
• Division of Hematology (DH)
• Blood containers, cell separators, processing
  systems
• IVDs for platelet antigen/antibody testing
• Bacterial detection systems
• Cord/Stem cell collection, processing system
• Minimally manipulated
• Call Dr. Sayah Nedjar or staff at 301-827-5307

43
Who Does What ?

• Office of Cellular, Tissue Gene Therapies
  (OCTGT)
• Cord/Stem cell collection, processing system
• More than minimally manipulated
• Call Dr. Stephanie L. Simek at 301-827-6536
• Office of Vaccines Research Review (OVRR)
• Division of Vaccines Related Products (DVRPA)
• Endotoxin testing supplies
• (The kits themselves are licensed biologicals)
• Call Dr. Paul Richman at 301-827-3070

44
CBER Device Submissions Received

• FY00 FY01 FY02
• PMAs (Traditional) 3 3
  1
• PMSs (Traditional) 5
  8 5
• 510(k)s (All Types) 34
  37 42
• BLAs (Original) 4 2
  2
• BLSs (Efficacy) 0 0
  0
• BLSs (Manufacturing, PAS) 124 47
  35
• Includes RTAs/RTFs, Transfers, Withdrawals

45
CBER Device Submissions Received (from 10/1/02
3/31/03)

• FY 03
• PMAs (Traditional) 1
• PMSs (180 Day) 1
• 510(k)s (All Types) 35
• BLAs (Original, Std) 0
• BLSs (Efficacy) 3
• BLSs (Manufacturing, PAS) 31
• ALL MDUFMA FY 05 GOALS MET
• Data as of 4/15/03

46
510(k)s Received
47
CBER 510(k)s Current Status(Receipts from
10/1/02 3/31/03)

• Under 1st Cycle
• 510(k) Type Recd SE NSE Other Review
  Complete
• Traditional 21 10 0 3 5
  3
• Abbreviated 6 3 0 0 2 1
• Special 8 7 1 0 0
  0
• Total 35 20 1 3 7
  4
• All data as of 4/15/03

48
CBER 510(k) Cycles(from Receipt to Final Action)

• Under 1st Cycle
• 510(k) Type (SE/NSE) (Average)
  Review Completed
• Traditional 10 1.1 5
  3
• Abbreviated 3 1.3
  2 1
• Special 8 1.0 0
  0
• Total 21 1.1
  7 4
• All data as of 4/15/03
• Cycles will increase with completion of
  pendings

49
Time to Final Decision FY 02(510(k) Receipt
Cohort from 10/1/01 9/30/02)

• FDA Time Total Time Cycles
• 510(k) Type n (Days, Ave) (Days, Ave)
  (Average)
• Traditional 18 141.2 175.5 1.89
• Abbreviated 7 124.4 165.3 2.00
• Special 4 38.8 50.0
  1.50
• Total 29 123.0 155.7
  1.86
• SE/NSEs Only Data as of 4/15/03

50
Time to Final Decision Current(510(k) Receipt
Cohort from 10/1/02 3/31/03)

• FDA Time Total Time
• 510(k) Type n (Days, Ave)
  (Days, Ave)
• Traditional 10 58.8
  61.0
• Abbreviated 3 60.0
  69.3
• Special 8 19.9
  19.9
• Total 21 44.1
  46.5
• SE/NSEs Only Data as of 4/15/03
• Times will increase with completion of pendings

51
Acknowledgements

• Dr. Mary Beth Jacobs, Ph.D., CBER/OBRR/IOD
• Michael A. Calabro, Ph.D. CBER/OBRR/IOD