1. CBER CBER 510(k) Issues Sheryl A. Kochman, MT(ASCP) Chief, Devices Review Branch DBA/OBRR/CBER IVD Roundtable – OIVD Workshop April 23, 2003

2. CBER Why does CBER review devices? l 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. CBER Intercenter Agreement Between CBER and CDRH (October 31, 1991) l 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.

4. CBER 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 t Immunohematology Reagents Blood Grouping Reagents Reagent Red Blood Cells Antihuman Globulins t Limulus amebocyte lysate (LAL) t Blood Borne pathogen tests* HIV 1/2 HIV Ag HBsAg HB core HCV HTLV I/II * examples only, not a complete list

5. CBER Intercenter Agreement (cont) l 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. l 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. CBER What devices does CBER review ?* l Medical devices that are dedicated systems intended for use in collection, processing, or administration of a licensed biological or analogous product t Includes Apheresis machines Blood Warmers Filters Plasma Thawers Refrigerators Stem Cell Concentrator t Excludes Administration sets Therapeutic devices sDialysis machines sIntraoperative blood salvage devices * As stated in the Intercenter Agreement

7. CBER Devices Reviewed at CBER (cont)* Certain In Vitro Reagents l Those intended for use in the processing of licensed biologicals and analogous products t Lectins t Protectins  Bovine albumin potentiating media l Leukocyte typing sera or other medical devices intended for use in the determination of tissue type l Quality assurance reagents intended for use in conjunction with a licensed biological reagents or in vitro tests

8. CBER Devices Reviewed at CBER (cont)* l 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. t Clinical laboratory devices with separate blood bank claims t Software programs for data management in a blood establishment t Dosimeters and thermal indicators t Microwave ovens used for thawing blood products

9. CBER Devices Reviewed at CBER (cont) l See also t 21 CFR 864.9050 through 864.9875 t 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. CBER 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. CBER What kinds of premarket device submissions does CBER review ? l Everything that CDRH does t But fewer of them l INDs and BLAs

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

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

14. CBER What are some of the public health issues that are unique to CBER ? l Ensuring safety and efficacy of biological therapeutic products l Management of those products t Recalls l Management of donors t Temporary deferral and subsequent re-entry t Permanent deferral t Counseling l Rapid response to emerging infectious agents t TSEs t West Nile Virus t SARS

15. CBER What are some of the outside groups CBER deals with ? l Significant outside interactions with: t Blood Products Advisory Committee t Advisory Committee on Blood Safety and Availability t PHS Blood FDA, CDC, NIH, DOD t Congress t Public perception of blood safety t Patient advocacy groups

16. CBER Scope of the Blood Industry Whole Blood l 13.9 million units collected/yr l 18 million components l 8 million donors l 3000 registered facilities l 3.5 million recipients Source Plasma l 12 million units collected/yr l Manufactured into 35 different plasma derivative products l 1 million donors l 80 licensed establishments

17. CBER 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. CBER What are some of the review issues that are important to CBER ? l Many of our products are Combination Products because they are linked by their labeling, i.e., a system t Licensed reagent(s) (biologicals) t Accessory reagents (devices) t Accessory instruments (devices) t Accessory software (devices) t Ancillary goods (devices) Pipettes Tubes Micro-well plates l Others are combination products because of their packaging t Therapeutic biological in a syringe

19. CBER What are some of the procedural issues that are different at CBER ? l 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. l We have different submission binding and filing formats. t Please see SOPPs 8007 and 8110 at: t http://www.fda.gov/cber/regsopp/regsopp.htm l We have a different address: FDA/CBER Document Control Center, HFM-99, Suite 200N 1401 Rockville Pike Rockville, MD 20852-1448 l We usually need more than one copy; please send at least two or call ahead and ask.

20. CBER Recent CBER Process Changes (To Enhance the Review Process) l New priority courier service for regulatory documents l New bar-coded tracking of regulatory documents l Close collaboration with CDRH l Least Burdensome training l Active problem solving during first cycle, not just problem finding l Down delegation to Division Directors

21. CBER Recent CBER Process Changes (cont) l Where possible, use CDRH policies l Set internal goals in parallel with CDRH t ex. 60 day response for 510(k) IVD submissions l Increased pre-submission meetings l Device subcommittee of RMCC

22. CBER Is everything unique or different at CBER ? l ABSOLUTELY NOT ! l We are subject to the same Congressional mandates as CDRH t FDAMA t MDUFMA l We support the use of pre-submittal (Pre-IDE) meetings t CBER SOPP 8101.1 http://www.fda.gov/cber/regsopp/81011.htm l We utilize:  Standards & guidances t Scientific workshops t Advisory committee recommendations

23. CBER How Do I Find a Predicate ? l Go to CBER’s web site for list of cleared devices 1 st t 510(k) Blood Establishment Computer Software http://www.fda.gov/cber/products/510ksoft.htm t Substantially Equivalent 510(k) Device Information http://www.fda.gov/cber/efoi/510k.htm t 510(k) Device Applications (Cleared Since 1996) http://www.fda.gov/cber/dap/510kman.htm l If you can’t find one on ours, try CDRH’s website

24. CBER What about guidance documents ? Most general CDRH guidances are applicable l 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 l 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 CBER-specific guidances l Draft Guidance for Industry: Premarket Notifications [510(k)s] for In Vitro HIV Drug Resistance Genotype Assays: Special Controls - 8/28/2001 l Draft Guidance for FDA Reviewers: Premarket Notification Submissions for Automated Testing Instruments Used in Blood Establishments - 8/3/2001 l Guidance for FDA Reviewers: Premarket Notification Submissions for Blood and Plasma Warmers - 7/19/2001 l Guidance for FDA Reviewers: Premarket Notification Submissions for Transfer Sets (Excluding Sterile Connecting Devices) - 7/19/2001

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

27. CBER CBER-specific guidances (cont) These CBER-specific guidances are available at: http://www.fda.gov/cber/blood/bldguid.htm l 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 l Draft Guidance for Industry: Application of Current Statutory Authority to Nucleic Acid Testing of Pooled Plasma- 11/26/1999

28. CBER CBER-specific guidances (cont) l 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 l 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 l Reviewer Guidance for a Premarket Notification Submission for Blood Establishment Computer Software - 1/13/1997

29. CBER CBER-specific guidances (cont) l Draft Guideline for the Validation of Blood Establishment Computer Systems - 9/28/1993 l 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. CBER Contacting CBER About Submissions l For pre-submission help: t Contact the person identified in the slides that follow based on the device you wish to discuss t If you cannot decide who to contact, contact the Center Ombudsman, Dr. Sheryl L. Lard-Whiteford l For post-submission help: t Contact your RPM first (see acknowledgement letter) The RPM can set up conference call or meeting with the review team t Contact Division management t Contact Office management (Dr. Mary Beth Jacobs for OBRR) t Contact the Center Ombudsman

31. CBER How to Contact CBER for Information l Contact the Office of Communication, Training & Manufacturers Assistance at: t Phone301-827-1800 or 800-835-4709 t E-mailMATT@CBER.FDA.GOV t Web site http://www.fda.gov/cber/pubinquire.htm l See our current organization charts and lists at: http://intranet.fda.gov/cber/admin/orgcht.htm l Visit our web site: http://www.fda.gov/cber/ l Guidance: http://www.fda.gov/cber/dap/devpubs.htm

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

33. CBER Office of Blood Research & Review l Jay S. Epstein, M.D., Director l Richard M. Lewis, Ph.D., Deputy Director l Mark J. Weinstein, Ph.D., Associate Deputy Director l John S. Finlayson, Ph.D., Associate Director for Science l Mary Elizabeth Jacobs, Ph.D., Associate Director for Regulatory Affairs l Edward Tabor, Ph.D., Associate Director for Medical Affairs l Linda A. Smallwood, Ph.D., Associate Director for Policy (BPAC contact)

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

35. CBER Division of Emerging & Transfusion Transmitted Diseases l Hira L. Nakhasi, Ph.D., Director l Paul A. Mied, Ph.D., Deputy Director l Indira K. Hewlett, Ph.D., Chief, Laboratory of Molecular Biology l Gerardo Kaplan, Ph.D., Chief, Laboratory of Hepatitis & Related Emerging Agents l David Asher, M.D., Chief, Laboratory of Bacterial, Parasitic, & Unconventional Agents

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

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

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

39. CBER Who Does What ? l Office of Blood Research & Review (OBRR) t Division of Blood Applications (DBA) t Devices Review Branch Immunohematology/HLA reagents, controls, instruments, and accessories Blood Establishment Computer Software (BECS) Meeting requests for the above sCall Sheryl Kochman or staff at 301-827-3503

40. CBER Who Does What ? l Office of Blood Research & Review (OBRR)(cont) t Division of Blood Applications (DBA)(cont) t Regulatory Project Management Branch Blood collection, mixing, weighing, storage systems Management and tracking of the reviews Meeting requests for all OBRR (except DRB) submissions sCall Dr. Sayah Nedjar or staff at 301-827-5307

41. CBER Who Does What ? l Office of Blood Research & Review (OBRR) (cont) t Division of Emerging & Transfusion Transmitted Diseases (DETTD) Blood borne pathogen reagents, kits, instruments HIV diagnostics, viral load test kits West Nile Virus TSEs sCall Dr. Sayah Nedjar or staff at 301-827-5307

42. CBER Who Does What ? l Office of Blood Research & Review (OBRR) (cont) t 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 sCall Dr. Sayah Nedjar or staff at 301-827-5307

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

44. CBER 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 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. CBER 510(k)s Received

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

48. CBER CBER 510(k) Cycles* (from Receipt to Final Action) Under 1 st 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. CBER 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) Traditional18 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. CBER 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)** Traditional10 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. CBER Acknowledgements l Dr. Mary Beth Jacobs, Ph.D., CBER/OBRR/IOD l Michael A. Calabro, Ph.D.; CBER/OBRR/IOD