# Presentation: 235628

## CBER 510(k) Issues

**Sheryl A. Kochman, MT(ASCP)**
**Chief, Devices Review Branch**
**DBA/OBRR/CBER**
**IVD Roundtable – 510(k)/OIVD Workshop**
** ****April 21, 2004**

## 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**_

## 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.**

## 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**

## 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).**

## 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**

## 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**

## 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**

## 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**

## 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**

## What kinds of premarket device submissions does CBER review ?

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

## 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**

## 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)**

**Notes:**
Syphilis tests were originally regulated as 510(k) reagents by CDC for use in public health programs.

## 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**

**Notes:**
Since CBER regulates both the therapeutic product and the devices used to test them, this creates some unique situations.  In many cases, the results of in vitro tests are key to ensuring the safety and efficacy of biological therapeutic products, e.g., blood components and derivatives.

If after release for distribution of those products, the in vitro reagents used in the testing and release are recalled, we then must evaluate whether or not the products tested with those in vitro reagents should also be recalled.

We also must use the results of the in vitro tests to determine whether or when a donor should be turned away from donating to protect the blood supply.

And as new infectious agents emerge, we are expected to react rapidly to determine whether or not the agents can be transmitted by blood.

## 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**

## 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**

## 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**

## 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**

## 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. **

## 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**

## 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**

## 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/81011.htm**_
**We utilize: **
**Standards & guidances**
**Scientific workshops**
**Advisory committee recommendations**

## How Do I Find a Predicate ?

**Go to CBER’s web site for list of cleared devices 1****st**
**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 can’t find one on ours, try CDRH’s website**

## 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**

## 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 **

## 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 **

## 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: In the Manufacture and Clinical Evaluation of In Vitro Tests to Detect Nucleic Acid Sequences of Human Immunodeficiency Virus Type 1 - 7/10/1998**

## CBER-specific guidances (cont)

**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 **
**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**** **

## Bundling Submissions for IVDs Regulated by CBER

**When the reagents and instruments can be used together and significant portions of multiple individual submissions would contain the same information,  the different components **_**can be**_** bundled but are **_**not required to be**_** bundled. **
**In some cases, separate BLA/Ss and 510(k)s should be submitted but are not required. **
**The submissions to be bundled should be specified in the cover letter submitted with the applications.**
**The biologics licensing agreement (BLA) user fee and review time would apply.  510(k) 90 day review time used for instrument but **_**clearance dependant on BLA/S approval**_**. **

## Bundling Submissions for IVDs Regulated by CBER

**In cases involving a BLA or Efficacy supplement where one submission in a bundle is delaying approval of the others, CBER may discuss mechanisms for “de-linking” the problem submission so that the others can be finalized.  **
**“****De-linking” of a 510(k) could be problematic since any changes in the pending BLA/Ss might require changes to the instrument and therefore submission of a new 510(k) for those changes.**
**The remaining portion of the bundle would be handled at a later date and the labeling would be revised to include the additional reagent.  **
**These cases primarily involve immunohematology reagents. **

## Bundling Submissions for IVDs Regulated by CBER

**For example, ABO/Rh blood grouping reagents that use the same clinical data set and the same labeling can be considered for bundling.  **
**If the ABO reagents are ready for approval, but the Anti-D reagent has a few issues remaining, CBER would consider allowing the applicant to revise the labeling to delete the references to Anti-D and approve only the ABO reagents.  **
**Upon subsequent approval of the Anti-D reagent, the labeling could be revised to include the references to Anti-D.  **

## 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**

## How to Contact CBER for Information

**Contact the Office of Communication, Training & Manufacturers Assistance at: **
**Phone****	****	****301-827-1800 or 800-****835-4709**
**E-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**_

## 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**

## Office of Blood Research & Review

**Jay S. Epstein, M.D., Director**
**Mary Elizabeth Jacobs, Ph.D., Deputy Director (Acting)**
**Mark J. Weinstein, Ph.D., Associate Deputy Director**
**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)**

**Notes:**
Note that Dr. Smallwood is the contact for BPAC.

## 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**

## 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**

## Division of Hematology

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

## Office of Vaccines Research & Review

**William M. Egan, Ph.D., Director (Acting)**
**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**

## 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, Division of Clinical Evaluation & Pharmacology/Toxicology**
**Ruth Solomon, M.D., Director (Acting),       Division of Human Tissues**

## 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) and related accessories**
**Meeting requests for the above**
**Call Sheryl Kochman or staff at 301-827-3503**

## 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**

## 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**

## 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**

## 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**