PROPOSED APPROACH 

TO REGULATION OF 

CELLULAR AND TISSUE-BASED 

PRODUCTS 

The Food and Drug Administration 

February 28, 1997
 
1
  PROPOSED APPROACH TO REGULATION OF 

CELLULAR AND TISSUE-BASED PRODUCTS 

[Docket Number 97N-0068] 
For further information regarding this document, contact: 
Sharon Carayiannis 
Center for Biologics Evaluation and Research (HFM-630) 
Food and Drug Administration 
1401 Rockville Pike, Suite 200N 
Rockville, MD 20852-1448 
301-594-3074 
Submit written comments on this document to: 
Dockets Management Branch (HFA-305) 
Food and Drug Administration 
12420 Parklawn Drive, Room 1-23 
Rockville, MD 20857 
Comments should be identified with the docket number found in the heading of this page. 
Submit written requests for additional copies of this document or any other CBER guidance to: 
Office of Communication, Training, and Manufacturers Assistance (HFM-40) 
Food and Drug Administration 
1401 Rockville Pike, Suite 200N 
Rockville, MD 20852-1448 
Send one self-addressed adhesive label to assist that office in processing your request. 
These documents may also be obtained by mail by calling the CBER Voice Information System at 1-800-835-4709 or 
301-827-1800, or by fax by calling the FAX Information System at 1-888-CBER-FAX or 301-827-3844. 
2
  Persons with access to the INTERNET may obtain these documents using, the World Wide Web (WWW), or 
bounce-back e-mail. For WWW access, connect to CBER at "http://www.fda.gov/cber/cberftp.html". To receive this 
document by bounce-back e-mail , send a message to "CELLTISSUE@A1.CBER.FDA.GOV". 
3
  TABLE OF CONTENTS 

Note: 	Page numbering may vary for documents distributed electronically. 
Executive Summary ...................................................................................................................   3
 
I. Introduction ...........................................................................................................................   5
 
II. Background ..........................................................................................................................   5
 
III.  Public health and regulatory concerns associated with cellular and tissue-based 

products ...........................................................................................................................   6
 
IV. 	Product factors (tissue characteristics and uses) affecting each area of   concern 
an overview ..................................................................................................................   7
 
A) Direct transmission of communicable disease ............................................................   7
 
B) Processing concerns .................................................................................................   7
 
C) Clinical safety and effectiveness concerns .................................................................   8
 
D) Promotion and labeling ............................................................................................   8
 
E ) FDA's baseline knowledge of cell and tissue industry ..............................................   8
 
V. The regulatory scheme: product concerns, product characteristics, and uses; required industry actions; and required regulatory submissions ..................................................... 

A) Direct Transmission of Communicable Disease - Donor Screening,           Donor/Product 

Testing .................................................................................................  9
 
1) Overview ......................................................................................................  9
 
2) Regulatory Requirements ..............................................................................  9
 
a) Row A1 .............................................................................................  9
 
b) Row A2 .............................................................................................  9
 
B) Control of Processing ..............................................................................................  11
 
1) Overview ......................................................................................................  11
 
2) Factors Affecting Processing Concerns and Clinical Safety and Effectiveness 

Concerns ...........................................................................................................  12
 
a) Non-cell/non-tissue components ........................................................  12
 
b) Manipulation .....................................................................................  13
 
c) Non-homologous function ................................................................. 15 

d) Metabolic function ............................................................................  16
 
4
  e) Reproductive Function ......................................................................  17
 
f) Structural Function ............................................................................  17
 
3) Regulatory Requirements ..............................................................................  17
 
a) Row B1 .............................................................................................  17
 
b) Row B2 .............................................................................................  17
 
c) Row B3 .............................................................................................  18
 
C) Clinical Safety and Effectiveness - Use-specific Concerns .......................................  19
 
1) Overview ......................................................................................................  19
 
2) Regulatory Requirements ..............................................................................  19
 
a) Row C1 .............................................................................................  19
 
b) Row C2 .............................................................................................  20
 
c) Row C3 .............................................................................................  20
 
  D) Promotion and Labeling ..........................................................................................  21
 
E) Monitoring and Education .......................................................................................  21
 
VI. Implementation of Regulatory Procedures .........................................................................  22
 
A) Stem cells ...............................................................................................................  22
 
1) Registration and Listing ...............................................................................  22
 
2) Communicable-Disease Screening and Testing ............................................  22
 
3) Processing Standards ..................................................................................  23
 
B) Demineralized bone ................................................................................................  24
 
VII. Conclusion ......................................................................................................................  24
 
Glossary of Terms as Used in this Document ..........................................................................  25
 
Table 1    Relationships among product concerns, product characteristics, regulatory approaches 
Table 2   Regulatory Framework for Cells and Tissue Related Products 
5
  PROPOSED APPROACH TO REGULATION OF 

CELLULAR AND TISSUE-BASED PRODUCTS

 February 28, 1997 
EXECUTIVE SUMMARY 
The Food and Drug Administration is proposing a new approach to the regulation of human cellular and 
tissue-based products. Tissues have long been transplanted in medicine for widespread uses--such as 
skin replacement after severe burns, tendons and ligaments to repair injuries, heart valves to replace 
defective ones, corneas to restore eyesight, and the use of human semen and implantation of eggs to 
help infertile couples start a family. In recent years, scientists have developed new techniques, many 
derived from biotechnology, that enhance and expand the use of human cells and tissues as therapeutic 
products. These new techniques hold the promise of some day providing therapies for cancer, AIDS, 
Parkinsons Disease, hemophilia, anemia, diabetes, and other serious conditions. 
The existing FDA approach to the regulation of human cellular and tissue-based products is highly 
fragmented. The agency has not previously clearly defined criteria for product characterization, 
sometimes resulting in confusion on the part of both industry and FDA reviewers. The new regulatory 
framework, as articulated in this document, would provide a unified approach to the regulation of both 
traditional and new products. The framework clearly specifies criteria for regulation, and would provide 
for harmonized review of applications by different Centers within the agency. Additionally, the 
framework would provide only the degree of government oversight necessary to protect the public 
health. For products with limited public health concerns, the new framework would allow flexibility and 
innovation without an application review process. 
This new framework would provide a tiered approach to cell and tissue regulation. Regulation would 
focus on three general areas: 1) preventing unwitting use of contaminated tissues with the potential for 
transmitting infectious diseases such as AIDS and hepatitis; 2) preventing improper handling or 
processing that might contaminate or damage tissues; 3) ensuring that clinical safety and effectiveness is 
demonstrated for tissues that are highly processed, are used for other than their normal function, are 
combined with non-tissue components, or are used for metabolic purposes. 
The agency would recommend, but not require, that screening and testing procedures be followed when 
reproductive tissues are used between sexually intimate partners, and when tissues are transplanted 
back into the person from whom they were obtained. The agency would require infectious disease 
screening and testing for cells and tissues transplanted from one person to another (except for 
reproductive tissues used between sexually intimate partners). The agency would also require that cells 
and tissues be handled according to procedures designed to prevent contamination and to preserve 
6
  tissue function and integrity. In general, there would be no agency submissions required regarding 
infectious disease controls and handling requirements. Thus, most conventional and reproductive tissues 
would not be subject to premarket approval requirements. (The agency would impose no requirements 
on cells and tissues transplanted within a patients body in a single surgical procedure.) 
Cells and tissues that were manipulated extensively, combined with non-tissue components, or were to 
be used for other than their normal functions would be regulated as biologics or devices requiring 
premarket approval by FDA. Metabolic cells and tissues, unless minimally manipulated and used for 
their normal function in the person from whom they were obtained or in close blood relatives of that 
person, also would be regulated as biologics requiring premarket approval by FDA. 
The agency would require that all tissue processing facilities register with the agency, and list their 
products, via a simple electronic system. And the agency would require that all labeling and promotion 
be clear, accurate, balanced, and non-misleading. 
This new system would provide a rational, comprehensive and comprehensible framework under which 
tissue processors could develop and market their products. It would ensure that innovation and product 
development in this rapidly growing medical field could proceed unhindered by unnecessary regulation. 
At the same time, it would provide physicians and patients with the assurance of safety that the public 
has come to expect from drugs, biologics, medical devices and other medical products overseen by the 
FDA. 
7
  I. INTRODUCTION 
The FDA has formulated a comprehensive approach to the regulation of human cellular and tissue-
based products. This approach would provide more appropriate oversight for the wide spectrum of 
cellular and tissue-based products that are now marketed or envisioned for the future. It would maintain 
or improve protection of the public and increase public confidence in these new technologies, while 
permitting significant innovation to go forward unfettered by unnecessary regulatory requirements. 
The approach does not encompass vascularized organs or minimally-manipulated bone marrow (both of 
which are regulated by the Health Resources and Services Administration), transfusable blood products 
(e.g., whole blood, red blood cells, platelets, and plasma), which the agency already comprehensively 
regulates,1 or tissues derived from animals.2 It also does not encompass other tissue-related products, 
such as products used in the propagation of cells or tissues, or that are secreted by or extracted from 
cells or tissues (e.g. human milk, collagen, urokinase, cytokines, and growth factors.) Such products 
often raise different manufacturing, safety, and effectiveness issues, and generally are covered by other 
rules, regulations, and/or standards. 
II. BACKGROUND 
The term  'tissues' covers a wide range of products used for many medical purposes.  In the past, most 
human tissue used in medicine was comprised of such body components as skin, bone, corneas, and 
heart valves that were transplanted for replacement purposes, and semen and ova implanted for 
reproductive purposes. Except for a small number of tissues previously regulated as devices since 
1993, FDA's regulation of the conventional tissues used for replacement purposes has focused on 
preventing the transmission of communicable disease, as authorized by the Public Health Service Act 
(PHS Act). Three years ago, FDA promulgated interim requirements that such conventional non
                                                                
1 The agency recognizes that it may be desirable to regulate traditional blood products in a 
manner more like the regulation of other cellular and tissue-based products (to the extent that they 
present similar issues), and will examine this issue in a future initiative. 
2  Transplantation of animal tissues into humans (xenograft transplantation) is not addressed in 
this document, as it raises different public health issues from those raised by transplantation of human 
tissue into humans. Among other things, the spectrum of infectious agents potentially transmitted via 
xenograft transplantation is not known, and infectious agents that produce minimal symptoms in animals 
may cause severe morbidity and mortality in humans. The Public Health Service published a draft 
Guideline on Infectious Disease Issues in Xenotransplantation in September 1996. (September 23, 
1996 Federal Register, 61 FR 49919). 
8
  reproductive tissues be tested for HIV and hepatitis and that their donors be screened for risk of 
infection. FDA has not previously regulated reproductive tissues. 
In recent years, scientists have developed innovative methods of manipulating and using human cells and 
tissues for therapeutic uses. For example, in what is known as somatic cell therapy, scientists are 
studying the use of human cells that have been manipulated in the laboratory to treat viral infections 
(including HIV infection), Parkinsons Disease, diabetes, and other diseases and conditions. Other 
tissue research includes the use of blood from the placental/umbilical cord, to treat diseases or 
conditions. In general, these forms of cellular and tissue therapy are regulated by FDA as biologics 
under both the PHS Act and the Federal Food, Drug, and Cosmetic Act (FDCA) , with premarketing 
approval requirements. 
III. PUBLIC HEALTH AND REGULATORY CONCERNS ASSOCIATED WITH 
CELLULAR AND TISSUE-BASED PRODUCTS. 
Cellular and tissue-based products and their potential uses are too diverse for a single set of regulatory 
requirements to be appropriate for all. In an effort to develop a comprehensive scheme that would treat 
like products alike, but that would establish appropriate regulatory distinctions among cellular and 
tissue-based products in areas where there were differences, the agency identified the principal public 
health concerns and attendant regulatory issues associated with the use of these products. Stated as 
questions, these five overarching public health and regulatory concerns are: 
A) 	 How can the transmission of communicable disease be prevented? 
B) 	 What processing controls are necessary, e.g., to prevent contamination that could result in an 
unsafe or ineffective product, and to preserve integrity and function so that products will work 
as they are intended? 
C)	  How can clinical safety and effectiveness be assured? 
D) 	 What labeling is necessary, and what kind of promotion is permissible, for proper use of the 
product? 
E) 	 How can the FDA best monitor and communicate with the cell and tissue industry? 
With these concerns in mind, the FDA differentiated cells and tissues and their uses by their risk relative 
to each concern, so as to enable the agency to provide only that level of oversight relevant to each of 
the individual areas of concern. Thus, under the plan, tissues would be regulated with a tiered approach 
based on risk and the necessity for FDA review. 
9
  IV. PRODUCT FACTORS (TISSUE CHARACTERISTICS AND USES) AFFECTING 
EACH AREA OF CONCERN - AN OVERVIEW 
The agency has identified the following key product factors relating to the above concerns. 
A) Direct transmission of communicable disease.  The level of public health concern about 
communicable disease varies depending in substantial part on the following factors: whether the cells or 
tissues are used in the same person from whom they were obtained (autologous use); whether the cells 
or tissues are used in a person different from whom they were obtained (allogeneic use); whether they 
are banked (stored), shipped, or processed in a facility that handles cells and tissues from multiple 
donors; whether the cells or tissues are minimally, or more-than-minimally, manipulated; whether the 
tissue is viable or nonviable; and for reproductive cells or tissue, whether they are obtained from a 
sexually-intimate partner of the transplant/insemination recipient. 
B) Processing concerns.  The level of concern relating to processing is dependent on the 
following factors: whether or not the cells or tissues are more-than-minimally manipulated; whether or 
not they are used for their normal (homologous) function; whether or not they are combined with non
cell/non-tissue components; and whether or not they are used for metabolic function.  As will be 
discussed below in VI B, Control of Processing, products that are more-than-minimally manipulated, or 
are used for purposes other than their normal function, or are combined with non-cell/non-tissue 
components, or are used for metabolic function, generally will be subject to more comprehensive 
regulation of processing than products not characterized by any of these factors, although some 
exceptions may apply. (For example, use for metabolic function would not in and of itself lead to more 
comprehensive processing regulation when the product was used in the person from whom it was 
obtained, or in a close blood relative of that person;3 use of minimally manipulated tissue for other than 
its normal function may lead to only limited additional regulation of processing, as appropriate to help 
                                                                
3  As a policy matter, the agency would not require investigational use exemptions and 
premarketing submissions for metabolic cells or tissues that were only minimally manipulated, were to be 
used for their normal function and were not combined with non-cell/non-tissue components, when those 
cells or tissues were to be used in the person from whom they were obtained or in a close blood relative 
of that person. Therefore, FDA would require no agency submissions other than registration, listing, 
and reporting of adverse events for such products used between close blood relatives. The products 
would still be subject to appropriate labeling and processing controls. 
A close blood relative (also referred to in this document as a family relative) is defined in this document 
as a first degree blood relative (i.e., parent, child, or sibling). "Unrelated" is used in this document to 
refer to someone other than a close blood relative of the donor. 
10
  ensure intended function). Products not characterized by any of these factors would be regulated under 
section 361 of the PHS Act, and would not be subject to premarketing requirements. Products 
characterized by one or more of these factors would be regulated under section 351 of the PHS Act 
and/or under the FDCA, and generally would be subject to some level of premarketing requirements. 
C) Clinical safety and effectiveness concerns.   Clinical safety and effectiveness concerns 
depend on the same factors as do processing concerns (i.e., extent of manipulation; homologous or 
non-homologous function (that is, whether or not tissue is used for its normal function); combination with 
non-cell/non-tissue components; and metabolic function). The kinds of information the agency will need 
to address these concerns may differ depending on whether the cellular or tissue-based product is to be 
used for a local structural purpose (i.e., reconstruction or repair), a reproductive purpose, or a 
metabolic purpose. As noted above for processing concerns, and as will be discussed below in section 
VI C, Clinical Safety and Effectiveness, products that are more-than-minimally manipulated, or are used 
for non-homologous function, or are combined with non-cell/non-tissue components, or are used for 
metabolic function, will generally be subject to more comprehensive regulatory controls than products 
without any of these factors. However, for some products subject to regulation under section 351 
and/or the FDCA (see section VI, A, Stem Cells) the agency anticipates establishing product-class
specific processing controls and product standards based on data demonstrating that such controls or 
standards ensure safety and effectiveness. For these products, applicants would be eligible to certify 
that these controls and standards have been met in lieu of submitting the underlying data to support such 
controls and standards. 
D) and E ) Promotion and labeling and the agency's baseline knowledge  of industry  are 
cross-cutting issues that apply to all cellular and tissue-based products, with the exception of cells and 
tissues obtained from and transplanted back into the same person during a single surgical procedure. 
V. THE REGULATORY SCHEME: PRODUCT CONCERNS, PRODUCT 
CHARACTERISTICS AND USES, REQUIRED INDUSTRY ACTIONS, AND REQUIRED 
REGULATORY SUBMISSIONS. 
The agency has developed a chart (Table 1) that outlines the five principal areas of public health or 
regulatory concern (rows A through E, as described below), the product factors that affect those 
concerns (and that are the basis for the subdivisions within rows A, B, and C), the industry actions that 
would be required to address each set of concerns, and the types of required notifications or 
submissions to the agency. Thus, to determine all the regulatory mechanisms that would apply to any 
particular product or use, one must look at all the items in the table. The table is provided only as a 
very short summary of the regulatory approach. As such, it is not intended to stand alone, but to be 
referred to in conjunction with this document. The following text elaborates on the issues as presented 
by row in Table 1. 
11
  A) Direct transmission of communicable disease - donor screening, donor/product 
testing.  
1) Overview. 
Transmission of communicable disease is a concern for all uses of all cellular or tissue-based products. 
However, the degree of risk, and the appropriate measures to control risk, vary with the source and use 
of the product. FDA intends to adjust its regulatory approach accordingly. 
Row A of Table 1 broadly distinguishes between cellular and tissue-based products for which the 
agency would not require communicable-disease controls (A1), and products for which it would require 
communicable-disease controls (A2). A2 is further subdivided according to the kinds of requirements 
and tests the agency would consider appropriate, based on the source, use, and characteristics of the 
tissue. Proposals for specific screening, testing, and related requirements for products in these 
categories are provided in Table 2. 
2)  Regulatory requirements. 
a) Row A1. The agency would not assert any regulatory control over cells or 
tissues that are removed from a patient and transplanted back into that patient during a single surgical 
procedure. The communicable disease risks, as well as safety and effectiveness risks, would generally 
be no different from those typically associated with surgery. Regulated products used in such 
procedures would continue to be regulated. 
b) Row A2. The use of allogeneic rather than autologous cellular or tissue-
based products increases the risk of transmission of communicable disease, because the donor from 
whom the cells or tissue was obtained could carry an infectious agent to which the recipient is 
susceptible. Also, for both autologous and allogeneic settings, the use of cellular or tissue-based 
products that are banked, transported, or processed in facilities with other cellular or tissue-based 
products increases the risk of transmission of communicable disease, because the products are 
susceptible to contamination or mix-up at each step of such procedures. For example, an infected 
product could cross-contaminate other cellular or tissue-based products stored in the same liquid 
nitrogen freezer, or could contaminate processing equipment, which, if not properly treated, could 
contaminate other tissue processed with that equipment. If contaminated tissue is not properly tested or 
labeled, health care workers as well as patients may be put at risk. 
Therefore, as shown in rows A2b and A2c of Table 1 and in Table 2, the agency intends to require 
establishments and persons that bank, ship, or process cells or tissues for allogeneic use (except 
reproductive tissues from sexually intimate partners of the intended recipient of the tissue) to follow 
specific donor screening and/or donor or product testing and/or product quarantine procedures. Test 
requirements will differ depending on whether the cells or tissues are nonviable (A2b) or viable (A2c). 
Viable cells and tissues that are rich in leukocytes (such as stem cells) can harbor human T-cell 
lymphotropic virus (HTLV) and cytomegalovirus (CMV), and thus would be required to be tested for 
12
  those viruses. Viable tissues that are not rich in leukocytes (such as corneas and skin), and nonviable 
tissues (which do not contain viable leukocytes) would not be subject to HTLV and CMV testing 
requirements. 
In general, the screening and testing would be required to be completed prior to final release of the cells 
or tissue for transplantation. The establishment or person responsible for determining suitability of 
release of cells or tissues would be responsible for ensuring that required screening and testing had been 
performed prior to final release of the material.4  For cells or tissue to be obtained from a living donor 
for allogeneic use, screening and testing would be required prior to collection of the cells or tissue 
(except in extenuating circumstances). 
Additionally, as shown in row A2a of Table 1 and in Table 2, the agency intends to recommend (but not 
require) that establishments and persons that bank, ship or process cells or tissues from multiple donors 
for autologous use, or reproductive cells or tissues for reproductive use obtained from sexually intimate 
partners of the intended recipients of the cells or tissues, also follow the screening and testing 
procedures prior to collecting the cells or tissue. The agency intends to require that such establishments 
and persons keep records and label their products as to whether or not recommended donor screening 
and testing was performed, and if performed, the results obtained. Untested products would be labeled 
as "untested for BIOHAZARDS." 
The screening and testing procedures would be recommended rather than required for such autologous 
or reproductive uses because 1) autologous use of cells and tissues raises lesser communicable-disease 
concerns than does allogeneic use; and 2) use of reproductive tissues from sexually intimate partners of 
intended recipients raises lesser communicable-disease concerns than other allogeneic uses of tissues 
because the recipient generally will have had prior exposure to the potential risk of receiving 
communicable disease from that partner. (In contrast, cells or tissue from family-related donors raise 
the same communicable-disease risks as do cells or tissue from unrelated donors, and consequently 
family-related donors would be subject to the same testing and screening procedures as are unrelated 
donors. However, the agency believes that it is appropriate to leave it up to the family and their 
physician to decide whether to use such tissue, and would not prohibit use even of contaminated 
material from closely-related donors.) 
Cells or tissue from donors who test positive for an infectious disease agent or who have positive risk 
                                                                
4  Cells and tissues processed or shipped to a consignee prior to determination of donor 
suitability would have to be under quarantine, accompanied by records assuring identification of the 
donor, and indicating that the material had not yet been determined to be suitable for transplantation, 
insemination, fertilization, further shipment or release. The consignee would be responsible for keeping 
such material in quarantine, and not shipping it further until donor screening tests had been completed. 
13
  factors (that is, whose behavior or experiences could have exposed them to infection) would be 
required to be labeled 'BIOHAZARD' or "UNTESTED FOR BIOHAZARD" as applicable, and 
could only be used for transplantation with the documented advance informed consent of the recipient. 
Autologous tissue from such donors would be required to be labeled 'FOR AUTOLOGOUS USE 
ONLY.'  In those situations in which cells or tissues from such donors are not destroyed, the material 
could be released from a bank or quarantine only upon documented concurrence of the recipients 
physician. Such situations would include cells or tissue to be used in the person from whom it was 
obtained or in a close blood relative (e.g., autologous stem cells); and reproductive tissue for 
reproductive use (e.g., semen) from a sexually intimate partner of the intended recipient or from a 
directed donor; medically necessary and otherwise unavailable cells or tissue (e.g., the tissue is a rare 
histocompatibility match in a setting where matching is critical). 
The agency would engage in rulemaking5 under section 361 of the PHS Act to establish procedures and 
standards for cellular and tissue-based products not subject to premarket requirements under the PHS 
Act or the FDCA. While under the section 361 rule there would be no required premarketing 
submissions to the agency concerning communicable-disease testing, the agency would have authority to 
inspect facilities subject to the requirements, and to take actions to prevent transmission of 
communicable disease (e.g., orders of retention, recall, and destruction of cellular and tissue-based 
products). 
Cellular and tissue-based products subject to premarket requirements because of processing or clinical 
attributes (see sections V B and V C below) would still be subject, unless the requirements were 
unnecessary in a particular situation, to the same core communicable-disease standards and procedures 
as are cellular and tissue-based products regulated under section 361, and would generally be subject 
to no additional submission requirements regarding these communicable-disease issues. To the extent 
that a product requiring premarketing approval were to raise additional communicable-disease concerns 
as a result of its source, processing, or use, additional standards or procedures could be required in the 
marketing application6 to address these concerns. 
B)  Control of Processing. 
                                                                
5 FDA published an interim rule (21 CFR Part 1270) that contains requirements for 
communicable disease controls for a subset of cellular and tissue-based products discussed in this 
document. FDA plans to finalize those requirements, and then engage in further rule making as is 
necessary, to achieve the purposes of this proposed regulatory scheme. 
6 For example, manipulation of cells or tissue can affect the infectivity, virulence, or other 
biological characteristics of adventitious agents in the tissue, thereby increasing communicable-disease 
risks, and potentially requiring new standards or procedures. 
14
  1) Overview. 
Row B of Table 1 differentiates products based on whether their characteristics and uses warrant 
handling and processing controls aimed only at preventing transmission of communicable disease (B2); 
or warrant processing controls aimed at providing assurance of clinical safety and effectiveness, 
including but not restricted to preventing transmission of communicable disease (B3). Autologous use of 
cells and tissues harvested and transplanted in a single surgical procedure would be subject to no FDA 
oversight (B1). Regulated products used with the cells or tissues or to process the cells or tissues 
would continue to be regulated. 
Improper handling can alter or destroy the integrity or function of cells or tissues. Improper handling 
also can allow cells or tissues to become contaminated (e.g, bacterial contamination during collection, 
processing, storage, or transplantation, or cross contamination from other contaminated tissues). 
Similarly, inadequately-controlled processing can alter or destroy the integrity or function of cells or 
tissues. Use of cells or tissues contaminated with an infectious agent obviously increases the risk of 
transmission of communicable disease. Use of cells or tissue with impaired integrity or function also 
increases the risk of transmission of communicable disease: tissue with impaired integrity or function can 
lead to transplantation failure, with attendant communicable disease risks (e.g., by increasing the 
patients susceptibility to communicable disease, or requiring additional transplantation procedures, with 
their attendant communicable-disease risks.) 
2) Factors Affecting Processing Concerns and Clinical Safety and Effectiveness 
Concerns. 
As previously discussed above, the factors affecting the level of concern regarding processing controls 
and product safety and effectiveness are: manipulation (i.e., whether the product is minimally or more-
than-minimally manipulated); homologous or non-homologous function; whether or not the cells or tissue 
are combined with non-cell/non-tissue components; and whether or not the product is used for 
metabolic function as opposed to reproductive or structural function. The agency describes these 
factors and their regulatory implications below. 
(a) Non-cell/non-tissue components. Cellular and tissue-based products 
may be combinations of cells or tissues with mechanical or synthetic components, with drugs, or with 
non-cell/non-tissue biologics. The largest and fastest growing class of such combination products are 
those containing synthetic or mechanical components. These components raise concerns about function, 
compatibility, and durability. Examples of such combination products would include epithelial cells on a 
biomatrix to cover burns; allogeneic pancreas cells in a capsule that allows exit of insulin but not entry of 
antibodies; and bone when combined with collagen or growth factors. 
The agency does not anticipate that its planned regulatory approach for cellular and tissue-based 
products would alter existing agency regulatory policies concerning cellular and tissue-based products 
containing non-cell/non-tissue components. These combination products are generally subject to 
15
  premarketing requirements. The decision as to which part of the agency has primary regulatory 
responsibility for such combination products will depend on the primary mode of action of the product. 
Combination products whose primary mode of action is that of a device are regulated by the Center for 
Devices and Radiological Health (CDRH). Combination products whose primary mode of action is that 
of a biologic are regulated by the Center for Biologics Evaluation and Research (CBER). Combination 
products whose primary mode of action is that of a drug are regulated by the Center for Drug 
Evaluation and Research (CDER). The agency intends to assure that its reviews of these products are 
consistently performed, regardless of which Center is responsible for the review. 
For combination products with synthetic or mechanical components (which comprise the largest class of 
combination products), clinical trials and marketing applications must address the clinical safety and 
effectiveness of the overall product, as well as the function and compatibility of the synthetic or 
mechanical components. The agencys principal concerns with the use of these materials are that they 
function correctly, that they last a predictable and adequate length of time, and that they are compatible 
with surrounding tissue. Clinical trials would thus be required under IND or IDE, as appropriate.7  
The agency is setting up a Tissue Reference Group to assist in making jurisdictional decisions and 
applying consistent policy to these products. The agency hopes thereby to resolve expeditiously any 
scientific or regulatory questions that arise as to where and how such products should be reviewed. The 
Tissue Reference Group will consist of three CBER and three CDRH employees. It will provide a 
single reference point for all tissue-related questions received by the Centers or the Office of the Chief 
Mediator and Ombudsman. 
b) Manipulation.  The agency would consider processing of structural tissue to 
be "minimal manipulation" when the processing does not alter the original relevant characteristics of the 
tissue. The relevant characteristics of structural tissue are those relating to the tissue's ability to carry out 
the function of reconstruction and/or repair. Thus, separation of structural tissue into components 
whose characteristics relating to reconstruction and/or repair are not altered would be minimal 
manipulation. Similarly, extraction or separation of cells from structural tissue, in which the remaining 
structural tissue's characteristics relating to carrying out reconstruction and/or repair were unaltered, 
would be considered minimal manipulation. Other examples of procedures that would be considered to 
constitute only minimal manipulation include cutting, grinding, and shaping; soaking in antibiotic solution; 
sterilization by ethylene oxide treatment or gamma irradiation; cell separation; lyophilization; 
                                                                
7  Tissue-based products  that are intended for diagnosis or therapeutic effect by physical action 
(including reconstruction or repair), and that contain synthetic or mechanical components, and achieve 
their primary mode of action by means other than metabolic or systemic action, are regulated as devices 
by CDRH. 
16
  cryopreservation; and freezing. 
In contrast, extraction of endogenous substances such as minerals or proteins from structural tissue 
would be considered more-than-minimal manipulation, because such modifications would ordinarily alter 
the tissue's relevant characteristics. 
The agency would consider processing of cells (both structural and non-structural) and non-structural 
tissues to be "minimal manipulation" when the processing does not alter the biological characteristics of 
the cells or tissue. The agency would consider processing of cells and non-structural tissues to be 
"more-than-minimal manipulation" when the processing alters the biological characteristics (and thus 
potentially the function or integrity) of the cells or tissue, or when adequate information does not exist to 
determine whether the processing will alter the biological characteristics of the cell or tissue. Examples 
of more-than-minimal manipulation of cells and tissues include cell expansion, encapsulation, activation, 
or genetic modification. 
Cells or tissues that are more-than-minimally manipulated would be subject to processing controls that 
generally would cover chemistry, manufacturing, and controls (CMCs), and to premarket requirements 
for determination of safety and effectiveness because manipulation has the potential, or is intended, to 
change the cell or tissue's biological characteristics or function. The agency has previously used the 
concept of manipulation to identify those cellular therapies for which premarket approval would be 
required. In the somatic cell and gene therapy statement published in October, 1993 (58 FR 53248), 
the agency stated: 
Cells subject to licensure as final biological products when intended for use as cell therapy 
include cells manipulated in a way that changes the biological characteristics of the cell 
population... 
As described for row B3 in section V B2c below, these products would continue to be subject to 
CMCs, including process controls and product specifications designed to ensure safety, purity, and 
potency, and to IND or IDE and marketing application procedures. The agency has prepared CMC 
guidances for some of these products. 
As additional information is generated about procedures in the "more-than-minimal-manipulation" 
category, the agency intends to consider them to be in the "minimal-manipulation" category when clinical 
data and experience show that the procedure does not alter the biological characteristics of the cells or 
non-structural tissue, or the relevant structure-related characteristics of structural tissue. This flexibility 
will permit product processing that has been found not to affect the pertinent characteristics of the 
product to be subjected to a lower level of regulation. 
In the somatic cell and gene therapy statement, the agency stated that it considered cell selection to 
17
  constitute more-than-minimal manipulation. After additional experience and deliberation, the agency 
now considers cell selection (e.g., selection of stem cells from amongst lymphocytes and mature cells of 
other lineages) to be minimal manipulation. 
In cases where the agency has not made known whether it considers a particular kind of processing to 
be minimal or more-than-minimal manipulation, individuals may request an opinion from the 
agencys Tissue Reference Group.  Individuals who believe that a particular kind of processing is only 
minimal manipulation and choose to proceed without seeking clarification assume the risk that they may 
be out of compliance with premarketing and labeling requirements if the agency determines that the 
processing is more-than-minimal manipulation. 
c) Homologous and non-homologous function.  The distinction between homologous 
and non-homologous function will differ depending on whether or not the product is a structural tissue. 
The agency considers structural tissue to be used for a homologous function when used to replace an 
analogous structural tissue that has been damaged or otherwise does not function adequately. 
Conversely, the agency would consider structural tissue to be performing a non-homologous function 
when used for a purpose different from that which it fulfills in its native state, or in a location of the body 
where such structural function does not normally occur. 
Examples of homologous uses of structural tissues include bone allograft obtained from a long bone but 
used in a vertebra; skin allograft obtained from the arm but used as a skin graft on the face; pericardium, 
a structural covering of the heart, used as a structural covering for the brain; human heart valves; and 
human dura mater, a fibrous covering of the brain, used as a covering. (Thus, the agency would 
redesignate human heart valves and human dura mater from devices to tissues subject to section 361 
oversight.) 
Examples of non-homologous use of structural tissue include amniotic membrane used for wound 
healing on the cornea, and cartilage placed under the sub-mucosal layer of the urinary bladder to change 
the angle of the ureter and thereby prevent backflow of urine from the bladder into the ureter. The 
amniotic membrane, which covers the amniotic sac in utero, would be intended to heal a damaged 
corneal epithelium by growing new corneal epithelial cells, a function it does not normally perform in 
utero. The cartilage would be acting as a structural support (its normal function), but in a location where 
such structural support does not normally exist. 
The agency considers cellular products to be used for a homologous function when they are used to 
perform their native function, and for a non-homologous function when they are used to perform other 
functions. An example of homologous use would be hematopoietic stem cells used for hematopoietic 
reconstitution of individuals with marrow aplasia, chemotherapy-induced marrow ablation, Fanconi's 
anemia, or severe combined immunodeficiency disease. An example of non-homologous use of the 
same cellular product would be treatment of some adrenal leukodystrophies (which are congenital 
18
  metabolic deficiencies), because the sponsor would be intending for the stem cells to perform a 
metabolic function other than hematopoietic reconstitution. 
As for manipulation, the agency would have increased safety and effectiveness concerns for cellular and 
tissue-based products that are used for non-homologous function, because there is less basis on which 
to predict the products behavior. Thus, a tendon used to replace a tendon, even one elsewhere in the 
body, is still being used for a homologous function and can reasonably be expected to function 
appropriately. However, without clinical trials, one cannot predict with any certainty how a tendon 
would act when used for a non-homologous function, such as to constrict a blood vessel  to prevent 
pulmonary embolism. 
As described above for manipulation, in cases where the agency has not made known whether it 
considers a particular use to be homologous or non-homologous, investigators may request an opinion 
from the agencys Tissue Reference Group.  Individuals who believe that a use is homologous and 
choose to proceed without seeking clarification assume the risk that they may be out of compliance with 
premarketing and labeling requirements if the agency determines that the use is non-homologous. 
d) Metabolic function.  Products with a metabolic mode of action usually rely 
on viable, functioning cells (e.g., pancreatic islet cells, pituitary cells, stem cells) for function. They 
therefore are sensitive to perturbations and may not retain normal function after the transplantation 
process. Failure or improper functioning of such products often can have a broad variety of systemic 
adverse effects, and can be life-threatening (e.g., hematopoietic stem cell replacement after marrow 
ablation by chemotherapy, pancreatic islet cell therapy for diabetes). Relatively few such products have 
an established history of safe use. (The agency believes that some autologous and family-related
allogeneic uses of hematopoietic stem cells may have such an established history.) 
As noted above, minimally manipulated cellular and tissue-based products with metabolic function raise 
greater clinical safety and effectiveness concerns than do products with structural or reproductive 
function. The agency intends to assert premarketing requirements over these products (except when the 
cells or tissues are used in the person from whom they were obtained or in a close blood relative of the 
donor, in which case as a policy matter the agency would not require premarket submissions). Thus, for 
example, the agency would not call for clinical safety and effectiveness information for autologous or 
family-related allogeneic use of minimally manipulated hematopoietic stem cells (for which no non
homologous use promotional claims were made), but would require clinical safety and effectiveness 
information for non-family-related allogeneic use of the same cells. As noted in B3 above and section 
IV below, the agency believes that, for minimally manipulated stem cells used allogeneically to 
reconstitute the cellular components of blood, sufficient clinical safety and effectiveness data may exist in 
the near future to enable the development of processing and product standards for certain uses that 
would obviate the need for applicants to submit CMC and clinical safety and effectiveness information 
prior to marketing. 
19
  e) Reproductive function. In contrast to other metabolic tissues, reproductive tissues 
raise less substantial issues of rejection, graft versus host disease, or compatibility. Indeed, unlike other 
tissue, they perform their normal biological functions in an allogeneic setting. Failure of reproductive 
tissue generally does not have life-threatening or systemic adverse effects except for fertility per se. 
Reproductive tissues have a long history of use in the medical community. (Assessments of pregnancy 
success rates for live births in clinics is currently being addressed by the Centers for Disease Control 
and Prevention, under the Fertility Clinics Success Rate and Certification Act of 1992.) 
f) Structural function.  Cells and tissues used for structural purposes generally raise 
different clinical safety and effectiveness concerns than do metabolic cells and tissues. Many structural 
cellular and tissue-based products raise limited safety concerns beyond adverse local effects. 
Depending on location, failure of most structural cellular and tissue-based products is unlikely to lead to 
life-threatening consequences.  In many cases, determination of effectiveness of structural therapies is 
more straightforward than is determination of effectiveness of metabolic therapies. 
Additionally, many structural tissue-based products rely predominantly on non-living tissues (e.g., 
tendons) for function.  They therefore usually are relatively insensitive to external factors and are more 
likely to retain normal function after the transplantation process.   Also, many structural tissue-based 
products are conventional tissues having a long and established history of safe use in the medical 
community. 
3) Regulatory requirements. 
a) Row B1. Autologous cells and tissues collected and transplanted in a single 
surgical procedure (e.g., skin or vein grafts) would not be subjected to any regulatory requirements. 
b) Row B2. Cells and tissues not collected from and transplanted into the same 
person in a single surgical procedure, and not having any of the factors that lead FDA to require section 
351 and/or FDCA regulation (i.e., they are minimally manipulated, for homologous use, without non
cell/non-tissue components, and not for metabolic use when from an unrelated donor), would be subject 
only to handling and processing requirements under section 361 of the PHS Act. The agency intends to 
promulgate, under section 361, good tissue practice requirements (GTPs) that would be aimed at 
preventing contamination and preserving product integrity and function through proper handling and 
processing practices. Apart from registration, listing, and reporting requirements, there would be no 
required FDA submissions; for example, there would be no premarketing approvals. All establishments 
or persons that recover, screen, test, procure, bank, process, transport or distribute cells or tissues for 
allogeneic use or from multiple donors would be subject to some or all of these requirements as 
appropriate. 
Examples of B2 products would include banked tissues, such as semen, human heart valves, powdered 
20
  lyophilized non-demineralized bone and other conventional tissues, as well as banked autologous and 
banked or unbanked family-related allogeneic peripheral and placental/umbilical cord blood stem cells. 
c) Row B3. Inadequately controlled or otherwise improper processing can 
result in products that are ineffective, and in products that are unsafe for reasons other than increasing 
the risk of transmission of communicable disease. For example, products may be unsafe because they 
are ineffective (e.g., nonviable stem cells used for hematopoietic reconstitution after chemotherapy) or 
because they function improperly (e.g., cells or tissue that inappropriately secrete a hormone may cause 
unwanted metabolic effects). Thus, processing controls for products that raise such clinical concerns 
often must be more comprehensive than those needed to address risks of transmission of communicable 
disease. 
As discussed in sections IV and V, cellular and tissue-based products that are more-than-minimally 
manipulated, or are used for non-homologous function, or in combination with non-tissue components, 
or for a metabolic purpose raise a higher level of processing concerns pertinent to assurance of clinical 
safety and effectiveness. The agency would subject such products/uses to processing-controls under 
section 351 of the PHS Act and/or under relevant sections of the FDCA.8 
Such processing controls generally would cover product chemistry, manufacturing, and controls 
(CMCs) and be subject to premarket submissions. However, if FDA determines that class-wide 
standards can be developed such that products in a specified product class are known to be clinically 
safe and effective when manufactured in accordance with certain defined product specifications and 
process controls, FDA could establish such standards through rulemaking and require premarketing 
submission of certification by the applicant that the products met the published standards, rather than a 
more detailed submission of the clinical data. 
For non-family-related allogeneic cord or peripheral blood stem cells for hematopoietic reconstitution, 
which in some cases have been studied without an investigational new drug exemption (IND), the 
agency intends to call for a phase in of IND and licensure submissions (see section VI, Implementation 
of Regulatory Procedures). If, prior to the end of the phase-in period, the agency has received 
adequate data and information to enable the agency to promulgate standards designed to ensure safety 
and effectiveness for particular uses of these products, FDA anticipates making a class-specific finding 
of safety and effectiveness for products meeting those standards (see section V C, Clinical Safety and 
                                                                
8  However, as a policy matter, the agency would not subject cells or tissues used for metabolic 
purposes to such regulation if the cells or tissues were used in the person from which they were obtained 
or in a close blood relative of the donor, and were minimally manipulated, without non-cell/non-tissue 
components, and for a homologous function. 
21
  Effectiveness, and section VI, Implementation of Regulatory Procedures) . Individuals pursuing 
licensure subsequent to the adoption of such standards would not have to submit clinical safety and 
effectiveness data to the agency in their premarketing applications, but would merely have to certify that 
they meet the standards. 
Examples of B3 products  used for metabolic function would include hematopoietic stem cells intended 
for use in recipients who are not close blood relatives of the cell donor or for uses other than to 
reconstitute the cellular components of the blood; cloned and/or activated lymphocyte therapies for 
cancer or infectious diseases; and hematopoietic stem cells that have been expanded or modified as part 
of gene therapy. 
Examples of B3 products used for structural function would include demineralized bone (which the 
agency plans to propose to classify as a class I device and to exempt from premarket submissions), and 
bone combined with collagen or growth factors. 
C) Clinical Safety and Effectiveness - Use-specific Concerns. 

1) Overview. 

Row C of Table 1 distinguishes products based on whether they have none of the factors relating to 
clinical safety or effectiveness that would lead FDA to require  section 351 or FDCA premarketing 
submissions requirements (C1); whether they have one or more of such factors and are used to achieve 
a local structural function (i.e., reconstruction or repair) (C2); and whether they have one or more of 
such factors and are used to achieve a reproductive or metabolic function (C3). 
Products described under C1 would be subject to no section 351 or FDCA requirements for clinical 
trials demonstrating safety and effectiveness. Products under C2 and C3 would be subject to section 
351 and/or FDCA requirements. Requirements for premarket clinical data submissions for C2 and C3 
cellular and tissue-based products would generally be as for other regulated products, tailored as 
appropriate to the characteristics of the product and the concerns raised by the specific indication and 
product. For serious and life-threatening illnesses, all other applicable policies (e.g., expedited review, 
treatment IND, accelerated approval) would be available to help speed product availability. 
C2 products are separated from C3 products to indicate that in general they would be subject to 
different safety and effectiveness endpoints to fulfill clinical trial requirements. Clinical trial requirements 
for C2 products (whether regulated as biologics or devices) would generally be consistent with those for 
devices for the same indication, whether regulated under INDs or IDEs (investigational device 
exemptions). Clinical trial requirements for C3 products would generally be consistent with those for 
new drugs or biologics for the same indication. 
2) Regulatory Requirements. 
a) Row C1. FDA would not require premarket review and approval for 
22
  cellular and tissue-based products that are minimally manipulated, are used for homologous function, do 
not contain non-cell/non-tissue components, and are for structural or reproductive use. Such products 
raise relatively limited clinical safety and effectiveness concerns, and thus would not be subject to 
premarket submission of clinical data. Additionally, as a policy matter the agency would not require 
premarket submission of clinical data for cellular or tissue-based products that are minimally 
manipulated, are used for homologous function, do not contain non-cell/non-tissue components, and are 
for metabolic use, when they are to be used autologously or in a close blood relative of the donor. 
Communicable-disease risks would be addressed under section 361 as discussed above in sections VI, 
A, 2, and VI, B, 2. 
Examples of such products would include heart valve and dura mater transplants, vein grafts, tendons to 
repair or replace tendons, autologous or family use of peripheral or cord blood stem cells for 
hematopoietic reconstitution, and human gametes (sperm and eggs), zygotes, and embryos intended for 
insemination, fertilization, or transfer. 
b) Row C2. The agency recognizes that cellular and tissue-based products for 
structural use raise different safety and effectiveness issues than do products for metabolic or 
reproductive use, and that they can be evaluated in a manner generally consistent with that of devices for 
the same indication, modified as appropriate for the nature of the product. (They may also be classified 
as devices). The agency outlined its approach for evaluating a major subset of such products in the 
May, 1996 Guidance on Applications for Products Composed of Living Autologous Cells Manipulated 
Ex Vivo and Intended for Structural Repair or Reconstruction (MAS Cells) and the CMC Guidance for 
Autologous Cell Therapy (1997). 
The agency recognizes that many of the highly manipulated cellular and tissue-based products intended 
for structural purposes often will be used for the same indication as are some devices, or will be 
classified as devices. It is the intent of CBER and CDRH to ensure consistent review of such products, 
whether regulated as devices or biologics, and to establish clinical effectiveness standards for structural 
cells regulated as biologics that would be consistent with those existing for comparable devices. 
However, different products may raise different safety, effectiveness, or durability concerns, and may be 
amenable to different methods for measuring outcomes. 
Some examples of C2 cellular and tissue-based products include manipulated cells  for autologous 
structural use (MAS cells)  such as expanded chondrocytes to repair damaged knee cartilage, and 
devices such as demineralized bone. (The agency does not intend for demineralized bone used alone to 
be subject to premarket submission requirements. The agency plans to propose to classify 
demineralized bone as a class I device and to exempt it from premarket submissions, as described in 
section VI.) 
c) Row C3.  Some examples of C3 cellular products include autologous 
23
  genetically-manipulated cellular therapies involving correction of genetic defects, non-family-related 
allogeneic cord or peripheral blood stem cells, stem cell therapies involving growth factors such as 
interleukin-3 and stem cell factor or gene therapy, activated lymphocytes for treatment of cancer, and 
cloned lymphocytes for the treatment of HIV infection or other infection. (See section VI A below 
regarding phase-in of licensure requirements for non-family-related allogeneic cord and blood stem 
cells.) 
D)   Promotion and Labeling. Row D of table 1 addresses the issue of potentially false or 
misleading claims. For cellular and tissue-based products regulated under section 361, labeling would 
need to be clear, accurate, balanced, and non-misleading. Such labeling could include what the tissue is 
and how it has been processed; the homologous uses of the tissue; and the communicable-disease 
screening, testing and quarantine procedures that were followed and results obtained. FDA intends to 
propose regulations to address labeling requirements under section 361 of the PHS Act. 
Products that are intended or promoted for use for a non-homologous function would fall outside the 
scope of the section 361 regulation the agency intends to promulgate, and would be subject to 
regulation as biological drugs or devices under section 351 of the PHS Act and/or the FDCA. For 
cellular and tissue-based products regulated under FDCA and/or section 351 of the PHS Act, the 
agency intends to regulate labeling under existing authorities therein. 
E)  Monitoring and Education.  At present, FDA does not know the full size and scope of 
the cell and tissue industry and its potential products. The agency believes that, in order for it to 
understand the issues raised by these new products and be able to educate the industry and keep it up 
to date regarding FDA policies, guidances, and requirements, as well as to enable the agency to inspect 
establishments for compliance with applicable laws and regulations, all establishments that recover, 
screen, test, procure, bank, process, transport or distribute cells or tissues from multiple or allogeneic 
donors, should register and list their products with FDA.  Therefore, the agency would require 
registration and listing for all such establishments and products over which FDA is asserting its 
jurisdiction under section 361 of the PHS Act, section 351 of the PHS Act, or the FDCA. The agency 
is developing a simple electronic filing system that it will use for establishment registration and product 
listing.  Registration and listing for products subject to section 361 oversight would not be required until 
the electronic system is in place. 
FDA does not intend to require that it be sent reports of errors and accidents that occur during 
processing and distribution of cellular and tissue-based products subject to section 361 controls. 
However, as part of the GTP requirements, establishments and persons will be required to identify and 
investigate errors and accidents, take appropriate corrective action, and maintain records of such failure 
assessments. The agency does intend to propose post-market adverse event reporting requirements 
relating to transmission of communicable disease. 
24
  The agency intends to apply registration and listing requirements in section 510 of the FDCA as well as 
existing post-market reporting requirements to those cellular and tissue-based products subject to 
regulation under section 351 of the PHS Act and/or the FDCA. The agency intends to propose 
regulations for registration, listing, GTPs, and post-market adverse event reporting of those cellular and 
tissue-based products regulated under section 361 of the PHS Act. 
VI.   IMPLEMENTATION OF REGULATORY PROCEDURES 
The agency intends to implement this regulatory plan in a step-by-step fashion. The agency intends to 
promulgate through notice and comment rule-making new regulatory requirements, and to allow for 
phase-in as appropriate. Some examples of how FDA intends to implement this regulatory plan for 
selected products are as follows. 
A) Stem cells. The agency intends to phase in its regulatory oversight of minimally 
manipulated hematopoietic stem cells derived from cord or peripheral blood and used for hematopoietic 
reconstitution in patients who are not close blood relatives of the donors from whom the cells were 
obtained. (Minimally manipulated hematopoietic stem cells to be used for their normal function in the 
person from whom they were obtained or in a close blood relative would be regulated under section 
361, and would not be subject to premarket application requirements.) The agency intends to phase in 
regulation of allogeneic use of these products as follows. 
1) Registration and Listing. FDA intends that all facilities that recover, screen, test, 
procure, bank, process, transport or distribute stem cells, derived from umbilical cord blood or 
peripheral blood, to treat, cure, diagnosis, or mitigate diseases in humans, be required to register with 
the FDA and list the products at their facility. Registration and listing would be accomplished through an 
electronic system that the agency is developing. 
2) Communicable-Disease Screening and Testing. The agency intends to require 
testing of blood samples from allogeneic donors of hematopoietic stem cells in order to prevent the 
transmission of communicable diseases. For peripheral blood stem cell donors, the donor's blood, and 
for umbilical cord blood donors, the mother's blood, would be required to be tested for HIV, 
cytomegalovirus, HTLV, syphilis and hepatitis infection (i.e., HBsAg, anti-HIV-1, anti-HIV-2, 
HIV-1-Ag, anti-HTLV-I/II, anti-HCV, a serologic test for syphilis, and anti-CMV).  The medical 
history and physical examination of prospective donors would include screening for high risk for HIV 
and hepatitis, Creutzfeldt Jacob Disease (CJD), and tuberculosis. 
The agency intends to recommend, but not require, that testing be performed when the stem cells will be 
used in the person from whom they were obtained. In such case, the agency would recommend only 
the following tests: HBsAg, anti-HCV, anti-HIV-1, anti-HIV-2, HIV-1-Ag, and anti-HTLV-I/II.  The 
agency also would recommend that the history and physical examination of the donor include screening 
25
  for high risk for HIV and hepatitis. The agency would require that record-keeping and labeling reveal 
which of the recommended tests were performed, and the results obtained from those tests, as well as 
which of the recommended tests were not performed. Appropriate labeling would be as follows: 
'tested and negative', 'tested and positive', or 'not tested for biohazards.' 
Ordinarily, cells or tissue would not be collected from a donor testing positive for any of these viruses, 
and if collected would be required to be destroyed. However, the agency recognizes that there may be 
circumstances justifying storing or using such cells or tissues. For example, in cases where a stem cell 
donor tests positive for a virus or has been found to be at risk of infection (even if testing negative), and 
the stem cells are intended for autologous use, for use in a close blood relative, or for use in a transplant 
recipient with a rare histocompatibility match, the agency intends to require that 1) the cells be labeled 
"BIOHAZARD", 2) autologous products also be labeled "FOR AUTOLOGOUS USE ONLY", 3) 
written advanced informed consent of the recipient be documented, and 4) there be documented 
concurrence of the recipient's physician before the cells could be released from a cell bank. 
3) Processing Standards. The agency intends to promulgate establishment controls, 
processing controls, and product standards under section 351 of the PHS Act. For minimally 
manipulated stem cells used for hematopoietic reconstitution, the agency believes that it may be possible 
to develop product standards (including manufacturing controls and product specifications aimed at 
ensuring product safety and efficacy) from existent published clinical trial data or data developed in the 
near future. FDA intends to invite professional groups and individuals to submit to the agency data and 
standards that they believe would ensure safety and effectiveness. If sufficient data are not available to 
develop processing and product standards after a specified period of time, the stem cell products would 
be subject to IND and marketing application requirements. 
FDA intends to list in the Federal Register relevant questions for developing the data and standards, and 
the deadline for submission of responses. Examples of the kind of information that the agency believes 
will be necessary to have in standards include criteria for acceptance of a unit (such as volume, storage 
temperature limits, limits on microbial or other contamination, viable cell number, and functionality), and 
procedures for handling, transporting, storing, and thawing materials, and for when and how 
contamination and viability testing should be carried out. 
Upon development and promulgation of standards designed to ensure safety, purity, and potency, FDA 
would issue licenses based on a certification by the applicant that the standards are met. The 
certification could be made in the same submission as the registration and listing. FDA would issue a 
license based on the certification submission. 
During the interim period, FDA would not call for licensure of such products for unrelated allogeneic 
use, but would require establishment registration and product listing. The agency also could perform 
inspections for applicable GMP compliance,  and could take enforcement action against facilities as 
26
  needed (for example, because of lack of appropriate communicable disease-testing). 
B) Demineralized bone.  FDA would consider demineralized bone (decalcified freeze dried 
bone allograft) to be an unclassified pre-Amendments device rather than a tissue under section 361 
because the bone is more-than minimally manipulated.9 FDA would seek a classification 
recommendation from the Orthopedic/Dental Advisory Panels. The device to be classified would be 
defined as including allograft bone that is processed ONLY to demineralize and preserve the bone, and 
ONLY intended to be used as a bone filler in orthopedic and/or dental procedures. 
Based on current information, FDA expects to propose that demineralized allograft bone be regulated 
as a Class I medical device exempted from premarket notification. In addition, FDA expects that it 
would also propose to exempt demineralized allograft bone from the GMP requirements except for 
certain requirements consistent with those proposed for human tissues regulated under section 361. 
To ensure that the GMP requirements applicable to demineralized bone are ultimately consistent with 
the requirements for human cellular and tissue-based products regulated under section 361, the Federal 
Register documents regarding the requirements for each would be published as companion documents. 
VII.  CONCLUSION 
The agency believes that the above-described proposed approach to the comprehensive regulation of 
cellular and tissue-based products would provide adequate protection of public health, both from the 
risks of transmission of communicable disease and from the risks of therapies that may be dangerous, 
while enabling investigators to develop new therapies and products with as little regulatory burden as 
possible. The agency intends for this regulatory scheme to encourage research and innovation, while at 
the same time set boundaries between the kinds of experimentation with human products that warrant 
only minimal FDA oversight and the kinds of experimentation with human products that warrant greater 
FDA oversight. 
                                                                
9  In contrast to how it would regulate demineralized bone, FDA would regulate powdered 
bone (freeze dried bone allograft) under section 361 (falling in rows B2a and C1 of Table 1), because 
the bone is only minimally manipulated - the processing does not change the integral structure of the 
bone. 
27
  GLOSSARY OF TERMS AS USED IN THIS DOCUMENT 

ablation  Removal or destruction 
allogeneic use  Cells or tissue transplanted from one person to another. 
autologous use   Cells or tissue removed from and transplanted back into the same 
person. 
close blood relative  A first degree blood relative (i.e., parent, child, or sibling). 
cord blood  Blood in the placenta and umbilical cord, e.g., blood taken at 
the time of birth 
family relative  A first degree blood relative (i.e., parent, child, or sibling). 
hematopoietic  Giving rise to the cellular elements of the blood (e.g., white blood 
cells, red blood cells, platelets). 
hematopoietic Stem cells  Cells capable of generating white blood cells, red blood cells, 
and platelets. For the purposes of this document, these would 
include progenitor cells that are committed to develop into a 
particular cellular lineage. Hematopoietic stem cells presently 
can be collected (as a very small fraction of the cells) from 
peripheral blood, placental/umbilical cord blood, and bone 
marrow, often for transplantation into patients whose own 
hematopoietic stem cells have been destroyed by anticancer 
treatment or disease 
homologous function  Use for the normal function of the cell or tissue, and, for 
structural tissue, use for a structural purpose in a location of the 
body where such functional purpose normally occurs (see P. 
15). 
MAS cells  Manipulated Autologous cells for Structural use 
metabolic use  For systemic effect. 
28
  minimal manipulation  Processing that does not alter the biological or relevant 
functional characteristics of cells or tissue (see P. 13). 
more-than-minimal manipulation  Processing that alters the biological or relevant functional 
characteristics of cells or tissue (see P. 13). 
non-homologous function  Use for other than the normal function of the cell or tissue, or 
for structural tissue, use for a structural purpose in a location of 
the body where such functional purpose does not normally 
occur (see P. 15). 
peripheral blood  Circulating blood (in contrast to, for example, blood in bone 
marrow) 
reproductive tissue  Semen, ova, embryos. 
reproductive use  To treat infertility. 
stem cells  Cells capable of replicating themselves and of generating more-
differentiated daughter cells. 
structural use  For anatomic reconstruction or repair. 
unrelated  Someone other than a close blood relative. 
29
  RELATED PRODUCTS 

PROPOSAL FOR SPECIFIC COMMUNICABLE DISEASE CONTROLS1
 
Testing2  Screening  Quarantine3 
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HIV    HCV    HBV    HTL    CMV    epo    amy   iss    ri   JD   TBsc   
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a  a  o  I  n 
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& 
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s 
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i 
s 
2a Autologous Banked Tissue 
Stem Cells  R  R  R  R  R 
Other Autologous Tissue  R  R  R  R 
2b Allogeneic, Nonviable Tissue  X  X  X  X  X  X  X  R 
2c Allogeneic, Viable Tissue 
Stem cells from Family-related donors  X  X  X  X  X  X  X  X  X       
Reproductive Tissue from Sexually Intimate Partners  R  R  R  R  R  R  R  R  R  R  R       
Other Reproductive Tissue (including directed donors)  X  X  X  X  X  X  X  X  X  X  X  X 
Other allogeneic Viable Tissue4  X  X  X  X  X  X  X  X  X  R 
Legend: 
X-required
 
R-recommended, for tests; labeling as: 'tested/negative' , or 'not tested for biohazards' will be required.
 
30
  notes: 
1Banked tissue for autologous use, from allogeneic family-related donors, from directed reproductive tissue 
donors, from sexually intimate partners, or in cases where there is a documented urgent medical need from a 
donor who has a positive risk factor and/or tested positive for an infectious disease agent, will not be required to 
be destroyed if: 
a) the product is labeled  'BIOHAZARD' or 'untested for BIOHAZARDS', as applicable 
b) autologous tissue is labeled  'FOR AUTOLOGOUS USE ONLY' 
c) written advance informed consent of the recipient is documented 
d) there is documented knowledge and authorization of the recipients physician 
Tissue unsuitable for transplantation may be used for non-clinical research purposes if labeled  'BIOHAZARD' or 
'untested for BIOHAZARDS', and  'FOR RESEARCH USE ONLY' 
2For autologous or allogeneic cord blood donors, a mother's sample may be used for screening and testing. 
3For allogeneic tissue that can be stored, quarantine for six months pending retesting of the donor will be required 
for all reproductive tissue, excluding sexually intimate partners. For other banked tissue and cells from living 
donors, quarantine for six months pending retest of the donor, or of the mother will be recommended, where 
appropriate and feasible, not required. 
4Requirements for HTLV and CMV testing only apply to leukocyte rich tissue (e.g. stem cells); they will not apply to 
cornea or skin donors. 
5For dura mater donors, in addition to history for risk factors, a gross and histological examination of brain tissue 
will also be required. 
31
  Table 1 
Relationsahmiopnsg p roduccto ncernsp_,r oduccth aracterirsetgiuclsa,t aopryp roaches 
ProducCto ncern  ProducCth aracteristic  IndustAryc tion 	 RegulatSouryb mission 
(ProduFcatc tors) 	 Required 
A. Diectr transmissioonf   1.  SURGERY  (C ellorst  issuea rer emovefrdom   1.  None.  1.  None 
communicabldei seas(ee .g.,a ndt ransplabnatceikd n tthoe  same persona  in 
donosrc reenainndtg esti ng) singsluer gipcraolc ed)u re 
2aA.U TOLOGOUSb anked/pesrsoed/schipped; 	 2a.S creening, testin2ga 2 b2 c.N o FDA submissiRoenqu.ri emetsn woul(cid:93) be seitn n ew 
recommended; othefirn arlu lfeo arl logetinsesiuce- relpatreodd uctsu ndesre ction36 1 
REPRODUCTIVE froms exualilyn timatpea rtner 	 GTPs wouldbe  required(,fi nalizatioofn  thien tefirniamrul l ea),n di nru iemaklng under 
e.gr.ec,o rdkeeplng,  section36s 1 and35 1 whichwo ulda ddm orep roduactsn dm ore 
labelinpgr,o duct  specifict estingr equirements. 
trackinrgeca, ns, 
notificatioofn  
communicacblfei Sease 
transismsion. 
2b.AL LOGENEIC, nonviabltises ue 	 2b,2 c.G TPswo uldbe  
requireed. gs.c,r eening, 
testing,r ecordkeeping, 
labelinpgr,o dutrcta cking, 
2cA.L LOGENEIC, viabletis sue 	 recans,n otificationo f 
communicabldeis ease 
transismsion. 
B. ControolfP  rocessi ng  1.  SURGERY  1.  None  1.  None 
Improper handling or( Celolrts i ssuea rer emovefdr oamn d 
inadequatcelyo ntroned  transplabnatcekid n ttoh esa me persona  in 
processinmga yr esulti n  single spurrogicceadlu re.) 
producoctn taminatioann d 
consequeconmtm unicable 
cfiSeasetr ansmission; 
2.M INIMALLY MANIPULATED & homologous 2.G TPs relatitnog   2.  No FDA submission regarding processing.  Requirements 
ori nf aRutrope r eserve  functi&o nno n ontis-suec omponents,  contaminaitinotne,g rity would be set in rulemaking under section 361. 
produictn tegarityn df unction,  and  andf unction. 
andc onsequeennth anced structurarle,p roductivoer,  
susceptibitloity   autologouslrelatemde-taaDboogleince ic 
communicadbilsee ase; 
3.  A marketing application would ordinarily be required to 
ori nf ailtuopr rees erve  3.  MORE-THAN-MINIMALLY MANIPULATED or 	 3. Woulhda vteo  foll ow  contain a CMC section.  If determinations are made that the 
produictn tegritya ndf unction non-homolofguonucsto irno onn -tissue  GMPs andh avset ricters afety and effectiveness of a product category can be assured 
with resultinugn saofre   componeonrtsu  nrelamteedt abofic 	 processicnogn trols by meeting product specifications and processing controls, then 
ineffecptivreo ducts.  encompasscilnign ical 
applicants would need only to submit a certification that they 
safeatyn de ffectiveness 
  meet the product specifications and processing controls. 
concerns.  ------------------------------
Table  1  (continued) 

C.  Clinical safety (not  1. Product is without any of factors a, b, c, or d.  1.  None.  1.  No FDA submission. 
restricted to 
communicable-disease 
risks); clinical 
effectiveness (including 
use-specific concerns). 
2.  Product Is for local, structural reconstruction  2.  Would have to  2.  Studies would have to be done under IND or IDE; Marketing 
Attributes of importance  or repair and has factors a, b, or c.  gather clinical safety  application would have to be submitted (BLA, 51O(k) or PMA); 
are:  and effectiveness data.  standard for determination of effectiveness would be consistent 
a)m ore than minimal  with that for devices.  Standards for manipulated autologous 
manipulation;  structural cells would be as described in MAS cell policy 
guidance. 
b)n on-homologouuss e; 
c)c ombinationw itnhon - 3.  Product is for reproductive or metabolic use  3.  Would have to  3.  Studies would have to be done under IND; marketing 
ceO/non-tissue  with factors a, b, c, or d.  gather clinical safety  application would have to be submitted (BLAI; standard for 
components;  and effectiveness data.  determination of effectiveness would be consistent with that 
for biologics. 
d)  metaboliucs e(o ther 
than reproductive)e xcept 
when used autologously  or 
Ina  closef amRym ember. 
D.  Promotion and labeling  All cellular and tissue-based products (excluding  Clear, accurate,  No FDA submission concerning labeling for products regulated 
cells and tissues that are removed from and  balanced and non- only under section 36 1 (providing claims are limited to those 
transplanted back into the same person In a single  misleading labeling  within homologous use).  For products regulated under section 
surgical procedure).  351 or as a device, the usual rules would apply concerning 
labeling. 
E;  Baseline Knowledge of 	 All cellular and tissue-based products (excluding  Notification of FDA  Registration and listing under new regulation under 361 or 
Industry 	 cells and tissues that are removed from and  under sec. 51 0 of the FDC Act. 
transplanted back into the same person in a single 
surgical procedure).  I 
PROPOSED NEW REGULATORY FRAMEWORK 

FOR HUMAN TISSUE 

CONCERN 1: DISEASE TRANSMISSION 
(Does the Tissue Pose a Risk of Transmitting Diseases 
Such as AIDS or Hepatitis?) 
Product Characteristic  Industry Action Required  Submission to FDA 
Tissue transplanted within  None  None 
one person during a single 
surgical procedure 
Tissue transplanted within  Disease screening and testing  None 
one person that has been  recommended; Good Tissue 
banked, processed, or shipped  Practices (GTPs) (handling, 
recordkeeping, and labeling 
procedures) would be 
required 
Tissue donated from one  Subject to GTPs; disease  None 
person to another  screening and testing would 
be required  I 
CONCERN 2: CONTROL OF PROCESSING 
(What Kinds of Handling and Processing Controls Would Be Necessary?) 
Product Characteristic  Industry Action Required  Submission to FDA 
Tissue transplanted within  None  None 
one person during a single 
surgical procedure 
Minimally processed  Would be subject to GTPs  None 
structuraP tissue used for its  relating to contamination, 
normal function and having  integrity, and function 
no nontissue parts; or 
reproductive tissue4 used for 
its normal function, and 
having no non-tissue parts 
Minimally processed  Would be subject to GTPs  None 
metabolic tissue5 transplanted  relating to contamination, 
into the same person, or into  integrity, and function 
a family member, used for its 
normal function, and having 
no nontissue parts 
Metabolic tissue transplanted  Would have more  Human testing exemptions 
to another person not related  comprehensive  processing  and marketing approval by 
to the donor; or that has been  controls than GTPs (to  FDA would be required.  (In 
manipulated, or is used for  address clinical  certain cases, certification to 
other than its normal  safety/effectiveness concerns)  standards may substitute for 
function, or has nontissue  data submission.) 
parts 
Structural tissue that has been  Would have more  Human testing exemptions 
manipulated, or is used for  comprehensive processing  and marketing approval by 
other than its normal  controls than GTPs (to  FDA would be required. 
function, or has nontissue  address clinical safety and 
parts  effectiveness concerns) 
3 Structutriaslscu oem prisseusc ht issausec  orneas, ligbaomneenstc,sa ,r tiltaegned,o ndsu,r am ater, 
andh eartv alves. 
4 Reproducttiivses cuoem prisseusc ht issauseo  vas,e mena,n de mbryos. 
5 Metaboltiics siuset  isstuhea atf fectthsef  unctoioftn h ee ntibroed y( e.gu.m,b iliccoarlsd t emc ells 
infusiendt ao p atietnort e constitthuect eel luellaerm enotfst  hep atienbtl'oso do,rp  ancreaitsilcce etl ls 
implantteotd r eadti abetes).  CONCERN 3: CLINICAL SAFETY 
(Does the Product Need FDA Approval for Safety/Effectiveness?) 
Product Characteristic  Industry Action Required  Submission to FDA 
Minimally processed  None  None 
structural tissue used for its 
normal function, and without 
nontissue parts; or 
metabolic tissue that is used 
in the same person or in a 
close relative of the donor 
that is minimally processed, 
used for its normal function, 
and has no nontissue parts. 
Tissue used for structural  Would have to gather clinical  Human testing exemptions 
reconstruction or repair that:  safety and effectiveness data  and marketing approval 
1) 
has been manipulated; or  required; standard for 
2) is used for other than its  effectiveness determination 
normal function; or  would be consistent with that 
3) is combined with nontissue  for comparable devices 
parts 
Metabolic tissue used in a  Would have to gather clinical  Human testing exemptions 
person not related to the  safety and effectiveness data  and marketing approval by 
donor, or that:  FDA required; standard for 
1) 
has been manipulated; or  effectiveness determination 
2) is used for other than its  would be consistent with that 
normal function; or  for biologics 
3) is combined with nontissue 
parts 
Reproductive tissue that is:  Would have to gather clinical  Human testing exemptions 
1) 
manipulated;  safety and effectiveness data  and marketing approval by 
2) used for other than its  FDA required; standard for 
normal function; or  effec tiveness determination 
3)combined with nontissue  would be consistent with that 
parts  for biologics.  I 
CONCERN 4: CLAIMS MADE BY MANUFACTURERS 
(What Regulation Is Needed of Product Labeling and Advertising?) 
Product Characteristic  Industry Action Required  Submission to FDA 
Tissue transplanted within  None  None 
one person during a single 
surgical procedure 
All other tissue  Clear, accurate, balanced, and  No FDA submission 
nonmisleading labeling and  concerning labeling for 
promotion  products regulated only under 
section 361; for products 
regulated under section 351 
and/or FDC Act, normal rules 
would apply 
CONCERN 5: BASELINE KNOWLEDGE OF INDUSTRY 
(Should Tissue Products Be Registered with FDA?) 
Product Characteristic  Industry Action Required  Submission to FDA 
Tissue transplanted within  None  None 
one person during a single 
surgical procedure 
All other tissue  Notification of FDA  Registration and listing under 
new regulation under 361 or 
under section 510 of the FDC 
Act