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CBER 510(k) Issues

Sheryl A. Kochman, MT(ASCP)

Chief, Devices Review Branch

DBA/OBRR/CBER

IVD Roundtable – OIVD Workshop April 23, 2003

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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

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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 FD&C Act, as well as any other authorities delegated to it, as appropriate.

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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

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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).

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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 productIncludes

• Apheresis machines Blood Warmers• Filters Plasma Thawers• Refrigerators Stem Cell Concentrator

Excludes • Administration sets• Therapeutic devices

Dialysis machinesIntraoperative blood salvage devices

* As stated in the Intercenter Agreement

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Devices Reviewed at CBER (cont)*Certain In Vitro ReagentsThose intended for use in the processing of

licensed biologicals and analogous productsLectinsProtectinsBovine 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

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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 claimsSoftware programs for data management in a

blood establishment Dosimeters and thermal indicatorsMicrowave ovens used for thawing blood

products

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Devices Reviewed at CBER (cont) See also

21 CFR 864.9050 through 864.9875List 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

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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

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What kinds of premarket device submissions does CBER review ?

Everything that CDRH doesBut fewer of them

INDs and BLAs

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Special Situations for IVDs* For diagnostic use only (except HIV and

retroviruses), CDRH regulates under MDAHIV 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

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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 MDACMV

Required for use in blood donor testing, CBER regulates under the PHS ActBlood borne pathogen tests (IND/BLA)

• Syphilis is an exception (reviewed under 510(k))Immunohematology reagents (BLA)

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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-entryPermanent deferralCounseling

Rapid response to emerging infectious agentsTSEsWest Nile VirusSARS

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What are some of the outside groups CBER deals with ?

Significant outside interactions with: Blood Products Advisory CommitteeAdvisory Committee on Blood Safety and AvailabilityPHS Blood

• FDA, CDC, NIH, DODCongressPublic perception of blood safetyPatient advocacy groups

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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

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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

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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

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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.

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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

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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

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Is everything unique or different at CBER ?

ABSOLUTELY NOT ! We are subject to the same Congressional mandates as CDRH

FDAMAMDUFMA

We support the use of pre-submittal (Pre-IDE) meetingsCBER SOPP 8101.1

http://www.fda.gov/cber/regsopp/81011.htm We utilize:

Standards & guidancesScientific workshopsAdvisory committee recommendations

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How Do I Find a Predicate ? Go to CBER’s web site for list of cleared devices 1st

510(k) Blood Establishment Computer Software http://www.fda.gov/cber/products/510ksoft.htmSubstantially Equivalent 510(k) Device Information http://www.fda.gov/cber/efoi/510k.htm510(k) Device Applications (Cleared Since 1996) http://www.fda.gov/cber/dap/510kman.htm

If you can’t find one on ours, try CDRH’s website

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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

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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

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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

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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

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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

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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

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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 managementContact Office management (Dr. Mary Beth Jacobs for

OBRR)Contact the Center Ombudsman

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How to Contact CBER for Information Contact the Office of Communication, Training &

Manufacturers Assistance at: Phone 301-827-1800 or 800-835-4709E-mail MATT@CBER.FDA.GOV Web site http://www.fda.gov/cber/pubinquire.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

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CBER Office of the Director Jesse L. Goodman, M.D., M.P.H., Center Director,

Previously Deputy for MedicineSpokesperson 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

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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)

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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

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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

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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

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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

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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

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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 aboveCall Sheryl Kochman or staff at 301-827-3503

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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)

submissionsCall Dr. Sayah Nedjar or staff at 301-827-5307

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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

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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 manipulatedCall Dr. Sayah Nedjar or staff at 301-827-5307

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Who Does What ? Office of Cellular, Tissue & Gene Therapies (OCTGT)

Cord/Stem cell collection, processing system

• More than minimally manipulatedCall 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

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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

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

FY 03PMAs (Traditional) 1PMSs (180 Day) 1510(k)s (All Types) 35BLAs (Original, Std) 0BLSs (Efficacy) 3BLSs (Manufacturing, PAS) 31

ALL MDUFMA FY 05 GOALS MET*

*Data as of 4/15/03

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510(k)s Received

0

5

10

15

20

25

30

35

40

45

FY00 FY01 FY02 FY03 (6 mo)

TraditionalAbbreviatedSpecial

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CBER 510(k)s – Current Status*(Receipts from 10/1/02 – 3/31/03)

Under 1st Cycle

510(k) Type Rec’d 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

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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

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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

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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

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