CBER Tissue Safety Team

Ruth Solomon, M.D.Director

Division of Human TissuesOCTGT/CBER/FDA

Blood Products Advisory CommitteeMay 1, 2008

Outline

Background What are HCT/Ps? How are they regulated? What is an Adverse Reaction? Which Adverse Reactions must be reported?

Tissue Safety Team Challenges Summary Data on Reports

WHAT ARE HCT/Ps?

What are HCT/Ps? Human cells, tissues or cellular or tissue

based products (HCT/Ps) means articles containing or consisting of

human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient

21 CFR 1271.3(d)

Examples of HCT/Ps Musculoskeletal tissues Skin Dura mater Cardiovascular tissues Ocular tissues

Reproductive tissues Hematopoietic stem/progenitor cells derived

from peripheral and cord blood Other cellular therapies

Not HCT/Ps Vascularized human organs Whole blood or blood components or

blood derivative products Secreted or extracted human products s.a.

milk, collagen, cell factors Minimally manipulated bone marrow for

homologous use and not combined with another article

Not HCT/Ps, cont. Ancillary products used in manufacture of

HCT/Ps Cells, tissues, and organs derived from

animals other than humans In vitro diagnostic products Blood vessels recovered with an organ,

intended for use in organ transplantation and labeled “For use in organ transplantation only”

HOW ARE HCT/Ps REGULATED BY FDA?

HCT/P Regulations(all effective 5/25/05)

21 CFR Part 1271 Establishment Registration and Product

Listing Donor Eligibility Current Good Tissue Practice—contains

requirements for adverse reaction reporting Legal Authority: Section 361 of Public

Health Service (PHS) Act—prevent the introduction, transmission, or spread of communicable disease

Regulatory Pathways “361” HCT/Ps

No pre-market review; follow Part 1271 only Compliance with regulations determined on inspection

Biological Products Follow Part 1271 and other applicable regulations Pre-market review and approval (BLA)—must show

safety, purity, potency Medical Devices

Follow Part 1271 and other applicable regulations Pre-market review and clearance/approval (510(k),

PMA)—must show safety and efficacy

ADVERSE REACTIONS

What is an Adverse Reaction?

Adverse reaction [1271.3(y)] (for “361” HCT/Ps) means a noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response

Adverse experience [600.80(a)] (for biological products) means any adverse event associated with the use of a biological product in humans, whether or not product related…

What Adverse Reactions Must Manufacturers Investigate?

Manufacturers must investigate Any adverse reaction involving a

communicable disease related to an HCT/P they made available for distribution

21 CFR 1271.350(a)(1)

Manufacturers are not required to investigate (but are encouraged to do so) Adverse reactions that do not involve a

communicable disease (e.g., product defects)

What Adverse Reactions Must Manufacturers Report?

Manufacturers must report to FDA any adverse reaction involving a communicable disease, if it: Is fatal Is life-threatening Results in permanent impairment or damage Necessitates medical or surgical intervention

21 CFR 1271.350(a)(1)

ExamplesReporting Required Bacterial infection

in HCT/P recipient Graft failure

surgeon believes is secondary to infection

Viral seroconversion of recipient suspected to be allograft related

Reporting not Required*

Package labeled incorrectly

Mechanical failure of graft

Allergic reaction Product damage Donor-transmitted

malignancy* Reports may be submitted, even if not required

How are Adverse Reactions Reported to FDA?

For Manufacturers: Use Form FDA 3500A (MedWatch) Report w/in 15 days of receipt of

information Via fax/mail21 CFR 1271.350(a)(2)

How are Adverse Reactions Reported to FDA?

For Voluntary Reporters: Use Form FDA 3500 (MedWatch) Via online, fax, mail, telephone Recommend prompt reporting to HCT/P

establishments (CBER does not forward consumer reports to manufacturer)

Sources of Reports

Reports received from various sources

Tissue Establishment

Consumer/Healthcare Professional

CBERMedSun

CDC, Other

MedWatch Office

CDRH

MedWatch Website

http://www.fda.gov/medwatch Provides information on the MedWatch

reporting program, reporting forms

CBER TISSUE SAFETY TEAM

Tissue Safety Team (TST) First CBER Safety Team First meeting in May 2004 Purpose:

Provide a coordinated, efficient approach to the receipt, routing, investigation, evaluation, documentation and trending of reported adverse reactions involving HCT/Ps across 5 Offices in CBER and beyond the Center

FDA’s Tissue Safety Team Includes multiple offices at CBER Reviews all MedWatch reports received Conducts follow-up on infectious adverse

reactions related to HCT/Ps Seeks additional information from clinician and

manufacturer as needed Evaluates cases at Tissue Safety Team

meetings SOPP 8508 describes procedures for handling

AR reportswww.fda.gov/cber/regsopp/8508.htm

FDA’s Tissue Safety Team

OBEOffice of Biostatistics and

Epidemiology

OCTGTOffice of Cellular, Tissue and Gene

Therapies

OCBQOffice of

Compliance and Biologics Quality

OCTMAOffice of Communication,

Training, and Manufacturer Assistance

ODOffice of the

Director

TST Points of Contact Outside of CBER

Outside of CBER, within FDA Center for Devices and Radiological Health Office of Regulatory Affairs Office of Crisis Management

Outside of FDA CDC

CDC Epidemic Intelligence Service (EIS) Officer at FDA HRSA CMS

Special government employee consulted on unusual cases

Tracking and Routing Reports Reports received by OBE—determine if

“361” HCT/P Enter into database If an infectious adverse reaction,

determine if High Priority (criteria) and immediately notify TST Working Group and begin follow-up

For other reports, determine if follow-up is needed (criteria)

High Priority Cases Fatality; infection with Clostridium sp., or

group A Streptococcus Serious viral disease or seroconversion (e.g.,

HIV, HBV, HCV); or CJD Two or more recipients of tissues or organs

from a single donor develop infections with the same organism

Same unusual organism cultured from recipient as was found in one or more recovery, pre-processing or post-processing cultures (on tissues) or environmental cultures

Clinical Follow-up: OBE Specific name/type of product/lot

number/ manufacturer Time interval from implantation to onset

of symptoms Culture results (e.g., transport fluid, pre-

implant, wound, explanted graft) Patient—immunosuppressed? Infection

prior to graft implant? Anything unusual about the surgery?

Clinical Information (cont.)

Medical or surgical interventions e.g., debridement, explant, antibiotics started or

changed Special handling or preparation of allograft

prior to implantation Devices implanted along with tissue? General impression/indicators that adverse

reaction was related to the allograft Results of hospital infection control

investigation, if any

Manufacturing Information: OCBQ

Processor’s investigation—conclusion? Donor medical records reviewed Processing methods reviewed—any

deviations? Environmental monitoring reviewed Pre- and post- processing culture results

—do any match recipient’s culture results?

Whether there are other complaints related to same donor—if so, same organism?

Challenges in HCT/P Adverse Reaction Surveillance

Limitations of passive surveillance (under-reporting, biases, etc.)

Distinguishing graft-attributable infections vs. common post-operative wound infections

Labor intensive follow-up activities Case closed when investigation complete and

based on the available information, further TST action is not indicated. Usually no conclusion that adverse reaction was due to graft

SUMMARY DATA ON HCT/P REPORTS

Reported Adverse Reactionsby Tissue Type

Reported Adverse Reactionsby Outcome

Reported Adverse Reactionsby Reporter

Further Information Tissue Home Page

http://www.fda.gov/cber/tiss.htm Tissue-Related Documents/Publications

http://www.fda.gov/cber/tissue/docs.htm For general questions contact Office of

Communication, Training and Manufacturers Assistance (OCTMA) at: matt@cber.fda.gov 301-827-1800

Questions?