[DOCKET NO.  ]
     
                         DRAFT
     
     DRAFT DOCUMENT CONCERNING THE REGULATION OF PERIPHERAL
     BLOOD HEMATOPOIETIC STEM CELL PRODUCTS INTENDED FOR
     TRANSPLANTATION OR FURTHER MANUFACTURE INTO INJECTABLE
                         PRODUCTS
                      FEBRUARY, 1996
                              
     For further information about this document, contact:
     Center for Biologics Evaluation and Research (HFM-630)
     Food and Drug Administration
     1401 Rockville Pike
     Rockville, MD 20852-1448
     301-594-3074
     
     Submit written comments on this document to:
     Dockets Management Branch  (HFA-305)
     Food and Drug Administration
     Rm. 1-23
     12420 Parklawn Dr.
     Rockville, MD  20857
     
     Submit requests for single copies of this document to:
     Division of Congressional and Public Affairs (HFM-44)
     Food and Drug Administration  
     1401 Rockville Pike, Suite 200N
     Rockville, MD  20852-1448
     301-594-1800
     FAX (Automated Information System)  800-835-4709
     INTERNET CBER_INFO@A1.CBER.FDA.GOV
     
     Comments and requests should be identified with the
     docket number found in brackets at the heading of this
     document.
     
     This guidance is an informal communication under 21 CFR
     10.90(b)(9) that reflects the best judgement of FDA
     employees at this time.  It does not create or confer any
     rights, privileges or benefits for or on any person, nor
     does it operate to bind or obligate FDA in any way.
                             
                             
                             
                             
                             
                             
                             
     DRAFT DOCUMENT CONCERNING THE REGULATION OF PERIPHERAL
     BLOOD HEMATOPOIETIC STEM CELL PRODUCTS INTENDED FOR
     TRANSPLANTATION OR FURTHER MANUFACTURE INTO INJECTABLE
                         PRODUCTS
                              
     PURPOSE
     
     The purpose of this document is to set forth the
     approach that Food and Drug Administration (FDA)
     believes is appropriate for the regulation of
     peripheral blood hematopoietic stem cell products
     (hereafter referred to as peripheral blood stem cell
     products) intended for transplantation or as source
     material for further manufacture into injectable
     products.  Prior to fully implementing this approach,
     FDA is providing individuals with an opportunity to
     comment on this draft document. FDA will publish in the
     Federal Register a Notice of Availability of this
     document, asking that comments be provided to the
     Dockets Management Branch (address provided on the
     cover page), by close of business on [insert date]. 
     
     I.   INTRODUCTION
     
     The field of hematologic transplantation has changed
     substantially during the last two decades.  Improved
     understanding of the diverse aspects of human
     hematologic precursors has facilitated their
     experimental manipulation.  Our knowledge of their
     localization in humans during both fetal and postnatal
     development, growth regulation, differentiation,
     homing, and phenotypic and functional characteristics
     has facilitated the development of new methods of
     transplantation.  Traditional bone marrow
     transplantation, involving extraction of bone marrow by
     aspiration from bone cavities and processing by density
     centrifugation, is increasingly being supplanted by
     novel approaches that include use of peripheral blood
     cells and procedures to purify and expand hematopoietic
     stem cells.  Human peripheral blood, which can be
     enriched in hematopoietic stem cells by a variety of
     interventions, has emerged as an alternative source of
     hematopoietic cells for bone marrow reconstitution.
     
     FDA has not required premarketing approval for many
     types of transplantation, including bone marrow
     transplantation. Federal oversight currently exists in
     two areas related to human bone marrow transplantation. 
     First, development of standards for unrelated donor
     marrow transplants as mandated in the Transplant
     Amendments Act of 1990 was originally assigned to the
     National Institutes of Health (NIH) and now is handled
     by the Health Resources and Services Administration. 
     Second, extensive manipulation of human blood, bone
     marrow or other sources, for the purpose of obtaining
     enriched stem cell populations, renders them a somatic
     cell therapy product subject to licensure by the FDA. 
     (For further information regarding somatic cell
     therapies, see "Application of Current Statutory
     Authorities to Human Somatic Cell Therapy Products and
     Gene Therapy Products; Notice", F.R. Vol. 58, No. 197,
     October 14, 1993.)
     
     Recently, the Agency has reviewed a number of
     applications for investigational new drugs (INDs), as
     well as investigational device exemptions (IDEs) and
     pre-market device applications including Premarket
     Approval Applications (PMAs) and premarket
     notifications (510(k)s), in which hematopoietic stem
     cells for transplantation were derived from peripheral
     blood.  Existing FDA statutory authorities apply to
     these new products and allow FDA to assess whether such
     areas as quality control, quality assurance, safety,
     purity, potency and efficacy are appropriately assessed
     prior to marketing.   This draft document outlines the
     current regulatory approach that FDA believes is
     appropriate for the regulation of stem cells derived
     from peripheral blood. 
     
     II.  BACKGROUND
     
     A.  Legal Authorities
     
     FDA regulates numerous products intended to prevent,
     treat, or diagnose diseases or injuries of man under
     legal authorities established in the Public Health
     Service Act (the PHS Act) and the Federal Food, Drug,
     and Cosmetic Act (the Act).  Section 351(a) of the PHS
     Act (42 U.S.C. 262(a)) identifies a biological product
     as "any virus, therapeutic serum, toxin, antitoxin,
     vaccine, blood, blood component or derivative,
     allergenic product, or analogous product, or
     arsphenamine or its derivatives (or any other trivalent
     organic arsenic compound), applicable to the
     prevention, treatment, or cure of diseases or injuries
     of man."  Section 201(g)(1) of the Act (21 U.S.C.
     321(g)(1)) defines "drugs", in part, as "articles
     intended for use in the diagnosis, cure, mitigation,
     treatment, or prevention of disease in man or other
     animals."  The term "device" is defined in section
     201(h) of the Act (21 U.S.C. 321(h)), in part, as "an
     instrument, apparatus, implement, machine, contrivance,
     implant, in vitro reagent, or other similar or related
     article(s) ... intended for use in the diagnosis of
     disease or other conditions, or in the cure,
     mitigation, treatment, or prevention of disease, in man
     or other animals, ... which does not achieve its
     primary intended purposes through chemical action
     within or on the body of man or other animals and which
     is not dependent upon being metabolized for the
     achievement of its primary intended purposes."  The
     definitions of both "drug" and "device" also include
     articles "intended to affect the structure or any
     function of the body."
     
     Section 351(a) of the PHS Act requires that biological
     products be manufactured at facilities holding active
     licenses.  Licenses are issued upon a showing that the
     establishments and products meet standards designed to
     insure the continued safety, purity and potency of such
     products(42 U.S.C. 262(d)).  A biological product's
     effectiveness for its intended uses must be shown as
     part of the statutory requirement for potency (21 CFR
     600.3(s)).  At the investigational stages, when the
     products are being studied in clinical trials to gather
     safety and effectiveness data, biological products are
     subject to the requirements of 21 CFR part 312.  FDA's
     regulations for MOST biological products currently
     specify the submission of both a product license
     application (PLA) (21 CFR 601.20) and an establishment
     license application (ELA) (21 CFR 601.1 through
     601.10).  Biologics establishments and products must
     meet the standards set forth in the regulations (21 CFR
     parts 600 through 680).
     
     Section 351(b) of the PHS Act prohibits falsely
     labeling or marketing a biological product.  Under
     section 361 of the PHS Act (42 U.S.C. 264), the agency
     may promulgate regulations to prevent the introduction,
     transmission, or spread of communicable diseases.
     
     Products considered to be biological products subject
     to the provisions of section 351 of the PHS Act are
     simultaneously also drugs or devices subject to the
     applicable provisions under the Act.  For example, the
     adulteration, misbranding, and registration provisions
     of the Act would apply to the product as a drug or
     device.
     
     Under section 501 of the Act (21 U.S.C. 351), both
     drugs and devices are considered adulterated for any of
     a number of specified reasons.  Included among these
     adulteration provisions is the requirement that the
     methods, facilities, and controls used for manufacture,
     processing, packing and holding or installation conform
     with current good manufacturing practice (CGMP)
     regulations (21 U.S.C. 351(a)(2)(B) and (h)).  The drug
     and device CGMP regulations are codified at 21 CFR
     parts 211 and 820. 
     
     Section 502 of the Act (21 U.S.C. 352) sets forth
     misbranding provisions that apply to drugs and devices. 
     Among other circumstances, a drug or device is
     considered misbranded if the labeling is false or
     misleading or if the labeling fails to bear adequate
     directions for use or adequate warnings against unsafe
     use (21 U.S.C. 352(a) and (f)).  Any drug or device is
     also misbranded if it is dangerous to health when used
     in the manner or the frequency suggested in the
     labeling (21 U.S.C. 352(j)).  For prescription drugs
     and restricted devices, section 502 of the Act
     describes certain information that must be included in
     all advertisements or other printed material (21 U.S.C.
     352(n) and (r)).  FDA's regulations also establish
     labeling and advertising requirements in more detail
     (21 CFR parts 201, 202, 610 and 801).
     
     Section 510 of the Act (21 U.S.C. 360) requires persons
     who own or operate establishments for the manufacture,
     preparation, propagation, compounding, or processing of
     drugs or devices (with certain exceptions) to register
     those establishments with FDA.  Individuals who must
     register their establishments under section 510 of the
     Act must also file a list of all the drugs and devices
     being made or processed at the establishment.  FDA's
     registration regulations are codified at 21 CFR parts
     207, 607, and 807.
     
          
     The interstate commerce nexus needed to require
     premarket approval under the statutory provisions
     governing biologics, drugs, and devices may be created
     in various ways in addition to shipment of the finished
     product by the manufacturer.  For example, even if a
     biological drug product is manufactured entirely with
     materials that have not crossed State lines, transport
     of the product into another State by an individual
     patient creates the interstate commerce nexus.  If a
     component used in the manufacture of the product moves
     interstate, the interstate commerce prerequisite for
     the prohibition against drug misbranding is also
     satisfied even when the finished product stays within
     the State.  Products that do not carry labeling
     approved in a PLA (or other applicable premarket
     approval) are misbranded under section 502(f)(1) of the
     Act (21 U.S.C. 352(f)(1); 21 CFR 201.5, 201.100(c)(2)). 
     Moreover, falsely labeling a biological product is
     prohibited under section 351(b) of the PHS Act without
     regard to interstate commerce (42 U.S.C. 262(b)).  The
     Act contains a presumption of interstate commerce for
     devices (section 709 of the Act (21 U.S.C. 379(a)).
     
     Both the PHS Act and the Act provide authority for
     enforcement of the various statutory requirements.  FDA
     is authorized to conduct inspections to determine
     compliance with regulatory requirements (42 U.S.C. 262
     and 21 U.S.C. 360h and 374).  Approved PLAs may be
     suspended or revoked (42 U.S.C. 262) and approval of
     NDAs and PMAs may be withdrawn (21 U.S.C. 355(e) and
     360e).  An order to recall biological products or
     devices may be issued under certain circumstances (42
     U.S.C. 262(d)(2) and 21 U.S.C. 360h.  Judicial actions,
     including seizures, injunctions, and criminal
     prosecutions, may also be initiated (42 U.S.C. 262(f)
     and 21 U.S.C. 332, 333, and 334).
     
     Although products regulated by FDA as biological
     products must also meet drug or device requirements,
     the agency does not require duplicate premarket
     approvals.  For example, if FDA requires a PLA to be
     submitted for the product as a biologic, the agency
     does not also require submission of a new drug
     application (NDA) or a device premarket approval
     application (PMA) for that same product.
     
     Some products may contain a combination of biological
     products, drugs and/or devices.  Under a provision of
     the Safe Medical Devices Act of 1990, FDA determines
     the primary mode of action of the combination products
     (21 U.S.C. 353(g)), then assigns the primary
     jurisdiction for review of the product within the
     agency based on that determination.  FDA has
     established procedures for designating the organization
     within FDA, i.e., the Center for Biologics Evaluation
     and Research (CBER), the Center for Drug Evaluation and
     Research (CDER), or the Center for Devices and
     Radiological Health (CDRH), to review combination
     products or any other products where the agency center
     with primary jurisdiction is unclear (21 CFR 3.1
     through 3.10).  CBER, CDER and CDRH have also entered
     into intercenter agreements to clarify the Centers'
     responsibilities for reviewing various kinds of
     products.
     
     B.  Regulation of Peripheral Blood Stem Cells
     
     This draft document is intended to present the approach
     that the FDA believes is appropriate for regulating
     human peripheral blood stem cells.  For the purpose of
     this document, peripheral blood stem cell products are
     defined as hematopoietic cells derived from peripheral
     blood to be administered to humans and applicable to
     the prevention, treatment, cure, diagnosis, or
     mitigation of disease or injuries in humans.  FDA
     believes that the safety, potency, and purity of these
     products is best assured at this time by regulating
     these products as biologics pursuant to the PHS Act (42
     U.S.C. 262) and that these products fall within the
     definition of drugs and are subject to the laws
     promulgated in the Act (21 U.S.C. 321(g)).  As
     biologicals, peripheral blood stem cell products are
     subject to establishment and product licensure to
     ensure product safety, purity, and potency (21 CFR,
     parts 600, 601, 610, and 640) and are subject to
     establishment registration and product listing (21 CFR,
     part 607) as well as to requirements of Current Good
     Manufacturing Practice (CGMP) regulations (21 CFR 211,
     606).  
     
     1.  Peripheral Blood Stem Cells intended for
     transplantation.  
     
     The peripheral blood stem cells are by nature blood and
     blood components.  In many cases, this material may be
     collected by establishments that also collect blood or
     other components for transfusion.  These facilities
     operate under existing industry standards and CGMPs for
     Finished Pharmaceuticals (21 CFR part 211),  CGMPs for
     Blood and Blood Components (21 CFR part 606), the
     General Biologic Product Standards (21 CFR parts 600
     and 610), and the Additional Standards for Human Blood
     and Blood Products (21 CFR part 640).  For blood and
     blood components intended for transfusion and shipped
     in interstate commerce, both the establishment and the
     product are required to be licensed.  These same
     provisions apply to peripheral blood stem cell products
     intended for transplantation.  FDA believes that the
     blood and blood component model as described above is
     the appropriate regulatory approach for non-manipulated
     PBSCs for transplantation.  However, FDA believes that
     manipulated PBSCs should be evaluated for safety and
     efficacy under IND and be subject to licensure.
     
           
     
     2.  Peripheral Blood Stem Cells as Source Materials for
     Further Manufacture.
     
          FDA requests that potential
               manufacturers of gene therapy
               products comment on the impact
               of the sections which apply to
               peripheral blood stem cells
               used as source material for
               further manufacture.  Those
               sections are entitled
               Peripheral Blood Stem Cells as
               Source Materials for Further
               Manufacture and Non-manipulated
               Peripheral Blood Stem Cells
               Subject to Licensure as Source
               Materials.
     
     Peripheral blood stem cell products intended for use as
     source materials for further manufacture into licensed
     biological products should also be licensed as
     biological products intended for further manufacture,
     unless regulated under the license of the final
     product.  If different from cells that are licensed by
     conformance to accepted PBSC standards, source
     materials may be subject to an IND.  Because the agency
     recognizes that blood cells intended for further
     manufacture may be provided by suppliers other than
     traditional blood establishments, such  products could,
     for example, be considered part of a cooperative
     manufacturing arrangement in which:  (1) two or more
     manufacturers perform different aspects of the
     manufacture of a product that ordinarily would warrant
     separate licensing, (2) neither performs nor is
     licensed to perform all aspects of the manufacture, and
     (3) each manufacturer holds product and establishment
     license applications.  In a shared manufacturing
     arrangement, FDA may accept for filing license
     applications for biological products intended for
     further manufacture that specify the licensed
     manufacturer or manufacturers to which the intermediate
     product will be shipped and approves such applications
     only after demonstration of safety and efficacy of the
     end product.  For example, human peripheral blood
     intended for use in the manufacture of stem cell
     products for hematopoietic support/reconstitution would
     be licensed as a blood product intended for further
     manufacture when shipped from one legal entity to
     another.  In such a shared manufacturing situation, FDA
     would license the biological product intended for
     further manufacture only after determining that the
     final product is safe and effective.  Autologous cells
     shipped in interstate commerce for use in the further
     manufacture of some autologous products (for example,
     gene therapy products) may be evaluated as part of the
     manufacturing of the final product.  For further
     information regarding cooperative manufacturing, refer
     to FDA's policy statement concerning cooperative
     manufacturing arrangements for licensed biological
     products, which was published in the Federal Register
     on November 25, 1992 (57 FR 55544).
     
     
     
     3.  Ancillary products for production of peripheral
     blood stem cells.
     
     The manufacture of peripheral blood stem cell products
     may involve the use of ancillary products in the
     manufacturing process.  These are not part of the final
     stem cell product and are intended to act solely on the
     cells and not have an independent effect on the
     patient.  The use of ancillary products may have an
     impact on the safety, purity, or potency of the final 
     products.  When these ancillary products are used in
     the manufacturing of hematopoietic stem cell products,
     they are subject to either drug or device CGMP's, as
     applicable. 
     
     Ancillary products which are not already regulated
     under an existing IND, IDE, NDA, PLA, PMA, or 510(k)
     meet the definition of devices and, if marketed, may be
     regulated under the medical device authorities of the
     Act, with the appropriate type of regulatory control
     being determined according to codified procedures,
     (e.g. investigational device exemption (IDE, 21 CFR
     part 812), premarket approval (PMA)(21 CFR part 814),
     premarket notification (510(k), 21 CFR 807.81 through
     807.97).  Manufacturers who wish to market ancillary
     products separately for use in the manufacturing of
     hematopoietic stem cell products should file either:
     (1) a 510(k), (2) a PMA, or (3) an amendment to an
     existing 510(k), PMA, NDA, or PLA, depending on the
     type of ancillary product.  Ancillary products which
     are approved devices, may be subject to a different
     regulatory mechanism if a manufacturer seeks the
     addition of an indication where the product is intended
     to have a direct effect on the patient.
          
     If the ancillary product used as a component in the
     manufacturing process is not the subject of an approved
     premarketing application, the manufacturers of the
     hematopoietic stem cell product should submit or
     cross-reference a description of the manufacturing
     process, specifications, qualification, and acceptance
     criteria of the ancillary product in their application. 
     This information may be filed by the sponsor of the IND
     for the hematopoietic stem cell product, may be filed
     in an IND or IDE by the manufacturer of an ancillary
     product, or may be made available by the manufacturer
     of the ancillary product in a master file format, as
     defined in 21 CFR 814.3(d) and discussed in 21 CFR
     814.20(c).
     
     Some ancillary products used in the manufacture of
     PBSCs will already be marketed as medical devices,
     drugs, or biological products.  When an ancillary
     product used as a component of the manufacturing
     process is marketed but is not labeled for the specific
     use, such use may initially be described under the IND
     for the final hematopoietic stem cell product.  Such
     use of ancillary products by manufacturers of
     investigational hematopoietic stem cell products is
     contingent upon the submission of complete descriptions
     of the use of the ancillary product in the
     manufacturing process.
     
     The manufacture of hematopoietic stem cell products may
     involve the addition of other components intentionally
     present as part of the final products.  Final products
     containing both a hematopoietic stem cell component and
     another drug or device component in the final product
     will be handled as combination products.
     
     The following draft statement describes the approach
     FDA believes is appropriate for regulating peripheral
     blood stem cell products.  As previously discussed,
     products that meet the biologic, drug, or device
     definition must also comply with other relevant
     provisions of the PHS Act and the Act.
     
     
     III.  DRAFT STATEMENT OF PROPOSED REGULATORY APPROACH
     
     A.  Peripheral Blood Stem Cell Products
     
     1.   Definition
     
     Peripheral blood stem cell products are defined as
     products containing hematopoietic progenitor cells
     derived from peripheral blood to be administered to
     humans and applicable to the prevention, treatment,
     cure, diagnosis, or mitigation of disease or injuries.
     
     These products can be considered in two groups based on
     the degree of manipulation necessary to obtain the
     final product or other considerations.
     
          a.  "Manipulated peripheral blood stem cells" are
               defined as 1) products obtained after one or more
               procedures have been performed to intentionally
               purge or enrich the starting material of a
               subset(s) of nucleated cells or 2) a product
               subject to licensure as a somatic cell therapy as
               defined in the Federal Register published on
               October 14, 1993 (58 FR 53248).  It should be
               noted that the present definition of "manipulated
               peripheral blood stem cell product" includes some
               products addressed in the FDA Application of
               Current Statutory Authorities to Human Somatic
               Cell Therapy and Gene Therapy Products document
               (58 FR 53248) and the additional products
               described in III.A.1.a. above.  Examples of
               procedures that result in manipulated products
               include centrifugal elutriation, negative or
               positive cell selection by monoclonal
               antibody-based technologies, cell populations
               expanded in vitro using cytokines or other
               procedures leading to a somatic cell therapy
               product.
     
          b.  Non-manipulated or minimally manipulated
               peripheral blood stem cells (hereafter referred to
               as non-manipulated cells) are defined as products
               that have not been subjected to a procedure(s)
               that selectively removes, enriches, expands or
               functionally alters specific nucleated cell
               populations.  Procedures performed ex vivo
               include: centrifugation and density gradient
               separation, lysis of contaminating erythrocytes,
               addition of medium for cryopreservation, transfer
               of product from collection devices to storage
               containers, and storage in liquid or frozen state. 
               The removal of polymorphonuclear leukocytes also
               would not be considered manipulation.  Non-manipulated peripheral blood stem cells may
               include stem cells mobilized in vivo by biological
               or drug products approved for such use.

2.   Manipulated Peripheral Blood Stem Cell Products Subject
to Licensure as Final Products When Intended for
Transplantation

       Manipulated peripheral blood stem cells intended for use
       in the prevention, treatment, cure, diagnosis, or
       mitigation of disease or injuries in humans are subject
       to IND regulations during clinical development and, as
       final biological products are subject to licensure.
       Examples include but are not limited to: 1) peripheral
       blood-derived mononuclear cells enriched for CD34+ cells;
       2) peripheral blood-derived mononuclear cells depleted of
       tumor cells; and 3) peripheral blood-derived mononuclear
       cells depleted of T lymphocytes using devices or products
       such as monoclonal antibodies and complement for
       hematopoietic reconstitution.  

3. Non-manipulated Peripheral Blood Stem Cells Subject to
CGMPs, Blood Establishment Registration, and licensure.
       
       When intended for use in the prevention, treatment, cure,
       diagnosis, or mitigation of disease or injuries in
       humans, FDA does not expect the submission of IND
       applications to evaluate safety and efficacy for
       hematopoietic stem cells that are isolated from
       peripheral blood without manipulation (III.A.1.b.). 
       However, if these products are intended for distribution
       in interstate commerce, licensure of the product and
       establishment is required. 

       FDA requires manufacturers of these products to register
       as blood establishments (21 CFR 607).  They must operate
       according to applicable blood CGMPs and are subject to
       FDA inspection.  Non-manipulated peripheral blood stem
       cells can be licensed when they meet the product
       specifications and standards for collection, processing,
       and storage.  These standards are presently under
       development by the FDA.  Because of the probable
       introduction into interstate commerce, manufacturers of
       products intended for use in allogeneic transplantation
       should obtain product and establishment licenses.

4.   Non-manipulated Peripheral Blood Stem Cells Subject to
Licensure as Source Materials

       Non-manipulated peripheral blood stem cells intended as a
       source material for further manufacture into a final
       hematopoietic stem cell product are also subject to
       licensure unless regulated under the license for the
       final product.   Often, source material is manufactured
       by other than the final product license holder and
       shipped from one legal entity to another.  Products to be
       utilized as source materials can only be approved when
       the final product (such as the genetically altered cell)
       is approved.  Examples include peripheral blood stem
       cells intended for ex vivo expansion or as targets of
       gene transfer and expression.  Evaluation of source
       material which is manufactured differently from accepted
       standards, may be subject to IND regulation.

B.  Ancillary Products Used During Production of Peripheral
Blood Stem Cell Products

       Numerous products will be used during the production of
       peripheral blood stem cell products.  A common
       characteristic of many of these products is that they are
       intended to act on the cells rather than to have an
       independent effect on the patient.  Additionally, the
       intended action of these products is not dependent upon
       incorporation into the peripheral blood stem cell product
       with maintenance of  the structural or functional
       integrity of the ancillary product is maintained.  These
       products meet the definition of medical devices.  They
       may be regulated as devices, with the type of regulatory
       control determined according to codified procedures. 
       Examples include, but are not limited to:  1) apheresis
       machines; 2) equipment for purging or selecting stem cell
       populations; 3) growth factors used for in vitro
       stimulation or expansion; and 4) collection and storage
       containers.

       In contrast to products described above, products
       administered directly to patients or products whose
       function requires incorporation into the hematopoietic
       stem cell product with maintenance to some degree of
       structural or functional integrity are not considered
       medical devices; rather, they are regulated as drugs or
       biological products.  Examples include, but are not
       limited to:  1) investigational agents administered to
       stem cell donors to mobilize the stem cell populations
       before collection of the product, e.g., unlicensed
       cytokines or cytokines not licensed for this indication;
       2) anticoagulants added to the collection container and
       infused with the product into the recipient; and 3)
       storage medium and cryoprotective agents added to the
       stored product and infused with the product into the
       recipient.

       IV.  COMMENTS

       Peripheral blood stem cell products used for hematologic
       transplantation constitute a new and emerging scientific
       area.  The Agency will review and consider written
       comments on the regulatory approach set forth in this
       notice.  Comments received will be considered in
       determining whether amendments to, or revisions of, the
       approach are warranted.  Two copies of any comments
       should be submitted, except that individuals may submit
       one copy.  Comments are to be identified with the docket
       number found in brackets in the heading of this document. 
       Comments received are available for public examination in
       the Dockets Management Branch (address above) between 9
       a.m. and 4 p.m., Monday through Friday.